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nord_28_4 | Related disorders of Acute Eosinophilic Pneumonia | Symptoms of the following disorders can be similar to those of AEP. Comparisons may be useful for a differential diagnosis.Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs that occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it may also affect children. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis) or as a result of pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions, and inhalation of toxic fumes, among other things. It usually develops within 24 to 48 hours after the original illness or injury and is a medical emergency. It may progress to failure of other organs. (For more information on this disorder, choose “acute respiratory distress” as your search term in the Rare Disease Database.)Pneumonia is an infection of the lungs. Symptoms such as fever, cough, large amounts of mucous production (sputum), fluid in the space surrounding the lungs (pleurisy) and/or chills occur. Chest pain, headache, diarrhea, sore throat and fever blisters may also develop. Shortness of breath, difficulty in breathing, decreased exercise tolerance and night sweats are characteristic. Pneumonia frequently occurs in middle-aged to older adults with various underlying diseases. However, it can occur in persons of all ages, statistically most often in winter and early spring. Pneumonia can be caused by various bacteria, viruses, and other infectious agents. AEP can potentially be mistaken for infectious pneumonia. | Related disorders of Acute Eosinophilic Pneumonia. Symptoms of the following disorders can be similar to those of AEP. Comparisons may be useful for a differential diagnosis.Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs that occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it may also affect children. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis) or as a result of pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions, and inhalation of toxic fumes, among other things. It usually develops within 24 to 48 hours after the original illness or injury and is a medical emergency. It may progress to failure of other organs. (For more information on this disorder, choose “acute respiratory distress” as your search term in the Rare Disease Database.)Pneumonia is an infection of the lungs. Symptoms such as fever, cough, large amounts of mucous production (sputum), fluid in the space surrounding the lungs (pleurisy) and/or chills occur. Chest pain, headache, diarrhea, sore throat and fever blisters may also develop. Shortness of breath, difficulty in breathing, decreased exercise tolerance and night sweats are characteristic. Pneumonia frequently occurs in middle-aged to older adults with various underlying diseases. However, it can occur in persons of all ages, statistically most often in winter and early spring. Pneumonia can be caused by various bacteria, viruses, and other infectious agents. AEP can potentially be mistaken for infectious pneumonia. | 28 | Acute Eosinophilic Pneumonia |
nord_28_5 | Diagnosis of Acute Eosinophilic Pneumonia | A diagnosis of AEP is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests especially bronchoalveolar lavage (BAL). The presence of other causes of pulmonary eosinophilia such as parasitic infections or exposure to certain drugs must be systematically investigated.Clinical Testing and Work-Up
An exam known as BAL, is key in the diagnosis of AEP. During a BAL, a narrow tube (flexible bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected by aspiration and then the tube is removed, allowing the cells to be studied. BAL fluid in individuals with AEP reveals abnormally high levels of eosinophils (greater than 25%). Fiberoptic bronchoscopy is performed under local anesthesia; it is performed through the intratracheal tube in patients with mechanical ventilation. Arterial blood gases demonstrate hypoxemia often severe, which may reflect right to left shunting in consolidated lung.Specific imaging techniques may be used to help confirm a diagnosis of AEP including chest x-ray, however abnormalities are not specific. Chest x-rays in individuals with AEP generally show white lines or hazy patches (infiltrates) in the lungs. Chest CT shows alveolar bilateral consolidation, with associated bilateral pleural effusion of mild to moderate severity, and interlobular septal thickening, which are suggestive of the disease.During the acute phase, pulmonary function tests typically show a restricted pattern. | Diagnosis of Acute Eosinophilic Pneumonia. A diagnosis of AEP is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests especially bronchoalveolar lavage (BAL). The presence of other causes of pulmonary eosinophilia such as parasitic infections or exposure to certain drugs must be systematically investigated.Clinical Testing and Work-Up
An exam known as BAL, is key in the diagnosis of AEP. During a BAL, a narrow tube (flexible bronchoscope) is slid down the windpipe into the lungs and a sterile solution is passed through the tube washing out (lavaging) cells. This fluid is collected by aspiration and then the tube is removed, allowing the cells to be studied. BAL fluid in individuals with AEP reveals abnormally high levels of eosinophils (greater than 25%). Fiberoptic bronchoscopy is performed under local anesthesia; it is performed through the intratracheal tube in patients with mechanical ventilation. Arterial blood gases demonstrate hypoxemia often severe, which may reflect right to left shunting in consolidated lung.Specific imaging techniques may be used to help confirm a diagnosis of AEP including chest x-ray, however abnormalities are not specific. Chest x-rays in individuals with AEP generally show white lines or hazy patches (infiltrates) in the lungs. Chest CT shows alveolar bilateral consolidation, with associated bilateral pleural effusion of mild to moderate severity, and interlobular septal thickening, which are suggestive of the disease.During the acute phase, pulmonary function tests typically show a restricted pattern. | 28 | Acute Eosinophilic Pneumonia |
nord_28_6 | Therapies of Acute Eosinophilic Pneumonia | Treatment
Individuals with AEP respond within days to high doses of corticosteroids, which usually are prescribed for two weeks. Corticosteroid therapy is initiated only after an infectious cause of pulmonary eosinophilia has been ruled out. Within the medical literature, the dose and duration of corticosteroid therapy has varied greatly, with a recent series suggesting that a two-week treatment is sufficient. There is no standardized dose for corticosteroid therapy in individuals with AEP. Individuals reported in the medical literature received intravenous corticosteroids initially, followed by oral administration afterward. In some cases, AEP improves without any treatment (spontaneous remission). There is no relapse after steroid therapy is stopped. The long term prognosis is excellent.Because the disorder often progresses rapidly, many individuals require admission into an intensive care unit to receive respiratory support. Respiratory support can consist of either invasive or noninvasive mechanical ventilation. Invasive ventilation provides respiratory support through intratracheal tube. Noninvasive ventilation providing respiratory support via a ventilator and a nasal or facial mask may suffice to support ventilation until rapid improvement is observed with corticosteroids, and weaning becomes possible (usually within less than one week). | Therapies of Acute Eosinophilic Pneumonia. Treatment
Individuals with AEP respond within days to high doses of corticosteroids, which usually are prescribed for two weeks. Corticosteroid therapy is initiated only after an infectious cause of pulmonary eosinophilia has been ruled out. Within the medical literature, the dose and duration of corticosteroid therapy has varied greatly, with a recent series suggesting that a two-week treatment is sufficient. There is no standardized dose for corticosteroid therapy in individuals with AEP. Individuals reported in the medical literature received intravenous corticosteroids initially, followed by oral administration afterward. In some cases, AEP improves without any treatment (spontaneous remission). There is no relapse after steroid therapy is stopped. The long term prognosis is excellent.Because the disorder often progresses rapidly, many individuals require admission into an intensive care unit to receive respiratory support. Respiratory support can consist of either invasive or noninvasive mechanical ventilation. Invasive ventilation provides respiratory support through intratracheal tube. Noninvasive ventilation providing respiratory support via a ventilator and a nasal or facial mask may suffice to support ventilation until rapid improvement is observed with corticosteroids, and weaning becomes possible (usually within less than one week). | 28 | Acute Eosinophilic Pneumonia |
nord_29_0 | Overview of Acute Intermittent Porphyria | SummaryAcute intermittent porphyria (AIP) is a rare metabolic disorder that is characterized by partial deficiency of the enzyme hydroxymethylbilane synthase (also known as porphobilinogen deaminase). This enzyme deficiency can result in the accumulation of porphyrin precursors in the body. This enzyme deficiency is caused by a mutation in the HMBS gene which is inherited as an autosomal dominant trait (only one HMBS gene copy is affected). However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a HMBS gene mutation do not develop symptoms of AIP. Additional factors such hormonal changes associated with puberty, the use of certain prescribed or recreational drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Symptoms include severe abdominal pain, constipation, a rapid heartbeat and increased blood pressure (tachycardia and hypertension), behavioral changes, seizures, and damage of the nerves to muscles (peripheral neuropathy) which can lead to profound muscle weakness (paralysis). Treatment is focused on preventing attacks by educating patients to avoid potential triggers. Acute attacks usually require hospital care and can be effectively treated with intravenous hematin.IntroductionAIP belongs to a group of disorders known as the porphyrias. This group of disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors which accumulate due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins found in all cells. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are often referred to as “cutaneous porphyrias.” The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Two porphyrias can have cutaneous and acute symptoms, sometimes together. Most forms of porphyria are genetic inborn errors of metabolism. AIP is an acute, hepatic form of porphyria. | Overview of Acute Intermittent Porphyria. SummaryAcute intermittent porphyria (AIP) is a rare metabolic disorder that is characterized by partial deficiency of the enzyme hydroxymethylbilane synthase (also known as porphobilinogen deaminase). This enzyme deficiency can result in the accumulation of porphyrin precursors in the body. This enzyme deficiency is caused by a mutation in the HMBS gene which is inherited as an autosomal dominant trait (only one HMBS gene copy is affected). However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a HMBS gene mutation do not develop symptoms of AIP. Additional factors such hormonal changes associated with puberty, the use of certain prescribed or recreational drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Symptoms include severe abdominal pain, constipation, a rapid heartbeat and increased blood pressure (tachycardia and hypertension), behavioral changes, seizures, and damage of the nerves to muscles (peripheral neuropathy) which can lead to profound muscle weakness (paralysis). Treatment is focused on preventing attacks by educating patients to avoid potential triggers. Acute attacks usually require hospital care and can be effectively treated with intravenous hematin.IntroductionAIP belongs to a group of disorders known as the porphyrias. This group of disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors which accumulate due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins found in all cells. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are often referred to as “cutaneous porphyrias.” The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Two porphyrias can have cutaneous and acute symptoms, sometimes together. Most forms of porphyria are genetic inborn errors of metabolism. AIP is an acute, hepatic form of porphyria. | 29 | Acute Intermittent Porphyria |
nord_29_1 | Symptoms of Acute Intermittent Porphyria | AIP can be associated with a range of symptoms and physical findings that can potentially involve multiple organ systems of the body. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can potentially cause life-threatening complications. It is important to note the highly variable nature of AIP and that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The symptoms of AIP usually occur as episodes or “attacks” that develop over course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may rarely occur at or just after puberty. Onset before puberty is extremely rare. Attacks are much more common in women than men, probably because of the menstrual cycle hormones. Approximately 3%-5% of affected individuals, predominately women, experience recurrent attacks, which are defined as more than 4 per year, for a period of many years.Abdominal pain, which is usually severe, is the most common symptom associated with AIP and often the initial sign of an attack. Abdominal pain is usually severe, steady (unremitting) and widespread (diffuse). Less often, abdominal pain is described as cramping. Pain may also occur in the neck, lower back, buttocks, or arms and legs.Gastrointestinal symptoms are also common during an attack and can include nausea, vomiting, constipation or diarrhea, and abdominal swelling (distention). A painful blockage or obstruction (ileus) of part of the small intestines may also occur. Difficulty passing urine (urinary retention) can also occur.Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and burning sensations that usually begin in the feet and sometimes the arms. Affected individuals may develop muscle weakness in the legs that may progress to affect the arms and the trunk of the body, eventually causing partial loss or impairment of motor function (motor paralysis). In rare cases, the muscles used to breathe can become involved and potentially cause life-threatening respiratory failure which requires mechanical ventilation.During attacks some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases, coma.Affected individuals may also experience a faster than normal heart rate (tachycardia) , high blood pressure (hypertension) and irregular heartbeats (cardiac arrhythmias). Seizures have also been reported. Abnormally low sodium levels (hyponatremia) may develop rapidly during an attack and contribute to the onset of seizures.Individuals with chronic AIP may develop complications that occur after many years (long-term complications) such as high blood pressure (hypertension), kidney damage potentially resulting in kidney failure, and liver cancers such as hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC). | Symptoms of Acute Intermittent Porphyria. AIP can be associated with a range of symptoms and physical findings that can potentially involve multiple organ systems of the body. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can potentially cause life-threatening complications. It is important to note the highly variable nature of AIP and that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The symptoms of AIP usually occur as episodes or “attacks” that develop over course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may rarely occur at or just after puberty. Onset before puberty is extremely rare. Attacks are much more common in women than men, probably because of the menstrual cycle hormones. Approximately 3%-5% of affected individuals, predominately women, experience recurrent attacks, which are defined as more than 4 per year, for a period of many years.Abdominal pain, which is usually severe, is the most common symptom associated with AIP and often the initial sign of an attack. Abdominal pain is usually severe, steady (unremitting) and widespread (diffuse). Less often, abdominal pain is described as cramping. Pain may also occur in the neck, lower back, buttocks, or arms and legs.Gastrointestinal symptoms are also common during an attack and can include nausea, vomiting, constipation or diarrhea, and abdominal swelling (distention). A painful blockage or obstruction (ileus) of part of the small intestines may also occur. Difficulty passing urine (urinary retention) can also occur.Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and burning sensations that usually begin in the feet and sometimes the arms. Affected individuals may develop muscle weakness in the legs that may progress to affect the arms and the trunk of the body, eventually causing partial loss or impairment of motor function (motor paralysis). In rare cases, the muscles used to breathe can become involved and potentially cause life-threatening respiratory failure which requires mechanical ventilation.During attacks some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases, coma.Affected individuals may also experience a faster than normal heart rate (tachycardia) , high blood pressure (hypertension) and irregular heartbeats (cardiac arrhythmias). Seizures have also been reported. Abnormally low sodium levels (hyponatremia) may develop rapidly during an attack and contribute to the onset of seizures.Individuals with chronic AIP may develop complications that occur after many years (long-term complications) such as high blood pressure (hypertension), kidney damage potentially resulting in kidney failure, and liver cancers such as hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC). | 29 | Acute Intermittent Porphyria |
nord_29_2 | Causes of Acute Intermittent Porphyria | AIP is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for developing symptoms of the disorder. Individuals with AIP have a mutation in the HMBS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.However, the majority of people with a mutation in this gene do not develop symptoms of AIP; additional factors, often called “triggers” are also required to cause symptomatic acute porphyria. These factors are not necessarily the same for each individual, and susceptibility to specific triggers may vary during a patient’s lifetime. Most of these triggers are believed to stimulate increased heme production (synthesis) in the liver and include certain drugs, excessive alcohol consumption, fasting or dieting (e.g. caloric restriction), stress, infections or certain hormonal (endocrine) factors, often in combination.The HMBS gene mutation that predisposes individuals to developing AIP is inherited in an autosomal dominant pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.The HMBS gene creates (encodes) the enzyme porphobilinogen deaminase (PBG-D), which is also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase. This enzyme is the third enzyme is the process of heme biosynthesis. Mutations in the HMBS gene lead to deficient levels of PBG-D in the body, which in turn can lead to the accumulation and release of porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) from the liver.Symptomatic AIP is always accompanied by increased production and excretion of porphyrin precursors. However, for reasons that are unknown, some affected individuals have elevated porphyrin precursors without symptoms of AIP. As discussed above, triggering factors are required for symptom development. The exact, underlying reasons why symptoms develop in some individuals with AIP are not fully understood. There are several theories as to the underlying pathogenesis of AIP. One theory states that a specific porphyrin precursor (most likely ALA) is a neurotoxin that damages nerve tissue. This theory is supported by the information obtained from patients who have had liver transplant, which corrects both the clinical and biochemical features of the condition. A second theory suggests that heme deficiency in nerve cells (neurons) contributes to the development of symptoms. More research is necessary to determine the exact underlying mechanisms that are involved in the development of symptomatic episodes in individuals with AIP. | Causes of Acute Intermittent Porphyria. AIP is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for developing symptoms of the disorder. Individuals with AIP have a mutation in the HMBS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.However, the majority of people with a mutation in this gene do not develop symptoms of AIP; additional factors, often called “triggers” are also required to cause symptomatic acute porphyria. These factors are not necessarily the same for each individual, and susceptibility to specific triggers may vary during a patient’s lifetime. Most of these triggers are believed to stimulate increased heme production (synthesis) in the liver and include certain drugs, excessive alcohol consumption, fasting or dieting (e.g. caloric restriction), stress, infections or certain hormonal (endocrine) factors, often in combination.The HMBS gene mutation that predisposes individuals to developing AIP is inherited in an autosomal dominant pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.The HMBS gene creates (encodes) the enzyme porphobilinogen deaminase (PBG-D), which is also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase. This enzyme is the third enzyme is the process of heme biosynthesis. Mutations in the HMBS gene lead to deficient levels of PBG-D in the body, which in turn can lead to the accumulation and release of porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) from the liver.Symptomatic AIP is always accompanied by increased production and excretion of porphyrin precursors. However, for reasons that are unknown, some affected individuals have elevated porphyrin precursors without symptoms of AIP. As discussed above, triggering factors are required for symptom development. The exact, underlying reasons why symptoms develop in some individuals with AIP are not fully understood. There are several theories as to the underlying pathogenesis of AIP. One theory states that a specific porphyrin precursor (most likely ALA) is a neurotoxin that damages nerve tissue. This theory is supported by the information obtained from patients who have had liver transplant, which corrects both the clinical and biochemical features of the condition. A second theory suggests that heme deficiency in nerve cells (neurons) contributes to the development of symptoms. More research is necessary to determine the exact underlying mechanisms that are involved in the development of symptomatic episodes in individuals with AIP. | 29 | Acute Intermittent Porphyria |
nord_29_3 | Affects of Acute Intermittent Porphyria | In Europe the prevalence of symptomatic AIP is reported to be 5.9 per million people in the general population., It is likely to be similar elsewhere in the world apart from Sweden where it is higher due to a founder effect. Recent population based genetic studies have shown that approximately 1 in 2000 of the population inherit a disease causing (pathogenic) mutation in the HMBS gene. This suggests that only 1% of those who inherit a pathogenic mutation will ever experience porphyria symptoms. AIP can occur in individuals of all ethnic backgrounds, although it may be less frequently reported in African-American individuals. Women are affected by symptomatic AIP more often than men. The disorder is most common in young or middle-aged women. | Affects of Acute Intermittent Porphyria. In Europe the prevalence of symptomatic AIP is reported to be 5.9 per million people in the general population., It is likely to be similar elsewhere in the world apart from Sweden where it is higher due to a founder effect. Recent population based genetic studies have shown that approximately 1 in 2000 of the population inherit a disease causing (pathogenic) mutation in the HMBS gene. This suggests that only 1% of those who inherit a pathogenic mutation will ever experience porphyria symptoms. AIP can occur in individuals of all ethnic backgrounds, although it may be less frequently reported in African-American individuals. Women are affected by symptomatic AIP more often than men. The disorder is most common in young or middle-aged women. | 29 | Acute Intermittent Porphyria |
nord_29_4 | Related disorders of Acute Intermittent Porphyria | Symptoms of the following disorders can be similar to those of AIP. Comparisons may be useful for a differential diagnosis.The acute attacks that characterize AIP are similar to those seen in three other forms of porphyria specifically variegate porphyria, hereditary coproporphyria, and ALA-Dehydratase deficiency porphyria. Collectively, these four forms of the porphyria are classified as the acute porphyrias. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, sometimes progressing to complete paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the patients. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering (myelin) of nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. This causes weakness of the muscles that are supplied by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, acute motor axonal neuropathy. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, including a heme precursor ALA, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease, cirrhosis, and hepatocellular carcinoma if left untreated. Untreated children can also suffer neurological crises similar to those seen in acute porphyria. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed. (For more information on this disorder, choose “tyrosinemia” as your search term in the Rare Disease Database.)Lead toxicity can cause symptoms that mimic acute porphyria (acute abdominal pain, constipation, neuropathy). Lead inhibits several of the enzymes of haem biosynthesis, which can therefore result in an increase in urine coproporphyrin and 5-aminolevulinic acid excretion, but not porphobilinogen excretion. It can also cause an increase in erythrocyte protoporphyrin concentration, although this is all the zinc-chelate form (zinc-protoporphyrin). The definitive test for lead poisoning is blood lead measurement. | Related disorders of Acute Intermittent Porphyria. Symptoms of the following disorders can be similar to those of AIP. Comparisons may be useful for a differential diagnosis.The acute attacks that characterize AIP are similar to those seen in three other forms of porphyria specifically variegate porphyria, hereditary coproporphyria, and ALA-Dehydratase deficiency porphyria. Collectively, these four forms of the porphyria are classified as the acute porphyrias. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, sometimes progressing to complete paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the patients. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering (myelin) of nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. This causes weakness of the muscles that are supplied by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, acute motor axonal neuropathy. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, including a heme precursor ALA, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease, cirrhosis, and hepatocellular carcinoma if left untreated. Untreated children can also suffer neurological crises similar to those seen in acute porphyria. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed. (For more information on this disorder, choose “tyrosinemia” as your search term in the Rare Disease Database.)Lead toxicity can cause symptoms that mimic acute porphyria (acute abdominal pain, constipation, neuropathy). Lead inhibits several of the enzymes of haem biosynthesis, which can therefore result in an increase in urine coproporphyrin and 5-aminolevulinic acid excretion, but not porphobilinogen excretion. It can also cause an increase in erythrocyte protoporphyrin concentration, although this is all the zinc-chelate form (zinc-protoporphyrin). The definitive test for lead poisoning is blood lead measurement. | 29 | Acute Intermittent Porphyria |
nord_29_5 | Diagnosis of Acute Intermittent Porphyria | A diagnosis of AIP can be difficult because most symptoms are nonspecific and occur episodically. A diagnosis is usually based upon identification of characteristic symptoms from a detailed patient history, a thorough clinical evaluation and certain specialized tests. AIP should be suspected in individuals with unexplained abdominal pain, especially repeated episodes and when occurring along with psychological symptoms, neurological findings with muscle weakness or unexplained hyponatraemia. Dark or reddish urine in such individuals is also suggestive of AIP. However, absence of this feature does not exclude AIP. Clinical Testing and WorkupScreening tests to measure the levels of the porphyrin precursor porphobilinogen (PBG) in urine are essential to confirm a diagnosis of acute porphyria. Acute attacks are always accompanied by increased production and excretion of PBG in AIP. If urinary PBG excretion is increased, then further testing (fecal and blood porphyrin measurement) is necessary to distinguish AIP from variegate porphyria or hereditary coproporphyria. This should not delay treatment of acutely unwell patients. Delta-aminolevulinic acid (ALA) excretion will also be elevated in urine samples from individuals with AIP, but measurement is less widely available and is not essential. These tests can be performed on a random (spot) urine sample that should be protected from light after collection and during transport to the laboratory. There is now good evidence that once urine PBG excretion is increased in AIP it takes many years to return to normal. Increased urine PBG excretion in a known AIP patient does not therefore prove that a patient is having an acute attack.Family TestingMolecular genetic testing is not essential to confirm a diagnosis as the porphyrin biochemical findings are characteristic. However molecular genetic testing to detect a mutation in the HMBS gene is usually required so that family members can be offered testing for this mutation. Genetic testing is available mainly from laboratories specializing in porphyria diagnosis.Patients and family members who have inherited AIP should be advised on how to limit their risk of any future acute attacks. This should include information about AIP and what causes attacks, how to check if a prescribed medication is safe or unsafe and details of relevant patient support groups. | Diagnosis of Acute Intermittent Porphyria. A diagnosis of AIP can be difficult because most symptoms are nonspecific and occur episodically. A diagnosis is usually based upon identification of characteristic symptoms from a detailed patient history, a thorough clinical evaluation and certain specialized tests. AIP should be suspected in individuals with unexplained abdominal pain, especially repeated episodes and when occurring along with psychological symptoms, neurological findings with muscle weakness or unexplained hyponatraemia. Dark or reddish urine in such individuals is also suggestive of AIP. However, absence of this feature does not exclude AIP. Clinical Testing and WorkupScreening tests to measure the levels of the porphyrin precursor porphobilinogen (PBG) in urine are essential to confirm a diagnosis of acute porphyria. Acute attacks are always accompanied by increased production and excretion of PBG in AIP. If urinary PBG excretion is increased, then further testing (fecal and blood porphyrin measurement) is necessary to distinguish AIP from variegate porphyria or hereditary coproporphyria. This should not delay treatment of acutely unwell patients. Delta-aminolevulinic acid (ALA) excretion will also be elevated in urine samples from individuals with AIP, but measurement is less widely available and is not essential. These tests can be performed on a random (spot) urine sample that should be protected from light after collection and during transport to the laboratory. There is now good evidence that once urine PBG excretion is increased in AIP it takes many years to return to normal. Increased urine PBG excretion in a known AIP patient does not therefore prove that a patient is having an acute attack.Family TestingMolecular genetic testing is not essential to confirm a diagnosis as the porphyrin biochemical findings are characteristic. However molecular genetic testing to detect a mutation in the HMBS gene is usually required so that family members can be offered testing for this mutation. Genetic testing is available mainly from laboratories specializing in porphyria diagnosis.Patients and family members who have inherited AIP should be advised on how to limit their risk of any future acute attacks. This should include information about AIP and what causes attacks, how to check if a prescribed medication is safe or unsafe and details of relevant patient support groups. | 29 | Acute Intermittent Porphyria |
nord_29_6 | Therapies of Acute Intermittent Porphyria | TreatmentThe treatment of AIP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hematologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected patient’s treatment. Genetic counseling may benefit affected individuals and their families. The objective of treatment is to manage symptoms, prevent complications and to suppress heme creation (synthesis) in the liver with hematin, which reduces the production of porphyrin precursors. Initial treatment steps also include stopping any medications that can potentially worsen AIP or cause an attack and ensuring proper caloric intake, which can include intravenous infusion of sufficient nutrients (glucose and salt). Carbohydrate loading in conjunction with good pain medication may be sufficient for mild attacks. An acute neurovisceral attack often necessitates hospitalization and may require treatment with human hemin. In the United States, affected individuals may be treated with Panhematin (hemin for injection), an enzyme inhibitor derived from red blood cells that is potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) approved Panhematin for the treatment of recurrent attacks of AIP related to the menstrual cycle in susceptible women, after a trial of glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. Based on much experience, it is used for treating and even preventing acute attacks, often without an initial trial of glucose, and has been found to be safe during pregnancy. In 2019, the FDA approved Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, including AIP. Givlaari aims to reduce the number of attacks patients experience. Normosang (heme arginate) is another heme preparation that can be used to treat individuals with AIP. Normosang is not available in the United States, but is used in many other countries where Panhematin is not available. Treatment for AIP also includes drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. The pain is usually very severe and generally requires opiates (e.g. morphine) for adequate relief. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Although many types of drugs are believed to be safe in individuals with AIP, recommendations about drugs for treating AIP are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Database. The EPNET/NAPOS Database should also be consulted. Additional treatment for individuals undergoing an attack including monitoring fluid and electrolyte balances. For example, if individuals develop hyponatremia, which can induce seizures, they should be treated by saline infusion. In some patients, an attack is precipitated by a low intake of carbohydrates in an attempt to lose weight. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal balanced diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods of time. If weight loss is desired, it is advisable to contact a physician and dietician. Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks and some affected women have been treated with gonadotropin-releasing hormone analogues to suppress ovulation and prevent frequent cyclic attacks. Some individuals who experience recurrent attacks may benefit from regular hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses. If a proper diagnosis has not been made, AIP can be particularly dangerous, especially if drugs which aggravate the disorder are administered. The prognosis of AIP is usually good if the disorder is recognized before severe nerve damage has occurred and if treatment and preventive measures are begun. Although symptoms usually resolve after an attack, some individuals may develop chronic pain. Nerve damage and associated muscle weakness from a severe attack improves over time, but such improvement may take many months to resolve fully. Liver transplantation has been used to treat some individuals with AIP, specifically individuals with severe disease who have failed to respond to other treatment options. A liver transplant in individuals with AIP is an option of last resort. Affected individuals who experience kidney failure may require a kidney transplant. Some individuals have required a combined kidney and liver transplant. | Therapies of Acute Intermittent Porphyria. TreatmentThe treatment of AIP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hematologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected patient’s treatment. Genetic counseling may benefit affected individuals and their families. The objective of treatment is to manage symptoms, prevent complications and to suppress heme creation (synthesis) in the liver with hematin, which reduces the production of porphyrin precursors. Initial treatment steps also include stopping any medications that can potentially worsen AIP or cause an attack and ensuring proper caloric intake, which can include intravenous infusion of sufficient nutrients (glucose and salt). Carbohydrate loading in conjunction with good pain medication may be sufficient for mild attacks. An acute neurovisceral attack often necessitates hospitalization and may require treatment with human hemin. In the United States, affected individuals may be treated with Panhematin (hemin for injection), an enzyme inhibitor derived from red blood cells that is potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) approved Panhematin for the treatment of recurrent attacks of AIP related to the menstrual cycle in susceptible women, after a trial of glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. Based on much experience, it is used for treating and even preventing acute attacks, often without an initial trial of glucose, and has been found to be safe during pregnancy. In 2019, the FDA approved Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, including AIP. Givlaari aims to reduce the number of attacks patients experience. Normosang (heme arginate) is another heme preparation that can be used to treat individuals with AIP. Normosang is not available in the United States, but is used in many other countries where Panhematin is not available. Treatment for AIP also includes drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. The pain is usually very severe and generally requires opiates (e.g. morphine) for adequate relief. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Although many types of drugs are believed to be safe in individuals with AIP, recommendations about drugs for treating AIP are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Database. The EPNET/NAPOS Database should also be consulted. Additional treatment for individuals undergoing an attack including monitoring fluid and electrolyte balances. For example, if individuals develop hyponatremia, which can induce seizures, they should be treated by saline infusion. In some patients, an attack is precipitated by a low intake of carbohydrates in an attempt to lose weight. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal balanced diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods of time. If weight loss is desired, it is advisable to contact a physician and dietician. Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks and some affected women have been treated with gonadotropin-releasing hormone analogues to suppress ovulation and prevent frequent cyclic attacks. Some individuals who experience recurrent attacks may benefit from regular hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses. If a proper diagnosis has not been made, AIP can be particularly dangerous, especially if drugs which aggravate the disorder are administered. The prognosis of AIP is usually good if the disorder is recognized before severe nerve damage has occurred and if treatment and preventive measures are begun. Although symptoms usually resolve after an attack, some individuals may develop chronic pain. Nerve damage and associated muscle weakness from a severe attack improves over time, but such improvement may take many months to resolve fully. Liver transplantation has been used to treat some individuals with AIP, specifically individuals with severe disease who have failed to respond to other treatment options. A liver transplant in individuals with AIP is an option of last resort. Affected individuals who experience kidney failure may require a kidney transplant. Some individuals have required a combined kidney and liver transplant. | 29 | Acute Intermittent Porphyria |
nord_30_0 | Overview of Acute Myeloid Leukemia | SummaryAcute myeloid leukemia (AML) is a group of blood and bone marrow cancers. This disorder is characterized by incomplete maturation of blood cells and reduced production of other normal hematopoietic stem cells. Hematopoietic stem cells are specialized cells that are formed in the bone marrow, the soft, spongy material found in the center of long bones. Hematopoietic stem cells develop, or mature, into the three main blood cells – red blood cells, white blood cells and platelets. In AML, a change in the genetic material (DNA) of a single immature cell, called a blast cell or a myeloblast cell causes the altered cell to continually reproduce itself. Eventually, these altered cells crowd out normal, healthy cells in the marrow. They also cause damage and scarring in the marrow, further disrupting the production of red cells, white cells, and platelets. These altered blast cells can be released into the bloodstream where they travel to other areas or organs in the body, potentially damaging these organs or interfering with their normal function. Without treatment, AML progresses rapidly (acute disease). AML is the most common acute form of leukemia in adults. Most people who develop this form of cancer are older adults; more than half of the affected individuals are 65 years old or older. Although uncommon, AML can occur in children.There are several subtypes of AML recognized in the 2016 World Health Organization classification:• AML with recurrent genetic abnormalities• AML with myelodysplasia-related changes• Therapy-related myeloid neoplasms• AML, not otherwise specified• Myeloid sarcoma• Myeloid proliferations related to Down syndromeThese subtypes are described in greater detail in the Causes section. Another subtype of AML is acute promyelocytic leukemia (APL). APL is not discussed in this report, although it is briefly described in the Related Disorders section. | Overview of Acute Myeloid Leukemia. SummaryAcute myeloid leukemia (AML) is a group of blood and bone marrow cancers. This disorder is characterized by incomplete maturation of blood cells and reduced production of other normal hematopoietic stem cells. Hematopoietic stem cells are specialized cells that are formed in the bone marrow, the soft, spongy material found in the center of long bones. Hematopoietic stem cells develop, or mature, into the three main blood cells – red blood cells, white blood cells and platelets. In AML, a change in the genetic material (DNA) of a single immature cell, called a blast cell or a myeloblast cell causes the altered cell to continually reproduce itself. Eventually, these altered cells crowd out normal, healthy cells in the marrow. They also cause damage and scarring in the marrow, further disrupting the production of red cells, white cells, and platelets. These altered blast cells can be released into the bloodstream where they travel to other areas or organs in the body, potentially damaging these organs or interfering with their normal function. Without treatment, AML progresses rapidly (acute disease). AML is the most common acute form of leukemia in adults. Most people who develop this form of cancer are older adults; more than half of the affected individuals are 65 years old or older. Although uncommon, AML can occur in children.There are several subtypes of AML recognized in the 2016 World Health Organization classification:• AML with recurrent genetic abnormalities• AML with myelodysplasia-related changes• Therapy-related myeloid neoplasms• AML, not otherwise specified• Myeloid sarcoma• Myeloid proliferations related to Down syndromeThese subtypes are described in greater detail in the Causes section. Another subtype of AML is acute promyelocytic leukemia (APL). APL is not discussed in this report, although it is briefly described in the Related Disorders section. | 30 | Acute Myeloid Leukemia |
nord_30_1 | Symptoms of Acute Myeloid Leukemia | Some symptoms of acute myeloid leukemia result from disruption of the normal formation of blood cells. There are three main types of blood cells – red blood cells, white blood cells, and platelets. These cells are formed in the bone marrow and they arise from hematopoietic stem cells, a type of adult stem cell. In AML, immature cells known as myeloblasts build up in the bone marrow, crowding out healthy cells and interfering with the normal production of blood cells. This leads to a deficiency of these mature blood cells, a condition called pancytopenia. Red blood cells deliver oxygen to the body, white blood cells help in fighting infections, and platelets allow the body to form clots to stop bleeding. A low level of circulating red blood cells is called anemia. A low level of white blood cells is called leukopenia. A low level of platelets is called thrombocytopenia. Because of the lack of healthy blood cells, affected individuals may experience weakness, fatigue, shortness of breath (dyspnea), recurrent infections (which can cause fever, body aches, and night sweats), and prolonged bleeding. Affected individuals may appear pale and they may bruise easily (including with minor injury or without a reason). There may be a loss in appetite and unintended weight loss. Inflammation of tissue in the mouth can cause swollen, bleeding gums, sores and be painful. Some individuals develop small red or purples spots on the skin called petechiae that are caused by bleeding under the skin, or larger, purple spots called ecchymoses caused by bleeding from ruptured blood vessels under the skin. Some people have chronic or severe nosebleeds. Some women will have abnormally heavy or prolonged bleeding during their menstrual periods (menorrhagia). Some people may have sternal tenderness, which refers to chronic pain or tenders in the breastbone (sternum). Affected individuals may have abnormally enlarged lymph nodes (lymphadenopathy). Less often, the liver and/or spleen may be enlarged, which is called hepatosplenomegaly.Some people with AML, mainly those who have not been treated or received a delayed diagnosis, develop hyperleukocytosis and leukostasis. Hyperleukocytosis means that a person’s white blood cell levels are at abnormally high levels. This can cause symptoms, particularly affecting the lungs or central nervous system. When symptoms occur, this is called leukostasis. Leukostasis can be characterized by headaches, confusion, seizures, visual disturbances, difficulty breathing, respiratory failure, or coma. Both conditions are medical emergencies, even in people without noticeable symptoms.Myeloid sarcoma is when a group of leukemic (malignant) cells form a mass or tumor outside of the bone marrow (extramedullary disease). This is a rare occurrence in AML. Common sites for a myeloid sarcoma include bone, soft tissues, lymph nodes, and the periosteum, a dense layer of fibrous tissue that covers bone. Myeloid sarcoma is also known as chloroma, granulocytic sarcoma, or myeloblastoma. Sometimes, a myeloid sarcoma will develop without any evidence of leukemic cells in the bone marrow or circulating blood. Some individuals will develop leukemia cutis, which is when cancer cells travel (migrate) to the skin. This can cause a variety of skin problems including spots, bumps, or rashes. Leukemia cutis is estimated to affect fewer than 10% of people with AML. Although uncommon, leukemic cells can spread to affect the brain and spinal cord (central nervous system). | Symptoms of Acute Myeloid Leukemia. Some symptoms of acute myeloid leukemia result from disruption of the normal formation of blood cells. There are three main types of blood cells – red blood cells, white blood cells, and platelets. These cells are formed in the bone marrow and they arise from hematopoietic stem cells, a type of adult stem cell. In AML, immature cells known as myeloblasts build up in the bone marrow, crowding out healthy cells and interfering with the normal production of blood cells. This leads to a deficiency of these mature blood cells, a condition called pancytopenia. Red blood cells deliver oxygen to the body, white blood cells help in fighting infections, and platelets allow the body to form clots to stop bleeding. A low level of circulating red blood cells is called anemia. A low level of white blood cells is called leukopenia. A low level of platelets is called thrombocytopenia. Because of the lack of healthy blood cells, affected individuals may experience weakness, fatigue, shortness of breath (dyspnea), recurrent infections (which can cause fever, body aches, and night sweats), and prolonged bleeding. Affected individuals may appear pale and they may bruise easily (including with minor injury or without a reason). There may be a loss in appetite and unintended weight loss. Inflammation of tissue in the mouth can cause swollen, bleeding gums, sores and be painful. Some individuals develop small red or purples spots on the skin called petechiae that are caused by bleeding under the skin, or larger, purple spots called ecchymoses caused by bleeding from ruptured blood vessels under the skin. Some people have chronic or severe nosebleeds. Some women will have abnormally heavy or prolonged bleeding during their menstrual periods (menorrhagia). Some people may have sternal tenderness, which refers to chronic pain or tenders in the breastbone (sternum). Affected individuals may have abnormally enlarged lymph nodes (lymphadenopathy). Less often, the liver and/or spleen may be enlarged, which is called hepatosplenomegaly.Some people with AML, mainly those who have not been treated or received a delayed diagnosis, develop hyperleukocytosis and leukostasis. Hyperleukocytosis means that a person’s white blood cell levels are at abnormally high levels. This can cause symptoms, particularly affecting the lungs or central nervous system. When symptoms occur, this is called leukostasis. Leukostasis can be characterized by headaches, confusion, seizures, visual disturbances, difficulty breathing, respiratory failure, or coma. Both conditions are medical emergencies, even in people without noticeable symptoms.Myeloid sarcoma is when a group of leukemic (malignant) cells form a mass or tumor outside of the bone marrow (extramedullary disease). This is a rare occurrence in AML. Common sites for a myeloid sarcoma include bone, soft tissues, lymph nodes, and the periosteum, a dense layer of fibrous tissue that covers bone. Myeloid sarcoma is also known as chloroma, granulocytic sarcoma, or myeloblastoma. Sometimes, a myeloid sarcoma will develop without any evidence of leukemic cells in the bone marrow or circulating blood. Some individuals will develop leukemia cutis, which is when cancer cells travel (migrate) to the skin. This can cause a variety of skin problems including spots, bumps, or rashes. Leukemia cutis is estimated to affect fewer than 10% of people with AML. Although uncommon, leukemic cells can spread to affect the brain and spinal cord (central nervous system). | 30 | Acute Myeloid Leukemia |
nord_30_2 | Causes of Acute Myeloid Leukemia | Leukemias are clonal disorders, which means that cancer arises from a change in one original cell. In AML, this occurs in a hematopoietic stem cell, specifically a myeloblast. A myeloblast is an immature precursor cell found in the bone marrow. This means that a myeloblast will change (mature or differentiate) into a healthy white blood cell called an agranulocyte or a monocyte. In AML, myeloblasts do not mature, and grow and multiply out-of-control. Because myeloblasts are immature cells, they cannot perform the normal functions of mature blood cells. These abnormal cells build up in the bone marrow, preventing the development of healthy red blood cells, white blood cells, and platelets. Leukemic myeloblasts also survive better than normal blood cells. People with AML eventually develop pancytopenia, a condition in which they lack healthy red and white blood cells and platelets. There is a genetic component in most people with AML. Most people have changes or alterations to specific genes. There are certain genes in the body that control how cells grow and divide and multiply and die. These genes are either oncogenes, which control cell growth and division, or tumor suppressor genes, which slow down cell division and make sure cells die at the right time. A change or alteration to an oncogene or a tumor suppressor gene can cause out-of-control cell growth and multiplication. These changes or alterations are usually acquired during a person’s life (they are not inherited), usually randomly for unknown reasons (de novo). People with AML usually have a change in a few genes, both oncogenes and tumor suppressor genes. Researchers believe that the interaction of these genetic changes plays a significant role in the development of AML.These genetic alterations are very important. They can be used by doctors to guide treatment and predict how the disease will progress. Understanding the genetic aspects of AML is difficult; this is a very complex topic. Doctors and researchers are still learning about how these changes play a role in the development and progression of AML. Patients and parents of affected children should discuss the genetic aspects of their individual situations with their physicians and entire medical team. The genetic changes in AML can be a change in a gene called a mutation. This is a permanent change in the DNA sequence that makes up the gene. Common mutations associated with AML including changes to the FLT3, NPM1, DNMT3A, IDH1 or IDH2, NRAS or KRAS, or RUNX1 genes. These gene changes contribute to the growth and spread of AML in the body. The identification of these genes has allowed researchers to look for targeted therapies, which are therapies that directly target the altered gene or the protein that the gene produces as a way to control the disease. Some people have translocations, which occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Chromosomes are in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Some genetic changes in AML are inversions in which there is a breakage within a single chromosome at two points and a “rejoining” of the chromosome with a reversal (inversion) of the two breakpoints. Researchers have been able to determine certain risk factors that, when present, increase a person’s chances of developing AML. These risk factors include several environmental factors including exposure to benzene, certain pesticides, ionizing radiation, and smoking. Most people with AML develop the disease without any known risk factors. Some people have therapy-related AML. In these people, AML results from treatments people underwent earlier in their lives. Often, this can be radiation therapy or chemotherapy that was used to treat a different form of cancer. Some people with AML have another blood disorder first, such as a form of myelodysplastic syndrome. Myelodysplastic syndromes are a rare group of blood disorders that occur because of disordered development of blood cells within the bone marrow. About half of the people who have a myelodysplastic syndrome eventually develop AML. Myelodysplastic syndromes were once called pre-leukemia or smoldering leukemia. In rare instances, people with other blood disorders such as essential thrombocythemia or polycythemia vera can eventually develop AML. This is much less likely, however, than it is in people with a myelodysplastic syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the NORD Rare Disease Database.)People who have certain rare disorders including Down syndrome, Fanconi anemia, ataxia-telangiectasia, and Bloom syndrome have a slightly increased risk of developing AML. (For more information, choose the specific disorder name as your search term in the NORD Rare Disease Database.) | Causes of Acute Myeloid Leukemia. Leukemias are clonal disorders, which means that cancer arises from a change in one original cell. In AML, this occurs in a hematopoietic stem cell, specifically a myeloblast. A myeloblast is an immature precursor cell found in the bone marrow. This means that a myeloblast will change (mature or differentiate) into a healthy white blood cell called an agranulocyte or a monocyte. In AML, myeloblasts do not mature, and grow and multiply out-of-control. Because myeloblasts are immature cells, they cannot perform the normal functions of mature blood cells. These abnormal cells build up in the bone marrow, preventing the development of healthy red blood cells, white blood cells, and platelets. Leukemic myeloblasts also survive better than normal blood cells. People with AML eventually develop pancytopenia, a condition in which they lack healthy red and white blood cells and platelets. There is a genetic component in most people with AML. Most people have changes or alterations to specific genes. There are certain genes in the body that control how cells grow and divide and multiply and die. These genes are either oncogenes, which control cell growth and division, or tumor suppressor genes, which slow down cell division and make sure cells die at the right time. A change or alteration to an oncogene or a tumor suppressor gene can cause out-of-control cell growth and multiplication. These changes or alterations are usually acquired during a person’s life (they are not inherited), usually randomly for unknown reasons (de novo). People with AML usually have a change in a few genes, both oncogenes and tumor suppressor genes. Researchers believe that the interaction of these genetic changes plays a significant role in the development of AML.These genetic alterations are very important. They can be used by doctors to guide treatment and predict how the disease will progress. Understanding the genetic aspects of AML is difficult; this is a very complex topic. Doctors and researchers are still learning about how these changes play a role in the development and progression of AML. Patients and parents of affected children should discuss the genetic aspects of their individual situations with their physicians and entire medical team. The genetic changes in AML can be a change in a gene called a mutation. This is a permanent change in the DNA sequence that makes up the gene. Common mutations associated with AML including changes to the FLT3, NPM1, DNMT3A, IDH1 or IDH2, NRAS or KRAS, or RUNX1 genes. These gene changes contribute to the growth and spread of AML in the body. The identification of these genes has allowed researchers to look for targeted therapies, which are therapies that directly target the altered gene or the protein that the gene produces as a way to control the disease. Some people have translocations, which occur when regions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Chromosomes are in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Some genetic changes in AML are inversions in which there is a breakage within a single chromosome at two points and a “rejoining” of the chromosome with a reversal (inversion) of the two breakpoints. Researchers have been able to determine certain risk factors that, when present, increase a person’s chances of developing AML. These risk factors include several environmental factors including exposure to benzene, certain pesticides, ionizing radiation, and smoking. Most people with AML develop the disease without any known risk factors. Some people have therapy-related AML. In these people, AML results from treatments people underwent earlier in their lives. Often, this can be radiation therapy or chemotherapy that was used to treat a different form of cancer. Some people with AML have another blood disorder first, such as a form of myelodysplastic syndrome. Myelodysplastic syndromes are a rare group of blood disorders that occur because of disordered development of blood cells within the bone marrow. About half of the people who have a myelodysplastic syndrome eventually develop AML. Myelodysplastic syndromes were once called pre-leukemia or smoldering leukemia. In rare instances, people with other blood disorders such as essential thrombocythemia or polycythemia vera can eventually develop AML. This is much less likely, however, than it is in people with a myelodysplastic syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the NORD Rare Disease Database.)People who have certain rare disorders including Down syndrome, Fanconi anemia, ataxia-telangiectasia, and Bloom syndrome have a slightly increased risk of developing AML. (For more information, choose the specific disorder name as your search term in the NORD Rare Disease Database.) | 30 | Acute Myeloid Leukemia |
nord_30_3 | Affects of Acute Myeloid Leukemia | Acute myeloid leukemia is the most common form of acute leukemia in adults, making up about 80% of people with acute leukemia. In the United States, it is estimated that 3-5 people per every 100,000 people in the general population has the disease. More than half the people diagnosed with AML are 65 years of age or older. Slightly more men than women are affected by the disease, and it occurs with slightly more frequency in people of European heritage. | Affects of Acute Myeloid Leukemia. Acute myeloid leukemia is the most common form of acute leukemia in adults, making up about 80% of people with acute leukemia. In the United States, it is estimated that 3-5 people per every 100,000 people in the general population has the disease. More than half the people diagnosed with AML are 65 years of age or older. Slightly more men than women are affected by the disease, and it occurs with slightly more frequency in people of European heritage. | 30 | Acute Myeloid Leukemia |
nord_30_4 | Related disorders of Acute Myeloid Leukemia | Symptoms of the following disorders can be similar to those of acute myeloid leukemia. Comparisons may be useful for a differential diagnosis.Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia. APL accounts for about 10%-15% of people with AML. It occurs in younger people more than other forms of AML, with a mean age of diagnosis in the early 30s. In APL, the initial symptom is often prolonged bleeding or blood clotting problems. Bleeding problems can be severe, even life-threatening in some people. People with APL have similar symptoms that are seen in other forms of AML. This is because they may lack sufficient levels of healthy red blood cells, white blood cells, and platelets. People with APL have a specific genetic change involving chromosomes 15 and 17. This change is a translocation (see the Causes section above). It results in the creation of fusion gene called PML/RARa. A fusion gene is an abnormal gene caused by the combination (fusion) of two separate genes. In APL, immature white blood cells called promyelocytes grow out of control. They accumulate in the bone marrow and crowd out healthy blood cells. They also damage the bone marrow hampering the formation of new, healthy blood cells. There are effective treatments for APL including all-trans retinoic acid and arsenic trioxide. Other medications may also be used to treat people with APL. Additional disorders that may need to be differentiated from AML include acute lymphoblastic leukemia, myelodysplastic syndromes, chronic myelogenous leukemia, myeloproliferative neoplasms, infectious mononucleosis, and an increase in the white blood cell count, which can mimic leukemia, but is usually caused by an infection or another disease (leukemoid reactions). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Acute Myeloid Leukemia. Symptoms of the following disorders can be similar to those of acute myeloid leukemia. Comparisons may be useful for a differential diagnosis.Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia. APL accounts for about 10%-15% of people with AML. It occurs in younger people more than other forms of AML, with a mean age of diagnosis in the early 30s. In APL, the initial symptom is often prolonged bleeding or blood clotting problems. Bleeding problems can be severe, even life-threatening in some people. People with APL have similar symptoms that are seen in other forms of AML. This is because they may lack sufficient levels of healthy red blood cells, white blood cells, and platelets. People with APL have a specific genetic change involving chromosomes 15 and 17. This change is a translocation (see the Causes section above). It results in the creation of fusion gene called PML/RARa. A fusion gene is an abnormal gene caused by the combination (fusion) of two separate genes. In APL, immature white blood cells called promyelocytes grow out of control. They accumulate in the bone marrow and crowd out healthy blood cells. They also damage the bone marrow hampering the formation of new, healthy blood cells. There are effective treatments for APL including all-trans retinoic acid and arsenic trioxide. Other medications may also be used to treat people with APL. Additional disorders that may need to be differentiated from AML include acute lymphoblastic leukemia, myelodysplastic syndromes, chronic myelogenous leukemia, myeloproliferative neoplasms, infectious mononucleosis, and an increase in the white blood cell count, which can mimic leukemia, but is usually caused by an infection or another disease (leukemoid reactions). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 30 | Acute Myeloid Leukemia |
nord_30_5 | Diagnosis of Acute Myeloid Leukemia | A diagnosis of acute myeloid leukemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling.Clinical Testing and Workup
Laboratory tests will include a complete blood count and a peripheral blood smear. A complete blood count will tell the doctor whether the levels of red blood cells, white blood cells and platelets are low, how much hemoglobin (the red, iron-rich, oxygen-containing pigment of the blood) is in the blood, and the portion of the blood that is made up of red blood cells. A peripheral blood smear is a test that involves studying a sample of the circulating blood in the body and is used to look for abnormalities in blood cells including changes in the shape of cells or the presence of immature blood cells (myeloblasts). A suspected diagnosis of AML can be confirmed by a bone marrow biopsy. A biopsy is a test that involves taking a sample of tissue (in this situation bone marrow tissue) and studying the sample under a microscope. Often, a tissue sample is taken from the hip bone. During a bone marrow biopsy, the skin and tissue over the bone is numbed with a local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. This may be painful and sometimes a mild, calming medication (sedative) may be offered beforehand. There may be bruising and discomfort for a few days after the procedure as well. After the sample is withdrawn, it is examined under a microscope by a pathologist, who is a specialist in the cause and development of disease, and who can diagnose disease through laboratory testing. Cytogenetic analysis may be used to help diagnose AML. Doctors know now that cancerous cells have certain genetic abnormalities or rearrangements. AML is associated with many different, specific genetic abnormalities. Cancerous cells are studied in order to detect these genetic changes.A procedure called immunophenotyping is often used to help distinguish blood cell cancers. This test involves using antibodies that react to certain markers (antigens) on the surface of cancer cells. This test can help to distinguish different types of leukemia from one another. The World Health Organization (WHO) has published diagnostic criteria for AML based on any of the following:• Greater than (≥) 20% blasts in blood or marrow (based on 200 nucleated cells from blood and 500 nucleated cells from bone marrow)• clonal, recurring cytogenetic abnormalities t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), and t(15;17)(q22;q12) (regardless of blast percentage)• myeloid sarcoma (regardless of blast percentage)The “t” in bullet two refers to a translocation and the “inv” refers to an inversion. These cytogenetic abnormalities are described in the Causes section above.Sometimes regular and specialized imaging techniques like traditional X-rays, computerized tomography (CT) scanning or magnetic resonance imaging (MRI) may be used to help to assess the extent of disease. A chest x-ray may be given to assess the lungs and other organs and bones in the chest. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain organ or tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. These tests can help to determine whether leukemia has spread to affect other organs or areas of the body. Some people may undergo a test called a lumbar puncture, also known as a spinal tap. This procedure is given if doctors suspect that AML has spread to the central nervous stem. During a lumbar puncture, a needle is inserted into the spinal canal in the lower back to retrieve a sample of cerebrospinal fluid (CSF). CSF is the fluid that surrounds the brain and spinal cord. | Diagnosis of Acute Myeloid Leukemia. A diagnosis of acute myeloid leukemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. During a complete physical examination, physicians may feel (i.e., palpate) the lymph nodes in certain regions to detect any swelling.Clinical Testing and Workup
Laboratory tests will include a complete blood count and a peripheral blood smear. A complete blood count will tell the doctor whether the levels of red blood cells, white blood cells and platelets are low, how much hemoglobin (the red, iron-rich, oxygen-containing pigment of the blood) is in the blood, and the portion of the blood that is made up of red blood cells. A peripheral blood smear is a test that involves studying a sample of the circulating blood in the body and is used to look for abnormalities in blood cells including changes in the shape of cells or the presence of immature blood cells (myeloblasts). A suspected diagnosis of AML can be confirmed by a bone marrow biopsy. A biopsy is a test that involves taking a sample of tissue (in this situation bone marrow tissue) and studying the sample under a microscope. Often, a tissue sample is taken from the hip bone. During a bone marrow biopsy, the skin and tissue over the bone is numbed with a local anesthetic, and a needle is inserted into the bone through which a bone marrow sample is withdrawn. This may be painful and sometimes a mild, calming medication (sedative) may be offered beforehand. There may be bruising and discomfort for a few days after the procedure as well. After the sample is withdrawn, it is examined under a microscope by a pathologist, who is a specialist in the cause and development of disease, and who can diagnose disease through laboratory testing. Cytogenetic analysis may be used to help diagnose AML. Doctors know now that cancerous cells have certain genetic abnormalities or rearrangements. AML is associated with many different, specific genetic abnormalities. Cancerous cells are studied in order to detect these genetic changes.A procedure called immunophenotyping is often used to help distinguish blood cell cancers. This test involves using antibodies that react to certain markers (antigens) on the surface of cancer cells. This test can help to distinguish different types of leukemia from one another. The World Health Organization (WHO) has published diagnostic criteria for AML based on any of the following:• Greater than (≥) 20% blasts in blood or marrow (based on 200 nucleated cells from blood and 500 nucleated cells from bone marrow)• clonal, recurring cytogenetic abnormalities t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), and t(15;17)(q22;q12) (regardless of blast percentage)• myeloid sarcoma (regardless of blast percentage)The “t” in bullet two refers to a translocation and the “inv” refers to an inversion. These cytogenetic abnormalities are described in the Causes section above.Sometimes regular and specialized imaging techniques like traditional X-rays, computerized tomography (CT) scanning or magnetic resonance imaging (MRI) may be used to help to assess the extent of disease. A chest x-ray may be given to assess the lungs and other organs and bones in the chest. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain organ or tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. These tests can help to determine whether leukemia has spread to affect other organs or areas of the body. Some people may undergo a test called a lumbar puncture, also known as a spinal tap. This procedure is given if doctors suspect that AML has spread to the central nervous stem. During a lumbar puncture, a needle is inserted into the spinal canal in the lower back to retrieve a sample of cerebrospinal fluid (CSF). CSF is the fluid that surrounds the brain and spinal cord. | 30 | Acute Myeloid Leukemia |
nord_30_6 | Therapies of Acute Myeloid Leukemia | Treatment
The diagnosis and therapeutic management of acute myeloid leukemia may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; specific genetic alterations present and specific AML subtype; the presence or absence of certain symptoms; whether leukemia has spread outside of the blood and bone marrow and what specific organ systems are involved; an individual’s age and general health; a person’s physical ability, ability to care for oneself, and ability to perform normal, daily activities (performance status); and/or other elements. Decisions concerning the use of specific drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Doctors may use these factors to establish a classification or stratification of risk for a person with AML to offer a prognosis and to best guide treatment.For most people, the initial treatment for AML is induction therapy. The goal of induction therapy is to achieve a complete remission of the disease. This involves the use of chemotherapy, a combination of drugs that are harmful to cancerous cells and tissue. Chemotherapy can reduce the number of cancerous cells in the body and prevent new cells from forming. For young adults (i.e. under 60 years of age), an anthracycline chemotherapy drug like daunorubicin or idarubicin in combination with cytarabine, is usually used and may be referred to as the “7 + 3 regimen” (7 days of therapy with cytarabine, plus 3 days of an anthracycline drug). There are other options as well including regimens with higher doses of cytarabine. These different options need to be discussed in detail with a patient’s physician and medical team. Induction therapy has very high success rates in achieving remission, but there are also high rates of cancer coming back, called a relapse. Induction therapy is a highly toxic treatment regimen and requires close monitoring.It is common for a small number of leukemic cells to remain after induction therapy. This may be referred to as minimal residual disease. Consequently, after induction therapy, individuals may undergo a second phase of treatment, called the consolidation phase or postinduction therapy. This is done after a person has had time to recover from the side effects of induction therapy, and is performed to destroy any cancerous cells that remain and achieve long-term remission. In general, consolidation therapy consists of more chemotherapy or an allogeneic stem cell transplant.Consolidation phase chemotherapy may consist of another round of the chemotherapy regimen used in induction therapy, different doses of drugs used in the initial induction therapy, or treatment with different drugs. For instance, higher doses of cytarabine either alone or in combination with other drugs are often used. One such combination is the FLAG-IDA regimen (cytarabine, fludarabine, granulocyte colony stimulating factor and idarubicin). New chemotherapy drugs and new regimens (combinations of drugs) are being studied in clinical trials. A physician may recommend that a person with AML join a clinical trial, especially if their disease seems resistant to standard treatment options.Sometimes, doctors may recommend an allogeneic stem cell transplant for consolidation therapy. Whether to undergo this procedure is based on many factors including those discussed in the second paragraph of this section. An allogeneic stem cell transplant is a type of bone marrow transplant. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, white blood cells, platelets). In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. In people with AML, this procedure follows treatment with strong doses of chemotherapy to wipe out leukemic cells. Sometimes, radiation therapy may also be used. In some people, the new (donated) cells that are infused into the patient will recognize any remaining leukemic cells as foreign and destroy them. This is called graft-versus-leukemia effect, but it does not always occur. Allogeneic stem cell transplants can be associated with severe, even life-threatening complications. Generally, this therapy is reserved for people who do not respond to other treatment options and younger patients who meet specific criteria.Some people such as certain older individuals who meet specific criteria may elect to undergo a reduced-intensity (nonmyeloablative) allogeneic stem cell transplant. These transplants involve an initial chemotherapy regimen given at lower doses (reduced intensity), and thus are mild enough for people who are not eligible for a regular allogeneic stem cell transplant.In 2017, the following drugs were approved to treat AML:Midostaurin (Rydapt) was approved for the treatment of adult patients with newly diagnosed FLT3 gene positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Rydapt is manufactured by Novartis Pharmaceuticals Corp.Idhifa (enasidenib) was approved to treat adult patients with relapsed or refractory AML who have a IDH2 gene mutation. The drug was approved for use with the RealTime IDH2 Assay, which is used to detect specific mutations in the IDH2 gene in patients with AML. Idhifa is manufactured by the Celgene Corporation. The RealTime IDH2 Assay is manufactured by Abbott Laboratories.Vyxeos was approved to treat adults with two types of AML: newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC). Vyxeos is a fixed-combination of chemotherapy drugs daunorubicin and cytarabine that is manufactured by Jazz Pharmaceuticals.Mylotarg (gemtuzumab ozogamicin) was approved to treat adults with newly diagnosed AML whose tumors express the CD33 antigen (CD33-positive AML) and to treat patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment. Mylotarg is manufactured by Pfizer Inc.In 2018, Tibsovo (ivosidenib) was approved to treat adult patients with relapsed or refractory AML who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic test used to detect specific mutations in the IDH1 gene in patients with AML. Tibsovo is manufactured by Agios Pharmaceuticals, Inc. The companion diagnostic test is made by Abbott Laboratories.More than 50% of people with AML experience a return of cancer, called a relapse. If relapse occurs within the first year, then physicians may recommend that individuals participate in a clinical trial for a new treatment option. Another option is to try another round of induction therapy with a different chemotherapy regimen and new drugs. If a relapse is over a year later, then physicians may recommend an allogeneic stem cell transplant, or they may recommend repeating the chemotherapy used during induction therapy, or they may recommend both. People who experience a relapse or for whom further treatment is ineffective, may be encouraged to participate in a clinical trial.There is no clear age that distinguishes between younger adult and older adult. In most studies, older adults have been defined as people over the age of 60. Treatment for older adults is difficult because they are more likely to have conditions unrelated to AML (e.g. heart disease, diabetes) that may limit treatment options. AML also tends to be more resistant to chemotherapy in older adults and they are more susceptible to side effects from treatment. There is no agreed upon, optimal approach to treating older adults with AML. Treatment for older adults is highly individualized.The treatment of AML in children is similar to that for younger adults. Induction therapy with chemotherapy, often cytarabine and anthracycline drugs including daunorubicin or doxorubicin, are used. However, there are different induction therapy regimens that can be used to treat children with AML. Decisions concerning treatment are made based on the factors discussed in the beginning of this section. As with adults, children with AML will go through a consolidation phase of treatment as well. Treatment of relapse in children is similar to treatment in younger adults. Physicians may recommend participation in a clinical trial. | Therapies of Acute Myeloid Leukemia. Treatment
The diagnosis and therapeutic management of acute myeloid leukemia may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), disorders of the blood and blood-forming tissues (hematologists), or the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; specific genetic alterations present and specific AML subtype; the presence or absence of certain symptoms; whether leukemia has spread outside of the blood and bone marrow and what specific organ systems are involved; an individual’s age and general health; a person’s physical ability, ability to care for oneself, and ability to perform normal, daily activities (performance status); and/or other elements. Decisions concerning the use of specific drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Doctors may use these factors to establish a classification or stratification of risk for a person with AML to offer a prognosis and to best guide treatment.For most people, the initial treatment for AML is induction therapy. The goal of induction therapy is to achieve a complete remission of the disease. This involves the use of chemotherapy, a combination of drugs that are harmful to cancerous cells and tissue. Chemotherapy can reduce the number of cancerous cells in the body and prevent new cells from forming. For young adults (i.e. under 60 years of age), an anthracycline chemotherapy drug like daunorubicin or idarubicin in combination with cytarabine, is usually used and may be referred to as the “7 + 3 regimen” (7 days of therapy with cytarabine, plus 3 days of an anthracycline drug). There are other options as well including regimens with higher doses of cytarabine. These different options need to be discussed in detail with a patient’s physician and medical team. Induction therapy has very high success rates in achieving remission, but there are also high rates of cancer coming back, called a relapse. Induction therapy is a highly toxic treatment regimen and requires close monitoring.It is common for a small number of leukemic cells to remain after induction therapy. This may be referred to as minimal residual disease. Consequently, after induction therapy, individuals may undergo a second phase of treatment, called the consolidation phase or postinduction therapy. This is done after a person has had time to recover from the side effects of induction therapy, and is performed to destroy any cancerous cells that remain and achieve long-term remission. In general, consolidation therapy consists of more chemotherapy or an allogeneic stem cell transplant.Consolidation phase chemotherapy may consist of another round of the chemotherapy regimen used in induction therapy, different doses of drugs used in the initial induction therapy, or treatment with different drugs. For instance, higher doses of cytarabine either alone or in combination with other drugs are often used. One such combination is the FLAG-IDA regimen (cytarabine, fludarabine, granulocyte colony stimulating factor and idarubicin). New chemotherapy drugs and new regimens (combinations of drugs) are being studied in clinical trials. A physician may recommend that a person with AML join a clinical trial, especially if their disease seems resistant to standard treatment options.Sometimes, doctors may recommend an allogeneic stem cell transplant for consolidation therapy. Whether to undergo this procedure is based on many factors including those discussed in the second paragraph of this section. An allogeneic stem cell transplant is a type of bone marrow transplant. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, white blood cells, platelets). In allogeneic stem cell transplantation, stem cells are donated from another person, usually from a closely matched family member. In people with AML, this procedure follows treatment with strong doses of chemotherapy to wipe out leukemic cells. Sometimes, radiation therapy may also be used. In some people, the new (donated) cells that are infused into the patient will recognize any remaining leukemic cells as foreign and destroy them. This is called graft-versus-leukemia effect, but it does not always occur. Allogeneic stem cell transplants can be associated with severe, even life-threatening complications. Generally, this therapy is reserved for people who do not respond to other treatment options and younger patients who meet specific criteria.Some people such as certain older individuals who meet specific criteria may elect to undergo a reduced-intensity (nonmyeloablative) allogeneic stem cell transplant. These transplants involve an initial chemotherapy regimen given at lower doses (reduced intensity), and thus are mild enough for people who are not eligible for a regular allogeneic stem cell transplant.In 2017, the following drugs were approved to treat AML:Midostaurin (Rydapt) was approved for the treatment of adult patients with newly diagnosed FLT3 gene positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Rydapt is manufactured by Novartis Pharmaceuticals Corp.Idhifa (enasidenib) was approved to treat adult patients with relapsed or refractory AML who have a IDH2 gene mutation. The drug was approved for use with the RealTime IDH2 Assay, which is used to detect specific mutations in the IDH2 gene in patients with AML. Idhifa is manufactured by the Celgene Corporation. The RealTime IDH2 Assay is manufactured by Abbott Laboratories.Vyxeos was approved to treat adults with two types of AML: newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC). Vyxeos is a fixed-combination of chemotherapy drugs daunorubicin and cytarabine that is manufactured by Jazz Pharmaceuticals.Mylotarg (gemtuzumab ozogamicin) was approved to treat adults with newly diagnosed AML whose tumors express the CD33 antigen (CD33-positive AML) and to treat patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment. Mylotarg is manufactured by Pfizer Inc.In 2018, Tibsovo (ivosidenib) was approved to treat adult patients with relapsed or refractory AML who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic test used to detect specific mutations in the IDH1 gene in patients with AML. Tibsovo is manufactured by Agios Pharmaceuticals, Inc. The companion diagnostic test is made by Abbott Laboratories.More than 50% of people with AML experience a return of cancer, called a relapse. If relapse occurs within the first year, then physicians may recommend that individuals participate in a clinical trial for a new treatment option. Another option is to try another round of induction therapy with a different chemotherapy regimen and new drugs. If a relapse is over a year later, then physicians may recommend an allogeneic stem cell transplant, or they may recommend repeating the chemotherapy used during induction therapy, or they may recommend both. People who experience a relapse or for whom further treatment is ineffective, may be encouraged to participate in a clinical trial.There is no clear age that distinguishes between younger adult and older adult. In most studies, older adults have been defined as people over the age of 60. Treatment for older adults is difficult because they are more likely to have conditions unrelated to AML (e.g. heart disease, diabetes) that may limit treatment options. AML also tends to be more resistant to chemotherapy in older adults and they are more susceptible to side effects from treatment. There is no agreed upon, optimal approach to treating older adults with AML. Treatment for older adults is highly individualized.The treatment of AML in children is similar to that for younger adults. Induction therapy with chemotherapy, often cytarabine and anthracycline drugs including daunorubicin or doxorubicin, are used. However, there are different induction therapy regimens that can be used to treat children with AML. Decisions concerning treatment are made based on the factors discussed in the beginning of this section. As with adults, children with AML will go through a consolidation phase of treatment as well. Treatment of relapse in children is similar to treatment in younger adults. Physicians may recommend participation in a clinical trial. | 30 | Acute Myeloid Leukemia |
nord_31_0 | Overview of Acute Promyelocytic Leukemia | SummaryAcute promyelocytic leukemia (APL) is a blood cancer characterized by a marked increase in a type of immature white blood cells known as promyelocytes. It develops in about 600 to 800 individuals each year in the United States, most often in adults around the age of 40 but also in children. The characteristic symptom of APL is the associated bleeding disorder (coagulopathy), which can lead to excessive bleeding but also to blood clot formation (thrombosis). In APL and other types of leukemia, the bone marrow is filled by malignant cells and is unable to produce functional cells. A decreased number of platelets (thrombocytopenia) is one of the contributing factors to the bleeding often present in APL. A decreased number of red blood cells (anemia) can lead to pallor and fatigue, while a decreased number of functional white blood cells (neutropenia) predispose affected individuals to infections. Fever, chills, night sweats and weight loss, which are collectively known as constitutional or “B” symptoms, are also common in APL. The treatment of APL is centered on elimination of the malignant cells and supportive care with transfusion of blood products to minimize the risk of bleeding or thrombosis, Medications, especially all-trans retinoic acid (ATRA; tretinoin) and arsenic trioxide allow malignant promyelocytes to mature into neutrophils, which are unable to proliferate and subsequently eliminated.IntroductionCirculating blood cells are formed in a region in the middle of large bones known as the bone marrow and are all derived from a primitive type of cell known as the hematopoietic stem cell. Hematopoiesis refers to the process of formation of blood cells from hematopoietic stem cells. The two principal lineages of blood cells are the myeloid and lymphoid cells. Cells derived from the myeloid lineage include red blood cells (erythrocytes), platelets (thrombocytes) and granulocytes and monocytes. A promyelocyte is a type of myeloid cell that normally matures to granulocytes. Eosinophils, neutrophils and basophils are the three types of mature granulocytes.Leukemia is defined as the uncontrolled proliferation of abnormal leukocytes in the blood and bone marrow. APL is a type of leukemia caused by the uncontrolled proliferation of promyelocytes that are arrested in their normal maturation process. It is a subtype of acute myeloid leukemia (AML), but it has its own uniquely different disease mechanism, clinical manifestations and treatment. APL is a medical emergency, as treatment must be initiated as soon as the disease is suspected in order to decrease the risk of complications associated with APL coagulopathy.The development of therapy for APL is a success story in the realm of cancer and leukemia treatment. Before modern treatments were developed, most affected individuals did not survive more than one month after diagnosis due to bleeding and/or infection. Research that elucidated the molecular mechanisms by which APL develops led to the development of ATRA, an oral medication that specifically targets the genetic defects in APL. Nowadays, with ATRA and other targeted therapies, such as arsenic trioxide (ATO), APL has shifted from an often-fatal disease to a highly curable form of leukemia. | Overview of Acute Promyelocytic Leukemia. SummaryAcute promyelocytic leukemia (APL) is a blood cancer characterized by a marked increase in a type of immature white blood cells known as promyelocytes. It develops in about 600 to 800 individuals each year in the United States, most often in adults around the age of 40 but also in children. The characteristic symptom of APL is the associated bleeding disorder (coagulopathy), which can lead to excessive bleeding but also to blood clot formation (thrombosis). In APL and other types of leukemia, the bone marrow is filled by malignant cells and is unable to produce functional cells. A decreased number of platelets (thrombocytopenia) is one of the contributing factors to the bleeding often present in APL. A decreased number of red blood cells (anemia) can lead to pallor and fatigue, while a decreased number of functional white blood cells (neutropenia) predispose affected individuals to infections. Fever, chills, night sweats and weight loss, which are collectively known as constitutional or “B” symptoms, are also common in APL. The treatment of APL is centered on elimination of the malignant cells and supportive care with transfusion of blood products to minimize the risk of bleeding or thrombosis, Medications, especially all-trans retinoic acid (ATRA; tretinoin) and arsenic trioxide allow malignant promyelocytes to mature into neutrophils, which are unable to proliferate and subsequently eliminated.IntroductionCirculating blood cells are formed in a region in the middle of large bones known as the bone marrow and are all derived from a primitive type of cell known as the hematopoietic stem cell. Hematopoiesis refers to the process of formation of blood cells from hematopoietic stem cells. The two principal lineages of blood cells are the myeloid and lymphoid cells. Cells derived from the myeloid lineage include red blood cells (erythrocytes), platelets (thrombocytes) and granulocytes and monocytes. A promyelocyte is a type of myeloid cell that normally matures to granulocytes. Eosinophils, neutrophils and basophils are the three types of mature granulocytes.Leukemia is defined as the uncontrolled proliferation of abnormal leukocytes in the blood and bone marrow. APL is a type of leukemia caused by the uncontrolled proliferation of promyelocytes that are arrested in their normal maturation process. It is a subtype of acute myeloid leukemia (AML), but it has its own uniquely different disease mechanism, clinical manifestations and treatment. APL is a medical emergency, as treatment must be initiated as soon as the disease is suspected in order to decrease the risk of complications associated with APL coagulopathy.The development of therapy for APL is a success story in the realm of cancer and leukemia treatment. Before modern treatments were developed, most affected individuals did not survive more than one month after diagnosis due to bleeding and/or infection. Research that elucidated the molecular mechanisms by which APL develops led to the development of ATRA, an oral medication that specifically targets the genetic defects in APL. Nowadays, with ATRA and other targeted therapies, such as arsenic trioxide (ATO), APL has shifted from an often-fatal disease to a highly curable form of leukemia. | 31 | Acute Promyelocytic Leukemia |
nord_31_1 | Symptoms of Acute Promyelocytic Leukemia | APL most commonly occurs in middle-aged individuals. The median age at diagnosis is around 40 years, meaning that half of cases occur in people under that age and the other half in people above that age. In APL, the bone marrow is overcrowded with malignant cells and eventually fails to produce normal blood cells required for normal functioning. Depletion of red blood cells (anemia) leads to symptoms such as fatigue and pallor, while a decreased number of functional white blood cells predispose affected individuals to infections. A decreased number of platelets (thrombocytopenia) increases the risk of bleeding and bruising.The most dangerous symptom of APL is the bleeding disorder (coagulopathy) associated with the disease. Coagulopathy is common in all types of leukemia, mainly due to thrombocytopenia. However, molecules present in APL cells can lead to a severe coagulopathy characterized by the breakdown of the clotting factors known as fibrinogen and fibrin (systemic fibrinolysis), and the development of a condition called disseminated intravascular coagulation (DIC). In DIC, the coagulation system of the body is abnormally activated, and coagulation factors are excessively consumed. This leads to numerous complications, including bleeding and the formation of blood clots (thrombosis). Bleeding in the skin and mucous membranes can manifest as small red or purple spots (petechiae) or patches (purpura) or as bruises (ecchymoses). Affected individuals may also bleed excessively from their gums or from sites of minor trauma such as vascular puncture sites. Other sites of bleeding include blood in the stools (hematochezia) due to gastrointestinal bleeding, blood in the urine (hematuria) due to bleeding in the genitourinary tract, excessive menstrual blood losses (menorrhagia) and excessive or recurrent nose bleeding (epistaxis). Bleeding inside the skull (intracranial hemorrhage) and pulmonary hemorrhage are the two most common causes of hemorrhagic death in APL. Symptoms of intracranial hemorrhage depend on the region of the brain that is affected and include arms and/or leg weakness, headaches, vomiting and a decreased level of consciousness. Pulmonary hemorrhage can lead to cough, shortness of breath (dyspnea) and coughing up blood (hemoptysis). In addition to excessive bleeding, APL-associated coagulopathy increases the likelihood of forming abnormal blood clots that can dislodge and obstruct blood vessels (thromboembolism). Occlusion of blood vessels in the lungs may result from a pulmonary embolism, while obstruction of vessels in the brain and the heart can respectively lead to a stroke and heart attack (myocardial infarction). DIC can also lead to organ dysfunction, most notably of the liver and kidneys.In addition to coagulopathy, constitutional symptoms are common at presentation. These symptoms, also called B symptoms, occur with many types of cancer and are also associated with some infections and autoimmune diseases. Although their exact cause is unknown, a probable contributing factor is the release of molecules that modulate immunity and inflammation (cytokines). These cytokines are thought to be released by the malignant cells. Constitutional symptoms include fever, fatigue, chills, weight loss, and drenching night sweats.Differentiation syndrome is a potentially severe complication of APL treatment that occurs in up to a quarter of patients. It most often occurs within 2 to 21 days after treatment initiation and is characterized by fever, rash, swelling due to accumulation of fluid (edema), shortness of breath (dyspnea), low blood pressure (hypotension), kidney and liver dysfunction and accumulation of fluid within or around the lungs (pleural effusion) and the heart (pericardial effusion). Another rare complication of APL treatment is called idiopathic intracranial hypertension. (For more information on this condition, choose “idiopathic intracranial hypertension” as your search term in the Rare Disease Database.)Most deaths due to APL occur early in the disease because of hemorrhage, infection or differentiation syndrome. Older age, male sex, high white blood cell count, increased creatinine levels (a marker of renal function) and abnormal fibrinogen levels (a coagulation factor) have been associated with an increased risk of early death in APL. White blood cell count is particularly important for risk stratification: APL with a white blood cell count of more than 10,000 cells per microliter is considered high-risk APL, while a white blood cell count under this value is considered standard-risk APL. Once the critical early period has passed, most patients are able to be cured. A large study carried on in the United States that included APL patients that had survived more than 48 hours after diagnosis found that 88% of individuals were alive after 5 years of follow-up. | Symptoms of Acute Promyelocytic Leukemia. APL most commonly occurs in middle-aged individuals. The median age at diagnosis is around 40 years, meaning that half of cases occur in people under that age and the other half in people above that age. In APL, the bone marrow is overcrowded with malignant cells and eventually fails to produce normal blood cells required for normal functioning. Depletion of red blood cells (anemia) leads to symptoms such as fatigue and pallor, while a decreased number of functional white blood cells predispose affected individuals to infections. A decreased number of platelets (thrombocytopenia) increases the risk of bleeding and bruising.The most dangerous symptom of APL is the bleeding disorder (coagulopathy) associated with the disease. Coagulopathy is common in all types of leukemia, mainly due to thrombocytopenia. However, molecules present in APL cells can lead to a severe coagulopathy characterized by the breakdown of the clotting factors known as fibrinogen and fibrin (systemic fibrinolysis), and the development of a condition called disseminated intravascular coagulation (DIC). In DIC, the coagulation system of the body is abnormally activated, and coagulation factors are excessively consumed. This leads to numerous complications, including bleeding and the formation of blood clots (thrombosis). Bleeding in the skin and mucous membranes can manifest as small red or purple spots (petechiae) or patches (purpura) or as bruises (ecchymoses). Affected individuals may also bleed excessively from their gums or from sites of minor trauma such as vascular puncture sites. Other sites of bleeding include blood in the stools (hematochezia) due to gastrointestinal bleeding, blood in the urine (hematuria) due to bleeding in the genitourinary tract, excessive menstrual blood losses (menorrhagia) and excessive or recurrent nose bleeding (epistaxis). Bleeding inside the skull (intracranial hemorrhage) and pulmonary hemorrhage are the two most common causes of hemorrhagic death in APL. Symptoms of intracranial hemorrhage depend on the region of the brain that is affected and include arms and/or leg weakness, headaches, vomiting and a decreased level of consciousness. Pulmonary hemorrhage can lead to cough, shortness of breath (dyspnea) and coughing up blood (hemoptysis). In addition to excessive bleeding, APL-associated coagulopathy increases the likelihood of forming abnormal blood clots that can dislodge and obstruct blood vessels (thromboembolism). Occlusion of blood vessels in the lungs may result from a pulmonary embolism, while obstruction of vessels in the brain and the heart can respectively lead to a stroke and heart attack (myocardial infarction). DIC can also lead to organ dysfunction, most notably of the liver and kidneys.In addition to coagulopathy, constitutional symptoms are common at presentation. These symptoms, also called B symptoms, occur with many types of cancer and are also associated with some infections and autoimmune diseases. Although their exact cause is unknown, a probable contributing factor is the release of molecules that modulate immunity and inflammation (cytokines). These cytokines are thought to be released by the malignant cells. Constitutional symptoms include fever, fatigue, chills, weight loss, and drenching night sweats.Differentiation syndrome is a potentially severe complication of APL treatment that occurs in up to a quarter of patients. It most often occurs within 2 to 21 days after treatment initiation and is characterized by fever, rash, swelling due to accumulation of fluid (edema), shortness of breath (dyspnea), low blood pressure (hypotension), kidney and liver dysfunction and accumulation of fluid within or around the lungs (pleural effusion) and the heart (pericardial effusion). Another rare complication of APL treatment is called idiopathic intracranial hypertension. (For more information on this condition, choose “idiopathic intracranial hypertension” as your search term in the Rare Disease Database.)Most deaths due to APL occur early in the disease because of hemorrhage, infection or differentiation syndrome. Older age, male sex, high white blood cell count, increased creatinine levels (a marker of renal function) and abnormal fibrinogen levels (a coagulation factor) have been associated with an increased risk of early death in APL. White blood cell count is particularly important for risk stratification: APL with a white blood cell count of more than 10,000 cells per microliter is considered high-risk APL, while a white blood cell count under this value is considered standard-risk APL. Once the critical early period has passed, most patients are able to be cured. A large study carried on in the United States that included APL patients that had survived more than 48 hours after diagnosis found that 88% of individuals were alive after 5 years of follow-up. | 31 | Acute Promyelocytic Leukemia |
nord_31_2 | Causes of Acute Promyelocytic Leukemia | APL is caused by the uncontrolled proliferation of promyelocytes, a type of immature cell from the myeloid lineage of blood cells. The hallmark of APL is genetic alterations involving the retinoic acid receptor alpha (RARA) gene. Retinoic acid (a derivative of vitamin A) is critical in the process of cellular maturation and specialization (differentiation) of many cells, including myeloid precursors. In normal cells, the RARA protein is bound to proteins and forms a complex that prevents genes involved in cellular differentiation from being read; this is called transcriptional repression. When retinoic acid binds to this protein complex, transcriptional repression is relieved, genes involved in cellular differentiation can be read, and promyelocytes can continue their maturation and differentiation process into mature granulocytes. In most patients with APL, RARA gene alterations occur due to exchange of genetic material (translocation) between chromosomes 15 and 17, where the RARA and PML genes are located, respectively. This translocation results in a fusion gene termed PML/RARA, which leads to an abnormal retinoic acid receptor that blocks the differentiation process that is normally induced by retinoic acid. The myeloid precursors are therefore “stuck” in the promyelocyte stage and accumulate in the bone marrow, and eventually the blood. The fusion gene PML/RARA that leads to APL is an acquired mutation and is not inherited. When patients enter a remission, cells containing the PML/RARA fusion gene are no longer detectable.The coagulopathy associated with APL is multifactorial. In addition to thrombocytopenia, which can lead to bleeding in many types of leukemia, other molecules present in promyelocytes contribute to the severity of the coagulopathy encountered in APL. Notably, tissue factor (TF), a molecule found on the surface of APL cells, activates the coagulation cascade. Annexin II is also present on the surface of APL cells and facilitates the activation of plasmin, a molecule that breaks down blood clots. Overall, the action of tissue factor and annexin II, in combination with other molecules, leads to excessive clotting (thrombosis), and excessive bleeding due to consumption of coagulation factors and excessive breakdown of clots. | Causes of Acute Promyelocytic Leukemia. APL is caused by the uncontrolled proliferation of promyelocytes, a type of immature cell from the myeloid lineage of blood cells. The hallmark of APL is genetic alterations involving the retinoic acid receptor alpha (RARA) gene. Retinoic acid (a derivative of vitamin A) is critical in the process of cellular maturation and specialization (differentiation) of many cells, including myeloid precursors. In normal cells, the RARA protein is bound to proteins and forms a complex that prevents genes involved in cellular differentiation from being read; this is called transcriptional repression. When retinoic acid binds to this protein complex, transcriptional repression is relieved, genes involved in cellular differentiation can be read, and promyelocytes can continue their maturation and differentiation process into mature granulocytes. In most patients with APL, RARA gene alterations occur due to exchange of genetic material (translocation) between chromosomes 15 and 17, where the RARA and PML genes are located, respectively. This translocation results in a fusion gene termed PML/RARA, which leads to an abnormal retinoic acid receptor that blocks the differentiation process that is normally induced by retinoic acid. The myeloid precursors are therefore “stuck” in the promyelocyte stage and accumulate in the bone marrow, and eventually the blood. The fusion gene PML/RARA that leads to APL is an acquired mutation and is not inherited. When patients enter a remission, cells containing the PML/RARA fusion gene are no longer detectable.The coagulopathy associated with APL is multifactorial. In addition to thrombocytopenia, which can lead to bleeding in many types of leukemia, other molecules present in promyelocytes contribute to the severity of the coagulopathy encountered in APL. Notably, tissue factor (TF), a molecule found on the surface of APL cells, activates the coagulation cascade. Annexin II is also present on the surface of APL cells and facilitates the activation of plasmin, a molecule that breaks down blood clots. Overall, the action of tissue factor and annexin II, in combination with other molecules, leads to excessive clotting (thrombosis), and excessive bleeding due to consumption of coagulation factors and excessive breakdown of clots. | 31 | Acute Promyelocytic Leukemia |
nord_31_3 | Affects of Acute Promyelocytic Leukemia | APL comprises 5 to 10% of all cases of adult acute myeloid leukemia. Each year in the United States, it develops in around 2.2 people per million, for a total of 600 to 800 individuals. Although APL can occur at any age, middle-aged adults are most commonly affected; the median age at diagnosis is around 40. Epidemiological studies have shown that APL is slightly more common in Hispanics and slightly less common in African Americans compared to other ethnic groups. In very rare cases, APL can occur after chemotherapy or radiation therapy for other cancers, especially when therapy involves a class of medication known as topoisomerase II inhibitors; this is called therapy-related APL. | Affects of Acute Promyelocytic Leukemia. APL comprises 5 to 10% of all cases of adult acute myeloid leukemia. Each year in the United States, it develops in around 2.2 people per million, for a total of 600 to 800 individuals. Although APL can occur at any age, middle-aged adults are most commonly affected; the median age at diagnosis is around 40. Epidemiological studies have shown that APL is slightly more common in Hispanics and slightly less common in African Americans compared to other ethnic groups. In very rare cases, APL can occur after chemotherapy or radiation therapy for other cancers, especially when therapy involves a class of medication known as topoisomerase II inhibitors; this is called therapy-related APL. | 31 | Acute Promyelocytic Leukemia |
nord_31_4 | Related disorders of Acute Promyelocytic Leukemia | The symptoms of APL are often nonspecific and difficult to recognize. The following disorders are among those that most commonly present with symptoms resembling those of APL. Comparisons may be useful for a differential diagnosis.Multiple types of leukemia exist, depending on the characteristic of the affected cells. The symptoms of most types of leukemia are similar to those of APL and include fever, fatigue, weight loss, night sweats, bleeding and predisposition to infections. Acute (AML) and chronic myeloid leukemias (CML) are derived from myeloid cells. As promyelocytes are from the myeloid lineage, APL is a subtype of AML. In contrast to APL, AML and CML, which affect cells of myeloid lineage, acute lymphoblastic (ALL) and chronic lymphocytic leukemia (CLL) affect cells of lymphoid lineage. Some types of leukemia such as ALL most commonly occur in children while other types such as CML and CLL tend to occur in older individuals. (For more information on a specific type of leukemia, choose the disease name or its acronym as your search term in the Rare Disease Database.)In contrast to leukemias, which are cancers that develop from the proliferation of abnormal white blood cells (leukocytes) in the blood and bone marrow, lymphomas are cancers of abnormal lymphocytes (a type of white blood cell) that develop in the lymph nodes and form solid masses. Lymphoma can also lead to constitutional symptoms. Several subtypes of lymphoma exist, depending on the characteristics of the affected cells. The two main categories of lymphoma are Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Many types of NHL exist, including diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, mantle cell lymphoma, and follicular lymphoma. (For more information on a specific type of lymphoma, choose the name of the disease as your search term in the Rare Disease Database.)Acquired aplastic anemia is a rare blood disorder caused by failure of the bone marrow to produce blood cells. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells results in low levels of red and white blood cells and platelets (pancytopenia). As in APL, symptoms of aplastic anemia are those of anemia, bleeding and infection. Although bone marrow failure can occur secondarily to other disorders, most cases of aplastic anemia are due to the immune system mistakenly targeting the bone marrow (autoimmunity). (For more information on this disorder, choose “Aplastic anemia” as your search term in the Rare Disease Database.)Acquired agranulocytosis is a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of granulocytes in the circulating blood. It may be caused by a variety of drugs, most commonly chemotherapeutic agents and antipsychotic medications (e.g., clozapine). People with acquired agranulocytosis are susceptible to a variety of bacterial infections. Not infrequently, painful ulcers also develop in mucous membranes that line the mouth and/or the gastrointestinal tract. (For more information on this disorder, choose “Acquired agranulocytosis” as your search term in the Rare Disease Database.)Abnormal bleeding can be caused by a myriad of conditions. Coagulopathies can be classified in multiple ways. They can be either inherited or acquired and can affect platelets and initial clot formation (primary hemostasis) or coagulation factors and clot solidification (secondary hemostasis). Hemophilia is an example of inherited coagulopathy due to a deficiency in clotting factor VIII or IX. Leukemia and immune thrombocytopenia are acquired disorders that affect the number of platelets and therefore primary hemostasis. Blood thinners such as warfarin, rivaroxaban and aspirin can potentially lead to bleeding, especially if administered doses are too high. Disseminated intravascular coagulation, which is often present in APL, has many other potential causes including dysregulated response to infection (sepsis), cancer, trauma and complication during delivery (obstetrical complications).Constitutional symptoms commonly occur in APL and can also occur in a variety of other conditions, such as cancer, infections, and autoimmune diseases. Examples of infections that can present in a similar way to APL include infectious mononucleosis, HIV/AIDS, tuberculosis and bone infection (osteomyelitis). Systemic lupus erythematosus (usually simply called “lupus”), rheumatoid arthritis and autoimmune inflammation of the blood vessels (arteritis) such as giant cell arteritis or Takayasu arteritis are some of the numerous autoimmune conditions that can present with constitutional symptoms and therefore mimic APL. | Related disorders of Acute Promyelocytic Leukemia. The symptoms of APL are often nonspecific and difficult to recognize. The following disorders are among those that most commonly present with symptoms resembling those of APL. Comparisons may be useful for a differential diagnosis.Multiple types of leukemia exist, depending on the characteristic of the affected cells. The symptoms of most types of leukemia are similar to those of APL and include fever, fatigue, weight loss, night sweats, bleeding and predisposition to infections. Acute (AML) and chronic myeloid leukemias (CML) are derived from myeloid cells. As promyelocytes are from the myeloid lineage, APL is a subtype of AML. In contrast to APL, AML and CML, which affect cells of myeloid lineage, acute lymphoblastic (ALL) and chronic lymphocytic leukemia (CLL) affect cells of lymphoid lineage. Some types of leukemia such as ALL most commonly occur in children while other types such as CML and CLL tend to occur in older individuals. (For more information on a specific type of leukemia, choose the disease name or its acronym as your search term in the Rare Disease Database.)In contrast to leukemias, which are cancers that develop from the proliferation of abnormal white blood cells (leukocytes) in the blood and bone marrow, lymphomas are cancers of abnormal lymphocytes (a type of white blood cell) that develop in the lymph nodes and form solid masses. Lymphoma can also lead to constitutional symptoms. Several subtypes of lymphoma exist, depending on the characteristics of the affected cells. The two main categories of lymphoma are Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Many types of NHL exist, including diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, mantle cell lymphoma, and follicular lymphoma. (For more information on a specific type of lymphoma, choose the name of the disease as your search term in the Rare Disease Database.)Acquired aplastic anemia is a rare blood disorder caused by failure of the bone marrow to produce blood cells. In acquired aplastic anemia, an almost complete absence of hematopoietic stem cells results in low levels of red and white blood cells and platelets (pancytopenia). As in APL, symptoms of aplastic anemia are those of anemia, bleeding and infection. Although bone marrow failure can occur secondarily to other disorders, most cases of aplastic anemia are due to the immune system mistakenly targeting the bone marrow (autoimmunity). (For more information on this disorder, choose “Aplastic anemia” as your search term in the Rare Disease Database.)Acquired agranulocytosis is a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of granulocytes in the circulating blood. It may be caused by a variety of drugs, most commonly chemotherapeutic agents and antipsychotic medications (e.g., clozapine). People with acquired agranulocytosis are susceptible to a variety of bacterial infections. Not infrequently, painful ulcers also develop in mucous membranes that line the mouth and/or the gastrointestinal tract. (For more information on this disorder, choose “Acquired agranulocytosis” as your search term in the Rare Disease Database.)Abnormal bleeding can be caused by a myriad of conditions. Coagulopathies can be classified in multiple ways. They can be either inherited or acquired and can affect platelets and initial clot formation (primary hemostasis) or coagulation factors and clot solidification (secondary hemostasis). Hemophilia is an example of inherited coagulopathy due to a deficiency in clotting factor VIII or IX. Leukemia and immune thrombocytopenia are acquired disorders that affect the number of platelets and therefore primary hemostasis. Blood thinners such as warfarin, rivaroxaban and aspirin can potentially lead to bleeding, especially if administered doses are too high. Disseminated intravascular coagulation, which is often present in APL, has many other potential causes including dysregulated response to infection (sepsis), cancer, trauma and complication during delivery (obstetrical complications).Constitutional symptoms commonly occur in APL and can also occur in a variety of other conditions, such as cancer, infections, and autoimmune diseases. Examples of infections that can present in a similar way to APL include infectious mononucleosis, HIV/AIDS, tuberculosis and bone infection (osteomyelitis). Systemic lupus erythematosus (usually simply called “lupus”), rheumatoid arthritis and autoimmune inflammation of the blood vessels (arteritis) such as giant cell arteritis or Takayasu arteritis are some of the numerous autoimmune conditions that can present with constitutional symptoms and therefore mimic APL. | 31 | Acute Promyelocytic Leukemia |
nord_31_5 | Diagnosis of Acute Promyelocytic Leukemia | The diagnosis of APL is based on a combination of patient history, physical examination and numerous laboratory tests. In cases where patients present with symptoms such as fever, fatigue and bruising or bleeding, a complete blood count (CBC) is usually performed to evaluate the number of red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). In APL, platelets and red blood cells are often low, and white blood cells might be low, normal or elevated (however, the number of functional white blood cells is usually decreased). The combination of low platelets (thrombocytopenia), red blood cells (anemia) and white blood cells (leukopenia) is known as pancytopenia and is a warning sign that requires further speedy investigation. The cells taken from a blood sample can also be evaluated by a physician specialized in disorders related to the blood (hematologist) to see if they are abnormal and potentially leukemic. Further evaluation usually requires bone marrow examination to assess for the presence of abnormal cells. Bone marrow samples are obtained by bone marrow aspiration and biopsy, which are respectively used to collect the liquid and solid portions of the bone marrow. The location of choice for bone marrow aspiration and biopsy is the hip bone (pelvic bone).Once cells are obtained, they can be evaluated in numerous ways to confirm the diagnosis of APL and characterize the affected cells. Flow cytometry is a laboratory method where cells are suspended in fluid and processed into an instrument known as a flow cytometer. The cells flow one at a time through a laser, and the pattern of light scattering and cell fluorescence allows identification of cells based on their size, shape and the presence or absence of specific markers on the cell surface (immunophenotyping). The genes and chromosomes of the affected cells can also be evaluated. Karyotyping is a method where chromosomes are stained and visualized under a microscope during cell division. Fluorescence in situ hybridization (FISH) is a technique where selected chromosomal regions are stained to identify large genetic insertions, deletions, or translocations. Polymerase chain reaction (PCR) is a DNA sequencing technique that allows the detection of mutations and smaller insertions and deletions. Next generation sequencing (NGS) is a method of evaluating multiple genes simultaneously for mutations.In addition to tests used to diagnose and characterize APL, numerous ancillary tests are performed to evaluate the health of the patient and to assess for complications related to the disease. Especially in the case of APL, evaluation of coagulation parameters is crucial. Coagulations tests typically performed in the diagnostic evaluation of APL include prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer (a product of clot breakdown) and fibrinogen levels. Other routine tests include measurement of levels of electrolytes, renal function tests, such as creatinine levels, cardiac function tests and liver function tests. | Diagnosis of Acute Promyelocytic Leukemia. The diagnosis of APL is based on a combination of patient history, physical examination and numerous laboratory tests. In cases where patients present with symptoms such as fever, fatigue and bruising or bleeding, a complete blood count (CBC) is usually performed to evaluate the number of red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). In APL, platelets and red blood cells are often low, and white blood cells might be low, normal or elevated (however, the number of functional white blood cells is usually decreased). The combination of low platelets (thrombocytopenia), red blood cells (anemia) and white blood cells (leukopenia) is known as pancytopenia and is a warning sign that requires further speedy investigation. The cells taken from a blood sample can also be evaluated by a physician specialized in disorders related to the blood (hematologist) to see if they are abnormal and potentially leukemic. Further evaluation usually requires bone marrow examination to assess for the presence of abnormal cells. Bone marrow samples are obtained by bone marrow aspiration and biopsy, which are respectively used to collect the liquid and solid portions of the bone marrow. The location of choice for bone marrow aspiration and biopsy is the hip bone (pelvic bone).Once cells are obtained, they can be evaluated in numerous ways to confirm the diagnosis of APL and characterize the affected cells. Flow cytometry is a laboratory method where cells are suspended in fluid and processed into an instrument known as a flow cytometer. The cells flow one at a time through a laser, and the pattern of light scattering and cell fluorescence allows identification of cells based on their size, shape and the presence or absence of specific markers on the cell surface (immunophenotyping). The genes and chromosomes of the affected cells can also be evaluated. Karyotyping is a method where chromosomes are stained and visualized under a microscope during cell division. Fluorescence in situ hybridization (FISH) is a technique where selected chromosomal regions are stained to identify large genetic insertions, deletions, or translocations. Polymerase chain reaction (PCR) is a DNA sequencing technique that allows the detection of mutations and smaller insertions and deletions. Next generation sequencing (NGS) is a method of evaluating multiple genes simultaneously for mutations.In addition to tests used to diagnose and characterize APL, numerous ancillary tests are performed to evaluate the health of the patient and to assess for complications related to the disease. Especially in the case of APL, evaluation of coagulation parameters is crucial. Coagulations tests typically performed in the diagnostic evaluation of APL include prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer (a product of clot breakdown) and fibrinogen levels. Other routine tests include measurement of levels of electrolytes, renal function tests, such as creatinine levels, cardiac function tests and liver function tests. | 31 | Acute Promyelocytic Leukemia |
nord_31_6 | Therapies of Acute Promyelocytic Leukemia | Treatment & Management
The treatment of APL is centered on all-trans retinoic acid (ATRA; tretinoin). The goal of this targeted therapy is to allow the differentiation of promyelocytes, which have been blocked by the PML/RARA fusion gene, into mature neutrophils. The treatment course is constituted of three phases: induction, consolidation, and maintenance. APL is a medical emergency, as treatment must be initiated as soon as the disease is suspected to decrease the risk of bleeding complications associated with APL coagulopathy.The first phase, induction, aims to put the patient in a state called complete remission (CR), where most malignant cells from the blood and bone marrow will be eliminated and production of normal blood cells (hematopoiesis) will be restored. Molecular complete remission is a more durable state of remission where the PML/RARA fusion gene is not detectable by polymerase chain reaction (PCR) testing. In the induction phase, oral ATRA is combined with different medications for as long as 60 days or until complete remission is achieved. Depending on the treatment regimen used, ATRA can be combined with idarubicin, daunorubicin and cytarabine, or arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO). Idarubicin and daunorubicin are chemotherapy agents that induce DNA damage and therefore kill malignant cells, while cytarabine prevents the synthesis of DNA in cells. As is the case for ATRA, ATO promotes the differentiation of promyelocytes into mature neutrophils, although it acts via a slightly different mechanism. GO is a medication that specifically targets CD33, a marker that is present on APL cells. ATRA and ATO are most often used together for treating APL, and GO is added for patients with high-risk APL due to elevated WBC counts.After complete remission is achieved, patients move to the consolidation phase, which aims to prevent relapse. In the United States, the most prescribed consolidation regimen includes 4 monthly cycles of daily ATO together with daily ATRA.A third phase, maintenance, has been used to prevent relapse and usually involves less intensive therapy. Research now indicates that patients who have previously achieved complete molecular remission with ATRA and ATO do not require maintenance therapy. In other patients, ATRA alone is often used for maintenance, although it might be combined with chemotherapy agents such as 6-mercaptopurine or methotrexate. During maintenance and follow up, patients must be monitored for possible disease relapse. Monitoring should be more frequent in the first year after remission is achieved since most relapses occur during that time period. PCR can be performed on blood samples to see if there is sustained molecular complete remission. If this is not the case, a bone marrow biopsy should be performed for confirmation of relapse and treatment for relapsed disease can be initiated. In cases of relapse or treatment resistance, a possible treatment option is a prolonged infusion of intravenous ATO followed by allogeneic hematopoietic stem cell (HSC) transplantation. The rationale behind HSC transplantation is that it makes possible the pre-transplantation administration (preparative regimen) of very high doses of chemotherapy medications that are very effective to control cancer but also damage healthy hematopoietic stem cells. The patient’s HSCs are then replaced with healthy HSCs via the transplantation. The stem cells can be obtained from the blood or bone marrow from a healthy donor (allogeneic transplantation) or from the patient’s own body (autologous transplantation) before the preparative regimen is initiated if a molecular remission was achieved. Another goal of the preparative regiment is to suppress the immune system to decrease the risk of graft rejection. Although effective, HSC transplantation is a high-risk procedure and is associated with numerous short- and long-term side effects. Patients therefore must be chosen and followed carefully throughout the entire process.In addition to therapy used to treat the leukemia itself, other essential considerations specific to the management of APL include control of the associated coagulopathy and prevention or treatment of differentiation syndrome. Close monitoring of coagulation parameters with transfusion of blood products is necessary to minimize the risk of bleeding and thrombosis. Blood has four main components: plasma, which is the fluid that contains proteins and coagulation factors, red blood cells, white blood cells and platelets. Commonly used blood products for the management of coagulopathies include platelets, fresh frozen plasma, and cryoprecipitate (a derivative of plasma proteins). Differentiation syndrome is treated with corticosteroids such as dexamethasone or prednisone. However, corticosteroids are sometimes given in advance with induction regimens in a preventive manner (prophylactically) to decrease the risk of differentiation syndrome. | Therapies of Acute Promyelocytic Leukemia. Treatment & Management
The treatment of APL is centered on all-trans retinoic acid (ATRA; tretinoin). The goal of this targeted therapy is to allow the differentiation of promyelocytes, which have been blocked by the PML/RARA fusion gene, into mature neutrophils. The treatment course is constituted of three phases: induction, consolidation, and maintenance. APL is a medical emergency, as treatment must be initiated as soon as the disease is suspected to decrease the risk of bleeding complications associated with APL coagulopathy.The first phase, induction, aims to put the patient in a state called complete remission (CR), where most malignant cells from the blood and bone marrow will be eliminated and production of normal blood cells (hematopoiesis) will be restored. Molecular complete remission is a more durable state of remission where the PML/RARA fusion gene is not detectable by polymerase chain reaction (PCR) testing. In the induction phase, oral ATRA is combined with different medications for as long as 60 days or until complete remission is achieved. Depending on the treatment regimen used, ATRA can be combined with idarubicin, daunorubicin and cytarabine, or arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO). Idarubicin and daunorubicin are chemotherapy agents that induce DNA damage and therefore kill malignant cells, while cytarabine prevents the synthesis of DNA in cells. As is the case for ATRA, ATO promotes the differentiation of promyelocytes into mature neutrophils, although it acts via a slightly different mechanism. GO is a medication that specifically targets CD33, a marker that is present on APL cells. ATRA and ATO are most often used together for treating APL, and GO is added for patients with high-risk APL due to elevated WBC counts.After complete remission is achieved, patients move to the consolidation phase, which aims to prevent relapse. In the United States, the most prescribed consolidation regimen includes 4 monthly cycles of daily ATO together with daily ATRA.A third phase, maintenance, has been used to prevent relapse and usually involves less intensive therapy. Research now indicates that patients who have previously achieved complete molecular remission with ATRA and ATO do not require maintenance therapy. In other patients, ATRA alone is often used for maintenance, although it might be combined with chemotherapy agents such as 6-mercaptopurine or methotrexate. During maintenance and follow up, patients must be monitored for possible disease relapse. Monitoring should be more frequent in the first year after remission is achieved since most relapses occur during that time period. PCR can be performed on blood samples to see if there is sustained molecular complete remission. If this is not the case, a bone marrow biopsy should be performed for confirmation of relapse and treatment for relapsed disease can be initiated. In cases of relapse or treatment resistance, a possible treatment option is a prolonged infusion of intravenous ATO followed by allogeneic hematopoietic stem cell (HSC) transplantation. The rationale behind HSC transplantation is that it makes possible the pre-transplantation administration (preparative regimen) of very high doses of chemotherapy medications that are very effective to control cancer but also damage healthy hematopoietic stem cells. The patient’s HSCs are then replaced with healthy HSCs via the transplantation. The stem cells can be obtained from the blood or bone marrow from a healthy donor (allogeneic transplantation) or from the patient’s own body (autologous transplantation) before the preparative regimen is initiated if a molecular remission was achieved. Another goal of the preparative regiment is to suppress the immune system to decrease the risk of graft rejection. Although effective, HSC transplantation is a high-risk procedure and is associated with numerous short- and long-term side effects. Patients therefore must be chosen and followed carefully throughout the entire process.In addition to therapy used to treat the leukemia itself, other essential considerations specific to the management of APL include control of the associated coagulopathy and prevention or treatment of differentiation syndrome. Close monitoring of coagulation parameters with transfusion of blood products is necessary to minimize the risk of bleeding and thrombosis. Blood has four main components: plasma, which is the fluid that contains proteins and coagulation factors, red blood cells, white blood cells and platelets. Commonly used blood products for the management of coagulopathies include platelets, fresh frozen plasma, and cryoprecipitate (a derivative of plasma proteins). Differentiation syndrome is treated with corticosteroids such as dexamethasone or prednisone. However, corticosteroids are sometimes given in advance with induction regimens in a preventive manner (prophylactically) to decrease the risk of differentiation syndrome. | 31 | Acute Promyelocytic Leukemia |
nord_32_0 | Overview of Acute Respiratory Distress Syndrome | Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs that occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it may also affect children. ARDS is a buildup of fluid in the small air sacs (alveoli) in the lungs. This makes it difficult for oxygen to get into the bloodstream. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis) or as a result of pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions, and inhalation of toxic fumes, among other things. It usually develops within 24 to 48 hours after the original illness or injury and is considered a medical emergency. It may progress to involvement of other organs. | Overview of Acute Respiratory Distress Syndrome. Acute respiratory distress syndrome (ARDS) is a type of severe, acute lung dysfunction affecting all or most of both lungs that occurs as a result of illness or injury. Although it is sometimes called adult respiratory distress syndrome, it may also affect children. ARDS is a buildup of fluid in the small air sacs (alveoli) in the lungs. This makes it difficult for oxygen to get into the bloodstream. Major symptoms may include breathing difficulties (dyspnea), rapid breathing (tachypnea), excessively deep and rapid breathing (hyperventilation) and insufficient levels of oxygen in the circulating blood (hypoxemia). ARDS may develop in conjunction with widespread infection in the body (sepsis) or as a result of pneumonia, trauma, shock, severe burns, aspiration of food into the lung, multiple blood transfusions, and inhalation of toxic fumes, among other things. It usually develops within 24 to 48 hours after the original illness or injury and is considered a medical emergency. It may progress to involvement of other organs. | 32 | Acute Respiratory Distress Syndrome |
nord_32_1 | Symptoms of Acute Respiratory Distress Syndrome | Typically, ARDS develops within 24 to 48 hours of the original illness or injury. It may become a life-threatening condition characterized by inflammation of the lungs, which may begin in one lung but eventually affects both, and leads to damage to the air sacs (alveoli) and surrounding small blood vessels. The damaged alveoli close down or fill up with fluid (lung edema), thereby losing their ability to oxygenate the blood and eliminate carbon dioxide. Patients experience increasingly severe respiratory distress, associated with decreasing oxygen levels in arterial blood and tissues.With the fluid buildup, the lungs become heavy, stiff, and unable to expand properly. Most patients require mechanical ventilation because of respiratory failure. The disorder may also be accompanied or followed by impairment of other vital functions, including cardiovascular, renal, hepatic, hematologic, and neurologic functions. Involvement of other organs in addition to the lungs may lead to a condition sometimes called multi-organ dysfunction syndrome.The person with ARDS may initially appear agitated as a result of breathing difficulty (rapid breathing or shortness of breath), but later may become lethargic and or even comatose. The patient may appear pale, and the hands and feet may have a bluish-gray tone because of the diminished level of oxygen in the blood | Symptoms of Acute Respiratory Distress Syndrome. Typically, ARDS develops within 24 to 48 hours of the original illness or injury. It may become a life-threatening condition characterized by inflammation of the lungs, which may begin in one lung but eventually affects both, and leads to damage to the air sacs (alveoli) and surrounding small blood vessels. The damaged alveoli close down or fill up with fluid (lung edema), thereby losing their ability to oxygenate the blood and eliminate carbon dioxide. Patients experience increasingly severe respiratory distress, associated with decreasing oxygen levels in arterial blood and tissues.With the fluid buildup, the lungs become heavy, stiff, and unable to expand properly. Most patients require mechanical ventilation because of respiratory failure. The disorder may also be accompanied or followed by impairment of other vital functions, including cardiovascular, renal, hepatic, hematologic, and neurologic functions. Involvement of other organs in addition to the lungs may lead to a condition sometimes called multi-organ dysfunction syndrome.The person with ARDS may initially appear agitated as a result of breathing difficulty (rapid breathing or shortness of breath), but later may become lethargic and or even comatose. The patient may appear pale, and the hands and feet may have a bluish-gray tone because of the diminished level of oxygen in the blood | 32 | Acute Respiratory Distress Syndrome |
nord_32_2 | Causes of Acute Respiratory Distress Syndrome | Typically, ARDS develops within 24 to 48 hours of the original illness or injury. It may become a life-threatening condition characterized by inflammation of the lungs, which may begin in one lung but eventually affects both, and leads to damage to the air sacs (alveoli) and surrounding small blood vessels. The damaged alveoli close down or fill up with fluid (lung edema), thereby losing their ability to oxygenate the blood and eliminate carbon dioxide. Patients experience increasingly severe respiratory distress, associated with decreasing oxygen levels in arterial blood and tissues.
With the fluid buildup, the lungs become heavy, stiff, and unable to expand properly. Most patients require mechanical ventilation because of respiratory failure. The disorder may also be accompanied or followed by impairment of other vital functions, including cardiovascular, renal, hepatic, hematologic, and neurologic functions. Involvement of other organs in addition to the lungs may lead to a condition sometimes called multi-organ dysfunction syndrome.The person with ARDS may initially appear agitated as a result of breathing difficulty (rapid breathing or shortness of breath), but later may become lethargic and or even comatose. The patient may appear pale, and the hands and feet may have a bluish-gray tone because of the diminished level of oxygen in the blood | Causes of Acute Respiratory Distress Syndrome. Typically, ARDS develops within 24 to 48 hours of the original illness or injury. It may become a life-threatening condition characterized by inflammation of the lungs, which may begin in one lung but eventually affects both, and leads to damage to the air sacs (alveoli) and surrounding small blood vessels. The damaged alveoli close down or fill up with fluid (lung edema), thereby losing their ability to oxygenate the blood and eliminate carbon dioxide. Patients experience increasingly severe respiratory distress, associated with decreasing oxygen levels in arterial blood and tissues.
With the fluid buildup, the lungs become heavy, stiff, and unable to expand properly. Most patients require mechanical ventilation because of respiratory failure. The disorder may also be accompanied or followed by impairment of other vital functions, including cardiovascular, renal, hepatic, hematologic, and neurologic functions. Involvement of other organs in addition to the lungs may lead to a condition sometimes called multi-organ dysfunction syndrome.The person with ARDS may initially appear agitated as a result of breathing difficulty (rapid breathing or shortness of breath), but later may become lethargic and or even comatose. The patient may appear pale, and the hands and feet may have a bluish-gray tone because of the diminished level of oxygen in the blood | 32 | Acute Respiratory Distress Syndrome |
nord_32_3 | Affects of Acute Respiratory Distress Syndrome | The incidence of ARDS varies widely, due to the different definitions of the disease, as well as demographic, cultural, and healthcare system related differences across countries. Acute respiratory distress syndrome can affect persons of any age who suffer acute injury or illness affecting the lungs. The incidence increases with age, ranging from 16 affected individuals per 100,000 persons aged 15-19 to 306 affected individuals per 100,000 persons between the ages of 75 and 84. There is no difference in the incidence between male and females when ARDS is associated with sepsis and most other causes. However, the incidence is slightly higher among females when trauma is the underlying cause leading to ARDS. Despite our improving understanding of ARDS over the last 20 years, the in hospital mortality for this condition still remains 40-50%, with the majority of deaths occurring within the first few weeks of disease onset. | Affects of Acute Respiratory Distress Syndrome. The incidence of ARDS varies widely, due to the different definitions of the disease, as well as demographic, cultural, and healthcare system related differences across countries. Acute respiratory distress syndrome can affect persons of any age who suffer acute injury or illness affecting the lungs. The incidence increases with age, ranging from 16 affected individuals per 100,000 persons aged 15-19 to 306 affected individuals per 100,000 persons between the ages of 75 and 84. There is no difference in the incidence between male and females when ARDS is associated with sepsis and most other causes. However, the incidence is slightly higher among females when trauma is the underlying cause leading to ARDS. Despite our improving understanding of ARDS over the last 20 years, the in hospital mortality for this condition still remains 40-50%, with the majority of deaths occurring within the first few weeks of disease onset. | 32 | Acute Respiratory Distress Syndrome |
nord_32_4 | Related disorders of Acute Respiratory Distress Syndrome | Symptoms of the following disorders can be similar to those of acute respiratory distress syndrome. Comparisons may be useful for a differential diagnosis:Severe acute respiratory syndrome (SARS) is a respiratory illness that began to be reported in Asia, North America and Europe in the spring of 2003. It begins with a fever greater than 100.4 degrees F. Other symptoms may include headache, an overall feeling of discomfort, body aches, and mild respiratory symptoms. After two to seven days, SARS patients may develop a dry, hacking cough and have trouble breathing. SARS appears to be spread by close person-to-person contact. For additional information on SARS, contact the Centers for Disease Control and Prevention or the World Health Organization.Pneumonia is an infection of the lungs. Symptoms such as fever, cough, large amounts of mucous production (sputum), fluid in the space surrounding the lungs (pleurisy) and/or chills occur. Chest pain, headache, diarrhea, sore throat and fever blisters may also develop. Shortness of breath, difficulty in breathing, decreased exercise tolerance and night sweats are characteristic. Pneumonia frequently occurs in middle-aged to older adults with various underlying diseases. However, it can occur in persons of all ages, statistically most often in winter and early spring. Pneumonia can be caused by various bacteria, viruses, and other infectious agents.Respiratory distress syndrome of the infant, also called hyaline membrane disease of the newborn, is characterized by respiratory distress seen especially in premature babies. A clear membrane is found lining the alveolar (air cell) ducts in the lungs and is associated with reduced amounts of lung wetting agents or emulsifier (surfactant). The surfactant is a lipoprotein based on lecithin that stabilizes alveolar membranes. When this surfactant is missing, breathing is difficult and may lead to collapse of a lung. The affected infant must be placed on some type of ventilation, either mechanical or physical, in order to continue breathing. (For more information on this disorder, choose “Respiratory Distress Syndrome, Infant” as your search term in the Rare Disease Database.) | Related disorders of Acute Respiratory Distress Syndrome. Symptoms of the following disorders can be similar to those of acute respiratory distress syndrome. Comparisons may be useful for a differential diagnosis:Severe acute respiratory syndrome (SARS) is a respiratory illness that began to be reported in Asia, North America and Europe in the spring of 2003. It begins with a fever greater than 100.4 degrees F. Other symptoms may include headache, an overall feeling of discomfort, body aches, and mild respiratory symptoms. After two to seven days, SARS patients may develop a dry, hacking cough and have trouble breathing. SARS appears to be spread by close person-to-person contact. For additional information on SARS, contact the Centers for Disease Control and Prevention or the World Health Organization.Pneumonia is an infection of the lungs. Symptoms such as fever, cough, large amounts of mucous production (sputum), fluid in the space surrounding the lungs (pleurisy) and/or chills occur. Chest pain, headache, diarrhea, sore throat and fever blisters may also develop. Shortness of breath, difficulty in breathing, decreased exercise tolerance and night sweats are characteristic. Pneumonia frequently occurs in middle-aged to older adults with various underlying diseases. However, it can occur in persons of all ages, statistically most often in winter and early spring. Pneumonia can be caused by various bacteria, viruses, and other infectious agents.Respiratory distress syndrome of the infant, also called hyaline membrane disease of the newborn, is characterized by respiratory distress seen especially in premature babies. A clear membrane is found lining the alveolar (air cell) ducts in the lungs and is associated with reduced amounts of lung wetting agents or emulsifier (surfactant). The surfactant is a lipoprotein based on lecithin that stabilizes alveolar membranes. When this surfactant is missing, breathing is difficult and may lead to collapse of a lung. The affected infant must be placed on some type of ventilation, either mechanical or physical, in order to continue breathing. (For more information on this disorder, choose “Respiratory Distress Syndrome, Infant” as your search term in the Rare Disease Database.) | 32 | Acute Respiratory Distress Syndrome |
nord_32_5 | Diagnosis of Acute Respiratory Distress Syndrome | The diagnosis is based on the presence of respiratory distress accompanied by low levels of oxygen in the blood and the presence of known risk factors such as sepsis, pneumonia, or trauma. Chest x-rays will show fluid filling spaces that should be filled with air. The presence of fluid in the air sacs and the “wet” breathing sounds sometimes made by patients may suggest congestive heart failure but a medical examination will often distinguish between that condition and ARDS. | Diagnosis of Acute Respiratory Distress Syndrome. The diagnosis is based on the presence of respiratory distress accompanied by low levels of oxygen in the blood and the presence of known risk factors such as sepsis, pneumonia, or trauma. Chest x-rays will show fluid filling spaces that should be filled with air. The presence of fluid in the air sacs and the “wet” breathing sounds sometimes made by patients may suggest congestive heart failure but a medical examination will often distinguish between that condition and ARDS. | 32 | Acute Respiratory Distress Syndrome |
nord_32_6 | Therapies of Acute Respiratory Distress Syndrome | TreatmentStandard therapy consists of mechanical ventilation, supplemental oxygen, prone positioning, use of paralytics, fluid management and a technique called positive end expiratory pressure (PEEP) to help push the fluid out of air sacs. These are combined with continuing treatment of the original illness or injury.Because people with ARDS are less able to fight lung infections, they may develop bacterial pneumonia during the course of the illness. Antibiotics are given to fight infection. Also, supportive treatment such as intravenous fluid or food may be needed. If other organ systems become involved, measures may be needed to support those organs.The introduction into standard practice of a recent recommendation to use smaller “tidal volumes” (the volume of each individual breath delivered by the ventilator) has resulted in improved survival outcomes. Earlier, ventilators were set to deliver 12 ml per kg of body weight. Now only 6 ml per kg of body weight are delivered. In addition, limiting the pressure delivered to the lung (driving pressure and plateau pressure) improves patient survival. | Therapies of Acute Respiratory Distress Syndrome. TreatmentStandard therapy consists of mechanical ventilation, supplemental oxygen, prone positioning, use of paralytics, fluid management and a technique called positive end expiratory pressure (PEEP) to help push the fluid out of air sacs. These are combined with continuing treatment of the original illness or injury.Because people with ARDS are less able to fight lung infections, they may develop bacterial pneumonia during the course of the illness. Antibiotics are given to fight infection. Also, supportive treatment such as intravenous fluid or food may be needed. If other organ systems become involved, measures may be needed to support those organs.The introduction into standard practice of a recent recommendation to use smaller “tidal volumes” (the volume of each individual breath delivered by the ventilator) has resulted in improved survival outcomes. Earlier, ventilators were set to deliver 12 ml per kg of body weight. Now only 6 ml per kg of body weight are delivered. In addition, limiting the pressure delivered to the lung (driving pressure and plateau pressure) improves patient survival. | 32 | Acute Respiratory Distress Syndrome |
nord_33_0 | Overview of Adams-Oliver Syndrome | Adams-Oliver syndrome (AOS) is a rare inherited condition present at birth that involves changes to the limbs and scalp. Symptoms may include areas of missing skin on the scalp, limb abnormalities, heart defects, neurological concerns, and issues with the eyes. AOS is caused by harmful changes (mutations) in the ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ genes. Some people with AOS do not have a mutation in one of these genes AOS has different inheritance patterns based on the gene involved. Mutations in these genes can follow either an autosomal dominant or recessive inheritance pattern. There is no cure for AOC. However, it can be managed by monitoring for and treating the symptoms. This is typically done by several different healthcare providers such as pediatricians, cardiologists, and plastic surgeons. | Overview of Adams-Oliver Syndrome. Adams-Oliver syndrome (AOS) is a rare inherited condition present at birth that involves changes to the limbs and scalp. Symptoms may include areas of missing skin on the scalp, limb abnormalities, heart defects, neurological concerns, and issues with the eyes. AOS is caused by harmful changes (mutations) in the ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ genes. Some people with AOS do not have a mutation in one of these genes AOS has different inheritance patterns based on the gene involved. Mutations in these genes can follow either an autosomal dominant or recessive inheritance pattern. There is no cure for AOC. However, it can be managed by monitoring for and treating the symptoms. This is typically done by several different healthcare providers such as pediatricians, cardiologists, and plastic surgeons. | 33 | Adams-Oliver Syndrome |
nord_33_1 | Symptoms of Adams-Oliver Syndrome | People with AOS may have the following symptoms: absence of areas of skin (aplasia cutis congenita); shortened or missing fingers, hands, toes and/or feet; heart problems present at birth; neurological concerns such as developmental delays and learning disabilities; kidney issues and eye problems.Symptoms can vary widely based on the gene involved. The most common symptom of AOC is an absence of areas of skin, which most commonly occurs around the scalp but can occur in other parts of the body. It can range from mild to severe. These areas of absent skin will often heal without treatment a couple of months after birth. However, in severely affected patients, there is a greater chance for infection, excessive bleeding (hemorrhage), seizures, high pressure within the skull (brain herniation) and cerebrospinal fluid leakage.In about 20% of patients, there may be long-lasting enlarged small blood vessels. This can create a marbled-like appearance on the skin. These fragile dilated blood vessels may bleed. In severely affected patients, there may be an issue with the skull due to a bone defect that causes areas of absent bone. This can lead to excessive bleeding and bacterial infections.Infants with AOS may have changes of the fingers, toes, hands and/or feet. Some infants may have very short fingers and/or toes. In severely affected patients, the fingers, toes, hands, feet and/or lower legs may be partially or completely missing. Also, there may be webbing of the toes (syndactyly) and/or underdeveloped toenails. In general, the lower half of the body (i.e., lower legs, feet, and toes) is more severely affected.About 23% of people with AOS have structural heart problems. These include incomplete development of the left side of the heart (hypoplastic left ventricle) or a hole in the heart (septal defects) that affects how the blood flows. Also, patients can experience high blood pressure in the arteries of the lungs (pulmonary hypertension).Around 35% of people with AOS have problems with brain development such as a much smaller head than expected (microcephaly), sac-like protrusion of the brain (encephalocele), and structural issues in the brain that can lead to epilepsy and seizures. These can be associated with developmental and intellectual problems.Less than 10% of people with AOS experience eye problems which may include clouding of the lens of the eyes (cataracts), eye misalignment (esotropia), and decline of the optic nerve (optic atrophy).Other symptoms such as a hole in the lip or roof of the mouth and extra nipples occur rarely in patients with AOS. | Symptoms of Adams-Oliver Syndrome. People with AOS may have the following symptoms: absence of areas of skin (aplasia cutis congenita); shortened or missing fingers, hands, toes and/or feet; heart problems present at birth; neurological concerns such as developmental delays and learning disabilities; kidney issues and eye problems.Symptoms can vary widely based on the gene involved. The most common symptom of AOC is an absence of areas of skin, which most commonly occurs around the scalp but can occur in other parts of the body. It can range from mild to severe. These areas of absent skin will often heal without treatment a couple of months after birth. However, in severely affected patients, there is a greater chance for infection, excessive bleeding (hemorrhage), seizures, high pressure within the skull (brain herniation) and cerebrospinal fluid leakage.In about 20% of patients, there may be long-lasting enlarged small blood vessels. This can create a marbled-like appearance on the skin. These fragile dilated blood vessels may bleed. In severely affected patients, there may be an issue with the skull due to a bone defect that causes areas of absent bone. This can lead to excessive bleeding and bacterial infections.Infants with AOS may have changes of the fingers, toes, hands and/or feet. Some infants may have very short fingers and/or toes. In severely affected patients, the fingers, toes, hands, feet and/or lower legs may be partially or completely missing. Also, there may be webbing of the toes (syndactyly) and/or underdeveloped toenails. In general, the lower half of the body (i.e., lower legs, feet, and toes) is more severely affected.About 23% of people with AOS have structural heart problems. These include incomplete development of the left side of the heart (hypoplastic left ventricle) or a hole in the heart (septal defects) that affects how the blood flows. Also, patients can experience high blood pressure in the arteries of the lungs (pulmonary hypertension).Around 35% of people with AOS have problems with brain development such as a much smaller head than expected (microcephaly), sac-like protrusion of the brain (encephalocele), and structural issues in the brain that can lead to epilepsy and seizures. These can be associated with developmental and intellectual problems.Less than 10% of people with AOS experience eye problems which may include clouding of the lens of the eyes (cataracts), eye misalignment (esotropia), and decline of the optic nerve (optic atrophy).Other symptoms such as a hole in the lip or roof of the mouth and extra nipples occur rarely in patients with AOS. | 33 | Adams-Oliver Syndrome |
nord_33_2 | Causes of Adams-Oliver Syndrome | AOS is known to be caused by harmful changes (mutations) in several genes: ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ. Symptoms vary based on which gene is involved. In about 50% of patients, no mutations in these genes are found.Most cases follow an autosomal dominant inheritance pattern through mutations in the ARHGAP31, DLL4, NOTCH1, and/or RBPJ gene. The ARHGAP31, DLL4, and NOTCH1 genes have shown incomplete penetrance. This means that people who carry mutations in these genes may not display symptoms for AOS. For the RBPJ gene, incomplete penetrance has not been shown. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular genetic condition. The non-working gene can be inherited from either parent or can be the result of a new harmful gene change (de novo mutation) in the affected individual that was not inherited from the parents. The chance of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.AOS that involves the EOGT or DOCK6 genes follow an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Some researchers suspect that the physical features associated with AOS may result from interrupted blood flow through certain arteries during fetal development. These features are seen in a group of developmental conditions called “subclavian artery supply disruption sequence (SASDS).” Other conditions in this group include Poland syndrome, Klippel-Feil syndrome, Moebius syndrome and Sprengel deformity. | Causes of Adams-Oliver Syndrome. AOS is known to be caused by harmful changes (mutations) in several genes: ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1, or RBPJ. Symptoms vary based on which gene is involved. In about 50% of patients, no mutations in these genes are found.Most cases follow an autosomal dominant inheritance pattern through mutations in the ARHGAP31, DLL4, NOTCH1, and/or RBPJ gene. The ARHGAP31, DLL4, and NOTCH1 genes have shown incomplete penetrance. This means that people who carry mutations in these genes may not display symptoms for AOS. For the RBPJ gene, incomplete penetrance has not been shown. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular genetic condition. The non-working gene can be inherited from either parent or can be the result of a new harmful gene change (de novo mutation) in the affected individual that was not inherited from the parents. The chance of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.AOS that involves the EOGT or DOCK6 genes follow an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Some researchers suspect that the physical features associated with AOS may result from interrupted blood flow through certain arteries during fetal development. These features are seen in a group of developmental conditions called “subclavian artery supply disruption sequence (SASDS).” Other conditions in this group include Poland syndrome, Klippel-Feil syndrome, Moebius syndrome and Sprengel deformity. | 33 | Adams-Oliver Syndrome |
nord_33_3 | Affects of Adams-Oliver Syndrome | AOS affects males and females in equal numbers. AOS occurs in about 44 out of every 10 million people and is present at birth. | Affects of Adams-Oliver Syndrome. AOS affects males and females in equal numbers. AOS occurs in about 44 out of every 10 million people and is present at birth. | 33 | Adams-Oliver Syndrome |
nord_33_4 | Related disorders of Adams-Oliver Syndrome | Symptoms of the following conditions can be like those of AOS. Comparisons may be useful for a differential diagnosis:Scalp-ear-nipple syndrome is a rare condition which involves areas of hairless skin on the scalp that is present at birth; ears are small and folded over; and underdeveloped or no nipples. Other symptoms of the condition include brittle nails, dental issues, kidney concerns and specific facial features such as a flat bridge of the nose and narrowed openings of the eyes.Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital condition associated with discolored patches of skin caused by widened surface blood vessels. Other symptoms can include skin abnormalities such as areas of absent skin; pink or dark red, irregularly shaped patches of skin; loss of muscle tissue on one side of the body; elevated fluid pressure within the eye; and undergrowth of one leg. CMTC occurs randomly for no apparent reason. It is thought that CMTC represents a form of genetic mosaicism, meaning that some cells have a harmful genetic change and other cells do not. (For more information on this disorder, choose “Cutis Marmorata Telangiectatica Congenita” as your search term in the Rare Disease Database.)Poland syndrome is a rare condition that is seen at birth. Associated features may be extremely variable fromperson to person. It is classically characterized by absence of chest wall muscles on one side of the body and abnormally short, webbed fingers of the hand on the same side . Other symptoms include the underdevelopment or absence of one breast/nipple; skeletal-related issues that can affect the ribs, shoulders, and arms; and, in rare cases, issues with the internal organs being located on the incorrect side of the chest. (For more information on this disorder, choose “Poland Syndrome” as your search term in the Rare Disease Database.)There are other conditions (e.g., focal dermal hypoplasia, trisomy 13 syndrome, Johanson-Blizzard syndrome, etc.) that may have symptoms of scalp and skull issues that occur in association with changes of the hands and feet. These disorders usually have other physical features that may differentiate them from Adams-Oliver syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)The following conditions may be associated with Adams-Oliver syndrome as secondary characteristics.Aplasia cutis congenita is a rare condition with a complicated pattern of inheritance. Babies are born with the absence of certain layers of skin, most often on the scalp, but also on the trunk and/or arms and legs. The affected area is typically covered with a thin, transparent membrane. The skull and/or underlying areas may be visible and incorrectly developed. Aplasia cutis congenita may be the primary disorder, or it may occur in association with other underlying disorders such as AOS. (For more information on this disorder, choose “Aplasia Cutis Congenita” as your search term in the Rare Disease Database.)Meningitis may occur in some children with Adams-Oliver syndrome who have severe defects of the scalp and skull. Meningitis is characterized by swelling of the membranes (meninges) around the brain or spinal cord. The disorder can occur in three different forms: adult, infantile, and neonatal. This inflammation may be caused by several types of bacteria, viruses, fungi, or malignant tumors. Chemical reactions to certain injections into the spinal canal can also cause meningitis. This inflammation can begin suddenly or develop gradually. Adult forms of meningitis are characterized by fever, headache, and a stiff neck, sometimes with aching muscles. Nausea, vomiting and other symptoms may occur. Treatment with antibiotics is usually effective against the infection. (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.) | Related disorders of Adams-Oliver Syndrome. Symptoms of the following conditions can be like those of AOS. Comparisons may be useful for a differential diagnosis:Scalp-ear-nipple syndrome is a rare condition which involves areas of hairless skin on the scalp that is present at birth; ears are small and folded over; and underdeveloped or no nipples. Other symptoms of the condition include brittle nails, dental issues, kidney concerns and specific facial features such as a flat bridge of the nose and narrowed openings of the eyes.Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital condition associated with discolored patches of skin caused by widened surface blood vessels. Other symptoms can include skin abnormalities such as areas of absent skin; pink or dark red, irregularly shaped patches of skin; loss of muscle tissue on one side of the body; elevated fluid pressure within the eye; and undergrowth of one leg. CMTC occurs randomly for no apparent reason. It is thought that CMTC represents a form of genetic mosaicism, meaning that some cells have a harmful genetic change and other cells do not. (For more information on this disorder, choose “Cutis Marmorata Telangiectatica Congenita” as your search term in the Rare Disease Database.)Poland syndrome is a rare condition that is seen at birth. Associated features may be extremely variable fromperson to person. It is classically characterized by absence of chest wall muscles on one side of the body and abnormally short, webbed fingers of the hand on the same side . Other symptoms include the underdevelopment or absence of one breast/nipple; skeletal-related issues that can affect the ribs, shoulders, and arms; and, in rare cases, issues with the internal organs being located on the incorrect side of the chest. (For more information on this disorder, choose “Poland Syndrome” as your search term in the Rare Disease Database.)There are other conditions (e.g., focal dermal hypoplasia, trisomy 13 syndrome, Johanson-Blizzard syndrome, etc.) that may have symptoms of scalp and skull issues that occur in association with changes of the hands and feet. These disorders usually have other physical features that may differentiate them from Adams-Oliver syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)The following conditions may be associated with Adams-Oliver syndrome as secondary characteristics.Aplasia cutis congenita is a rare condition with a complicated pattern of inheritance. Babies are born with the absence of certain layers of skin, most often on the scalp, but also on the trunk and/or arms and legs. The affected area is typically covered with a thin, transparent membrane. The skull and/or underlying areas may be visible and incorrectly developed. Aplasia cutis congenita may be the primary disorder, or it may occur in association with other underlying disorders such as AOS. (For more information on this disorder, choose “Aplasia Cutis Congenita” as your search term in the Rare Disease Database.)Meningitis may occur in some children with Adams-Oliver syndrome who have severe defects of the scalp and skull. Meningitis is characterized by swelling of the membranes (meninges) around the brain or spinal cord. The disorder can occur in three different forms: adult, infantile, and neonatal. This inflammation may be caused by several types of bacteria, viruses, fungi, or malignant tumors. Chemical reactions to certain injections into the spinal canal can also cause meningitis. This inflammation can begin suddenly or develop gradually. Adult forms of meningitis are characterized by fever, headache, and a stiff neck, sometimes with aching muscles. Nausea, vomiting and other symptoms may occur. Treatment with antibiotics is usually effective against the infection. (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.) | 33 | Adams-Oliver Syndrome |
nord_33_5 | Diagnosis of Adams-Oliver Syndrome | The diagnosis of Adams-Oliver syndrome can be made when an infant has both the absence of skin of the scalp and changes of the fingers, hands, toes, and/or feet. Also, a diagnosis can be made if an individual both has aplasia cutis congenita or changes of the fingers, hands, toes and/or feet, and has a first-degree relative with AOS. Lastly, a diagnosis can be made when an individual has either of these two main features: the absence of skin or malformation of the fingers, hands, toes, and/or feet, and a single mutation in the autosomal dominant related gene (ARHGAP31, DLL4, NOTCH1, or RBPJ) or two mutations in an autosomal recessive related gene (DOCK6 or EOGT). | Diagnosis of Adams-Oliver Syndrome. The diagnosis of Adams-Oliver syndrome can be made when an infant has both the absence of skin of the scalp and changes of the fingers, hands, toes, and/or feet. Also, a diagnosis can be made if an individual both has aplasia cutis congenita or changes of the fingers, hands, toes and/or feet, and has a first-degree relative with AOS. Lastly, a diagnosis can be made when an individual has either of these two main features: the absence of skin or malformation of the fingers, hands, toes, and/or feet, and a single mutation in the autosomal dominant related gene (ARHGAP31, DLL4, NOTCH1, or RBPJ) or two mutations in an autosomal recessive related gene (DOCK6 or EOGT). | 33 | Adams-Oliver Syndrome |
nord_33_6 | Therapies of Adams-Oliver Syndrome | TreatmentThe treatment of Adams-Oliver syndrome is directed towards the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic and plastic surgeons, cardiologists, ophthalmologists, physical therapists, and other health care professionals may be needed for an individual’s treatment and surveillance of skin, limb, cardiovascular, neurological and eye concerns.In many patients, scalp defects may heal without treatment within the first few months of life. Skin grafting, skull surgery and/or other surgical procedures may be required for individuals with AOS who have skull problems. Wearing helmets may be recommended for some children with AOS to prevent trauma to the head and potential damage to the wide blood vessels.Physical therapy, surgery, and/or the use of artificial limbs may be recommended for children who have a partial or complete absence of fingers, toes, hands, feet and/or lower legs.A complete medical evaluation should be done to look for potential concerns with the heart. Cardiovascular issues such as structural heart problems may require surgery.Monitoring for symptoms on a yearly basis is recommended for infants with AOS. Echocardiographs should be done every year until the age of three for signs of pulmonary hypertension. For neurological concerns, affected children should have a neurological exam and assessment of psychomotor development every year. For eye concerns, affected children should see a pediatric ophthalmologist up until the age of three to look for any problems with the eyes.Genetic counseling is recommended for individuals with AOS and their families. Other treatments for this disorder are symptomatic and supportive. | Therapies of Adams-Oliver Syndrome. TreatmentThe treatment of Adams-Oliver syndrome is directed towards the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic and plastic surgeons, cardiologists, ophthalmologists, physical therapists, and other health care professionals may be needed for an individual’s treatment and surveillance of skin, limb, cardiovascular, neurological and eye concerns.In many patients, scalp defects may heal without treatment within the first few months of life. Skin grafting, skull surgery and/or other surgical procedures may be required for individuals with AOS who have skull problems. Wearing helmets may be recommended for some children with AOS to prevent trauma to the head and potential damage to the wide blood vessels.Physical therapy, surgery, and/or the use of artificial limbs may be recommended for children who have a partial or complete absence of fingers, toes, hands, feet and/or lower legs.A complete medical evaluation should be done to look for potential concerns with the heart. Cardiovascular issues such as structural heart problems may require surgery.Monitoring for symptoms on a yearly basis is recommended for infants with AOS. Echocardiographs should be done every year until the age of three for signs of pulmonary hypertension. For neurological concerns, affected children should have a neurological exam and assessment of psychomotor development every year. For eye concerns, affected children should see a pediatric ophthalmologist up until the age of three to look for any problems with the eyes.Genetic counseling is recommended for individuals with AOS and their families. Other treatments for this disorder are symptomatic and supportive. | 33 | Adams-Oliver Syndrome |
nord_34_0 | Overview of ADCY5-Related Dyskinesia | SummaryADCY5-related dyskinesia is a neurologic disorder with a variety of movement abnormalities. Dyskinesia means that affected individuals have trouble controlling voluntary movements. Voluntary movements are any movements that a person does intentionally such as lifting their arms, walking, or turning one’s head. Affected individuals experience uncontrolled, involuntary movements including sudden jerks, writhing motions, twitches, twisting, or tremors. The arms and legs, neck, and face are commonly affected. Symptoms usually begin during infancy, childhood, or adolescence and continue throughout life, although there are periods of time when no symptoms occur (remission). The severity of the disorder can vary significantly from one person to another. Intelligence and life span are generally not affected. ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. This variation may be inherited from a parent, or it may occur spontaneously as a new variation without a previous family history (de novo mutation). | Overview of ADCY5-Related Dyskinesia. SummaryADCY5-related dyskinesia is a neurologic disorder with a variety of movement abnormalities. Dyskinesia means that affected individuals have trouble controlling voluntary movements. Voluntary movements are any movements that a person does intentionally such as lifting their arms, walking, or turning one’s head. Affected individuals experience uncontrolled, involuntary movements including sudden jerks, writhing motions, twitches, twisting, or tremors. The arms and legs, neck, and face are commonly affected. Symptoms usually begin during infancy, childhood, or adolescence and continue throughout life, although there are periods of time when no symptoms occur (remission). The severity of the disorder can vary significantly from one person to another. Intelligence and life span are generally not affected. ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. This variation may be inherited from a parent, or it may occur spontaneously as a new variation without a previous family history (de novo mutation). | 34 | ADCY5-Related Dyskinesia |
nord_34_1 | Symptoms of ADCY5-Related Dyskinesia | Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about ADCY5-related dyskinesia is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or additional factors influencing the disorder, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. All affected individuals have episodes of abnormal, uncontrolled movements especially affecting the arms and legs, face, or neck. These movements can be choreiform, myoclonic, or dystonic. Choreiform movements are continuous rapid, jerky and sometimes writhing (athetotic) movements. Myoclonic movements are rapid, brief muscle contractions that cause sudden jerky or twitching movements. Dystonic movements are characterized by sustained and sometimes repetitive muscle contractions leading to muscle spasms and abnormal postures. Abnormal movements can occur continuously during the day and, sometimes, can occur at night disturbing sleep. Disrupted sleep can result in fatigue and sleepiness during the day. Some individuals experience ballistic (large amplitude) movements at night or upon awaking. Ballism is the abrupt contraction of muscles, particularly those of arm and legs muscles causing flailing, swinging movements of the arms and legs. Abnormal movements are more common when affected individuals attempt to make deliberate, voluntary movements such as changing positions or reaching for things. Episodes of abnormal movements can be worsened or triggered by anxiety or stress. In some individuals, the disorder is worsened when drowsy or tired. In some people, episodes or symptoms are more common or worse in the morning. Prolonged inactivity, excitement, and being sick have also been reported as possible triggers. Abnormal movements can be painful, but some are not. The onset of abnormal movements usually occurs during infancy, childhood, or throughout the teen-aged years. During infancy, affected infants may experience diminished muscle tone (hypotonia), particularly affecting the trunk, which is all of the body except for the head and arms and legs (axial hypotonia). These infants may be described as being “floppy.” Some affected infants have had difficulty swallowing (dysarthria), while others have been described as extremely irritable. As affected infants and children age, there may be delays in attaining developmental milestones especially motor milestones like crawling, sitting up, or walking because of the abnormal movements. In severely-affected individuals, abnormal movements may make walking extremely difficult requiring assistance to walk or use of an ambulatory device such as a wheelchair. Mildly-affected individuals may have little problems walking, but may appear a little clumsy. Some affected individuals will walk, but have a slow, uncoordinated manner of walking (abnormal gait), while others may fall frequently. Axial hypotonia improves with age. Although, in some individuals, residual diminished muscle tone affecting the neck (cervical hypotonia) can remain. Cervical hypotonia can cause the head to droop or hang toward the chest (neck flexion). A characteristic finding that occurs in some affected individuals is facial twitching. Mild abnormal movements including those of facial muscles can result in frustration or awkwardness in social situations. Facial twitching usually involves the muscles around the eyes and mouth. In some instances, facial twitching in infants and young children can lead to delays in attaining speech and/or difficulty being understood due to poor articulation (dysarthria). Some individuals have difficulty staring at a fixed object (gaze impersistence) and also experience oculomotor apraxia, in which there are problems moving the eyes voluntarily. How the disorder affects people over time can be very different. Movement disorders may be continual or may come and go (episodic). They can last from a few seconds to hours or longer. Their frequency and duration can change over time. Some affected individuals have long periods of time where the symptoms go away (remission). For some people, symptoms remain generally stable throughout life. Sometimes, symptoms get slowly worse during childhood and adolescence before stabilizing; in other people the disorder has gone into remission in the teenage years. Several reports state that in many people symptoms improved on their own during middle age. There have been reports of heart (cardiac) abnormalities in some affected individuals. It is not yet known whether these heart abnormalities are potential complications of the disorder or coincidental findings. Some researchers have speculated as to whether neuropsychiatric abnormalities like depression, anxiety, and psychosis are also complications of this disorder. More research is necessary to fully understand the complex and highly variable signs and symptoms associated with ADCY5-related dyskinesia. | Symptoms of ADCY5-Related Dyskinesia. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about ADCY5-related dyskinesia is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or additional factors influencing the disorder, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. All affected individuals have episodes of abnormal, uncontrolled movements especially affecting the arms and legs, face, or neck. These movements can be choreiform, myoclonic, or dystonic. Choreiform movements are continuous rapid, jerky and sometimes writhing (athetotic) movements. Myoclonic movements are rapid, brief muscle contractions that cause sudden jerky or twitching movements. Dystonic movements are characterized by sustained and sometimes repetitive muscle contractions leading to muscle spasms and abnormal postures. Abnormal movements can occur continuously during the day and, sometimes, can occur at night disturbing sleep. Disrupted sleep can result in fatigue and sleepiness during the day. Some individuals experience ballistic (large amplitude) movements at night or upon awaking. Ballism is the abrupt contraction of muscles, particularly those of arm and legs muscles causing flailing, swinging movements of the arms and legs. Abnormal movements are more common when affected individuals attempt to make deliberate, voluntary movements such as changing positions or reaching for things. Episodes of abnormal movements can be worsened or triggered by anxiety or stress. In some individuals, the disorder is worsened when drowsy or tired. In some people, episodes or symptoms are more common or worse in the morning. Prolonged inactivity, excitement, and being sick have also been reported as possible triggers. Abnormal movements can be painful, but some are not. The onset of abnormal movements usually occurs during infancy, childhood, or throughout the teen-aged years. During infancy, affected infants may experience diminished muscle tone (hypotonia), particularly affecting the trunk, which is all of the body except for the head and arms and legs (axial hypotonia). These infants may be described as being “floppy.” Some affected infants have had difficulty swallowing (dysarthria), while others have been described as extremely irritable. As affected infants and children age, there may be delays in attaining developmental milestones especially motor milestones like crawling, sitting up, or walking because of the abnormal movements. In severely-affected individuals, abnormal movements may make walking extremely difficult requiring assistance to walk or use of an ambulatory device such as a wheelchair. Mildly-affected individuals may have little problems walking, but may appear a little clumsy. Some affected individuals will walk, but have a slow, uncoordinated manner of walking (abnormal gait), while others may fall frequently. Axial hypotonia improves with age. Although, in some individuals, residual diminished muscle tone affecting the neck (cervical hypotonia) can remain. Cervical hypotonia can cause the head to droop or hang toward the chest (neck flexion). A characteristic finding that occurs in some affected individuals is facial twitching. Mild abnormal movements including those of facial muscles can result in frustration or awkwardness in social situations. Facial twitching usually involves the muscles around the eyes and mouth. In some instances, facial twitching in infants and young children can lead to delays in attaining speech and/or difficulty being understood due to poor articulation (dysarthria). Some individuals have difficulty staring at a fixed object (gaze impersistence) and also experience oculomotor apraxia, in which there are problems moving the eyes voluntarily. How the disorder affects people over time can be very different. Movement disorders may be continual or may come and go (episodic). They can last from a few seconds to hours or longer. Their frequency and duration can change over time. Some affected individuals have long periods of time where the symptoms go away (remission). For some people, symptoms remain generally stable throughout life. Sometimes, symptoms get slowly worse during childhood and adolescence before stabilizing; in other people the disorder has gone into remission in the teenage years. Several reports state that in many people symptoms improved on their own during middle age. There have been reports of heart (cardiac) abnormalities in some affected individuals. It is not yet known whether these heart abnormalities are potential complications of the disorder or coincidental findings. Some researchers have speculated as to whether neuropsychiatric abnormalities like depression, anxiety, and psychosis are also complications of this disorder. More research is necessary to fully understand the complex and highly variable signs and symptoms associated with ADCY5-related dyskinesia. | 34 | ADCY5-Related Dyskinesia |
nord_34_2 | Causes of ADCY5-Related Dyskinesia | ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The ADCY5 gene produces a specialized protein (enzyme) called adenylate cyclase 5. Researchers do not fully understand all of the functions of this enzyme. One function is that the enzyme changes (converts) a molecule called adenosine triphosphate into a different molecule called cyclic adenosine monophosphate or cAMP. Adenosine triphosphate helps to supply energy for the cells’ activities, while cyclic adenosine monophosphate has several functions including activating or stimulating other proteins to perform a variety of functions. The exact reason a variation in the ADCY5 gene causes dyskinesia is not fully understood. ADCY5-related dyskinesia can be inherited from a parent or it can occur as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Some individuals develop ADCY5-related dyskinesia from somatic mosaicism. In somatic mosaicism, the variation in the ADCY5 gene that causes the disorder occurs after fertilization and is not inherited. The disease-causing (pathogenic) variation is found in some cells of the body, but not in other cells. The severity of the disorder in these individuals depends on the percentage of cells affected, and is less severe than individuals who have a disease-causing variation in all of their cells. | Causes of ADCY5-Related Dyskinesia. ADCY5-related dyskinesia is caused by a variation (mutation) in the ADCY5 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The ADCY5 gene produces a specialized protein (enzyme) called adenylate cyclase 5. Researchers do not fully understand all of the functions of this enzyme. One function is that the enzyme changes (converts) a molecule called adenosine triphosphate into a different molecule called cyclic adenosine monophosphate or cAMP. Adenosine triphosphate helps to supply energy for the cells’ activities, while cyclic adenosine monophosphate has several functions including activating or stimulating other proteins to perform a variety of functions. The exact reason a variation in the ADCY5 gene causes dyskinesia is not fully understood. ADCY5-related dyskinesia can be inherited from a parent or it can occur as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Some individuals develop ADCY5-related dyskinesia from somatic mosaicism. In somatic mosaicism, the variation in the ADCY5 gene that causes the disorder occurs after fertilization and is not inherited. The disease-causing (pathogenic) variation is found in some cells of the body, but not in other cells. The severity of the disorder in these individuals depends on the percentage of cells affected, and is less severe than individuals who have a disease-causing variation in all of their cells. | 34 | ADCY5-Related Dyskinesia |
nord_34_3 | Affects of ADCY5-Related Dyskinesia | ADCY5-related dyskinesia affects males and females in equal numbers. The exact number of people who have this disorder is unknown. Rare disorders like ADCY5-dyskinesia often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The disorder is almost certainly underrecognized and underdiagnosed. | Affects of ADCY5-Related Dyskinesia. ADCY5-related dyskinesia affects males and females in equal numbers. The exact number of people who have this disorder is unknown. Rare disorders like ADCY5-dyskinesia often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The disorder is almost certainly underrecognized and underdiagnosed. | 34 | ADCY5-Related Dyskinesia |
nord_34_4 | Related disorders of ADCY5-Related Dyskinesia | Symptoms of the following disorders can be similar to those of ADCY5-related dyskinesia. Comparisons may be useful for a differential diagnosis.Cerebral palsy is a general term that covers a group of disorders that involve impairment of muscle control or coordination resulting from injury to the brain during its early stages of development (the fetal, perinatal or early childhood stages). There may be problems associated with involuntary movements, vision, hearing, communication skills, perception levels, intellect and seizures. Individuals with cerebral palsy often experience delays in reaching developmental milestones. The specific symptoms associated with cerebral palsy vary greatly from one person to another. Some individuals with cerebral palsy develop dyskinesia and individuals who have ADCY5-related dyskinesia have been misdiagnosed with the dyskinetic form of cerebral palsy.Other disorders can cause movement disorders similar to those seen in ADCY5-related dyskinesia including Sydenham chorea, benign hereditary chorea, spinocerebellar ataxia, ataxia telangiectasia, familial paroxysmal movement disorders (kinesigenic or non-kinesigenic), various mitochondrial disorders, and metabolic encephalopathies including Lesch-Nyhan disorder and inborn errors of amino acid metabolism such as the urea cycle disorders or organic acidurias. A disorder called myoclonus-dystonia can also resemble ADCY5-related dyskinesia; about 30%-50% of these cases are caused by a variation in the SGCE gene. Most of these disorders have additional signs or symptoms that distinguish them from ADCY5-related dyskinesia. There are also rare, non-metabolic genetic disorders that can cause movement disorders that have been linked to specific genes including the GNAO1, NKX2-1, and PDE10A genes. In adolescents and adults, several disorders that doctors may differentiate include Huntington’s disease, multiple sclerosis, tardive dyskinesia, neuroacanthocytosis, and denatorubral-pallidoluysian atrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of ADCY5-Related Dyskinesia. Symptoms of the following disorders can be similar to those of ADCY5-related dyskinesia. Comparisons may be useful for a differential diagnosis.Cerebral palsy is a general term that covers a group of disorders that involve impairment of muscle control or coordination resulting from injury to the brain during its early stages of development (the fetal, perinatal or early childhood stages). There may be problems associated with involuntary movements, vision, hearing, communication skills, perception levels, intellect and seizures. Individuals with cerebral palsy often experience delays in reaching developmental milestones. The specific symptoms associated with cerebral palsy vary greatly from one person to another. Some individuals with cerebral palsy develop dyskinesia and individuals who have ADCY5-related dyskinesia have been misdiagnosed with the dyskinetic form of cerebral palsy.Other disorders can cause movement disorders similar to those seen in ADCY5-related dyskinesia including Sydenham chorea, benign hereditary chorea, spinocerebellar ataxia, ataxia telangiectasia, familial paroxysmal movement disorders (kinesigenic or non-kinesigenic), various mitochondrial disorders, and metabolic encephalopathies including Lesch-Nyhan disorder and inborn errors of amino acid metabolism such as the urea cycle disorders or organic acidurias. A disorder called myoclonus-dystonia can also resemble ADCY5-related dyskinesia; about 30%-50% of these cases are caused by a variation in the SGCE gene. Most of these disorders have additional signs or symptoms that distinguish them from ADCY5-related dyskinesia. There are also rare, non-metabolic genetic disorders that can cause movement disorders that have been linked to specific genes including the GNAO1, NKX2-1, and PDE10A genes. In adolescents and adults, several disorders that doctors may differentiate include Huntington’s disease, multiple sclerosis, tardive dyskinesia, neuroacanthocytosis, and denatorubral-pallidoluysian atrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 34 | ADCY5-Related Dyskinesia |
nord_34_5 | Diagnosis of ADCY5-Related Dyskinesia | A diagnosis of ADCY5-related dyskinesia is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There are no published guidelines for diagnosis. A diagnosis is suspected in infants, children or adolescents with characteristic movement symptoms (e.g. choreiform, myoclonic, dystonic movements) who do not have a structural abnormality of the brain. Clues which may be helpful in diagnosis include facial abnormalities and nocturnal disturbances, but not all individuals experience or have these symptoms. A diagnosis is confirmed through molecular genetic testing. Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variations in the ADCY5 gene, but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having ADCY5-related dyskinesia and the sample will undergo whole exome sequencing (WES). WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the ADCY5 gene that are known to cause disease, or variations in other genes known to cause symptoms similar to this syndrome. Before molecular genetic testing, affected individuals may undergo specialized imaging techniques to rule out other conditions. These techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI, which is the preferred method of imaging, uses a magnetic and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. These specialized imaging techniques can show structural abnormalities or damage to the brain that can cause movement disorders. | Diagnosis of ADCY5-Related Dyskinesia. A diagnosis of ADCY5-related dyskinesia is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There are no published guidelines for diagnosis. A diagnosis is suspected in infants, children or adolescents with characteristic movement symptoms (e.g. choreiform, myoclonic, dystonic movements) who do not have a structural abnormality of the brain. Clues which may be helpful in diagnosis include facial abnormalities and nocturnal disturbances, but not all individuals experience or have these symptoms. A diagnosis is confirmed through molecular genetic testing. Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variations in the ADCY5 gene, but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having ADCY5-related dyskinesia and the sample will undergo whole exome sequencing (WES). WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the ADCY5 gene that are known to cause disease, or variations in other genes known to cause symptoms similar to this syndrome. Before molecular genetic testing, affected individuals may undergo specialized imaging techniques to rule out other conditions. These techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI, which is the preferred method of imaging, uses a magnetic and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. These specialized imaging techniques can show structural abnormalities or damage to the brain that can cause movement disorders. | 34 | ADCY5-Related Dyskinesia |
nord_34_6 | Therapies of ADCY5-Related Dyskinesia | Treatment
The treatment of ADCY5-related dyskinesia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric and adult neurologists (physicians who specialize in diagnosing and treating disorders of the brain and central nervous system), ophthalmologists (physicians specializing in the diagnosis and treatment of eye disorders), speech therapists, physical therapists, occupational therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with ADCY5-related dyskinesia. Various medications have been tried to treat individuals or families affected by ADCY5-related dyskinesia. The effectiveness of these medications is variable and when beneficial may eventually become less effective over time. Specific medications that have been tried to treat affected individuals include acetazolamide, propranolol, levetiracetam, tetrabenazine, benzodiazepines, and trihexyphenidyl, as well as other medications. Affected individuals may benefit from counseling to learn how to best deal with anxiety, which is known to trigger episodes and worsen symptoms. Affected infants and children may benefit from physical therapy, occupational therapy, and speech therapy as necessary. Periodic reassessments and adjustment of services should be provided to all children. Additional medical, social, and/or vocational services including specialized learning programs may be beneficial for some individuals. Periodic evaluation for heart abnormalities may also be recommended because of the possibility that ADCY5-related dyskinesia can be associated with heart abnormalities in some people. | Therapies of ADCY5-Related Dyskinesia. Treatment
The treatment of ADCY5-related dyskinesia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric and adult neurologists (physicians who specialize in diagnosing and treating disorders of the brain and central nervous system), ophthalmologists (physicians specializing in the diagnosis and treatment of eye disorders), speech therapists, physical therapists, occupational therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with ADCY5-related dyskinesia. Various medications have been tried to treat individuals or families affected by ADCY5-related dyskinesia. The effectiveness of these medications is variable and when beneficial may eventually become less effective over time. Specific medications that have been tried to treat affected individuals include acetazolamide, propranolol, levetiracetam, tetrabenazine, benzodiazepines, and trihexyphenidyl, as well as other medications. Affected individuals may benefit from counseling to learn how to best deal with anxiety, which is known to trigger episodes and worsen symptoms. Affected infants and children may benefit from physical therapy, occupational therapy, and speech therapy as necessary. Periodic reassessments and adjustment of services should be provided to all children. Additional medical, social, and/or vocational services including specialized learning programs may be beneficial for some individuals. Periodic evaluation for heart abnormalities may also be recommended because of the possibility that ADCY5-related dyskinesia can be associated with heart abnormalities in some people. | 34 | ADCY5-Related Dyskinesia |
nord_35_0 | Overview of Addison’s Disease | SummaryAddison's disease is a rare disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of cells of the adrenal glands (adrenal cortex). The symptoms of classic Addison's disease, also known as primary adrenal insufficiency, result from the insufficient production of these two hormones, cortisol and aldosterone. Major symptoms include fatigue, gastrointestinal abnormalities, and changes in skin color (pigmentation). Behavior and mood changes may also occur in some individuals with Addison's disease. Increased excretion of water and low blood pressure (hypotension) can lead to extremely low concentrations of water in the body (dehydration). The symptoms of Addison's usually develop slowly, but sometimes can develop rapidly, a serious condition called acute adrenal failure. In most cases, Addison's disease occurs when the body's immune system mistakenly attacks the adrenal glands causing slowly progressive damage to the adrenal cortex. | Overview of Addison’s Disease. SummaryAddison's disease is a rare disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of cells of the adrenal glands (adrenal cortex). The symptoms of classic Addison's disease, also known as primary adrenal insufficiency, result from the insufficient production of these two hormones, cortisol and aldosterone. Major symptoms include fatigue, gastrointestinal abnormalities, and changes in skin color (pigmentation). Behavior and mood changes may also occur in some individuals with Addison's disease. Increased excretion of water and low blood pressure (hypotension) can lead to extremely low concentrations of water in the body (dehydration). The symptoms of Addison's usually develop slowly, but sometimes can develop rapidly, a serious condition called acute adrenal failure. In most cases, Addison's disease occurs when the body's immune system mistakenly attacks the adrenal glands causing slowly progressive damage to the adrenal cortex. | 35 | Addison’s Disease |
nord_35_1 | Symptoms of Addison’s Disease | The symptoms of Addison’s disease can vary from one individual to another. Symptoms usually develop slowly over time and are usually vague and common to many conditions (nonspecific). This often leads to delays in the proper diagnosis of Addison’s disease. In rare cases, the symptoms of Addison’s disease can develop rapidly causing a condition called acute adrenal failure.Fatigue is the most common symptom of Addison’s disease. Another common initial symptom of Addison’s disease is the development of patches of skin that are darker than the surrounding skin (hyperpigmentation). This discoloration most commonly occurs near scars, by skin creases such as the knuckles, and on the mucous membranes such as the gums. Skin abnormalities can precede the development of other symptoms by months or years, but do not occur in every person.Some individuals with Addison’s disease may also develop a condition called vitiligo in which white patches may appear on different areas of the body. This may vary from one or two small spots on the skin or multiple, larger affected areas. Black freckles may develop on the forehead, face or shoulders in some cases.A variety of gastrointestinal symptoms may be present including nausea, vomiting, and abdominal pain. Diarrhea is less common, but may also occur. Affected individuals may have a poor appetite and unintentional weight loss and may develop progressive fatigue and muscle weakness. Muscle pain (myalgia), muscle spasms and joint pain may also occur. Dehydration can also affect individuals with Addison’s disease.An additional symptom that may occur is low blood pressure (hypotension), which can cause lightheadedness or dizziness upon standing. Temporary loss of consciousness (syncope) can occur in some cases. Addison’s disease can also lead to changes in emotion and behavior. The disorder has been associated with irritability, depression, and poor concentration.Individuals with Addison’s disease may have cravings for salt or salty foods and low blood sugar (glucose) levels. Women with Addison’s disease may have irregular menstrual periods, lose body hair and have a decreased sexual drive.In some cases, symptoms of Addison’s disease may appear suddenly, a condition called acute adrenal failure or an addisonian crisis. During an addisonian crisis, affected individuals may develop a sudden loss of strength; severe pain in the lower back, abdomen or legs; vomiting and diarrhea potentially causing dehydration; and low blood pressure and loss of consciousness. An addisonian crisis is a medical emergency that can cause life-threatening complications such as shock or kidney failure if not treated. A crisis is usually set off when affected individuals are under stress such as during an accident, trauma, surgery or severe infection. | Symptoms of Addison’s Disease. The symptoms of Addison’s disease can vary from one individual to another. Symptoms usually develop slowly over time and are usually vague and common to many conditions (nonspecific). This often leads to delays in the proper diagnosis of Addison’s disease. In rare cases, the symptoms of Addison’s disease can develop rapidly causing a condition called acute adrenal failure.Fatigue is the most common symptom of Addison’s disease. Another common initial symptom of Addison’s disease is the development of patches of skin that are darker than the surrounding skin (hyperpigmentation). This discoloration most commonly occurs near scars, by skin creases such as the knuckles, and on the mucous membranes such as the gums. Skin abnormalities can precede the development of other symptoms by months or years, but do not occur in every person.Some individuals with Addison’s disease may also develop a condition called vitiligo in which white patches may appear on different areas of the body. This may vary from one or two small spots on the skin or multiple, larger affected areas. Black freckles may develop on the forehead, face or shoulders in some cases.A variety of gastrointestinal symptoms may be present including nausea, vomiting, and abdominal pain. Diarrhea is less common, but may also occur. Affected individuals may have a poor appetite and unintentional weight loss and may develop progressive fatigue and muscle weakness. Muscle pain (myalgia), muscle spasms and joint pain may also occur. Dehydration can also affect individuals with Addison’s disease.An additional symptom that may occur is low blood pressure (hypotension), which can cause lightheadedness or dizziness upon standing. Temporary loss of consciousness (syncope) can occur in some cases. Addison’s disease can also lead to changes in emotion and behavior. The disorder has been associated with irritability, depression, and poor concentration.Individuals with Addison’s disease may have cravings for salt or salty foods and low blood sugar (glucose) levels. Women with Addison’s disease may have irregular menstrual periods, lose body hair and have a decreased sexual drive.In some cases, symptoms of Addison’s disease may appear suddenly, a condition called acute adrenal failure or an addisonian crisis. During an addisonian crisis, affected individuals may develop a sudden loss of strength; severe pain in the lower back, abdomen or legs; vomiting and diarrhea potentially causing dehydration; and low blood pressure and loss of consciousness. An addisonian crisis is a medical emergency that can cause life-threatening complications such as shock or kidney failure if not treated. A crisis is usually set off when affected individuals are under stress such as during an accident, trauma, surgery or severe infection. | 35 | Addison’s Disease |
nord_35_2 | Causes of Addison’s Disease | Most cases of Addison’s disease occur due to damage or destruction of the adrenal cortex, the outermost layers of the adrenal glands (zona fasciulata, which secretes cortisol and zona glomerulosa, which secretes aldosterone). Symptoms usually do not develop until 90 percent of the adrenal cortex has been damaged.When Addison’s disease is caused by the inability of the adrenal cortex to produce hormones such as cortisol and aldosterone, it is referred to as primary adrenal insufficiency. When the adrenal glands are undamaged, but cannot produce these hormones for other reasons such as due to abnormalities of the pituitary gland, the condition is referred to as secondary adrenal insufficiency (For more information on secondary adrenal insufficiency see the Related Disorders section below).In approximately 75 percent of cases of Addison’s disease (primary adrenal insufficiency), damage to the adrenal cortex results from an autoimmune reaction. For reasons not completely understood, the body’s natural immune defenses (antibodies, lymphocytes, etc.) mistakenly attack healthy tissue, in this case healthy cells of the adrenal gland. Autoimmune Addison’s disease may occur by itself (as an isolated condition) or as part of a large disorder specifically the autoimmune polyendocrine syndromes I (APS type-1) and II (Schmidt syndrome).In the past, tuberculosis was the major cause of Addison’s disease and still remains a major cause of the disorder in developing countries. Less common causes of Addison’s disease include repeated infections especially fungal infections, the spread of cancer from another area of the body to the adrenal glands, bleeding (hemorrhaging) into the adrenal gland, and the abnormal accumulation of a fatty-like substance with the adrenals (amyloidosis). (For more information on these disorders, choose “tuberculosis” and/or “amyloidosis” as your search terms in the Rare Disease Database.)Addison’s disease occurs due to failure of the adrenal glands to produce sufficient amounts of the hormones, cortisol and aldosterone. Hormones are chemicals produced by glands that control and regulate certain activities of cells or organs of the body. The characteristic symptoms of Addison’s disease result from low levels of cortisol and aldosterone in the body.Cortisol affects how the body responds to stress and is released in greater quantities when a person is under stress. Cortisol has many additional functions in the body including helping to maintain blood pressure and cardiovascular function, helping to regulate the amount of water in the body, playing a role in controlling blood sugar levels by balancing the effects of insulin and assisting in proper immune system function and in the breakdown (metabolism) of carbohydrates, fats and proteins.Aldosterone affects the sodium and potassium ion equilibrium (electrolyte imbalance) in the body, as well as helping to maintain water levels and, therefore, blood pressure and blood volume. Deficiency of aldosterone hinders the kidney’s ability to filter salt and water, resulting in low blood pressure.The adrenal glands also produce androgen, a steroid hormone that controls the development of certain secondary sexual characteristics such as hair growth. Deficiency of androgen can cause loss of body hair and diminished sex drive in women. In males, androgen is primarily produced in the testes, not the adrenal glands. Therefore, males do not express signs of decreased androgens as Addison’s disease is an adrenal disease.In rare cases, Addison’s disease has run in families suggesting that, in these cases, individuals may have a genetic predisposition to developing the disorder. A genetic predisposition means that a person may carry a gene or gene(s) for a disease but the disease may not be expressed unless other factors (such as something in the environment) trigger the disease. | Causes of Addison’s Disease. Most cases of Addison’s disease occur due to damage or destruction of the adrenal cortex, the outermost layers of the adrenal glands (zona fasciulata, which secretes cortisol and zona glomerulosa, which secretes aldosterone). Symptoms usually do not develop until 90 percent of the adrenal cortex has been damaged.When Addison’s disease is caused by the inability of the adrenal cortex to produce hormones such as cortisol and aldosterone, it is referred to as primary adrenal insufficiency. When the adrenal glands are undamaged, but cannot produce these hormones for other reasons such as due to abnormalities of the pituitary gland, the condition is referred to as secondary adrenal insufficiency (For more information on secondary adrenal insufficiency see the Related Disorders section below).In approximately 75 percent of cases of Addison’s disease (primary adrenal insufficiency), damage to the adrenal cortex results from an autoimmune reaction. For reasons not completely understood, the body’s natural immune defenses (antibodies, lymphocytes, etc.) mistakenly attack healthy tissue, in this case healthy cells of the adrenal gland. Autoimmune Addison’s disease may occur by itself (as an isolated condition) or as part of a large disorder specifically the autoimmune polyendocrine syndromes I (APS type-1) and II (Schmidt syndrome).In the past, tuberculosis was the major cause of Addison’s disease and still remains a major cause of the disorder in developing countries. Less common causes of Addison’s disease include repeated infections especially fungal infections, the spread of cancer from another area of the body to the adrenal glands, bleeding (hemorrhaging) into the adrenal gland, and the abnormal accumulation of a fatty-like substance with the adrenals (amyloidosis). (For more information on these disorders, choose “tuberculosis” and/or “amyloidosis” as your search terms in the Rare Disease Database.)Addison’s disease occurs due to failure of the adrenal glands to produce sufficient amounts of the hormones, cortisol and aldosterone. Hormones are chemicals produced by glands that control and regulate certain activities of cells or organs of the body. The characteristic symptoms of Addison’s disease result from low levels of cortisol and aldosterone in the body.Cortisol affects how the body responds to stress and is released in greater quantities when a person is under stress. Cortisol has many additional functions in the body including helping to maintain blood pressure and cardiovascular function, helping to regulate the amount of water in the body, playing a role in controlling blood sugar levels by balancing the effects of insulin and assisting in proper immune system function and in the breakdown (metabolism) of carbohydrates, fats and proteins.Aldosterone affects the sodium and potassium ion equilibrium (electrolyte imbalance) in the body, as well as helping to maintain water levels and, therefore, blood pressure and blood volume. Deficiency of aldosterone hinders the kidney’s ability to filter salt and water, resulting in low blood pressure.The adrenal glands also produce androgen, a steroid hormone that controls the development of certain secondary sexual characteristics such as hair growth. Deficiency of androgen can cause loss of body hair and diminished sex drive in women. In males, androgen is primarily produced in the testes, not the adrenal glands. Therefore, males do not express signs of decreased androgens as Addison’s disease is an adrenal disease.In rare cases, Addison’s disease has run in families suggesting that, in these cases, individuals may have a genetic predisposition to developing the disorder. A genetic predisposition means that a person may carry a gene or gene(s) for a disease but the disease may not be expressed unless other factors (such as something in the environment) trigger the disease. | 35 | Addison’s Disease |
nord_35_3 | Affects of Addison’s Disease | Addison’s disease affects males and females in equal numbers. Approximately 1 in 100,000 people in United States have Addison’s disease. The overall prevalence is estimated to be between 40 and 60 people per million of the general population. Because cases of Addison’s disease may go undiagnosed, it is difficult to determine its true frequency in the general population. Addison’s disease can potentially affect individuals of any age, but usually occurs in individuals between 30-50 years of age. Addison’s disease was first identified in the medical literature in 1855 by a physician named Thomas Addison. | Affects of Addison’s Disease. Addison’s disease affects males and females in equal numbers. Approximately 1 in 100,000 people in United States have Addison’s disease. The overall prevalence is estimated to be between 40 and 60 people per million of the general population. Because cases of Addison’s disease may go undiagnosed, it is difficult to determine its true frequency in the general population. Addison’s disease can potentially affect individuals of any age, but usually occurs in individuals between 30-50 years of age. Addison’s disease was first identified in the medical literature in 1855 by a physician named Thomas Addison. | 35 | Addison’s Disease |
nord_35_4 | Related disorders of Addison’s Disease | Symptoms of the following disorders can be similar to those of Addison’s disease. Comparisons may be useful for a differential diagnosis.ACTH deficiency is a rare disorder that arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. It is a form of secondary adrenal insufficiency. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to unintentional weight loss, lack of appetite, weakness, nausea, vomiting, and low blood pressure (hypotension). ACTH deficiency is a disorder that usually starts during adulthood, although a few cases have begun during childhood. Low blood levels of sugar and sodium and high potassium levels (hypoglycemia, hyponatremia and hyperkalemia) also occur. The pituitary hormone ACTH may be undetectable in blood tests, and the level of the adrenal hormone cortisol is abnormally low. Some adrenal hormones that are decreased include cortisol and aldosterone. Hormones that are precursors of male sex hormones known as “androgens” may also be reduced. Although males with this disorder usually have a normal hair pattern, females have very little pubic and underarm (axillary) hair. In contrast to Addison’s disease, skin pigmentation usually remains normal. Emotional and behavioral changes may occur as well. (For more information on this disorder, choose “ACTH deficiency” as your search term in the Rare Disease Database.)Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged. The adrenal gland produces “male” sex hormones (androgens) in both males and females because these are overproduced in certain forms of CAH. The external genitals of some females with this disorder become masculinized to various degrees. Lack of glucocorticoids, especially cortisol, causes various problems. Lack of mineralocorticoids, primarily aldosterone, causes salt and water imbalances which may be life threatening. (For more information on this disorder, choose “Adrenal Hyperplasia” as your search term in the Rare Disease Database.)Adrenoleukodystrophy is an X-linked recessive genetic disorder caused by an abnormality in the ABCD1 gene on the X chromosome. This condition affects the white matter of the nervous system and the adrenal cortex. Some affected individuals have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. Some of those affected experience serious neurological problems that can affect mental function and lead to disability and reduced life span. This condition has been categorized into six types based on symptoms and age of onset: childhood cerebral ALD, adolescent cerebral ALD, adrenomyeloneuropathy, adult cerebral ALD, adrenal insufficiency only and ALD that occurs in females. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database.)Autoimmune polyendocrine syndrome type II, also known as Schmidt syndrome, is a rare autoimmune disorder in which there is a steep drop in production of several essential hormones by the glands that secrete these hormones. When first described, this disorder was thought to involve only adrenal insufficiency (Addison’s disease) and thyroid insufficiency (Hashimoto’s thyroiditis). However, over time, as more patients were studied, the scope of the disorder was expanded to include disorders of other underperforming endocrine glands. These include the gonads, which secrete sex hormones; the pancreas which secretes insulin and is intimately tied up with diabetes mellitus; and sometimes the parathyroid glands. Failure of the endocrine glands to function is usually accompanied by signs of malnutrition because the ability of the intestinal tract to absorb nutrients is reduced dramatically. Since the combination of affected glands differs from patient to patient, the signs of this disorder are diverse. Most cases of this disorder are sporadic although some clinical researchers believe that there is a familial or hereditary trait associated with AIPS-II. If so, it may involve a complex interaction among many genes. (For more information on this disorder, choose “Schmidt syndrome” as your search term in the Rare Disease Database.)Autoimmune polyendocrine syndrome type I, (APS type 1) also known as APECED syndrome, is a rare genetic syndrome involving the autoimmune system. It is a combination of several distinct disorders and is defined as the subnormal functioning of several endocrine glands at the same time (concurrently). The acronym APECED stands for autoimmune polyendocrinopathy (APE), candidiasis (C) and ectodermal dysplasia (ED). Autoimmune disease affecting one gland is frequently followed by the impairment of other glands. In this syndrome two major patterns of failure have been described. Beginning in childhood, yeast infections of either the mouth or nails are usually one of the first apparent symptoms of APS type-I. Low plasma levels of calcium and phosphate (hypoparathyroidism) are often diagnosed before adrenal dystrophy. There may be an inability to adequately absorb nutrients with resulting diarrhea. Anemia, autoimmune thyroid disease, and loss or delay of sexual development may also occur. The combination of ectodermal dysplasia with candidiasis or hypoparathyroidism may also indicate an APS type-1 patient. In addition to hypoparathyroidism, lack of tooth enamel (enamel dystrophy), loss of hair (alopecia) and absence of pigment in areas of the skin (vitiligo) may also present. An eye disorder, corneal dystrophy (keratopathy), may also occur. There may be failure of sexual development, yeast infections of the mouth and nails (candidiasis), and the inability to properly absorb nutrients from food (malabsorption). Patients may develop liver disease or insulin- dependent diabetes as well as any combination of the various disorders. (For more information on this disorder, choose “APS type-1” as your search term in the Rare Disease Database.) | Related disorders of Addison’s Disease. Symptoms of the following disorders can be similar to those of Addison’s disease. Comparisons may be useful for a differential diagnosis.ACTH deficiency is a rare disorder that arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. It is a form of secondary adrenal insufficiency. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to unintentional weight loss, lack of appetite, weakness, nausea, vomiting, and low blood pressure (hypotension). ACTH deficiency is a disorder that usually starts during adulthood, although a few cases have begun during childhood. Low blood levels of sugar and sodium and high potassium levels (hypoglycemia, hyponatremia and hyperkalemia) also occur. The pituitary hormone ACTH may be undetectable in blood tests, and the level of the adrenal hormone cortisol is abnormally low. Some adrenal hormones that are decreased include cortisol and aldosterone. Hormones that are precursors of male sex hormones known as “androgens” may also be reduced. Although males with this disorder usually have a normal hair pattern, females have very little pubic and underarm (axillary) hair. In contrast to Addison’s disease, skin pigmentation usually remains normal. Emotional and behavioral changes may occur as well. (For more information on this disorder, choose “ACTH deficiency” as your search term in the Rare Disease Database.)Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged. The adrenal gland produces “male” sex hormones (androgens) in both males and females because these are overproduced in certain forms of CAH. The external genitals of some females with this disorder become masculinized to various degrees. Lack of glucocorticoids, especially cortisol, causes various problems. Lack of mineralocorticoids, primarily aldosterone, causes salt and water imbalances which may be life threatening. (For more information on this disorder, choose “Adrenal Hyperplasia” as your search term in the Rare Disease Database.)Adrenoleukodystrophy is an X-linked recessive genetic disorder caused by an abnormality in the ABCD1 gene on the X chromosome. This condition affects the white matter of the nervous system and the adrenal cortex. Some affected individuals have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. Some of those affected experience serious neurological problems that can affect mental function and lead to disability and reduced life span. This condition has been categorized into six types based on symptoms and age of onset: childhood cerebral ALD, adolescent cerebral ALD, adrenomyeloneuropathy, adult cerebral ALD, adrenal insufficiency only and ALD that occurs in females. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database.)Autoimmune polyendocrine syndrome type II, also known as Schmidt syndrome, is a rare autoimmune disorder in which there is a steep drop in production of several essential hormones by the glands that secrete these hormones. When first described, this disorder was thought to involve only adrenal insufficiency (Addison’s disease) and thyroid insufficiency (Hashimoto’s thyroiditis). However, over time, as more patients were studied, the scope of the disorder was expanded to include disorders of other underperforming endocrine glands. These include the gonads, which secrete sex hormones; the pancreas which secretes insulin and is intimately tied up with diabetes mellitus; and sometimes the parathyroid glands. Failure of the endocrine glands to function is usually accompanied by signs of malnutrition because the ability of the intestinal tract to absorb nutrients is reduced dramatically. Since the combination of affected glands differs from patient to patient, the signs of this disorder are diverse. Most cases of this disorder are sporadic although some clinical researchers believe that there is a familial or hereditary trait associated with AIPS-II. If so, it may involve a complex interaction among many genes. (For more information on this disorder, choose “Schmidt syndrome” as your search term in the Rare Disease Database.)Autoimmune polyendocrine syndrome type I, (APS type 1) also known as APECED syndrome, is a rare genetic syndrome involving the autoimmune system. It is a combination of several distinct disorders and is defined as the subnormal functioning of several endocrine glands at the same time (concurrently). The acronym APECED stands for autoimmune polyendocrinopathy (APE), candidiasis (C) and ectodermal dysplasia (ED). Autoimmune disease affecting one gland is frequently followed by the impairment of other glands. In this syndrome two major patterns of failure have been described. Beginning in childhood, yeast infections of either the mouth or nails are usually one of the first apparent symptoms of APS type-I. Low plasma levels of calcium and phosphate (hypoparathyroidism) are often diagnosed before adrenal dystrophy. There may be an inability to adequately absorb nutrients with resulting diarrhea. Anemia, autoimmune thyroid disease, and loss or delay of sexual development may also occur. The combination of ectodermal dysplasia with candidiasis or hypoparathyroidism may also indicate an APS type-1 patient. In addition to hypoparathyroidism, lack of tooth enamel (enamel dystrophy), loss of hair (alopecia) and absence of pigment in areas of the skin (vitiligo) may also present. An eye disorder, corneal dystrophy (keratopathy), may also occur. There may be failure of sexual development, yeast infections of the mouth and nails (candidiasis), and the inability to properly absorb nutrients from food (malabsorption). Patients may develop liver disease or insulin- dependent diabetes as well as any combination of the various disorders. (For more information on this disorder, choose “APS type-1” as your search term in the Rare Disease Database.) | 35 | Addison’s Disease |
nord_35_5 | Diagnosis of Addison’s Disease | A diagnosis of Addison’s disease is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Often a diagnosis is made incidentally during a routine exam when a blood test shows low levels of sodium or high levels of potassium. A diagnosis may be confirmed through a variety of specialized tests including the ACTH stimulation test, insulin-induced hypoglycemia test and x-ray examination.The ACTH stimulation test measures the amount of cortisol in the blood. During this test, adrenocorticohormone (ACTH) is injected into the body, stimulating production of cortisol. If the test fails to stimulate adequate cortisol production, it indicates that the adrenal glands are damaged or not functioning properly.The insulin-induced hypoglycemia test may be used to determine if the symptoms of Addison’s disease are due to problems with the pituitary gland. This test measures blood sugar (glucose) levels before and after the injection of fast-acting insulin, which should lead to a drop in glucose and a rise in cortisol.X-ray imaging techniques such as computed tomography (CT scan) of the abdomen may be taken to check the size of the adrenal glands and to detect other signs of disease such as calcification of the adrenal glands. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of an organ’s tissue structure. | Diagnosis of Addison’s Disease. A diagnosis of Addison’s disease is suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. Often a diagnosis is made incidentally during a routine exam when a blood test shows low levels of sodium or high levels of potassium. A diagnosis may be confirmed through a variety of specialized tests including the ACTH stimulation test, insulin-induced hypoglycemia test and x-ray examination.The ACTH stimulation test measures the amount of cortisol in the blood. During this test, adrenocorticohormone (ACTH) is injected into the body, stimulating production of cortisol. If the test fails to stimulate adequate cortisol production, it indicates that the adrenal glands are damaged or not functioning properly.The insulin-induced hypoglycemia test may be used to determine if the symptoms of Addison’s disease are due to problems with the pituitary gland. This test measures blood sugar (glucose) levels before and after the injection of fast-acting insulin, which should lead to a drop in glucose and a rise in cortisol.X-ray imaging techniques such as computed tomography (CT scan) of the abdomen may be taken to check the size of the adrenal glands and to detect other signs of disease such as calcification of the adrenal glands. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of an organ’s tissue structure. | 35 | Addison’s Disease |
nord_35_6 | Therapies of Addison’s Disease | Treatment
The treatment of Addison’s disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Individuals with Addison’s disease are treated by replacing the deficient steroid hormones (cortisol and aldosterone). Cortisol is replaced by the drug hydrocortisone and aldosterone is replaced by the drug fludrocortisone. The dosage of these drugs is different for each individual and the dosage may be increased during infection, trauma, surgery and other stressful situations to prevent an acute adrenal crisis. Individuals should be encouraged to increase the salt intake in their diets.An adrenal crisis demands immediate hormonal investigation and intravenous (injected directly into a blood vessel) administration of high-dose hydrocortisone and fluid (salt water) and electrolyte replacement; a short-term course of other drugs called vasopressors may be needed to maintain blood pressure. Affected individuals should carry a card or wear a tag stating that they have Addison’s disease. | Therapies of Addison’s Disease. Treatment
The treatment of Addison’s disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Individuals with Addison’s disease are treated by replacing the deficient steroid hormones (cortisol and aldosterone). Cortisol is replaced by the drug hydrocortisone and aldosterone is replaced by the drug fludrocortisone. The dosage of these drugs is different for each individual and the dosage may be increased during infection, trauma, surgery and other stressful situations to prevent an acute adrenal crisis. Individuals should be encouraged to increase the salt intake in their diets.An adrenal crisis demands immediate hormonal investigation and intravenous (injected directly into a blood vessel) administration of high-dose hydrocortisone and fluid (salt water) and electrolyte replacement; a short-term course of other drugs called vasopressors may be needed to maintain blood pressure. Affected individuals should carry a card or wear a tag stating that they have Addison’s disease. | 35 | Addison’s Disease |
nord_36_0 | Overview of Adenoid Cystic Carcinoma | Adenoid cystic carcinoma (ACC) is a relatively rare form of cancer that most commonly develops in the salivary glands or other regions of the head and neck. ACC can occur in other parts of the body, such as the breast, skin, cervix in females, prostate gland in males and various other areas. ACC tumors are characterized by a distinctive histological pattern of abnormal “nests” or cords of certain cells (epithelial cells) that surround and/or infiltrate ducts or glandular structures within the affected organ. These structures are typically filled with a mucous-like material or contain abnormal fibrous membranes. Such characteristics are apparent during microscopic evaluation of tumor cells from a biopsy sample. ACC is considered a low-grade malignancy that has a history of slow growth. ACC can be aggressively invasive and infiltrate nearby lymph nodes as well as the “sheaths” or coatings surrounding nerve fibers (perineural spaces). This form of cancer can recur later at the site where it first developed (local recurrence) or spread to distant body sites (metastatic disease), particularly the lungs, in approximately 50% of patients. ACC typically occurs during adulthood, around the ages of 40 to 60, but has also been diagnosed in children and adolescents. | Overview of Adenoid Cystic Carcinoma. Adenoid cystic carcinoma (ACC) is a relatively rare form of cancer that most commonly develops in the salivary glands or other regions of the head and neck. ACC can occur in other parts of the body, such as the breast, skin, cervix in females, prostate gland in males and various other areas. ACC tumors are characterized by a distinctive histological pattern of abnormal “nests” or cords of certain cells (epithelial cells) that surround and/or infiltrate ducts or glandular structures within the affected organ. These structures are typically filled with a mucous-like material or contain abnormal fibrous membranes. Such characteristics are apparent during microscopic evaluation of tumor cells from a biopsy sample. ACC is considered a low-grade malignancy that has a history of slow growth. ACC can be aggressively invasive and infiltrate nearby lymph nodes as well as the “sheaths” or coatings surrounding nerve fibers (perineural spaces). This form of cancer can recur later at the site where it first developed (local recurrence) or spread to distant body sites (metastatic disease), particularly the lungs, in approximately 50% of patients. ACC typically occurs during adulthood, around the ages of 40 to 60, but has also been diagnosed in children and adolescents. | 36 | Adenoid Cystic Carcinoma |
nord_36_1 | Symptoms of Adenoid Cystic Carcinoma | There are three histological tumor growth patterns common to ACC: cribriform, tubular and solid. The cribriform growth pattern is most common and appears as a “Swiss cheese” pattern in histological stains. The cribriform and tubular growth patterns are less aggressive. Tumors exhibiting a solid pattern are more likely to spread, have been associated with activating pathogenic variants (mutations) in the NOTCH1 gene and have a worse prognosis.ACC most commonly arises in the salivary glands or other areas within the head and neck region. Symptoms of ACC of the salivary glands may include numbness of the lower lip and/or other facial areas; nerve impairment causing weakness of certain facial muscles; ongoing pain; and/or other associated abnormalities. The specific symptoms observed vary between patients and depend on both the size of the tumor and specific salivary gland and nerve(s) affected by the malignancy.The lacrimal gland is the gland that produces tears. Symptoms of lacrimal gland ACC include a bulging eye (proptosis) or changes in vision. Although lacrimal gland ACC appears to occur predominantly during adulthood, there have been some reports of the disease in children and adolescents. ACC may also arise in certain skin regions (primary cutaneous ACC). Such malignancies primarily develop on the scalp and external ear canal, potentially resulting in pain, discharge of pus and/or blood and/or other symptoms. The development of isolated or multiple reddish (erythematous) nodules or plaques that vary in size typically characterize ACC of the skin. ACC of the skin is due to abnormal cell growth and tends to invade local soft tissue and bone aggressively. Other primary sites of tumor development include the arms or legs and trunk. Although associated symptoms may vary, findings may include pain, increased sensitivity, or perceiving pain from stimuli not normally associated with pain. In addition, individuals with involvement of the scalp may experience hair loss around tumor growth. ACC of the skin can be aggressive and may be associated with infiltration of nerves and, in rare cases, result in distant metastases. In addition, many affected individuals have local recurrences that may develop months or years after surgical removal of the initial lesion.
ACC may also arise within certain organs of the lower or upper respiratory tract, breast, esophagus, cervix (females), and prostate gland (males). Descriptions of these forms of ACC are provided in the following paragraphs.ACC of the lower respiratory tract most frequently develops in mucous glands of the trachea, particularly the upper third. In individuals with tracheal ACC, tumor growth gradually causes obstruction of the windpipe, resulting in difficult or labored breathing; hoarseness; and/or a high-pitched, respiratory sound upon the intake of breath (stridor). Additional symptoms may include a general feeling of ill health (malaise), weight loss, pain, recurrent inflammation of the lungs (pneumonitis), and/or the coughing up of blood.In ACC of the lower respiratory tract, malignancy tends to infiltrate regional lymph nodes and may spread along nerves to bone, particularly the spine (vertebrae). More rarely, sites of metastases may include the lungs, liver, brain, kidneys or other regions.In some individuals, ACC may also arise in mucous glands of the voice box (larynx), which lies between the throat and the trachea. ACC of the larynx most commonly arises in the region beneath the glottis, which is the slit-like opening between the vocal cords. In addition, these tumors may regionally invade the vocal cords. Tumor growth in the subglottic region gradually results in difficulty breathing upon exertion, shortness of breath, and eventual airway obstruction. When the malignancy develops above the opening; between the vocal cords, it may eventually result in persistent hoarseness, change in speech, difficulty swallowing, and soreness of the throat. In some individuals with ACC of the larynx, a mass may be seen in the neck area. Because this malignancy tends to infiltrate nerves, some affected individuals may also experience associated pain or discomfort. Laryngeal ACC may spread through the bloodstream, as well as via the nerves. Metastatic disease most typically occurs in the lungs; however, other sites may include bone or the brain.ACC of the esophagus, which is extremely rare, has the same cellular structure and composition as ACC of the salivary glands and other areas of the body. As with ACC of the salivary gland, esophageal ACC is a slow-growing malignancy that may be prone to perineural invasion, local recurrences and distant metastases. Initially, affected individuals may have problems swallowing solids. With increasing tumor growth, they may have difficulties swallowing soft foods as well as liquids, including even saliva in some cases. This typically results in regurgitation of food and liquids, with associated weight loss.ACC may also arise in the breast. However, the disease course may be markedly different from primary ACC in other regions of the body. For example, ACC of the breast is considered a less aggressive malignancy that is not as likely to invade regional lymph nodes, metastasize or locally recur. Compared to other forms of triple negative breast cancer, ACC is low-grade and progresses slowly. Researchers attribute such characteristics to several possible factors, such as slower overall tumor growth, relatively small tumor size and an increased ability to remove all traces of such malignancies surgically. However, this malignancy tends to invade adjacent tissue and infiltrate nerves. In addition, although considered extremely rare, local recurrences may develop and metastatic disease may occur months or years after surgical removal of the primary tumor. The most common site of metastatic disease is the lung. Other, more rarely reported areas of metastasis include lymph nodes, soft tissue, bone, brain and kidneys. Incomplete removal of the primary tumor contributes to rare cases of local recurrence and metastasis. Less than 0.1% of all breast carcinomas are diagnosed as ACC.According to reports in the medical literature, only one breast is affected. To date, no cases have been reported in which both breasts developed ACC. ACC of the breast is characterized by the excessive growth of two specific cell types (luminal and basaloid) in specific patterns.Patients develop a slowly enlarging, moveable mass that may cause tenderness or pain, unlike some other forms of breast cancer. Tumors tend to develop in the region of the nipple or areola (the pigmented, circular area of skin surrounding the nipple). Findings associated with other malignancies in this region include bloody discharge, indentation of the nipple, and/or tumor invasion of the chest muscle, appear to be uncommon in association with ACC.In females, ACC may also arise in the cervix, particularly after menopause. Initial symptoms include a watery or bloodstained discharge or vaginal bleeding in association with a relatively large cervical mass. ACC of the cervix frequently recurs locally, spreads to lymph nodes/vessels and perineural spaces and metastasizes to distant organs. ACC accounts for 0.1% of all cervical cancer cases and is very aggressive.In males, ACC may arise in the prostate gland. This rare form of ACC is considered a subtype of prostate adenocarcinoma, a common form of prostate cancer. Symptoms may include poor flow of urine, increased frequency of urination and/or difficulties beginning urination due to enlargement of the prostate gland and associated obstruction of the urinary tract.
Rarely, ACC may arise in other regions of the body. The specific symptoms and clinical course may vary from person to person, depending upon the primary tumor site, size, nature, progression and other factors. | Symptoms of Adenoid Cystic Carcinoma. There are three histological tumor growth patterns common to ACC: cribriform, tubular and solid. The cribriform growth pattern is most common and appears as a “Swiss cheese” pattern in histological stains. The cribriform and tubular growth patterns are less aggressive. Tumors exhibiting a solid pattern are more likely to spread, have been associated with activating pathogenic variants (mutations) in the NOTCH1 gene and have a worse prognosis.ACC most commonly arises in the salivary glands or other areas within the head and neck region. Symptoms of ACC of the salivary glands may include numbness of the lower lip and/or other facial areas; nerve impairment causing weakness of certain facial muscles; ongoing pain; and/or other associated abnormalities. The specific symptoms observed vary between patients and depend on both the size of the tumor and specific salivary gland and nerve(s) affected by the malignancy.The lacrimal gland is the gland that produces tears. Symptoms of lacrimal gland ACC include a bulging eye (proptosis) or changes in vision. Although lacrimal gland ACC appears to occur predominantly during adulthood, there have been some reports of the disease in children and adolescents. ACC may also arise in certain skin regions (primary cutaneous ACC). Such malignancies primarily develop on the scalp and external ear canal, potentially resulting in pain, discharge of pus and/or blood and/or other symptoms. The development of isolated or multiple reddish (erythematous) nodules or plaques that vary in size typically characterize ACC of the skin. ACC of the skin is due to abnormal cell growth and tends to invade local soft tissue and bone aggressively. Other primary sites of tumor development include the arms or legs and trunk. Although associated symptoms may vary, findings may include pain, increased sensitivity, or perceiving pain from stimuli not normally associated with pain. In addition, individuals with involvement of the scalp may experience hair loss around tumor growth. ACC of the skin can be aggressive and may be associated with infiltration of nerves and, in rare cases, result in distant metastases. In addition, many affected individuals have local recurrences that may develop months or years after surgical removal of the initial lesion.
ACC may also arise within certain organs of the lower or upper respiratory tract, breast, esophagus, cervix (females), and prostate gland (males). Descriptions of these forms of ACC are provided in the following paragraphs.ACC of the lower respiratory tract most frequently develops in mucous glands of the trachea, particularly the upper third. In individuals with tracheal ACC, tumor growth gradually causes obstruction of the windpipe, resulting in difficult or labored breathing; hoarseness; and/or a high-pitched, respiratory sound upon the intake of breath (stridor). Additional symptoms may include a general feeling of ill health (malaise), weight loss, pain, recurrent inflammation of the lungs (pneumonitis), and/or the coughing up of blood.In ACC of the lower respiratory tract, malignancy tends to infiltrate regional lymph nodes and may spread along nerves to bone, particularly the spine (vertebrae). More rarely, sites of metastases may include the lungs, liver, brain, kidneys or other regions.In some individuals, ACC may also arise in mucous glands of the voice box (larynx), which lies between the throat and the trachea. ACC of the larynx most commonly arises in the region beneath the glottis, which is the slit-like opening between the vocal cords. In addition, these tumors may regionally invade the vocal cords. Tumor growth in the subglottic region gradually results in difficulty breathing upon exertion, shortness of breath, and eventual airway obstruction. When the malignancy develops above the opening; between the vocal cords, it may eventually result in persistent hoarseness, change in speech, difficulty swallowing, and soreness of the throat. In some individuals with ACC of the larynx, a mass may be seen in the neck area. Because this malignancy tends to infiltrate nerves, some affected individuals may also experience associated pain or discomfort. Laryngeal ACC may spread through the bloodstream, as well as via the nerves. Metastatic disease most typically occurs in the lungs; however, other sites may include bone or the brain.ACC of the esophagus, which is extremely rare, has the same cellular structure and composition as ACC of the salivary glands and other areas of the body. As with ACC of the salivary gland, esophageal ACC is a slow-growing malignancy that may be prone to perineural invasion, local recurrences and distant metastases. Initially, affected individuals may have problems swallowing solids. With increasing tumor growth, they may have difficulties swallowing soft foods as well as liquids, including even saliva in some cases. This typically results in regurgitation of food and liquids, with associated weight loss.ACC may also arise in the breast. However, the disease course may be markedly different from primary ACC in other regions of the body. For example, ACC of the breast is considered a less aggressive malignancy that is not as likely to invade regional lymph nodes, metastasize or locally recur. Compared to other forms of triple negative breast cancer, ACC is low-grade and progresses slowly. Researchers attribute such characteristics to several possible factors, such as slower overall tumor growth, relatively small tumor size and an increased ability to remove all traces of such malignancies surgically. However, this malignancy tends to invade adjacent tissue and infiltrate nerves. In addition, although considered extremely rare, local recurrences may develop and metastatic disease may occur months or years after surgical removal of the primary tumor. The most common site of metastatic disease is the lung. Other, more rarely reported areas of metastasis include lymph nodes, soft tissue, bone, brain and kidneys. Incomplete removal of the primary tumor contributes to rare cases of local recurrence and metastasis. Less than 0.1% of all breast carcinomas are diagnosed as ACC.According to reports in the medical literature, only one breast is affected. To date, no cases have been reported in which both breasts developed ACC. ACC of the breast is characterized by the excessive growth of two specific cell types (luminal and basaloid) in specific patterns.Patients develop a slowly enlarging, moveable mass that may cause tenderness or pain, unlike some other forms of breast cancer. Tumors tend to develop in the region of the nipple or areola (the pigmented, circular area of skin surrounding the nipple). Findings associated with other malignancies in this region include bloody discharge, indentation of the nipple, and/or tumor invasion of the chest muscle, appear to be uncommon in association with ACC.In females, ACC may also arise in the cervix, particularly after menopause. Initial symptoms include a watery or bloodstained discharge or vaginal bleeding in association with a relatively large cervical mass. ACC of the cervix frequently recurs locally, spreads to lymph nodes/vessels and perineural spaces and metastasizes to distant organs. ACC accounts for 0.1% of all cervical cancer cases and is very aggressive.In males, ACC may arise in the prostate gland. This rare form of ACC is considered a subtype of prostate adenocarcinoma, a common form of prostate cancer. Symptoms may include poor flow of urine, increased frequency of urination and/or difficulties beginning urination due to enlargement of the prostate gland and associated obstruction of the urinary tract.
Rarely, ACC may arise in other regions of the body. The specific symptoms and clinical course may vary from person to person, depending upon the primary tumor site, size, nature, progression and other factors. | 36 | Adenoid Cystic Carcinoma |
nord_36_2 | Causes of Adenoid Cystic Carcinoma | The exact cause of adenoid cystic carcinoma is unknown. However, current research suggests that genetic changes (chromosomal rearrangements, pathogenic variants in genes or other DNA alterations) are the underlying basis of cellular malignant transformation in many cancers, including ACC.Researchers speculate that a protein produced by the fusion of two transcription factor genes, MYB-NFIB, plays a role in the development of ACC tumors. Upregulation of MYB or a related protein MYBL1 is found in up to 90-95 % of ACC tumors. Activating pathogenic variants in the NOTCH1 gene have also been detected in ACC tumors and occur in 15-20% of patients with recurrent/metastatic disease. Patients with activating pathogenic variants (mutations) in the NOTCH1 gene have a worse prognosis. | Causes of Adenoid Cystic Carcinoma. The exact cause of adenoid cystic carcinoma is unknown. However, current research suggests that genetic changes (chromosomal rearrangements, pathogenic variants in genes or other DNA alterations) are the underlying basis of cellular malignant transformation in many cancers, including ACC.Researchers speculate that a protein produced by the fusion of two transcription factor genes, MYB-NFIB, plays a role in the development of ACC tumors. Upregulation of MYB or a related protein MYBL1 is found in up to 90-95 % of ACC tumors. Activating pathogenic variants in the NOTCH1 gene have also been detected in ACC tumors and occur in 15-20% of patients with recurrent/metastatic disease. Patients with activating pathogenic variants (mutations) in the NOTCH1 gene have a worse prognosis. | 36 | Adenoid Cystic Carcinoma |
nord_36_3 | Affects of Adenoid Cystic Carcinoma | Every year, about 1,200 individuals are diagnosed with ACC in the United States. 58% of ACC patients exhibit tumors in the oral cavity, salivary glands and pharynx, 17% in the respiratory system, 12% in the breast and the remaining 13% of tumors occur in other areas of the body such as on the skin, lacrimal glands, prostate, etc. ACC makes up 10% of all tumors of the head and neck region.ACC tends to appear more often in individuals between the ages of 40 and 60, with 58 being the median age. About 60% of patients with ACC are females, likely due to the higher prevalence of ACC in female specific primary sites (breast and genital system) compared to male specific primary sites. However, the average age at disease onset may vary from person to person, depending upon the form of ACC present and other factors. ACC primarily affects adults, but some forms, such as ACC of the lacrimal glands have been reported in childhood and adolescence.ACC of the salivary glands, the most common form of the disease, is thought to account for approximately 25 percent of malignant salivary gland tumors. It typically develops from early to late adulthood.ACC of the lower respiratory tract accounts for less than one percent (0.1 to 0.2 percent) of all primary lung tumors. It appears to affect males and females relatively equally, and most commonly occurs during the fifth decade of life.ACC of the larynx has been reported in individuals ranging in age from 25 to 75 years, with most cases occurring in the fifth to sixth decade of life. Males and females appear to be equally affected.ACC of the skin generally affects adults with the average age at diagnosis around 59 years. ACC of the skin occurs more frequently in women compared to men and has not shown to affect one racial group more than others.Primary ACC of the breast is extremely rare, representing less than one percent of all breast cancers (0.1 %). This form of ACC primarily occurs in females. In the few reported cases among males, disease presentation and course have been similar to that seen in affected females. This malignancy tends to become apparent during mid to late adulthood.ACC of the cervix typically becomes apparent after menopause. However, there are a few reports of the disease in younger females.ACC of the prostate tends to develop during or after middle age with the average age of patients being 50. | Affects of Adenoid Cystic Carcinoma. Every year, about 1,200 individuals are diagnosed with ACC in the United States. 58% of ACC patients exhibit tumors in the oral cavity, salivary glands and pharynx, 17% in the respiratory system, 12% in the breast and the remaining 13% of tumors occur in other areas of the body such as on the skin, lacrimal glands, prostate, etc. ACC makes up 10% of all tumors of the head and neck region.ACC tends to appear more often in individuals between the ages of 40 and 60, with 58 being the median age. About 60% of patients with ACC are females, likely due to the higher prevalence of ACC in female specific primary sites (breast and genital system) compared to male specific primary sites. However, the average age at disease onset may vary from person to person, depending upon the form of ACC present and other factors. ACC primarily affects adults, but some forms, such as ACC of the lacrimal glands have been reported in childhood and adolescence.ACC of the salivary glands, the most common form of the disease, is thought to account for approximately 25 percent of malignant salivary gland tumors. It typically develops from early to late adulthood.ACC of the lower respiratory tract accounts for less than one percent (0.1 to 0.2 percent) of all primary lung tumors. It appears to affect males and females relatively equally, and most commonly occurs during the fifth decade of life.ACC of the larynx has been reported in individuals ranging in age from 25 to 75 years, with most cases occurring in the fifth to sixth decade of life. Males and females appear to be equally affected.ACC of the skin generally affects adults with the average age at diagnosis around 59 years. ACC of the skin occurs more frequently in women compared to men and has not shown to affect one racial group more than others.Primary ACC of the breast is extremely rare, representing less than one percent of all breast cancers (0.1 %). This form of ACC primarily occurs in females. In the few reported cases among males, disease presentation and course have been similar to that seen in affected females. This malignancy tends to become apparent during mid to late adulthood.ACC of the cervix typically becomes apparent after menopause. However, there are a few reports of the disease in younger females.ACC of the prostate tends to develop during or after middle age with the average age of patients being 50. | 36 | Adenoid Cystic Carcinoma |
nord_36_4 | Related disorders of Adenoid Cystic Carcinoma | Depending upon the tumor site, some benign (noncancerous) growths may appear similar to primary ACC tumor development. However, ACC typically exhibits additional symptoms that distinguish it from benign growths. Microscopic examination of tumor cells and other diagnostic testing are essential in differentiating between the two.The term “adenoid cystic carcinoma of the esophagus” is used to describe two different, rare forms of cancer. “True” ACC of the esophagus is extremely rare, with only a few cases reported in the medical literature. The more common of the two entities, which is more appropriately termed “basaloid squamous carcinoma,” has been reported in individuals who range in age from approximately 35 to 85 years. Although initial reports indicated that females are primarily affected, later descriptions have found a higher incidence in males. | Related disorders of Adenoid Cystic Carcinoma. Depending upon the tumor site, some benign (noncancerous) growths may appear similar to primary ACC tumor development. However, ACC typically exhibits additional symptoms that distinguish it from benign growths. Microscopic examination of tumor cells and other diagnostic testing are essential in differentiating between the two.The term “adenoid cystic carcinoma of the esophagus” is used to describe two different, rare forms of cancer. “True” ACC of the esophagus is extremely rare, with only a few cases reported in the medical literature. The more common of the two entities, which is more appropriately termed “basaloid squamous carcinoma,” has been reported in individuals who range in age from approximately 35 to 85 years. Although initial reports indicated that females are primarily affected, later descriptions have found a higher incidence in males. | 36 | Adenoid Cystic Carcinoma |
nord_36_5 | Diagnosis of Adenoid Cystic Carcinoma | The diagnosis of adenoid cystic carcinoma is based upon a thorough clinical evaluation, characteristic symptoms and physical findings, a detailed patient history and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells.Biopsies play a major role in the evaluation and treatment plans of all forms of ACC. A biopsy involves the removal of a small portion of the diseased tissue for examination by a pathologist. Biopsies allow for a diagnosis of ACC, making it a more powerful test compared to other laboratory tests that can only evaluate and measure the disease.In individuals with ACC of the salivary glands, physical examination may reveal the presence of a hard fixed mass, and certain neurologic symptoms, such as facial numbness, weakness or pain due to involvement of particular nerves. In some patients, a diagnostic technique may be performed in which a thin, hollow needle is used to withdraw small samples of tissue from the salivary glands (fine-needle biopsy).Specialized imaging techniques may be used to help evaluate the size, placement and extension of the tumor and to serve as an aid for future surgical procedures in individuals with ACC of the salivary glands or other regions of the head and neck. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. Laboratory tests and specialized imaging tests are performed to determine possible infiltration of regional lymph nodes and the presence of distant metastases.Salivary cancers are hard to diagnose, and careful pathological review of histology combined with analysis of the MYB/MYBL1 genes may be necessary for a correct diagnosis. Identification of fusion between the two transcription factor genes MYB and NFIB may also be associated with ACC and help to confirm the diagnosis.Among individuals with ACC of the lower respiratory tract, such as tracheal ACC, diagnostic testing often includes the use of a flexible instrument, inserted through the mouth or nose that produces an image of the trachea and the air passages of the lungs. During this procedure, biopsy samples are also obtained for microscopic evaluation. In addition, a series of procedures may be performed to evaluate the function of the lungs, particularly among older individuals being considered as surgical candidates.Diagnostic testing for ACC of the larynx may include direct visual examination with a flexible, tube-like instrument (direct laryngoscopy) or indirect observation of the larynx’s interior with a mirror. Small samples of laryngeal tissue are also removed for microscopic examination.In those with ACC of the esophagus, diagnostic testing may include barium x-ray procedures, during which a mixture containing water and a metallic chemical (barium) is swallowed. Because barium is impenetrable by x-rays, subsequent imaging of the digestive tract may help to reveal the nature and extent of the esophageal tumor. Diagnostic procedures may also include endoscopy, during which a flexible, tube-like instrument is used to visualize the esophagus and to obtain biopsy samples. Microscopic evaluation of biopsy samples may help to differentiate between “true ACC” and other forms of esophageal cancer.In females with ACC of the breast, mammograms are typically performed. Fine-needle biopsy, microscopic evaluation of tumor tissue and other laboratory techniques may then be performed to confirm ACC and to help characterize the nature of the malignancy. Some researchers suggest that the diagnosis and initial treatment of ACC of the breast should include surgical removal and microscopic evaluation of the malignancy. Unlike with many other forms of breast cancer, routine sampling of regional lymph nodes during initial surgery may be of questionable value, since involvement of regional lymph nodes is thought to be extremely rare with ACC of the breast.In females with cervical ACC, diagnostic testing may include specialized tests to detect abnormal cellular changes in the cervix (cervical smear test), examination of the cervix with a magnifying instrument (colposcopy) and biopsy.In males with ACC of the prostate gland, clinical examination of the prostate may reveal the presence of a hard mass. Diagnostic testing may include blood studies, specialized imaging of the urinary tract (pyelography), the use of high-frequency sound waves to create an image of the prostate and other internal organs (ultrasonography), biopsies and/or other tests.When diagnosing ACC of the skin, it is important to eliminate the possible diagnosis of other skin cancers such as basal cell carcinoma (BCC) and primary cutaneous cribriform apocrine carcinoma (PCCAC). Metastasis to the skin from primary ACC in another organ must also be ruled out. | Diagnosis of Adenoid Cystic Carcinoma. The diagnosis of adenoid cystic carcinoma is based upon a thorough clinical evaluation, characteristic symptoms and physical findings, a detailed patient history and a variety of specialized tests. Such testing includes microscopic evaluation of tumor cells.Biopsies play a major role in the evaluation and treatment plans of all forms of ACC. A biopsy involves the removal of a small portion of the diseased tissue for examination by a pathologist. Biopsies allow for a diagnosis of ACC, making it a more powerful test compared to other laboratory tests that can only evaluate and measure the disease.In individuals with ACC of the salivary glands, physical examination may reveal the presence of a hard fixed mass, and certain neurologic symptoms, such as facial numbness, weakness or pain due to involvement of particular nerves. In some patients, a diagnostic technique may be performed in which a thin, hollow needle is used to withdraw small samples of tissue from the salivary glands (fine-needle biopsy).Specialized imaging techniques may be used to help evaluate the size, placement and extension of the tumor and to serve as an aid for future surgical procedures in individuals with ACC of the salivary glands or other regions of the head and neck. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. Laboratory tests and specialized imaging tests are performed to determine possible infiltration of regional lymph nodes and the presence of distant metastases.Salivary cancers are hard to diagnose, and careful pathological review of histology combined with analysis of the MYB/MYBL1 genes may be necessary for a correct diagnosis. Identification of fusion between the two transcription factor genes MYB and NFIB may also be associated with ACC and help to confirm the diagnosis.Among individuals with ACC of the lower respiratory tract, such as tracheal ACC, diagnostic testing often includes the use of a flexible instrument, inserted through the mouth or nose that produces an image of the trachea and the air passages of the lungs. During this procedure, biopsy samples are also obtained for microscopic evaluation. In addition, a series of procedures may be performed to evaluate the function of the lungs, particularly among older individuals being considered as surgical candidates.Diagnostic testing for ACC of the larynx may include direct visual examination with a flexible, tube-like instrument (direct laryngoscopy) or indirect observation of the larynx’s interior with a mirror. Small samples of laryngeal tissue are also removed for microscopic examination.In those with ACC of the esophagus, diagnostic testing may include barium x-ray procedures, during which a mixture containing water and a metallic chemical (barium) is swallowed. Because barium is impenetrable by x-rays, subsequent imaging of the digestive tract may help to reveal the nature and extent of the esophageal tumor. Diagnostic procedures may also include endoscopy, during which a flexible, tube-like instrument is used to visualize the esophagus and to obtain biopsy samples. Microscopic evaluation of biopsy samples may help to differentiate between “true ACC” and other forms of esophageal cancer.In females with ACC of the breast, mammograms are typically performed. Fine-needle biopsy, microscopic evaluation of tumor tissue and other laboratory techniques may then be performed to confirm ACC and to help characterize the nature of the malignancy. Some researchers suggest that the diagnosis and initial treatment of ACC of the breast should include surgical removal and microscopic evaluation of the malignancy. Unlike with many other forms of breast cancer, routine sampling of regional lymph nodes during initial surgery may be of questionable value, since involvement of regional lymph nodes is thought to be extremely rare with ACC of the breast.In females with cervical ACC, diagnostic testing may include specialized tests to detect abnormal cellular changes in the cervix (cervical smear test), examination of the cervix with a magnifying instrument (colposcopy) and biopsy.In males with ACC of the prostate gland, clinical examination of the prostate may reveal the presence of a hard mass. Diagnostic testing may include blood studies, specialized imaging of the urinary tract (pyelography), the use of high-frequency sound waves to create an image of the prostate and other internal organs (ultrasonography), biopsies and/or other tests.When diagnosing ACC of the skin, it is important to eliminate the possible diagnosis of other skin cancers such as basal cell carcinoma (BCC) and primary cutaneous cribriform apocrine carcinoma (PCCAC). Metastasis to the skin from primary ACC in another organ must also be ruled out. | 36 | Adenoid Cystic Carcinoma |
nord_36_6 | Therapies of Adenoid Cystic Carcinoma | Treatment
The therapeutic management of individuals with ACC may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses and other specialists (depending upon the primary tumor site).For many individuals with ACC, standard therapy includes surgical removal of the primary tumor and affected tissue followed by radiation and in some patients, chemotherapy. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. Various types of radiation may be used, depending on cancer type, location, stage and grade, prior treatments, etc.–including conventional external radiotherapy (e.g., standard photon and/or electron treatments) and/or, in some selected cases, neutron radiation.ACC tumors usually are resistant to chemotherapy with only a small proportion deriving significant or sustained benefits. Systemic therapy including chemotherapy has not been approved by the U.S. Food and Drug Administration for the treatment of ACC. However, patients with ACC who have progressive disease may be eligible to participate in a clinical trial of a specific drug therapy or may consider use of multi-targeted tyrosine kinase inhibitors as suggested by recent clinical guidelines set forth by ASCO and NCCN (See Clinical Trials section below).Tumor profiling (molecular analysis of alterations in DNA, RNA and proteins) is becoming increasingly important in helping physician researchers to select the best systemic therapy. Approximately 15-25% of recurrent/metastatic ACC patients have tumors with variants in the NOTCH pathway (primarily in the NOTCH1 gene) that tend to be more aggressive. These patients may want to consider participating in a clinical trial of a NOTCH inhibitor.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade), whether the tumor has spread to lymph nodes or distant sites, individual’s age and general health and/or other factors. Decisions concerning the use of particular interventions are made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference and other appropriate factors.Long-term follow-up is essential with ACC in ensuring the prompt detection and treatment of local recurrences and metastatic disease. Because the lungs are a common location of metastasis, physicians recommend regular CT scans of the lungs. Other standard therapies for individuals with ACC include symptomatic and supportive measures as required. | Therapies of Adenoid Cystic Carcinoma. Treatment
The therapeutic management of individuals with ACC may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses and other specialists (depending upon the primary tumor site).For many individuals with ACC, standard therapy includes surgical removal of the primary tumor and affected tissue followed by radiation and in some patients, chemotherapy. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. Various types of radiation may be used, depending on cancer type, location, stage and grade, prior treatments, etc.–including conventional external radiotherapy (e.g., standard photon and/or electron treatments) and/or, in some selected cases, neutron radiation.ACC tumors usually are resistant to chemotherapy with only a small proportion deriving significant or sustained benefits. Systemic therapy including chemotherapy has not been approved by the U.S. Food and Drug Administration for the treatment of ACC. However, patients with ACC who have progressive disease may be eligible to participate in a clinical trial of a specific drug therapy or may consider use of multi-targeted tyrosine kinase inhibitors as suggested by recent clinical guidelines set forth by ASCO and NCCN (See Clinical Trials section below).Tumor profiling (molecular analysis of alterations in DNA, RNA and proteins) is becoming increasingly important in helping physician researchers to select the best systemic therapy. Approximately 15-25% of recurrent/metastatic ACC patients have tumors with variants in the NOTCH pathway (primarily in the NOTCH1 gene) that tend to be more aggressive. These patients may want to consider participating in a clinical trial of a NOTCH inhibitor.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade), whether the tumor has spread to lymph nodes or distant sites, individual’s age and general health and/or other factors. Decisions concerning the use of particular interventions are made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference and other appropriate factors.Long-term follow-up is essential with ACC in ensuring the prompt detection and treatment of local recurrences and metastatic disease. Because the lungs are a common location of metastasis, physicians recommend regular CT scans of the lungs. Other standard therapies for individuals with ACC include symptomatic and supportive measures as required. | 36 | Adenoid Cystic Carcinoma |
nord_37_0 | Overview of Adenylosuccinate Lyase Deficiency | SummaryAdenylosuccinate lyase deficiency is an inherited metabolic disorder that is characterized into three categories (fatal neonatal form, type I and type II), each of which has a specific age of onset and severity of symptoms. Individuals with this disorder may have symptoms such as slowing of thought and physical movement, seizures, muscle weakness and may exhibit behaviors associated with autism. This syndrome has been diagnosed in individuals around the world and its incidence is not yet known.IntroductionAdenylosuccinate lyase deficiency (ASLD) is a rare, inherited metabolic disorder caused by a genetic change which lowers the effectiveness of the enzyme adenylosuccinate lyase (ASL). The disorder causes the buildup of two chemicals in body fluids (such as cerebrospinal fluid, plasma, and urine) that aren’t normally seen in healthy individuals. These two chemicals are succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine. The symptoms and the physical findings associated with ASLD vary greatly from person to person. People with ASLD can have a mix of neurological symptoms such as:Differences in body structure that are specifically related to this disorder (dysmorphic features) are not common. However, when they do occur, they are usually subtle and may include slowed growth, skull differences such as a small head circumference (microcephaly) or flattened back of the head (flat occiput), occasional deviation of the eye (intermittent divergent strabismus), small nose with anteverted nostrils, long and smooth philtrum, thin upper lip and low set ears.Adenylosuccinate lyase deficiency is categorized as a purine biosynthesis disorder. Purines are nucleotides that play vital roles in the cells, particularly in the process of building up or breaking down complex chemicals (intermediary metabolism) and in providing energy for cellular activity (energy-transforming reactions). Purines also serve as building blocks of nucleic acids and thus participate in molecular mechanisms by which genetic information is stored. Biosynthesis is how an organism makes different molecules and is often used to describe the synthesis of molecules that are particularly important for the organism to survive. ASLD changes the body’s ability to make these important purines. Researchers are still debating how these genetic and molecular mechanisms cause the symptoms seen in people with ASLD. | Overview of Adenylosuccinate Lyase Deficiency. SummaryAdenylosuccinate lyase deficiency is an inherited metabolic disorder that is characterized into three categories (fatal neonatal form, type I and type II), each of which has a specific age of onset and severity of symptoms. Individuals with this disorder may have symptoms such as slowing of thought and physical movement, seizures, muscle weakness and may exhibit behaviors associated with autism. This syndrome has been diagnosed in individuals around the world and its incidence is not yet known.IntroductionAdenylosuccinate lyase deficiency (ASLD) is a rare, inherited metabolic disorder caused by a genetic change which lowers the effectiveness of the enzyme adenylosuccinate lyase (ASL). The disorder causes the buildup of two chemicals in body fluids (such as cerebrospinal fluid, plasma, and urine) that aren’t normally seen in healthy individuals. These two chemicals are succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine. The symptoms and the physical findings associated with ASLD vary greatly from person to person. People with ASLD can have a mix of neurological symptoms such as:Differences in body structure that are specifically related to this disorder (dysmorphic features) are not common. However, when they do occur, they are usually subtle and may include slowed growth, skull differences such as a small head circumference (microcephaly) or flattened back of the head (flat occiput), occasional deviation of the eye (intermittent divergent strabismus), small nose with anteverted nostrils, long and smooth philtrum, thin upper lip and low set ears.Adenylosuccinate lyase deficiency is categorized as a purine biosynthesis disorder. Purines are nucleotides that play vital roles in the cells, particularly in the process of building up or breaking down complex chemicals (intermediary metabolism) and in providing energy for cellular activity (energy-transforming reactions). Purines also serve as building blocks of nucleic acids and thus participate in molecular mechanisms by which genetic information is stored. Biosynthesis is how an organism makes different molecules and is often used to describe the synthesis of molecules that are particularly important for the organism to survive. ASLD changes the body’s ability to make these important purines. Researchers are still debating how these genetic and molecular mechanisms cause the symptoms seen in people with ASLD. | 37 | Adenylosuccinate Lyase Deficiency |
nord_37_1 | Symptoms of Adenylosuccinate Lyase Deficiency | Three categories of adenylosuccinate lyase deficiency have been recognized. The first is the fatal neonatal form, where babies have encephalopathy with lack of spontaneous movement, respiratory failure and intractable seizures. There may be some prenatal indications such as the fetus being small in size (IUGR), having a small head (microcephaly), a low level of fetal movement (hypokinesia) and a loss of fetal heart rate variability. Adenylosuccinate lyase deficiency type I (ASLD-I), the severe childhood form, is only associated with neurological differences. These may include severe slowing of thought and movement (psychomotor impairment), epilepsy, low muscle tone in the trunk of the body (axial hypotonia) with normal tendon reflexes and features associated with autism including absent or poor eye contact, stereotypies, tantrums, agitation and a tendency toward turning aggression onto oneself. Patients with type II adenylosuccinate lyase deficiency (ASLD-II) have mild to moderate clinical features in comparison. They may have slight to moderate psychomotor impairment, show temporary changes in hearing and vision (transient auditory and visual contact disturbance), but do not have epilepsy. | Symptoms of Adenylosuccinate Lyase Deficiency. Three categories of adenylosuccinate lyase deficiency have been recognized. The first is the fatal neonatal form, where babies have encephalopathy with lack of spontaneous movement, respiratory failure and intractable seizures. There may be some prenatal indications such as the fetus being small in size (IUGR), having a small head (microcephaly), a low level of fetal movement (hypokinesia) and a loss of fetal heart rate variability. Adenylosuccinate lyase deficiency type I (ASLD-I), the severe childhood form, is only associated with neurological differences. These may include severe slowing of thought and movement (psychomotor impairment), epilepsy, low muscle tone in the trunk of the body (axial hypotonia) with normal tendon reflexes and features associated with autism including absent or poor eye contact, stereotypies, tantrums, agitation and a tendency toward turning aggression onto oneself. Patients with type II adenylosuccinate lyase deficiency (ASLD-II) have mild to moderate clinical features in comparison. They may have slight to moderate psychomotor impairment, show temporary changes in hearing and vision (transient auditory and visual contact disturbance), but do not have epilepsy. | 37 | Adenylosuccinate Lyase Deficiency |
nord_37_2 | Causes of Adenylosuccinate Lyase Deficiency | Adenylosuccinate lyase deficiency (ASLD) is a type of metabolic disorder. Metabolism is the process in which organisms take in various organic materials, use them to build cellular structures and for energy, and expel any waste products. Adenylosuccinate lyase is important in the production of purines (guanine and adenine), which are molecules that are important for the structure of genetic information and in providing sources of energy. ASLD is caused when the enzyme adenylosuccinate lyase is less functional than normal. In particular, adenylosuccinate lyase normally converts succinylaminoimidazole carboxamide ribotide into aminoimidazole carbozamide ribotide in this purine pathway. When adenylosuccinate lyase is not functioning well, succinylaminoimidazole carbozamide ribotide gets converted into succinylaminoimidazole carbozamide riboside. Further down in this pathway, adenylosuccinate lyase also converts adenylosuccinate into adenine monophosphate. When adenosyccinate lyase is not functioning well, adenylosuccinate gets converted into succinyladenosine. Therefore, in individuals in whom adenylosuccinate lyase is not functioning well, doctors can detect two compounds in body fluids that are normally undetectable: aminoimidazole carbozamide riboside and succinyladenosine. These compounds can be found in different fluids in the body including in plasma (a component of blood) and in cerebral spinal fluid (the fluid that surrounds the nerves in our spine). ASLD is an autosomal recessive genetic disorder. Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. | Causes of Adenylosuccinate Lyase Deficiency. Adenylosuccinate lyase deficiency (ASLD) is a type of metabolic disorder. Metabolism is the process in which organisms take in various organic materials, use them to build cellular structures and for energy, and expel any waste products. Adenylosuccinate lyase is important in the production of purines (guanine and adenine), which are molecules that are important for the structure of genetic information and in providing sources of energy. ASLD is caused when the enzyme adenylosuccinate lyase is less functional than normal. In particular, adenylosuccinate lyase normally converts succinylaminoimidazole carboxamide ribotide into aminoimidazole carbozamide ribotide in this purine pathway. When adenylosuccinate lyase is not functioning well, succinylaminoimidazole carbozamide ribotide gets converted into succinylaminoimidazole carbozamide riboside. Further down in this pathway, adenylosuccinate lyase also converts adenylosuccinate into adenine monophosphate. When adenosyccinate lyase is not functioning well, adenylosuccinate gets converted into succinyladenosine. Therefore, in individuals in whom adenylosuccinate lyase is not functioning well, doctors can detect two compounds in body fluids that are normally undetectable: aminoimidazole carbozamide riboside and succinyladenosine. These compounds can be found in different fluids in the body including in plasma (a component of blood) and in cerebral spinal fluid (the fluid that surrounds the nerves in our spine). ASLD is an autosomal recessive genetic disorder. Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. | 37 | Adenylosuccinate Lyase Deficiency |
nord_37_3 | Affects of Adenylosuccinate Lyase Deficiency | All forms of adenylosuccinate lyase deficiency affect males and females in equal numbers. The age of onset and frequency is different between the different types. People with the fatal neonatal form and type I begin showing symptoms within the first few months of life. In type II, people begin showing symptoms within the first few years of life. Of known cases of ASLD, 5-10% of cases are the neonatal form, 70-80% are type I, and 15-20% are type II (Donti, 2016).ASLD has been diagnosed in individuals from a number of countries (Australia, Belgium, Czech Republic, Colombia, Italy, France, Germany, Malaysia, Morocco, Netherlands, Norway, Poland, Portugal, Spain, Turkey, United Kingdom and the United States of America). The majority of individuals with this condition are in Belgium and Netherlands. | Affects of Adenylosuccinate Lyase Deficiency. All forms of adenylosuccinate lyase deficiency affect males and females in equal numbers. The age of onset and frequency is different between the different types. People with the fatal neonatal form and type I begin showing symptoms within the first few months of life. In type II, people begin showing symptoms within the first few years of life. Of known cases of ASLD, 5-10% of cases are the neonatal form, 70-80% are type I, and 15-20% are type II (Donti, 2016).ASLD has been diagnosed in individuals from a number of countries (Australia, Belgium, Czech Republic, Colombia, Italy, France, Germany, Malaysia, Morocco, Netherlands, Norway, Poland, Portugal, Spain, Turkey, United Kingdom and the United States of America). The majority of individuals with this condition are in Belgium and Netherlands. | 37 | Adenylosuccinate Lyase Deficiency |
nord_37_4 | Related disorders of Adenylosuccinate Lyase Deficiency | Related disorders of Adenylosuccinate Lyase Deficiency. | 37 | Adenylosuccinate Lyase Deficiency |
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nord_37_5 | Diagnosis of Adenylosuccinate Lyase Deficiency | A diagnosis of adenylosuccinate lyase deficiency should be considered in infants with seizures, delayed milestones, muscle weakness and/or autistic features. The diagnosis is based on elevated levels of two compounds in body fluids such as plasma, urine and cerebrospinal fluid (the fluid that surrounds the spinal nerves). These two compounds are called succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine, and they are not usually detectable in these fluids. Sequencing of the ADSL gene can identify the disease-causing genetic change (pathogenic variant).For families where both parents are known to be carriers of adenylosuccinate lyase deficiency, prenatal diagnosis can be performed via chorionic villus sampling or amniotic fluid sampling. These two tests occur during pregnancy where a doctor uses an ultrasound to guide a needle and extract cells from either the placenta or from the fluid surrounding the fetus. These cells can be analyzed using molecular analysis of the ADSL gene. | Diagnosis of Adenylosuccinate Lyase Deficiency. A diagnosis of adenylosuccinate lyase deficiency should be considered in infants with seizures, delayed milestones, muscle weakness and/or autistic features. The diagnosis is based on elevated levels of two compounds in body fluids such as plasma, urine and cerebrospinal fluid (the fluid that surrounds the spinal nerves). These two compounds are called succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine, and they are not usually detectable in these fluids. Sequencing of the ADSL gene can identify the disease-causing genetic change (pathogenic variant).For families where both parents are known to be carriers of adenylosuccinate lyase deficiency, prenatal diagnosis can be performed via chorionic villus sampling or amniotic fluid sampling. These two tests occur during pregnancy where a doctor uses an ultrasound to guide a needle and extract cells from either the placenta or from the fluid surrounding the fetus. These cells can be analyzed using molecular analysis of the ADSL gene. | 37 | Adenylosuccinate Lyase Deficiency |
nord_37_6 | Therapies of Adenylosuccinate Lyase Deficiency | Treatment Current treatments are available to control seizures, although drug resistance can occur. Studies have been done to identify treatments specific for ASLD (such as D-ribose, uridine and S-adenosyl-1-methionine), but these experimental treatments have not been proven to be beneficial. | Therapies of Adenylosuccinate Lyase Deficiency. Treatment Current treatments are available to control seizures, although drug resistance can occur. Studies have been done to identify treatments specific for ASLD (such as D-ribose, uridine and S-adenosyl-1-methionine), but these experimental treatments have not been proven to be beneficial. | 37 | Adenylosuccinate Lyase Deficiency |
nord_38_0 | Overview of Adie Syndrome | Adie syndrome, or Holmes-Adie syndrome, is a rare neurological disorder affecting the pupil of the eye. In most patients the pupil is larger than normal (dilated) and slow to react in response to direct light. Absent or poor tendon reflexes are also associated with this disorder. In most individuals, the cause is unknown (idiopathic), but Adie syndrome can occur as due to other conditions such as trauma, surgery, lack of blood flow (ischemia) or infection. In rare cases localized disturbance of sweat secretion is associated with Adie syndrome (Ross syndrome). Adie syndrome involves a usually non progressive and limited damage to the autonomic nervous system, which is the portion of the nervous system that controls or regulates certain involuntary body functions including the reaction of the pupils to stimuli.The term Adie syndrome is used when both abnormalities of the pupil and loss of deep tendon reflexes are present. However, these findings may not develop at the same time. When only abnormalities affecting the pupil are present, the disorder may be referred to as Adie’s pupil, Adie’s tonic pupil or, most commonly, tonic pupil. When a person’s pupils are of unequal size, the term anisocoria may be used. | Overview of Adie Syndrome. Adie syndrome, or Holmes-Adie syndrome, is a rare neurological disorder affecting the pupil of the eye. In most patients the pupil is larger than normal (dilated) and slow to react in response to direct light. Absent or poor tendon reflexes are also associated with this disorder. In most individuals, the cause is unknown (idiopathic), but Adie syndrome can occur as due to other conditions such as trauma, surgery, lack of blood flow (ischemia) or infection. In rare cases localized disturbance of sweat secretion is associated with Adie syndrome (Ross syndrome). Adie syndrome involves a usually non progressive and limited damage to the autonomic nervous system, which is the portion of the nervous system that controls or regulates certain involuntary body functions including the reaction of the pupils to stimuli.The term Adie syndrome is used when both abnormalities of the pupil and loss of deep tendon reflexes are present. However, these findings may not develop at the same time. When only abnormalities affecting the pupil are present, the disorder may be referred to as Adie’s pupil, Adie’s tonic pupil or, most commonly, tonic pupil. When a person’s pupils are of unequal size, the term anisocoria may be used. | 38 | Adie Syndrome |
nord_38_1 | Symptoms of Adie Syndrome | Normally the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited. In most patients with Adie syndrome the affected pupil is larger than normal (dilated) all the time and does not constrict very much or not at all in response to direct light. In many cases it is not ideally round but slightly ovally distorted. The pupil will constrict slowly when focusing (=accommodating) on objects close at hand (normally referred to as near response). If the pupil is observed with a loupe or microscope a typical behavior can be observed both spontaneously or during near response: Some sectors of the sphincter muscles constrict and others don’t. This reminds of the movement of an earthworm. Eventually, after months or years, the pupil, which was initially larger than the unaffected pupil, will become smaller than the unaffected pupil. When no longer focusing on the close at hand object, the affected pupil may remain smaller than normal or grow larger (re-dilate) at an abnormally slow rate, sometimes taking as long as several minutes to return to its original (i.e. dilated) size. Some individuals may not have symptoms associated with the affected pupil. Sometimes blurry vision or sensitivity to bright lights (photophobia) can occur. Individuals with Adie syndrome have absent or poor (sluggish) deep tendon reflexes as well. Deep tendon reflexes are involuntary muscle contractions that occur to a sudden stimulus. For example, the patellar reflex occurs in the area just below the kneecap (patella). A physician may tap this area with a small rubber hammer, which should cause the lower leg to kick out; in individuals with Adie syndrome this reflex response is poor or does not occur. Headache, facial pain, or emotional fluctuations may occur in some patients. The disorder does not ordinarily cause severe disability. Adie syndrome usually affects the pupil of one eye, although the other eye may eventually become affected as well. There have been some reports in the medical literature that individuals with Adie syndrome may experience other abilities of autonomic function such as issues with cardiovascular function. | Symptoms of Adie Syndrome. Normally the pupil gets smaller (constricts) in the presence of light or when focusing on nearby objects. The pupil normally opens wider (dilates) in dim light or darkness, when focusing on far away objects, or when a person is excited. In most patients with Adie syndrome the affected pupil is larger than normal (dilated) all the time and does not constrict very much or not at all in response to direct light. In many cases it is not ideally round but slightly ovally distorted. The pupil will constrict slowly when focusing (=accommodating) on objects close at hand (normally referred to as near response). If the pupil is observed with a loupe or microscope a typical behavior can be observed both spontaneously or during near response: Some sectors of the sphincter muscles constrict and others don’t. This reminds of the movement of an earthworm. Eventually, after months or years, the pupil, which was initially larger than the unaffected pupil, will become smaller than the unaffected pupil. When no longer focusing on the close at hand object, the affected pupil may remain smaller than normal or grow larger (re-dilate) at an abnormally slow rate, sometimes taking as long as several minutes to return to its original (i.e. dilated) size. Some individuals may not have symptoms associated with the affected pupil. Sometimes blurry vision or sensitivity to bright lights (photophobia) can occur. Individuals with Adie syndrome have absent or poor (sluggish) deep tendon reflexes as well. Deep tendon reflexes are involuntary muscle contractions that occur to a sudden stimulus. For example, the patellar reflex occurs in the area just below the kneecap (patella). A physician may tap this area with a small rubber hammer, which should cause the lower leg to kick out; in individuals with Adie syndrome this reflex response is poor or does not occur. Headache, facial pain, or emotional fluctuations may occur in some patients. The disorder does not ordinarily cause severe disability. Adie syndrome usually affects the pupil of one eye, although the other eye may eventually become affected as well. There have been some reports in the medical literature that individuals with Adie syndrome may experience other abilities of autonomic function such as issues with cardiovascular function. | 38 | Adie Syndrome |
nord_38_2 | Causes of Adie Syndrome | In most instances, the exact cause of Adie syndrome is unknown (idiopathic). It is believed that most cases result from inflammation or damage to the ciliary ganglion, a cluster of nerve cells found in the eye socket (orbit) just behind the eyes, or damage to the post-ganglionic nerves. The ciliary ganglion is part of the parasympathetic nervous system, which is itself part of the autonomic nervous system. The parasympathetic nervous system relaxes the body and inhibits or slows down high energy functions. The ciliary ganglion supplies nerves (innervates) to the eye. These nerves carry signals that help to control the pupil’s response to stimuli such as growing smaller or larger in response to light, dark or other stimuli. These nerves communicate with the iris sphincter muscle, the muscle that controls how much light enters the pupil (causing the pupil to either contract or grow larger). However, most of the cells of the ciliary ganglion (97%) serve accommodation and supply the ciliary muscle which adjusts the crystalline lens of the eye to near vision.In Adie syndrome, both these nerve cells are damaged. Because there are so many nerve cells serving accommodation usually a sufficient amount survive. Therefore, accommodation difficulties are not obvious or less obvious. Eventually, the damaged nerves may regenerate, but some do so improperly (aberrant regeneration). Because the nerve cells serving the pupillary sphincter are very few it is unlikely that many of them regenerate and restore the pupillary light reflex. However, cells that supply the ciliary muscle may regenerate and innervate not only the ciliary muscle but also the pupillary sphincter muscle (aberrant regeneration). This explains why the near response in a tonic pupil is present but slow. It is being elicited by nerve cells that were designed for accommodation, a slower movement than pupillary constriction. In most instances, damage to the ciliary ganglion or the postganglionic nerves is believed to be caused by a viral infection. There is evidence that also autoimmune processes may play a role. Tumor, trauma, and inflammation (especially syphilis) have also been linked to Adie syndrome. The syndrome has also occurred as a complication of surgery to the area of the eye socket. It is also seen in giant cell arteritis, a severe vasculitis of the elderly. There are rare cases where a tonic pupil has occurred as a paraneoplastic disorder, but so far only in patients were the malignant disease already was known.The loss of deep tendon reflexes is believed to be caused by damage to the dorsal root ganglions, a cluster of nerve cells in the root of spinal nerves. | Causes of Adie Syndrome. In most instances, the exact cause of Adie syndrome is unknown (idiopathic). It is believed that most cases result from inflammation or damage to the ciliary ganglion, a cluster of nerve cells found in the eye socket (orbit) just behind the eyes, or damage to the post-ganglionic nerves. The ciliary ganglion is part of the parasympathetic nervous system, which is itself part of the autonomic nervous system. The parasympathetic nervous system relaxes the body and inhibits or slows down high energy functions. The ciliary ganglion supplies nerves (innervates) to the eye. These nerves carry signals that help to control the pupil’s response to stimuli such as growing smaller or larger in response to light, dark or other stimuli. These nerves communicate with the iris sphincter muscle, the muscle that controls how much light enters the pupil (causing the pupil to either contract or grow larger). However, most of the cells of the ciliary ganglion (97%) serve accommodation and supply the ciliary muscle which adjusts the crystalline lens of the eye to near vision.In Adie syndrome, both these nerve cells are damaged. Because there are so many nerve cells serving accommodation usually a sufficient amount survive. Therefore, accommodation difficulties are not obvious or less obvious. Eventually, the damaged nerves may regenerate, but some do so improperly (aberrant regeneration). Because the nerve cells serving the pupillary sphincter are very few it is unlikely that many of them regenerate and restore the pupillary light reflex. However, cells that supply the ciliary muscle may regenerate and innervate not only the ciliary muscle but also the pupillary sphincter muscle (aberrant regeneration). This explains why the near response in a tonic pupil is present but slow. It is being elicited by nerve cells that were designed for accommodation, a slower movement than pupillary constriction. In most instances, damage to the ciliary ganglion or the postganglionic nerves is believed to be caused by a viral infection. There is evidence that also autoimmune processes may play a role. Tumor, trauma, and inflammation (especially syphilis) have also been linked to Adie syndrome. The syndrome has also occurred as a complication of surgery to the area of the eye socket. It is also seen in giant cell arteritis, a severe vasculitis of the elderly. There are rare cases where a tonic pupil has occurred as a paraneoplastic disorder, but so far only in patients were the malignant disease already was known.The loss of deep tendon reflexes is believed to be caused by damage to the dorsal root ganglions, a cluster of nerve cells in the root of spinal nerves. | 38 | Adie Syndrome |
nord_38_3 | Affects of Adie Syndrome | Adie syndrome affects females more often than males by a ratio by some estimates of 2.6:1 for cases where the cause is unknown. Young adults usually between the ages of 25 to 45 are most commonly affected. The prevalence of Adie’s pupil (not the full syndrome) is approximately 2 people per 1,000 in the general population. The exact incidence or prevalence of Adie syndrome itself is unknown. | Affects of Adie Syndrome. Adie syndrome affects females more often than males by a ratio by some estimates of 2.6:1 for cases where the cause is unknown. Young adults usually between the ages of 25 to 45 are most commonly affected. The prevalence of Adie’s pupil (not the full syndrome) is approximately 2 people per 1,000 in the general population. The exact incidence or prevalence of Adie syndrome itself is unknown. | 38 | Adie Syndrome |
nord_38_4 | Related disorders of Adie Syndrome | Symptoms of the following disorders can be similar to those of Adie syndrome. Comparisons may be useful for a differential diagnosis:Ross syndrome is a variant of Adie syndrome in which affected individuals experience an impaired ability to sweat normally (anhidrosis) in association with Adie pupil and loss of deep tendon reflexes. The inability to sweat properly may result in the body attempting to compensate, resulting in certain areas of the body sweating excessively. Affected individuals may experience heat intolerance due to the sweating abnormalities. More than 40 cases of Ross syndrome have been reported in the medical literature. The exact underlying cause of this disorder is unknown. Argyll Robertson pupil is a condition in which the pupils are small and constrict poorly to light, but do react to accommodation. Argyll Robertson pupil is most commonly associated with syphilis, but may simply be a long-standing bilateral tonic pupil. Many other conditions can cause the characteristic eye symptoms of Adie syndrome including paralysis of the third facial nerve (third nerve palsy), Guillain-Barre syndrome, Miller-Fisher syndrome, Charcot-Marie-Tooth disease, Parry-Romberg syndrome, diabetes, chronic alcoholism, botulism, sarcoidosis, multiple sclerosis, and multiple system atrophy.
Aside from diseases, many other factors can cause pupil dilation. Certain drugs can cause the pupil to dilate. For example, transdermal scopolamine is a drug for motion sickness which comes in the form of a patch. If a patient accidentally gets the product in his or her eye (e.g., not washing the hands when finished with the kit) this may cause a dilated pupil. Another common cause is contact to plants containing scopolamine such as angels trumpet or jimson weed. Other drugs can cause dilated pupils or a delay in the response of eye muscles to light and darkness.In lesions of the dorsal midbrain a pupil disorder is seen that can be confused with a tonic pupil: Both pupils are slightly dilated, do not or very slowly react to light but to near focusing. However, the near response is in this case prompt and fast, not tonic. Even the re-dilation after near fixation is promptly and fast. Additionally, those patients are not able to perform a fast and correct upward movement of their eyes. | Related disorders of Adie Syndrome. Symptoms of the following disorders can be similar to those of Adie syndrome. Comparisons may be useful for a differential diagnosis:Ross syndrome is a variant of Adie syndrome in which affected individuals experience an impaired ability to sweat normally (anhidrosis) in association with Adie pupil and loss of deep tendon reflexes. The inability to sweat properly may result in the body attempting to compensate, resulting in certain areas of the body sweating excessively. Affected individuals may experience heat intolerance due to the sweating abnormalities. More than 40 cases of Ross syndrome have been reported in the medical literature. The exact underlying cause of this disorder is unknown. Argyll Robertson pupil is a condition in which the pupils are small and constrict poorly to light, but do react to accommodation. Argyll Robertson pupil is most commonly associated with syphilis, but may simply be a long-standing bilateral tonic pupil. Many other conditions can cause the characteristic eye symptoms of Adie syndrome including paralysis of the third facial nerve (third nerve palsy), Guillain-Barre syndrome, Miller-Fisher syndrome, Charcot-Marie-Tooth disease, Parry-Romberg syndrome, diabetes, chronic alcoholism, botulism, sarcoidosis, multiple sclerosis, and multiple system atrophy.
Aside from diseases, many other factors can cause pupil dilation. Certain drugs can cause the pupil to dilate. For example, transdermal scopolamine is a drug for motion sickness which comes in the form of a patch. If a patient accidentally gets the product in his or her eye (e.g., not washing the hands when finished with the kit) this may cause a dilated pupil. Another common cause is contact to plants containing scopolamine such as angels trumpet or jimson weed. Other drugs can cause dilated pupils or a delay in the response of eye muscles to light and darkness.In lesions of the dorsal midbrain a pupil disorder is seen that can be confused with a tonic pupil: Both pupils are slightly dilated, do not or very slowly react to light but to near focusing. However, the near response is in this case prompt and fast, not tonic. Even the re-dilation after near fixation is promptly and fast. Additionally, those patients are not able to perform a fast and correct upward movement of their eyes. | 38 | Adie Syndrome |
nord_38_5 | Diagnosis of Adie Syndrome | A diagnosis of Adie syndrome can be made by a thorough clinical evaluation and a detailed patient history. A complete eye examination by an ophthalmologist is recommended. An eye doctor may use water-downed (diluted) pilocarpine to test the pupil’s reaction. Pilocarpine, given in the form of eye drops, is a drug that causes the pupils to grow smaller (constrict). In individuals with Adie syndrome, the affected pupil, which does not constrict in response to light, will constrict in response to dilute pilocarpine (0.05 – 0.1%) to which a normal pupil would not constrict. If the pupil dilation is caused by contact with scopolamine or atropine, the pupil will not constrict even to higher concentrations (0.5 – 1%) which cause normal pupils to constrict vigorously.In some patients with tonic pupils constriction is observed when the conjunctiva is touched or irritated e.g. when grating onions.
An eye doctor may also compare the size of the affected eye versus the unaffected eye in darkness and light as well as evaluating the response of the pupil when focusing on an object close at hand. An eye doctor may use a slit-lamp, a device that allows an eye doctor examine the eyes under high magnification, to detect segmental paralysis and a flattened border of the pupil so that the pupil appears irregularly-shaped. In some instances, worm-like (vermiform) movements of the iris can be seen under slit-lamp examination. In most cases the pupil seems slightly ‘ovally’ distorted. | Diagnosis of Adie Syndrome. A diagnosis of Adie syndrome can be made by a thorough clinical evaluation and a detailed patient history. A complete eye examination by an ophthalmologist is recommended. An eye doctor may use water-downed (diluted) pilocarpine to test the pupil’s reaction. Pilocarpine, given in the form of eye drops, is a drug that causes the pupils to grow smaller (constrict). In individuals with Adie syndrome, the affected pupil, which does not constrict in response to light, will constrict in response to dilute pilocarpine (0.05 – 0.1%) to which a normal pupil would not constrict. If the pupil dilation is caused by contact with scopolamine or atropine, the pupil will not constrict even to higher concentrations (0.5 – 1%) which cause normal pupils to constrict vigorously.In some patients with tonic pupils constriction is observed when the conjunctiva is touched or irritated e.g. when grating onions.
An eye doctor may also compare the size of the affected eye versus the unaffected eye in darkness and light as well as evaluating the response of the pupil when focusing on an object close at hand. An eye doctor may use a slit-lamp, a device that allows an eye doctor examine the eyes under high magnification, to detect segmental paralysis and a flattened border of the pupil so that the pupil appears irregularly-shaped. In some instances, worm-like (vermiform) movements of the iris can be seen under slit-lamp examination. In most cases the pupil seems slightly ‘ovally’ distorted. | 38 | Adie Syndrome |
nord_38_6 | Therapies of Adie Syndrome | In most instances, treatment will not be necessary. Glasses may be prescribed to correct blurred vision; sunglasses can help individuals with sensitivity to light. Therapy using dilute pilocarpine may improve poor depth perception and relieve glare in some patients. The loss of deep tendon reflexes is permanent. | Therapies of Adie Syndrome. In most instances, treatment will not be necessary. Glasses may be prescribed to correct blurred vision; sunglasses can help individuals with sensitivity to light. Therapy using dilute pilocarpine may improve poor depth perception and relieve glare in some patients. The loss of deep tendon reflexes is permanent. | 38 | Adie Syndrome |
nord_39_0 | Overview of ADNP Syndrome | SummaryADNP syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a neurodevelopmental genetic disorder caused by changes (mutations) in the ADNP gene. These mutations occur spontaneously in the majority (97%) of reported patients, meaning there has been no family history of the disorder (de novo mutations). The hallmark features of the syndrome are intellectual disability, global developmental delays, global motor planning delays and autism spectrum disorder or autistic features. Although ADNP syndrome was only discovered in 2014, it is projected to be one of the most frequent single gene causes of autism.The genetic changes that cause ADNP syndrome vary from person to person. The symptoms can also vary and can cause a wide range of medical, developmental, intellectual and behavioral changes. The most common characteristics found in those with ADNP syndrome are developmental delays (100%), intellectual delays (100%), motor planning delays (96%) of varying degrees, delayed or absent speech (98%) and autism spectrum disorder including autistic features (93%). Autistic features in ADNP syndrome are quite similar and most children display a very happy demeanor similar to Angelman syndrome as infants and toddlers. Feeding and gastrointestinal problems (83%) are also very common. Additional symptoms are low or weak muscle tone in newborns and infants (hypotonia) (78%), neonatal/infant feeding disorders, sensory processing disorder, sleep disorder, high pain threshold and additional symptoms and behavioral disorders of varying levels of severity. The disorder can potentially affect multiple systems of the body including the brain, heart, immune system, gastrointestinal system, endocrine system, and musculoskeletal system. The specific signs and symptoms associated with the disorder can vary greatly from one individual to another but the majority of children exhibit distinctive facial features. Many infants (>80%) develop early primary tooth eruption and often have a happy disposition and unprovoked episodes of laughter and smiling. Parents report that approximately 50% of the children develop breathing irregularities (breath holding episodes) and episodes of developmental regression of speech that is usually regained over time with intensive therapy. | Overview of ADNP Syndrome. SummaryADNP syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a neurodevelopmental genetic disorder caused by changes (mutations) in the ADNP gene. These mutations occur spontaneously in the majority (97%) of reported patients, meaning there has been no family history of the disorder (de novo mutations). The hallmark features of the syndrome are intellectual disability, global developmental delays, global motor planning delays and autism spectrum disorder or autistic features. Although ADNP syndrome was only discovered in 2014, it is projected to be one of the most frequent single gene causes of autism.The genetic changes that cause ADNP syndrome vary from person to person. The symptoms can also vary and can cause a wide range of medical, developmental, intellectual and behavioral changes. The most common characteristics found in those with ADNP syndrome are developmental delays (100%), intellectual delays (100%), motor planning delays (96%) of varying degrees, delayed or absent speech (98%) and autism spectrum disorder including autistic features (93%). Autistic features in ADNP syndrome are quite similar and most children display a very happy demeanor similar to Angelman syndrome as infants and toddlers. Feeding and gastrointestinal problems (83%) are also very common. Additional symptoms are low or weak muscle tone in newborns and infants (hypotonia) (78%), neonatal/infant feeding disorders, sensory processing disorder, sleep disorder, high pain threshold and additional symptoms and behavioral disorders of varying levels of severity. The disorder can potentially affect multiple systems of the body including the brain, heart, immune system, gastrointestinal system, endocrine system, and musculoskeletal system. The specific signs and symptoms associated with the disorder can vary greatly from one individual to another but the majority of children exhibit distinctive facial features. Many infants (>80%) develop early primary tooth eruption and often have a happy disposition and unprovoked episodes of laughter and smiling. Parents report that approximately 50% of the children develop breathing irregularities (breath holding episodes) and episodes of developmental regression of speech that is usually regained over time with intensive therapy. | 39 | ADNP Syndrome |
nord_39_1 | Symptoms of ADNP Syndrome | Although researchers have established a clear syndromic presentation with characteristic or “core” symptoms associated with pathogenic variants in the ADNP gene, much about the disorder is not fully understood. Several factors have impeded the identification of a complete picture of the associated symptoms and prognosis; these include the small number of identified children, the lack of large clinical studies, and a lack of understanding of moderating effects of genetic background, the presence of additional gene variants, or environmental contributions. Therefore, it is important to note that every child is unique and that affected individuals may not have all of the symptoms discussed below.Many infants (78%) present with hypotonia and, thus, can appear abnormally “floppy.” Cerebral imaging shows structural brain abnormalities in slightly over half of the patient population (56%). Other neurological problems may exist. Individuals with ADNP syndrome may develop seizures (16%). Many parents report absent like seizures as infants along with breath holding episodes. Reported brain abnormalities include wide ventricles (29%), cerebral atrophy (18%), delayed myelination (9%) and white matter lesions (8%). Approximately 50% of children with ADNP syndrome have had one or more episodes of developmental regression of speech.Hypotonia and oral movement problems such as oral motor apraxia and oral motor dyspraxia (oral motor dysfunction) are often seen together in children with ADNP syndrome. This contributes to causing the majority of infants to experience feeding difficulties (83%). Poor sucking or chewing ability may occur in infancy. Swallowing problems may also be seen and there can be a risk of food or drink ending up in the lungs (aspiration). Some children who have difficulties with feeding may benefit from thickened liquids and some may require a feeding tube for nutrition. Missed milestones such as delays in sitting and holding up ones head are seen in infancy and children have mild to severe global developmental delays. Walking independently is often delayed until a few years later in childhood and children may have an unusual manner of walking (abnormal gait). Most children experience mild to moderate global motor planning delays. As they age, they will exhibit mild to severe intellectual disability. There are often delays in developing speech. Some children may not be able to speak, while others speak a few words or in short sentences. Apraxia or other oral motor disorders specifically affecting the tongue appear to cause the most difficulty in the majority of the non-verbal children. Children with ADNP syndrome in their younger years tend to be easily amused and have a happy demeanor similar to Angleman syndrome. This often delays diagnosis for behavior disorders such as autism even when the child displays many autistic features early in life. Sleep disorders can also occur, including sleep apnea, frequent waking throughout the night as well as early waking. There may be bladder training delays. The majority of affected children may meet the criteria for autism spectrum disorder and may exhibit poor social interaction and mild to severe repetitive (stereotypic) behaviors such as repetitive speech, rocking back and forth, hand flapping, hand clapping, rubbing fingers or snapping fingers (93%).The majority of children with ADNP syndrome seek direct “adult” interaction. Specifically, at a very young age they appear to enjoy direct social interactions with adults and often smile, laugh and make eye contact. This is atypical for autism but it is very typical for ADNP syndrome. This often delays the autism diagnosis even when the child displays many autistic features at a young age. Sensory sensitivities, interests, and aversions (resulting in both seeking and avoiding sensory stimuli) are often seen (67%), with oral sensory seeking behaviors most prevalent. Because of this, children tend to lick their hands or other objects often, chew on non-edible items, gag, and put objects in their mouth. They often have an obsession for music and water play. They also tend to place tablets and other lit objects or devises directly in front of their eyes for stimulation. In addition to autism and sensory sensitivities and aversions, children may have a variety of behavioral issues including attention deficit hyperactivity disorder, obsessive compulsive disorder, temper tantrums and aggression, mood disorders, and anxiety.Children with ADNP syndrome often have a high pain threshold (64%). Many parents report that their child does not seem to feel pain, some reporting fractures with no sign of uncomfortableness or destress. Low perception of pain in conjunction with communication issues can make it difficult for parents to know when their child has pain or an injury.Gastrointestinal symptoms are common. Affected individuals can develop backflow of stomach acids into the esophagus (gastroesophageal reflux). This has been reported as mild to severe. Some children require the placement of a feeding tube due to severe feeding problems. Episodes of chronic constipation and diarrhea are seen in almost all children with ADNP syndrome. Other symptoms include cyclic vomiting, delayed digestion, and irritable or inflammatory bowel conditions.
Some children as they grow past the toddler years have an abnormal increased appetite and have difficulties feeling full (hyperphagia), similar to Prader Willi syndrome. This can lead to excessive weight gain. Some children also develop an abnormally increased desire to drink water. Some affected individuals may have congenital heart defects (38%). Ventricle or atrial septal defect is a common heart defect in ADNP syndrome. Additional congenital heart defects that have been reported in ADNP syndrome include enlargement of the main artery that supplies oxygen-rich blood to the body (aorta), the abnormal location of the aortic arch on the right side of the body instead of the left (right aortic arch), an abnormally rapid heartrate (tachycardia), and mitral valve prolapse. Affected individuals may also have an abnormal opening between the main artery of the lungs (pulmonary artery) and the aorta (patent ductus arteriosus), narrowing (stenosis) of blood vessels of the pulmonary artery system (peripheral pulmonary artery stenosis), or tetralogy of Fallot, a specific combination of heart defects. Affected individuals have distinctive facial features including a prominent forehead, high hairline, droopy eyelids (ptosis), thin upper lip, broad nasal bridge, malformed ears, eyes that are farther apart than normal (hypertelorism), and crossed eyes (strabismus). Affected individuals may see objects that are farther away clearer than they see objects that are close up (farsightedness or hypermetropia). Cortical vision impairment has also been reported in multiple affected children. Some infants experience early eruption of their baby (deciduous or primary) teeth, showing a full set of baby teeth by the first birthday, including molars. To date, this has not been reported in any other known syndrome making it potentially unique to ADNP syndrome. The teeth may be abnormally small, jagged, and discolored. Because of early tooth eruption, some children develop tooth decay as toddlers due to the decrease in enamel. Some affected individuals have underdeveloped (hypoplastic) fingernails and toenails, extra fingers or toes (polydactyly), and abnormally small pinkies that are fixed or ‘locked’ in a bent position (clinodactyly). Certain joints of fingers may be abnormally prominent. Additional symptoms include abnormally loose (lax) joints that have a larger range of motion than normal (hyperlaxity), abnormal sideways curvature of the spine (scoliosis), and recurrent infections, especially upper respiratory and urinary tract. These recurrent infections may indicate an underlying problem with the immune system. Some children exhibit growth delays and will be shorter than expected for their age and gender (short stature). Some children have tended to develop truncal obesity, in which the trunk of the body is affected as opposed to the arms and legs. There have also been reports that some children have difficulty regulating their body temperature and many have cold feet and hands. Parents also report that children spike fevers extremely fast. | Symptoms of ADNP Syndrome. Although researchers have established a clear syndromic presentation with characteristic or “core” symptoms associated with pathogenic variants in the ADNP gene, much about the disorder is not fully understood. Several factors have impeded the identification of a complete picture of the associated symptoms and prognosis; these include the small number of identified children, the lack of large clinical studies, and a lack of understanding of moderating effects of genetic background, the presence of additional gene variants, or environmental contributions. Therefore, it is important to note that every child is unique and that affected individuals may not have all of the symptoms discussed below.Many infants (78%) present with hypotonia and, thus, can appear abnormally “floppy.” Cerebral imaging shows structural brain abnormalities in slightly over half of the patient population (56%). Other neurological problems may exist. Individuals with ADNP syndrome may develop seizures (16%). Many parents report absent like seizures as infants along with breath holding episodes. Reported brain abnormalities include wide ventricles (29%), cerebral atrophy (18%), delayed myelination (9%) and white matter lesions (8%). Approximately 50% of children with ADNP syndrome have had one or more episodes of developmental regression of speech.Hypotonia and oral movement problems such as oral motor apraxia and oral motor dyspraxia (oral motor dysfunction) are often seen together in children with ADNP syndrome. This contributes to causing the majority of infants to experience feeding difficulties (83%). Poor sucking or chewing ability may occur in infancy. Swallowing problems may also be seen and there can be a risk of food or drink ending up in the lungs (aspiration). Some children who have difficulties with feeding may benefit from thickened liquids and some may require a feeding tube for nutrition. Missed milestones such as delays in sitting and holding up ones head are seen in infancy and children have mild to severe global developmental delays. Walking independently is often delayed until a few years later in childhood and children may have an unusual manner of walking (abnormal gait). Most children experience mild to moderate global motor planning delays. As they age, they will exhibit mild to severe intellectual disability. There are often delays in developing speech. Some children may not be able to speak, while others speak a few words or in short sentences. Apraxia or other oral motor disorders specifically affecting the tongue appear to cause the most difficulty in the majority of the non-verbal children. Children with ADNP syndrome in their younger years tend to be easily amused and have a happy demeanor similar to Angleman syndrome. This often delays diagnosis for behavior disorders such as autism even when the child displays many autistic features early in life. Sleep disorders can also occur, including sleep apnea, frequent waking throughout the night as well as early waking. There may be bladder training delays. The majority of affected children may meet the criteria for autism spectrum disorder and may exhibit poor social interaction and mild to severe repetitive (stereotypic) behaviors such as repetitive speech, rocking back and forth, hand flapping, hand clapping, rubbing fingers or snapping fingers (93%).The majority of children with ADNP syndrome seek direct “adult” interaction. Specifically, at a very young age they appear to enjoy direct social interactions with adults and often smile, laugh and make eye contact. This is atypical for autism but it is very typical for ADNP syndrome. This often delays the autism diagnosis even when the child displays many autistic features at a young age. Sensory sensitivities, interests, and aversions (resulting in both seeking and avoiding sensory stimuli) are often seen (67%), with oral sensory seeking behaviors most prevalent. Because of this, children tend to lick their hands or other objects often, chew on non-edible items, gag, and put objects in their mouth. They often have an obsession for music and water play. They also tend to place tablets and other lit objects or devises directly in front of their eyes for stimulation. In addition to autism and sensory sensitivities and aversions, children may have a variety of behavioral issues including attention deficit hyperactivity disorder, obsessive compulsive disorder, temper tantrums and aggression, mood disorders, and anxiety.Children with ADNP syndrome often have a high pain threshold (64%). Many parents report that their child does not seem to feel pain, some reporting fractures with no sign of uncomfortableness or destress. Low perception of pain in conjunction with communication issues can make it difficult for parents to know when their child has pain or an injury.Gastrointestinal symptoms are common. Affected individuals can develop backflow of stomach acids into the esophagus (gastroesophageal reflux). This has been reported as mild to severe. Some children require the placement of a feeding tube due to severe feeding problems. Episodes of chronic constipation and diarrhea are seen in almost all children with ADNP syndrome. Other symptoms include cyclic vomiting, delayed digestion, and irritable or inflammatory bowel conditions.
Some children as they grow past the toddler years have an abnormal increased appetite and have difficulties feeling full (hyperphagia), similar to Prader Willi syndrome. This can lead to excessive weight gain. Some children also develop an abnormally increased desire to drink water. Some affected individuals may have congenital heart defects (38%). Ventricle or atrial septal defect is a common heart defect in ADNP syndrome. Additional congenital heart defects that have been reported in ADNP syndrome include enlargement of the main artery that supplies oxygen-rich blood to the body (aorta), the abnormal location of the aortic arch on the right side of the body instead of the left (right aortic arch), an abnormally rapid heartrate (tachycardia), and mitral valve prolapse. Affected individuals may also have an abnormal opening between the main artery of the lungs (pulmonary artery) and the aorta (patent ductus arteriosus), narrowing (stenosis) of blood vessels of the pulmonary artery system (peripheral pulmonary artery stenosis), or tetralogy of Fallot, a specific combination of heart defects. Affected individuals have distinctive facial features including a prominent forehead, high hairline, droopy eyelids (ptosis), thin upper lip, broad nasal bridge, malformed ears, eyes that are farther apart than normal (hypertelorism), and crossed eyes (strabismus). Affected individuals may see objects that are farther away clearer than they see objects that are close up (farsightedness or hypermetropia). Cortical vision impairment has also been reported in multiple affected children. Some infants experience early eruption of their baby (deciduous or primary) teeth, showing a full set of baby teeth by the first birthday, including molars. To date, this has not been reported in any other known syndrome making it potentially unique to ADNP syndrome. The teeth may be abnormally small, jagged, and discolored. Because of early tooth eruption, some children develop tooth decay as toddlers due to the decrease in enamel. Some affected individuals have underdeveloped (hypoplastic) fingernails and toenails, extra fingers or toes (polydactyly), and abnormally small pinkies that are fixed or ‘locked’ in a bent position (clinodactyly). Certain joints of fingers may be abnormally prominent. Additional symptoms include abnormally loose (lax) joints that have a larger range of motion than normal (hyperlaxity), abnormal sideways curvature of the spine (scoliosis), and recurrent infections, especially upper respiratory and urinary tract. These recurrent infections may indicate an underlying problem with the immune system. Some children exhibit growth delays and will be shorter than expected for their age and gender (short stature). Some children have tended to develop truncal obesity, in which the trunk of the body is affected as opposed to the arms and legs. There have also been reports that some children have difficulty regulating their body temperature and many have cold feet and hands. Parents also report that children spike fevers extremely fast. | 39 | ADNP Syndrome |
nord_39_2 | Causes of ADNP Syndrome | ADNP syndrome is caused by a change (mutation) in the activity-dependent neuroprotective protein (ADNP) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.Researchers have determined that the ADNP gene produces a protein called activity-dependent neuroprotective protein that helps to regulate as many as 400 other genes in the body. These genes and the proteins they produce are extremely important for the proper development and maturation of the brain and other organs. Collectively, they are involved with almost every system of the body. ADNP syndrome occurs most frequently as a new (sporadic or de novo) mutation, which means that in most reported patients, the gene mutation has occurred at the time of the formation of the egg or sperm/during embryonic development for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent; however, several hereditary cases have been reported, in most instances when the mutation is at the end of the protein, probably resulting in a very mild presentation of symptoms. If a person with ADNP syndrome were to have a child, they could pass the altered ADNP gene on to their children through autosomal dominant inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary for the appearance of the disease. The mutated gene encoding a dysfunctional protein can be inherited from either parent, or can be the result of a new mutation in the affected individual. The risk of passing the mutated gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Investigators have determined that the ADNP gene is located on the long arm (q) of chromosome 20 (20q12). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20q12” refers to band 12 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | Causes of ADNP Syndrome. ADNP syndrome is caused by a change (mutation) in the activity-dependent neuroprotective protein (ADNP) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.Researchers have determined that the ADNP gene produces a protein called activity-dependent neuroprotective protein that helps to regulate as many as 400 other genes in the body. These genes and the proteins they produce are extremely important for the proper development and maturation of the brain and other organs. Collectively, they are involved with almost every system of the body. ADNP syndrome occurs most frequently as a new (sporadic or de novo) mutation, which means that in most reported patients, the gene mutation has occurred at the time of the formation of the egg or sperm/during embryonic development for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent; however, several hereditary cases have been reported, in most instances when the mutation is at the end of the protein, probably resulting in a very mild presentation of symptoms. If a person with ADNP syndrome were to have a child, they could pass the altered ADNP gene on to their children through autosomal dominant inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary for the appearance of the disease. The mutated gene encoding a dysfunctional protein can be inherited from either parent, or can be the result of a new mutation in the affected individual. The risk of passing the mutated gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Investigators have determined that the ADNP gene is located on the long arm (q) of chromosome 20 (20q12). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20q12” refers to band 12 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome. | 39 | ADNP Syndrome |
nord_39_3 | Affects of ADNP Syndrome | ADNP syndrome affects females and males in equal numbers. The exact number of people who have this disorder is unknown. According to one estimate, about 1 in 20,000 people in the general population in the United States and Europe have the disorder. Rare disorders like ADNP syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. ADNP syndrome is believed to account for about .17% of individuals with autism, making it one of the most common, single-gene causes of an autism spectrum disorder. Approximately 205 affected children have been identified worldwide in the medical literature and as reported by the ADNP Kids Research Foundation as of January 2019. | Affects of ADNP Syndrome. ADNP syndrome affects females and males in equal numbers. The exact number of people who have this disorder is unknown. According to one estimate, about 1 in 20,000 people in the general population in the United States and Europe have the disorder. Rare disorders like ADNP syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. ADNP syndrome is believed to account for about .17% of individuals with autism, making it one of the most common, single-gene causes of an autism spectrum disorder. Approximately 205 affected children have been identified worldwide in the medical literature and as reported by the ADNP Kids Research Foundation as of January 2019. | 39 | ADNP Syndrome |
nord_39_4 | Related disorders of ADNP Syndrome | Symptoms of the following disorders can be similar to those of ADNP syndrome. Comparisons may be useful for a differential diagnosis.Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22q13 region or a disease-causing mutation of the SHANK3 gene. Although the range and severity of symptoms may vary, PMS is generally thought to be characterized by neonatal hypotonia, normal growth, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features. Heart defects and autistic behaviors are also common in this disorder. (For more information on this disorder, choose “Phelan-McDermid” as your search term in the Rare Disease Database.)Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Smith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances, and self-injurious or attention-seeking behaviors. The specific symptoms present in each patient can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of chromosome is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by mutations in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. (For more information on this disorder, choose “Smith-Magenis” as your search term in the Rare Disease Database.).Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth. The disorder may be characterized by abnormalities of the head and facial area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes (hypertrichosis); and sparse scalp hair. In addition, affected infants and children typically have short fifth fingers and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes; and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, hypotonia, abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Mutations in five different genes, ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1, have been found to cause CSS. Researchers believe the disease can follow autosomal dominant inheritance in some families,but usually appears to be the result of a new gene mutation in the affected child. (For more information on this disorder, choose “Coffin Siris” as your search term in the Rare Disease Database.)Additional similar rare genetic disorders associated with developmental delays, intellectual disability, seizures, and other symptoms commonly found in individuals with ADNP syndrome include:Rett syndrome
FOXG1 syndrome
FOXP1 syndrome
Fragile X syndrome
Prader-Willi syndrome
Pitt-Hopkins syndrome
Kleefstra syndrome
MECP2 duplication syndrome
CH2D-related neurodevelopmental disorders
15q duplication syndrome. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database. | Related disorders of ADNP Syndrome. Symptoms of the following disorders can be similar to those of ADNP syndrome. Comparisons may be useful for a differential diagnosis.Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22q13 region or a disease-causing mutation of the SHANK3 gene. Although the range and severity of symptoms may vary, PMS is generally thought to be characterized by neonatal hypotonia, normal growth, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features. Heart defects and autistic behaviors are also common in this disorder. (For more information on this disorder, choose “Phelan-McDermid” as your search term in the Rare Disease Database.)Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Smith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances, and self-injurious or attention-seeking behaviors. The specific symptoms present in each patient can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of chromosome is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by mutations in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. (For more information on this disorder, choose “Smith-Magenis” as your search term in the Rare Disease Database.).Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth. The disorder may be characterized by abnormalities of the head and facial area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes (hypertrichosis); and sparse scalp hair. In addition, affected infants and children typically have short fifth fingers and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes; and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, hypotonia, abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Mutations in five different genes, ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1, have been found to cause CSS. Researchers believe the disease can follow autosomal dominant inheritance in some families,but usually appears to be the result of a new gene mutation in the affected child. (For more information on this disorder, choose “Coffin Siris” as your search term in the Rare Disease Database.)Additional similar rare genetic disorders associated with developmental delays, intellectual disability, seizures, and other symptoms commonly found in individuals with ADNP syndrome include:Rett syndrome
FOXG1 syndrome
FOXP1 syndrome
Fragile X syndrome
Prader-Willi syndrome
Pitt-Hopkins syndrome
Kleefstra syndrome
MECP2 duplication syndrome
CH2D-related neurodevelopmental disorders
15q duplication syndrome. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database. | 39 | ADNP Syndrome |
nord_39_5 | Diagnosis of ADNP Syndrome | A diagnosis of ADNP syndrome may be suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Premature tooth eruption and abnormal tooth development when occurring along with developmental delays or intellectual disabilities and autism symptoms can also lead to a suspicion of ADNP syndrome. The diagnosis of ADNP syndrome is confirmed by molecular genetic testing that can detect mutations in the ADNP gene. Testing for mutations in the ADNP gene is included in whole genome sequencing. Clinical Testing and Workup
Imaging techniques such as magnetic resonance imaging (MRI) may be used to aid in a diagnosis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal distinctive changes including atypical white matter lesions, abnormally-wide, fluid-filled cavities called ventricles, and cysts within specific areas of the brain (choroid cysts).These findings alone are not sufficient for a diagnosis of ADNP syndrome. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with the disorder. | Diagnosis of ADNP Syndrome. A diagnosis of ADNP syndrome may be suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Premature tooth eruption and abnormal tooth development when occurring along with developmental delays or intellectual disabilities and autism symptoms can also lead to a suspicion of ADNP syndrome. The diagnosis of ADNP syndrome is confirmed by molecular genetic testing that can detect mutations in the ADNP gene. Testing for mutations in the ADNP gene is included in whole genome sequencing. Clinical Testing and Workup
Imaging techniques such as magnetic resonance imaging (MRI) may be used to aid in a diagnosis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal distinctive changes including atypical white matter lesions, abnormally-wide, fluid-filled cavities called ventricles, and cysts within specific areas of the brain (choroid cysts).These findings alone are not sufficient for a diagnosis of ADNP syndrome. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with the disorder. | 39 | ADNP Syndrome |
nord_39_6 | Therapies of ADNP Syndrome | Treatment
The treatment of ADNP syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children (pediatric neurologists), neurologists, a physician who specializes in the diagnosis and treatment of disorders of the eye (ophthalmologists), a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract (gastroenterologist), a physician who specializes in the diagnosis and treatment of disorders of the heart in children (pediatric cardiologist), speech pathologist, physical therapist, occupational therapist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well.Genetic counseling is recommended for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with ADNP syndrome. Infants with ADNP syndrome should be evaluated for feeding issues treated with standard methods if necessary. Surgery may be necessary to treat certain complications associated with ADNP syndrome including cardiac defects. Eyeglasses or surgery may help with vision and other eye problems. Assistive and augmentative communication devices can help children express thoughts, wants, needs and ideas. Medications may be tried to treat seizures and certain neuropsychiatric conditions including sleep disorders or behavioral problems. Some children with sleep disorders have responded positively to melatonin treatment. Affected children may benefit from occupational, physical, and speech therapy and should be done frequently due to difficulties in learning and motor planning. Some children require daily year round therapy. Water and music therapy have also been beneficial for some affected children. ABA therapy has been beneficial for most affected children with autism. Additional medical, social, and/or vocation services including specialized learning programs may be necessary. Behavioral modification therapy may be useful, especially if self-injurious behavior is present. | Therapies of ADNP Syndrome. Treatment
The treatment of ADNP syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children (pediatric neurologists), neurologists, a physician who specializes in the diagnosis and treatment of disorders of the eye (ophthalmologists), a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract (gastroenterologist), a physician who specializes in the diagnosis and treatment of disorders of the heart in children (pediatric cardiologist), speech pathologist, physical therapist, occupational therapist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well.Genetic counseling is recommended for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with ADNP syndrome. Infants with ADNP syndrome should be evaluated for feeding issues treated with standard methods if necessary. Surgery may be necessary to treat certain complications associated with ADNP syndrome including cardiac defects. Eyeglasses or surgery may help with vision and other eye problems. Assistive and augmentative communication devices can help children express thoughts, wants, needs and ideas. Medications may be tried to treat seizures and certain neuropsychiatric conditions including sleep disorders or behavioral problems. Some children with sleep disorders have responded positively to melatonin treatment. Affected children may benefit from occupational, physical, and speech therapy and should be done frequently due to difficulties in learning and motor planning. Some children require daily year round therapy. Water and music therapy have also been beneficial for some affected children. ABA therapy has been beneficial for most affected children with autism. Additional medical, social, and/or vocation services including specialized learning programs may be necessary. Behavioral modification therapy may be useful, especially if self-injurious behavior is present. | 39 | ADNP Syndrome |
nord_40_0 | Overview of Adult Neuronal Ceroid Lipofuscinosis | SummaryAdult neuronal ceroid lipofuscinosis (ANCL) is a general term for several rare genetic disorders that belong to a group of progressive, degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses (NCLs). These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Onset of ANCL is usually around the age of 30, but these disorders can occur during the teen-aged years or in people more than 50 years old. The NCLs as a group are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body. This is accompanied by progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. ANCL is sometimes called Kufs disease. Historically, Kufs disease was broken down into type A or type B. The ANCLs are caused by changes (mutations) in different genes and can have different signs and symptoms.IntroductionBefore the identification of the underlying genes, the neuronal ceroid lipofuscinoses or NCLs were broken down by age of onset. Kufs disease was the name for the adult onset form. However, many researchers now feel that it is more appropriate to classify these disorders based upon the gene that is affected rather than by age of onset. Several genes that are known to cause neuronal ceroid lipofuscinoses can have the onset of symptoms in adulthood. | Overview of Adult Neuronal Ceroid Lipofuscinosis. SummaryAdult neuronal ceroid lipofuscinosis (ANCL) is a general term for several rare genetic disorders that belong to a group of progressive, degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses (NCLs). These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Onset of ANCL is usually around the age of 30, but these disorders can occur during the teen-aged years or in people more than 50 years old. The NCLs as a group are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body. This is accompanied by progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. ANCL is sometimes called Kufs disease. Historically, Kufs disease was broken down into type A or type B. The ANCLs are caused by changes (mutations) in different genes and can have different signs and symptoms.IntroductionBefore the identification of the underlying genes, the neuronal ceroid lipofuscinoses or NCLs were broken down by age of onset. Kufs disease was the name for the adult onset form. However, many researchers now feel that it is more appropriate to classify these disorders based upon the gene that is affected rather than by age of onset. Several genes that are known to cause neuronal ceroid lipofuscinoses can have the onset of symptoms in adulthood. | 40 | Adult Neuronal Ceroid Lipofuscinosis |
nord_40_1 | Symptoms of Adult Neuronal Ceroid Lipofuscinosis | ANCL or Kufs disease was generally broken down into type A and type B. The signs and symptoms of these two subtypes often overlap and the distinction between the two is not always clear. Symptoms typically become worse over time. Generally, type A is associated with progressive myoclonic epilepsy (PME). PME is a condition characterized by both muscle contractions (myoclonus) and seizures (epilepsy). Some individuals experience difficulties in coordinating voluntary movements (ataxia) or difficulty speaking (dysarthria).Type B often has similar symptoms to type A. However, individuals may also experience abnormalities of movement and coordination including ataxia and involuntary movements such as tics or tremors, including those affecting the face (facial dyskinesia). Some individuals develop a decline in intellectual and cognitive ability (dementia) and changes in behavior and other psychiatric abnormalities. Seizures are rare in type B, but can occur.More recently, disease has been described that begins in adulthood with vision loss but may not have further symptoms. | Symptoms of Adult Neuronal Ceroid Lipofuscinosis. ANCL or Kufs disease was generally broken down into type A and type B. The signs and symptoms of these two subtypes often overlap and the distinction between the two is not always clear. Symptoms typically become worse over time. Generally, type A is associated with progressive myoclonic epilepsy (PME). PME is a condition characterized by both muscle contractions (myoclonus) and seizures (epilepsy). Some individuals experience difficulties in coordinating voluntary movements (ataxia) or difficulty speaking (dysarthria).Type B often has similar symptoms to type A. However, individuals may also experience abnormalities of movement and coordination including ataxia and involuntary movements such as tics or tremors, including those affecting the face (facial dyskinesia). Some individuals develop a decline in intellectual and cognitive ability (dementia) and changes in behavior and other psychiatric abnormalities. Seizures are rare in type B, but can occur.More recently, disease has been described that begins in adulthood with vision loss but may not have further symptoms. | 40 | Adult Neuronal Ceroid Lipofuscinosis |
nord_40_2 | Causes of Adult Neuronal Ceroid Lipofuscinosis | Changes (mutations) in several different genes can cause adult neuronal ceroid lipofuscinosis. These include the CLN6 gene for type A and the CTSF gene for type B. There are also people with adult onset of neuronal ceroid lipofuscinosis due to changes in the PPT1 gene, the CLN5 gene, CTSD gene, and the GRN gene. Adult onset disease that affects vision or the heart has been found to be caused by changes in the CLN3 gene, and the MFSD8 gene. Some very specific changes in the DNAJC5 gene can also cause adult onset neuronal ceroid lipofuscinoses. Most types of ANCL are inherited in an autosomal recessive manner. These types of diseases appear in adults whose parents were not affected by the same disease. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.One type of ANCL caused by specific alterations in the DNAJC5 gene is inherited in an autosomal dominant manner (Parry disease). This type of disease is passed down from an affected adult to their children, who have a 1 in 2 chance of being affected. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The genes that cause ANCL produce proteins. These proteins have specific roles in the body, including breaking down proteins and other substances in the body. When a gene is altered, the protein it produces is deficient, absent or ineffective. The missing or abnormal protein can interfere with the breakdown of certain fatty, granular substances called pigmented lipids (lipopigments: ceroid and lipofuscin). These materials accumulate within nerve cells (neurons) of the brain as well as other tissues of the body and their presence can be used to help obtain a diagnosis. The faulty protein can result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. | Causes of Adult Neuronal Ceroid Lipofuscinosis. Changes (mutations) in several different genes can cause adult neuronal ceroid lipofuscinosis. These include the CLN6 gene for type A and the CTSF gene for type B. There are also people with adult onset of neuronal ceroid lipofuscinosis due to changes in the PPT1 gene, the CLN5 gene, CTSD gene, and the GRN gene. Adult onset disease that affects vision or the heart has been found to be caused by changes in the CLN3 gene, and the MFSD8 gene. Some very specific changes in the DNAJC5 gene can also cause adult onset neuronal ceroid lipofuscinoses. Most types of ANCL are inherited in an autosomal recessive manner. These types of diseases appear in adults whose parents were not affected by the same disease. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.One type of ANCL caused by specific alterations in the DNAJC5 gene is inherited in an autosomal dominant manner (Parry disease). This type of disease is passed down from an affected adult to their children, who have a 1 in 2 chance of being affected. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The genes that cause ANCL produce proteins. These proteins have specific roles in the body, including breaking down proteins and other substances in the body. When a gene is altered, the protein it produces is deficient, absent or ineffective. The missing or abnormal protein can interfere with the breakdown of certain fatty, granular substances called pigmented lipids (lipopigments: ceroid and lipofuscin). These materials accumulate within nerve cells (neurons) of the brain as well as other tissues of the body and their presence can be used to help obtain a diagnosis. The faulty protein can result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. | 40 | Adult Neuronal Ceroid Lipofuscinosis |
nord_40_3 | Affects of Adult Neuronal Ceroid Lipofuscinosis | Adult neuronal ceroid lipofuscinoses are extremely rare disorders. The prevalence is estimated to be about 1.5 people per 9,000,000 in the general population. Prevalence is the total numbers of individuals with a disease at a given time. Studies into the incidence of ANCL have varied based on the country conducting the study. Estimates range from 1.5-7 infants per 100,000 live births. Incidence is the number of new people born with a disorder in a given year. | Affects of Adult Neuronal Ceroid Lipofuscinosis. Adult neuronal ceroid lipofuscinoses are extremely rare disorders. The prevalence is estimated to be about 1.5 people per 9,000,000 in the general population. Prevalence is the total numbers of individuals with a disease at a given time. Studies into the incidence of ANCL have varied based on the country conducting the study. Estimates range from 1.5-7 infants per 100,000 live births. Incidence is the number of new people born with a disorder in a given year. | 40 | Adult Neuronal Ceroid Lipofuscinosis |
nord_40_4 | Related disorders of Adult Neuronal Ceroid Lipofuscinosis | Symptoms of the following disorders can be similar to those of adult neuronal ceroid lipofuscinosis. Comparisons may be useful for a differential diagnosis.Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. There are around 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. Certain lysosomal storage disorders may have late or adult onset of symptoms. These disorders can be confused with ANCL. (For more information on these disorders, choose “lysosomal storage diseases” as your search term in the Rare Disease Database.)Additional disorders that may need to be distinguished from ANCL include the progressive myoclonic epilepsies such as Lafora disease or Unverricht-Lundborg disease, early-onset dementias, Creutzfeldt-Jakob disease, mitochondrial disorders such as MERRF syndrome, and Ramsay-Hunt syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Adult Neuronal Ceroid Lipofuscinosis. Symptoms of the following disorders can be similar to those of adult neuronal ceroid lipofuscinosis. Comparisons may be useful for a differential diagnosis.Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. There are around 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases. Certain lysosomal storage disorders may have late or adult onset of symptoms. These disorders can be confused with ANCL. (For more information on these disorders, choose “lysosomal storage diseases” as your search term in the Rare Disease Database.)Additional disorders that may need to be distinguished from ANCL include the progressive myoclonic epilepsies such as Lafora disease or Unverricht-Lundborg disease, early-onset dementias, Creutzfeldt-Jakob disease, mitochondrial disorders such as MERRF syndrome, and Ramsay-Hunt syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 40 | Adult Neuronal Ceroid Lipofuscinosis |
nord_40_5 | Diagnosis of Adult Neuronal Ceroid Lipofuscinosis | A diagnosis of adult neuronal ceroid lipofuscinosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The tests used may be different based on the specific subtype of ANCL. These tests can include enzyme assays, the study of affected tissue under an electron microscope, and molecular genetic testing to identify changes in genes that can cause disease.Clinical Testing and Workup
Enzymes assays are tests that measure the activity of specific enzymes. In some types of ANCL, reduced enzyme activity can be demonstrated on an assay. For example, ANCL caused by the CTSF gene will show reduced activity of cathepsin F, the enzyme produced by the CTSF gene, on an enzyme assay.Some types of ANCL require that affected tissue is surgically removed and studied under an electron microscope. This can show the buildup of storage material within the affected tissue.Molecular genetic testing or gene sequencing can confirm a diagnosis of ANCL. The aim is to detect mutations in specific genes known to cause the various subtypes.These tests are available only at specialized laboratories. | Diagnosis of Adult Neuronal Ceroid Lipofuscinosis. A diagnosis of adult neuronal ceroid lipofuscinosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The tests used may be different based on the specific subtype of ANCL. These tests can include enzyme assays, the study of affected tissue under an electron microscope, and molecular genetic testing to identify changes in genes that can cause disease.Clinical Testing and Workup
Enzymes assays are tests that measure the activity of specific enzymes. In some types of ANCL, reduced enzyme activity can be demonstrated on an assay. For example, ANCL caused by the CTSF gene will show reduced activity of cathepsin F, the enzyme produced by the CTSF gene, on an enzyme assay.Some types of ANCL require that affected tissue is surgically removed and studied under an electron microscope. This can show the buildup of storage material within the affected tissue.Molecular genetic testing or gene sequencing can confirm a diagnosis of ANCL. The aim is to detect mutations in specific genes known to cause the various subtypes.These tests are available only at specialized laboratories. | 40 | Adult Neuronal Ceroid Lipofuscinosis |
nord_40_6 | Therapies of Adult Neuronal Ceroid Lipofuscinosis | TreatmentThe treatment of adult neuronal ceroid lipofuscinosis is directed toward the specific symptoms that are apparent in each individual. There are no disease-specific treatments for ANCL yet. Treatment may require the coordinated efforts of a team of specialists. General internists, metabolic geneticists, neurologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential.Genetic counseling is recommended for affected individuals and their families. | Therapies of Adult Neuronal Ceroid Lipofuscinosis. TreatmentThe treatment of adult neuronal ceroid lipofuscinosis is directed toward the specific symptoms that are apparent in each individual. There are no disease-specific treatments for ANCL yet. Treatment may require the coordinated efforts of a team of specialists. General internists, metabolic geneticists, neurologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential.Genetic counseling is recommended for affected individuals and their families. | 40 | Adult Neuronal Ceroid Lipofuscinosis |
nord_41_0 | Overview of Adult Polyglucosan Body Disease | Summary Adult polyglucosan body disease (APBD) is a rare, genetic disorder characterized by a deficiency of glycogen-branching enzyme, resulting in the accumulation of polyglucosan bodies in muscle, nerve and various other tissues of the body. Polyglucosan bodies are composed of large, complex, sugar-based molecules. APBD may be characterized by dysfunction of the central and peripheral nervous systems. The central nervous system (CNS) refers to the brain and spinal cord. The peripheral nerves extend from the CNS to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary body functions. In individuals with APBD, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; progressive urinary difficulties; occasionally mild cognitive impairment or dementia; deficiencies in the autonomic nervous system; and/or other abnormalities. APBD is caused by mutations in the glycogen branching enzyme gene (GBE1) and is inherited in an autosomal recessive pattern.Introduction APBD was first described in the medical literature as a clinical entity in 1980 (Robitaille Y et. al). The mutation that causes the disorder is in the same gene that causes Andersen's disease (glycogen storage disease type IV), a severe liver disorder that affects infants. The only difference is that in Andersen's disease, GBE is completely dysfunctional, whereas in APBD it retains some residual activity. | Overview of Adult Polyglucosan Body Disease. Summary Adult polyglucosan body disease (APBD) is a rare, genetic disorder characterized by a deficiency of glycogen-branching enzyme, resulting in the accumulation of polyglucosan bodies in muscle, nerve and various other tissues of the body. Polyglucosan bodies are composed of large, complex, sugar-based molecules. APBD may be characterized by dysfunction of the central and peripheral nervous systems. The central nervous system (CNS) refers to the brain and spinal cord. The peripheral nerves extend from the CNS to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary body functions. In individuals with APBD, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; progressive urinary difficulties; occasionally mild cognitive impairment or dementia; deficiencies in the autonomic nervous system; and/or other abnormalities. APBD is caused by mutations in the glycogen branching enzyme gene (GBE1) and is inherited in an autosomal recessive pattern.Introduction APBD was first described in the medical literature as a clinical entity in 1980 (Robitaille Y et. al). The mutation that causes the disorder is in the same gene that causes Andersen's disease (glycogen storage disease type IV), a severe liver disorder that affects infants. The only difference is that in Andersen's disease, GBE is completely dysfunctional, whereas in APBD it retains some residual activity. | 41 | Adult Polyglucosan Body Disease |
nord_41_1 | Symptoms of Adult Polyglucosan Body Disease | Symptoms and severity can vary greatly from one person to another. Typically, symptoms develop around the fifth decade of life. The initial sign is many times related to neurogenic bladder: specifically, an increased need to urinate that may eventually progress to cause a near complete loss of bladder control (urinary incontinence). In some cases, urinary difficulties may precede other symptoms by one or two decades. Another common early sign of APBD disease is a feeling of numbness or weakness in the hands and feet (paresthesia). Affected individuals may experience an inability to lift the front part of the foot (foot drop), which results in the need to drag the front of the foot on the ground when walking. Affected individuals may experience weakness in the arms and legs. Eventually, affected individuals may develop progressively increased muscle tone and stiffness of the legs (spasticity), causing difficulty walking. Most individuals may eventually need assistance walking (e.g., cane or walker), and ultimately the use of a wheelchair may be required. Some affected individuals may develop mild cognitive impairment, most commonly, mild attention and memory deficits. In some cases, cognitive problems may worsen, resulting in progressive loss of memory and intellectual abilities (dementia). | Symptoms of Adult Polyglucosan Body Disease. Symptoms and severity can vary greatly from one person to another. Typically, symptoms develop around the fifth decade of life. The initial sign is many times related to neurogenic bladder: specifically, an increased need to urinate that may eventually progress to cause a near complete loss of bladder control (urinary incontinence). In some cases, urinary difficulties may precede other symptoms by one or two decades. Another common early sign of APBD disease is a feeling of numbness or weakness in the hands and feet (paresthesia). Affected individuals may experience an inability to lift the front part of the foot (foot drop), which results in the need to drag the front of the foot on the ground when walking. Affected individuals may experience weakness in the arms and legs. Eventually, affected individuals may develop progressively increased muscle tone and stiffness of the legs (spasticity), causing difficulty walking. Most individuals may eventually need assistance walking (e.g., cane or walker), and ultimately the use of a wheelchair may be required. Some affected individuals may develop mild cognitive impairment, most commonly, mild attention and memory deficits. In some cases, cognitive problems may worsen, resulting in progressive loss of memory and intellectual abilities (dementia). | 41 | Adult Polyglucosan Body Disease |
nord_41_2 | Causes of Adult Polyglucosan Body Disease | APBD is caused by a mutation in the GBE1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular domain, this can affect many organ systems of the body, including the brain.APBD has traditionally been classified as an autosomal recessive disorder. Broadly, recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from both parents. However, although APBD has been classified as an autosomal recessive disorder, there have been many instances of APBD patients who carry the gene for the p.Y329S mutation in the heterozygous state (meaning they have the mutation in one copy of the GBE1 gene, but not in the other copy). These heterozygous patients should be asymptomatic carriers, yet they manifest symptoms of the disease and have been labeled as “manifesting heterozygotes”. These patients also have no other mutation in the 16 exons of the gene. Exons are specific segments of a gene that code for the protein produced by that gene. A study in 2015 (Akman et al. 2015) has discovered that in a cohort of 35 patients with APBD, 16 heterozygous patients for the p.Y329S mutation were compound heterozygotes for 2 mutations: p.Y329S as well as a mutation that affects a noncoding segment of DNA on the gene (intronic mutation). This intronic mutation resulted in a shortened (truncated) unstable protein. No patient had this intronic mutation in both copies of the GBE1 gene, possibly suggesting perinatal mortality.A chart of all 40 known GBE1 gene mutations can be found here:
https://apbdrf.org/resources/genetics-101The two most common mutations are p.Y329S and the deep intronic mutation.The GBE1 gene contains instructions for producing (encoding) a protein called glycogen branching enzyme or GBE. This enzyme is required for the proper building (synthesis) of glycogen, which is a complex sugar that normally is broken down (metabolized) into a simple sugar known as glucose. Glucose is one of the main sources of energy in the body. Because of mutations in the GBE1 gene, there are insufficient levels of functional GBE. This results in improperly formed glycogen, which accumulates in various tissues of the body in a form called polyglucosan bodies. Specifically, polyglucosan bodies may accumulate in star-shaped nerve cells known as astrocytes in the brain and spinal cord (central nervous system) and in the processes (axons) that extend from nerve cells as well as in peripheral nerves and the lung, heart, liver, kidneys, and even skin cells. Tissue reduction (atrophy), tissue loss (necrosis), and/or loss of the fatty sheath surrounding nerve fibers (demyelination) may occur. The mechanism by which the polyglucosan bodies cause nerve damage in axons is suggested to be their clogging (Lossos et al. 2009), which, in a neuronal culture, leads to cell death (Kakhlon et al. 2013). | Causes of Adult Polyglucosan Body Disease. APBD is caused by a mutation in the GBE1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular domain, this can affect many organ systems of the body, including the brain.APBD has traditionally been classified as an autosomal recessive disorder. Broadly, recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from both parents. However, although APBD has been classified as an autosomal recessive disorder, there have been many instances of APBD patients who carry the gene for the p.Y329S mutation in the heterozygous state (meaning they have the mutation in one copy of the GBE1 gene, but not in the other copy). These heterozygous patients should be asymptomatic carriers, yet they manifest symptoms of the disease and have been labeled as “manifesting heterozygotes”. These patients also have no other mutation in the 16 exons of the gene. Exons are specific segments of a gene that code for the protein produced by that gene. A study in 2015 (Akman et al. 2015) has discovered that in a cohort of 35 patients with APBD, 16 heterozygous patients for the p.Y329S mutation were compound heterozygotes for 2 mutations: p.Y329S as well as a mutation that affects a noncoding segment of DNA on the gene (intronic mutation). This intronic mutation resulted in a shortened (truncated) unstable protein. No patient had this intronic mutation in both copies of the GBE1 gene, possibly suggesting perinatal mortality.A chart of all 40 known GBE1 gene mutations can be found here:
https://apbdrf.org/resources/genetics-101The two most common mutations are p.Y329S and the deep intronic mutation.The GBE1 gene contains instructions for producing (encoding) a protein called glycogen branching enzyme or GBE. This enzyme is required for the proper building (synthesis) of glycogen, which is a complex sugar that normally is broken down (metabolized) into a simple sugar known as glucose. Glucose is one of the main sources of energy in the body. Because of mutations in the GBE1 gene, there are insufficient levels of functional GBE. This results in improperly formed glycogen, which accumulates in various tissues of the body in a form called polyglucosan bodies. Specifically, polyglucosan bodies may accumulate in star-shaped nerve cells known as astrocytes in the brain and spinal cord (central nervous system) and in the processes (axons) that extend from nerve cells as well as in peripheral nerves and the lung, heart, liver, kidneys, and even skin cells. Tissue reduction (atrophy), tissue loss (necrosis), and/or loss of the fatty sheath surrounding nerve fibers (demyelination) may occur. The mechanism by which the polyglucosan bodies cause nerve damage in axons is suggested to be their clogging (Lossos et al. 2009), which, in a neuronal culture, leads to cell death (Kakhlon et al. 2013). | 41 | Adult Polyglucosan Body Disease |
nord_41_3 | Affects of Adult Polyglucosan Body Disease | Adult polyglucosan body disease is a rare disorder that appears to affect males and females in equal proportions. Familial clustering is observed in about 30% of cases especially among Ashkenazi Jewish populations. More than 50 cases have been reported in the medical literature. | Affects of Adult Polyglucosan Body Disease. Adult polyglucosan body disease is a rare disorder that appears to affect males and females in equal proportions. Familial clustering is observed in about 30% of cases especially among Ashkenazi Jewish populations. More than 50 cases have been reported in the medical literature. | 41 | Adult Polyglucosan Body Disease |
nord_41_4 | Related disorders of Adult Polyglucosan Body Disease | A wide variety of disorders can be mistaken for APBD. Such disorders include multiple sclerosis, hereditary spastic paraplegia, adrenomyeloneuropathy, amyotrophic lateral sclerosis, metachromatic leukodystrophy, and Pelizaeus-Merzbacher disease. Men with primarily urinary symptoms may be mistaken for having an enlarged prostate (prostate hypertrophy). | Related disorders of Adult Polyglucosan Body Disease. A wide variety of disorders can be mistaken for APBD. Such disorders include multiple sclerosis, hereditary spastic paraplegia, adrenomyeloneuropathy, amyotrophic lateral sclerosis, metachromatic leukodystrophy, and Pelizaeus-Merzbacher disease. Men with primarily urinary symptoms may be mistaken for having an enlarged prostate (prostate hypertrophy). | 41 | Adult Polyglucosan Body Disease |
nord_41_5 | Diagnosis of Adult Polyglucosan Body Disease | A diagnosis is made based upon a thorough clinical evaluation, identification of characteristic findings, a detailed patient history, and a variety of specialized tests. Clinical Testing and Workup
Direct examination of tissue by a pathologist (electron and light microscopy) can help reach a definitive diagnosis. The microscopic examination of a sample of nerve tissue (sural nerve biopsy) reveals the presence of characteristic polyglucosan bodies. These bodies may also be present in other disorders and may occur in the normal course of aging. However, in individuals with APBD, the polyglucosan bodies are mostly and almost uniquely in the fibers extending from nerve cells (axons) as opposed to the body of the cells (where they are in Lafora disease). The presence of the amorphic polyglucosan bodies in the fibers is key to the diagnosis. However, as taking a sural nerve biopsy is an uncomfortable surgical procedure, a biochemical test of GBE activity in blood cells combined with the genetic screening has replaced the biopsy as the diagnostic method of choice. Reduced activity of the enzyme, GBE, can be measured (assayed) in cultured skin cells (fibroblasts) or white blood cells (lymphocytes) found in the peripheral blood. In addition, a specialized imaging technique known as magnetic resonance imaging (MRI) may show abnormalities in the conduction tissue (white matter) of the brain.In some cases, molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the GBE1 gene known to cause APBD, but is available only as a diagnostic service at specialized laboratories. | Diagnosis of Adult Polyglucosan Body Disease. A diagnosis is made based upon a thorough clinical evaluation, identification of characteristic findings, a detailed patient history, and a variety of specialized tests. Clinical Testing and Workup
Direct examination of tissue by a pathologist (electron and light microscopy) can help reach a definitive diagnosis. The microscopic examination of a sample of nerve tissue (sural nerve biopsy) reveals the presence of characteristic polyglucosan bodies. These bodies may also be present in other disorders and may occur in the normal course of aging. However, in individuals with APBD, the polyglucosan bodies are mostly and almost uniquely in the fibers extending from nerve cells (axons) as opposed to the body of the cells (where they are in Lafora disease). The presence of the amorphic polyglucosan bodies in the fibers is key to the diagnosis. However, as taking a sural nerve biopsy is an uncomfortable surgical procedure, a biochemical test of GBE activity in blood cells combined with the genetic screening has replaced the biopsy as the diagnostic method of choice. Reduced activity of the enzyme, GBE, can be measured (assayed) in cultured skin cells (fibroblasts) or white blood cells (lymphocytes) found in the peripheral blood. In addition, a specialized imaging technique known as magnetic resonance imaging (MRI) may show abnormalities in the conduction tissue (white matter) of the brain.In some cases, molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the GBE1 gene known to cause APBD, but is available only as a diagnostic service at specialized laboratories. | 41 | Adult Polyglucosan Body Disease |
nord_41_6 | Therapies of Adult Polyglucosan Body Disease | Treatment
To date, there is no specific therapy for individuals with APBD. Treatment is aimed at the specific symptoms present in each person. Treatment generally requires a team approach and may include neurologists, general internists, urologists, specialists in behavioral neurology, specialists in physical medicine rehabilitation, psychologists, and medical social workers. Genetic counseling is recommended for affected individuals and their families.Antispasmodic medications may be considered for individuals with neurogenic bladder. Some individuals may require the use of an indwelling or an in-and-out catheter in order to drain urine from the bladder. An indwelling catheter is a tube that is inserted into the bladder and left in place in order to drain urine. An in-and-out catheter is used one time to drain urine and then removed. Physical and occupational therapy is of benefit for some affected individuals. The disorder may progress so that devices that help affected people to continue their daily activities, such as braces, hand splints, limb supports, or wheelchairs, are necessary. Affected individuals who are restricted to bed may be made more comfortable with adjustable beds, water mattresses, and/or sheepskin mattress pads.In cases with cognitive impairment, behavioral modification and other cognitive aids may be considered. | Therapies of Adult Polyglucosan Body Disease. Treatment
To date, there is no specific therapy for individuals with APBD. Treatment is aimed at the specific symptoms present in each person. Treatment generally requires a team approach and may include neurologists, general internists, urologists, specialists in behavioral neurology, specialists in physical medicine rehabilitation, psychologists, and medical social workers. Genetic counseling is recommended for affected individuals and their families.Antispasmodic medications may be considered for individuals with neurogenic bladder. Some individuals may require the use of an indwelling or an in-and-out catheter in order to drain urine from the bladder. An indwelling catheter is a tube that is inserted into the bladder and left in place in order to drain urine. An in-and-out catheter is used one time to drain urine and then removed. Physical and occupational therapy is of benefit for some affected individuals. The disorder may progress so that devices that help affected people to continue their daily activities, such as braces, hand splints, limb supports, or wheelchairs, are necessary. Affected individuals who are restricted to bed may be made more comfortable with adjustable beds, water mattresses, and/or sheepskin mattress pads.In cases with cognitive impairment, behavioral modification and other cognitive aids may be considered. | 41 | Adult Polyglucosan Body Disease |
nord_42_0 | Overview of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia | SummaryAdult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, progressive neurological disease that causes brain tissue known as white matter to waste away (leukodystrophy), forming lesions in certain brain areas due to disease-causing variants in the CSF1R (colony-stimulating factor-1 receptor) gene. ALSP is one type of leukodystrophy disorder, estimated by some studies to account for 10 to 25% of adult-onset leukodystrophies. Lesions of this white matter lead to major changes in personality, thinking (cognition), and muscle function, eventually causing people with this disorder to develop dementia and later decline into a vegetative state. Aside from the presence of a specific gene variant, the brains of people with ALSP show characteristic microscopic changes and patterns of atrophy on brain imaging that distinguish ALSP patients from those with other neurological conditions. Symptoms of ALSP overlap with frontotemporal dementia and other disorders associated with dementia such as Alzheimer disease as well as other neurological disorders such as Parkinson's disease, multiple sclerosis, schizophrenia and several others, making diagnosis difficult unless genetic testing is done. Symptoms can vary considerably from one person with ALSP to the next (even in the same family). Currently, brain biopsy is not necessary for diagnosis because genetic testing is available.IntroductionALSP was previously known as two separate disorders: hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). Once both disorders were linked to CSF1R gene variants, they became known as ALSP. | Overview of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. SummaryAdult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, progressive neurological disease that causes brain tissue known as white matter to waste away (leukodystrophy), forming lesions in certain brain areas due to disease-causing variants in the CSF1R (colony-stimulating factor-1 receptor) gene. ALSP is one type of leukodystrophy disorder, estimated by some studies to account for 10 to 25% of adult-onset leukodystrophies. Lesions of this white matter lead to major changes in personality, thinking (cognition), and muscle function, eventually causing people with this disorder to develop dementia and later decline into a vegetative state. Aside from the presence of a specific gene variant, the brains of people with ALSP show characteristic microscopic changes and patterns of atrophy on brain imaging that distinguish ALSP patients from those with other neurological conditions. Symptoms of ALSP overlap with frontotemporal dementia and other disorders associated with dementia such as Alzheimer disease as well as other neurological disorders such as Parkinson's disease, multiple sclerosis, schizophrenia and several others, making diagnosis difficult unless genetic testing is done. Symptoms can vary considerably from one person with ALSP to the next (even in the same family). Currently, brain biopsy is not necessary for diagnosis because genetic testing is available.IntroductionALSP was previously known as two separate disorders: hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). Once both disorders were linked to CSF1R gene variants, they became known as ALSP. | 42 | Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia |
nord_42_1 | Symptoms of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia | Early symptoms of ALSP often include mild psychological or cognitive changes, but, while rare, can present as disturbances in motor function, such as difficulty walking, falling, and slowness of movements. Eventually, as damage in the brain becomes more extensive, psychological, cognitive and motor symptoms exist together. Initial symptoms and rate of disease progression vary quite a bit from one individual to the next, including those within the same family when the condition is inherited. Psychiatric features of ALSP include changes in personality and the development of anxiety, depression, lack of interest in things (apathy), irritability, distractibility, socially inappropriate behaviors (disinhibition) and cravings for certain types of food (for example eating only ice cream). Cognitive features include the development of dementia, with a general decline in mental functioning, including memory loss, word-finding and language difficulties (aphasia), difficulty planning voluntary muscle movements (apraxia), poor attention, poor judgment and problem solving and reduced impulse control. Brain degeneration in ALSP also affects what is known as the pyramidal system in the brain. These are nerve tracts that travel from the cerebral cortex (responsible for control of voluntary movements) to the brainstem or the spinal cord. Damage to these tracts in ALSP causes overactive reflexes (hyperreflexia); increased muscle tone, meaning muscles stay stiff and contracted at rest (hypertonicity); muscle spasms with increased movement (spasticity); weakness of one side of the body (hemiparesis) or in all four limbs (quadriparesis); reduced coordination; changes in vision; difficulty walking; difficulty swallowing; slurred speech; and heightened emotional responses, meaning patients may cry or laugh at inappropriate times (pseudobulbar palsy). Symptoms similar to Parkinson's disease, such as increased muscle stiffness (rigidity), tremors, a slowing of movement (bradykinesia), a shuffling gait and a reduction or loss of facial expression (hypomimic face or masked facies) can occur in ALSP as well. In ALSP, these symptoms are referred to as Parkinsonism and are not helped by increasing dopamine levels with medications like levodopa, which would ordinarily improve symptoms in Parkinson's disease. Changes to sensory nerves can also occur, making it more difficult for patients to sense pain, touch, vibration and changes in body position. Frequently, the patients cannot recognize the right or left side of the body. Less commonly, seizures can accompany ALSP, occurring in approximately 30% of patients with the diagnosis. The seizures usually occur at the onset of the illness. As the disease worsens, patients enter a state where they can no longer walk or speak and need total care with all daily living functions. They also lose control of bladder and bowel sphincter functions (double incontinent). Most patients with ALSP die from pneumonia. | Symptoms of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. Early symptoms of ALSP often include mild psychological or cognitive changes, but, while rare, can present as disturbances in motor function, such as difficulty walking, falling, and slowness of movements. Eventually, as damage in the brain becomes more extensive, psychological, cognitive and motor symptoms exist together. Initial symptoms and rate of disease progression vary quite a bit from one individual to the next, including those within the same family when the condition is inherited. Psychiatric features of ALSP include changes in personality and the development of anxiety, depression, lack of interest in things (apathy), irritability, distractibility, socially inappropriate behaviors (disinhibition) and cravings for certain types of food (for example eating only ice cream). Cognitive features include the development of dementia, with a general decline in mental functioning, including memory loss, word-finding and language difficulties (aphasia), difficulty planning voluntary muscle movements (apraxia), poor attention, poor judgment and problem solving and reduced impulse control. Brain degeneration in ALSP also affects what is known as the pyramidal system in the brain. These are nerve tracts that travel from the cerebral cortex (responsible for control of voluntary movements) to the brainstem or the spinal cord. Damage to these tracts in ALSP causes overactive reflexes (hyperreflexia); increased muscle tone, meaning muscles stay stiff and contracted at rest (hypertonicity); muscle spasms with increased movement (spasticity); weakness of one side of the body (hemiparesis) or in all four limbs (quadriparesis); reduced coordination; changes in vision; difficulty walking; difficulty swallowing; slurred speech; and heightened emotional responses, meaning patients may cry or laugh at inappropriate times (pseudobulbar palsy). Symptoms similar to Parkinson's disease, such as increased muscle stiffness (rigidity), tremors, a slowing of movement (bradykinesia), a shuffling gait and a reduction or loss of facial expression (hypomimic face or masked facies) can occur in ALSP as well. In ALSP, these symptoms are referred to as Parkinsonism and are not helped by increasing dopamine levels with medications like levodopa, which would ordinarily improve symptoms in Parkinson's disease. Changes to sensory nerves can also occur, making it more difficult for patients to sense pain, touch, vibration and changes in body position. Frequently, the patients cannot recognize the right or left side of the body. Less commonly, seizures can accompany ALSP, occurring in approximately 30% of patients with the diagnosis. The seizures usually occur at the onset of the illness. As the disease worsens, patients enter a state where they can no longer walk or speak and need total care with all daily living functions. They also lose control of bladder and bowel sphincter functions (double incontinent). Most patients with ALSP die from pneumonia. | 42 | Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia |
nord_42_2 | Causes of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia | ALSP is caused by an abnormal CSF1R gene variant that codes for the protein colony-stimulating factor-1 receptor found on many cell membranes, including those in the central nervous system, or CNS (consisting of the brain and spinal cord). This receptor plays a role in cell growth and cell specialization where cells take on specific functions in the body. Without a normally-functioning CSF-1 receptor, structural changes to the nerve cell, or neuron, eventually occur. Axons, the portions of neurons that transmit signals to the next neuron, are covered in a myelin sheath, or the white matter that is destroyed in ALSP and other leukodystrophies. In ALSP, the formation of swellings known as spheroids within axons causes immune cells known as macrophages to destroy myelin sheathing, further damaging nerve cell function. Microglia, another type of macrophage immune cell of the CNS that's responsible for maintaining brain tissue, are highly dependent on the CSF-1 receptor. When the receptor is inhibited, microglia become underactive and are destroyed. Macrophages and microglia take on a pigmented appearance in brain biopsies of ALSP patients. ALSP is an autosomal dominant genetic condition, meaning only a single copy of the disease-causing CSF1R gene variant is necessary to cause ALSP. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual, known as a de novo mutation where the mutation has never before been present in the family. The latter case is referred to as a sporadic, rather than an inherited, case of ALSP. In autosomal dominant conditions, there's a 50% chance the affected individual will pass the altered gene to their child, with the risk of inheritance being the same for males and females. | Causes of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. ALSP is caused by an abnormal CSF1R gene variant that codes for the protein colony-stimulating factor-1 receptor found on many cell membranes, including those in the central nervous system, or CNS (consisting of the brain and spinal cord). This receptor plays a role in cell growth and cell specialization where cells take on specific functions in the body. Without a normally-functioning CSF-1 receptor, structural changes to the nerve cell, or neuron, eventually occur. Axons, the portions of neurons that transmit signals to the next neuron, are covered in a myelin sheath, or the white matter that is destroyed in ALSP and other leukodystrophies. In ALSP, the formation of swellings known as spheroids within axons causes immune cells known as macrophages to destroy myelin sheathing, further damaging nerve cell function. Microglia, another type of macrophage immune cell of the CNS that's responsible for maintaining brain tissue, are highly dependent on the CSF-1 receptor. When the receptor is inhibited, microglia become underactive and are destroyed. Macrophages and microglia take on a pigmented appearance in brain biopsies of ALSP patients. ALSP is an autosomal dominant genetic condition, meaning only a single copy of the disease-causing CSF1R gene variant is necessary to cause ALSP. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual, known as a de novo mutation where the mutation has never before been present in the family. The latter case is referred to as a sporadic, rather than an inherited, case of ALSP. In autosomal dominant conditions, there's a 50% chance the affected individual will pass the altered gene to their child, with the risk of inheritance being the same for males and females. | 42 | Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia |
nord_42_3 | Affects of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia | The estimated number of people thought to have ALSP in the United States is 10,000 with similar estimates in Europe and Japan. Average age of diagnosis is 43 years old, but symptoms have been reported to occur in patients as young as 18, and 95% of ALSP patients start having symptoms before age 60. Both men and women are equally affected but symptoms usually appear earlier in women, at age 40 versus 47 for men. Life expectancy ranges from 2 to over 30 years, with an average life expectancy of 8 years after symptom onset. | Affects of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. The estimated number of people thought to have ALSP in the United States is 10,000 with similar estimates in Europe and Japan. Average age of diagnosis is 43 years old, but symptoms have been reported to occur in patients as young as 18, and 95% of ALSP patients start having symptoms before age 60. Both men and women are equally affected but symptoms usually appear earlier in women, at age 40 versus 47 for men. Life expectancy ranges from 2 to over 30 years, with an average life expectancy of 8 years after symptom onset. | 42 | Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia |
nord_42_4 | Related disorders of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia | Many symptoms of ALSP overlap with other neurological disorders, including other types of leukodystrophies. Genetic testing is required for accurate diagnosis. Based on symptoms, ALSP is most similar to the following disorders: Frontotemporal dementias (FTDs) are a group of neurodegenerative disorders associated with shrinking of the frontal and temporal anterior lobes of the brain. Symptoms include marked changes in social behavior and personality, and/or problems with language. People with behavior changes may have disinhibition (with socially inappropriate behavior), apathy and loss of empathy, hyperorality (eating excessive amounts of food or attempting to consume inedible things), agitation, compulsive behavior and various other changes. Examples of problems with language include difficulty speaking or understanding speech. Some people with FTD also develop a motor syndrome such as Parkinsonism or motor neuron disease (which may be associated with various additional symptoms). (For more information on this condition search for “frontotemporal degeneration” in the Rare Disease Database.) Multiple sclerosis (MS) is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occurs unpredictability, vary in intensity, and at many sites thus the name, multiple sclerosis. During the course of the disease, patients may have attacks (relapses or exacerbations), gradually worsen (progression), or stabilize. The randomness of the location of damage can result in a wide range of neurological symptoms, which may vary from person to person. (For more information on this condition search for “multiple sclerosis” in the Rare Disease Database.) Parkinson's disease is a slowly progressive neurologic condition characterized by involuntary trembling (resting tremor), muscular stiffness or inflexibility (rigidity), slowness of movement (bradykinesia) and difficulty carrying out voluntary movements (akinesia). Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal from one nerve cell to another in the brain. | Related disorders of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. Many symptoms of ALSP overlap with other neurological disorders, including other types of leukodystrophies. Genetic testing is required for accurate diagnosis. Based on symptoms, ALSP is most similar to the following disorders: Frontotemporal dementias (FTDs) are a group of neurodegenerative disorders associated with shrinking of the frontal and temporal anterior lobes of the brain. Symptoms include marked changes in social behavior and personality, and/or problems with language. People with behavior changes may have disinhibition (with socially inappropriate behavior), apathy and loss of empathy, hyperorality (eating excessive amounts of food or attempting to consume inedible things), agitation, compulsive behavior and various other changes. Examples of problems with language include difficulty speaking or understanding speech. Some people with FTD also develop a motor syndrome such as Parkinsonism or motor neuron disease (which may be associated with various additional symptoms). (For more information on this condition search for “frontotemporal degeneration” in the Rare Disease Database.) Multiple sclerosis (MS) is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal cord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occurs unpredictability, vary in intensity, and at many sites thus the name, multiple sclerosis. During the course of the disease, patients may have attacks (relapses or exacerbations), gradually worsen (progression), or stabilize. The randomness of the location of damage can result in a wide range of neurological symptoms, which may vary from person to person. (For more information on this condition search for “multiple sclerosis” in the Rare Disease Database.) Parkinson's disease is a slowly progressive neurologic condition characterized by involuntary trembling (resting tremor), muscular stiffness or inflexibility (rigidity), slowness of movement (bradykinesia) and difficulty carrying out voluntary movements (akinesia). Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), causing a decrease in dopamine levels in the brain. Dopamine is a neurotransmitter, which is a chemical that sends a signal from one nerve cell to another in the brain. | 42 | Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia |
nord_42_5 | Diagnosis of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia | Diagnosis of ALSP is made by a neurologist. ALSP is diagnosed through genetic testing that identifies a CSF1R gene variant associated with the disease. However, family history, clinical signs and brain imaging results are integral in raising suspicions enough to order genetic testing. When symptoms affecting cognition and movements or when seizures combined with either cognitive or motor symptoms are present before or by age 60, suspicion for ALSP should be raised. Cognitive testing by psychiatrists, neurologists or psychologists can identify behaviors that confirm frontal lobe dysfunction (e.g., reduced inhibition), especially when subtle, that is associated with ALSP. Specific patterns of brain deterioration on MRI and CT scans can further raise suspicion. These include the existence of lesions of white matter on both sides of the cerebrum (the largest, most exterior part of the brain that controls more complex functions) that in earlier stages of ALSP are less symmetric but become more symmetric and extensive as the disease progresses. White matter lesions in ALSP are most common in the frontal and parietal brain lobes of the cerebrum and the white matter around the lateral ventricles (periventricular deep white matter), making the ventricles appear enlarged in imaging. Also apparent in brain scans is thinning of the corpus callosum (a bundle of white matter, or myelinated, nerve fibers that connect the right and left halves of the brain so that they can communicate with one another) and small calcifications (from calcium deposits) in the white matter around the frontal and parietal brain lobes. Detection of high levels of neurofilament light chain, a protein that serves as an indicator of axonal damage, has been found in the blood and cerebrospinal fluid of ALSP patients and may aid clinicians in formulating their diagnosis. | Diagnosis of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. Diagnosis of ALSP is made by a neurologist. ALSP is diagnosed through genetic testing that identifies a CSF1R gene variant associated with the disease. However, family history, clinical signs and brain imaging results are integral in raising suspicions enough to order genetic testing. When symptoms affecting cognition and movements or when seizures combined with either cognitive or motor symptoms are present before or by age 60, suspicion for ALSP should be raised. Cognitive testing by psychiatrists, neurologists or psychologists can identify behaviors that confirm frontal lobe dysfunction (e.g., reduced inhibition), especially when subtle, that is associated with ALSP. Specific patterns of brain deterioration on MRI and CT scans can further raise suspicion. These include the existence of lesions of white matter on both sides of the cerebrum (the largest, most exterior part of the brain that controls more complex functions) that in earlier stages of ALSP are less symmetric but become more symmetric and extensive as the disease progresses. White matter lesions in ALSP are most common in the frontal and parietal brain lobes of the cerebrum and the white matter around the lateral ventricles (periventricular deep white matter), making the ventricles appear enlarged in imaging. Also apparent in brain scans is thinning of the corpus callosum (a bundle of white matter, or myelinated, nerve fibers that connect the right and left halves of the brain so that they can communicate with one another) and small calcifications (from calcium deposits) in the white matter around the frontal and parietal brain lobes. Detection of high levels of neurofilament light chain, a protein that serves as an indicator of axonal damage, has been found in the blood and cerebrospinal fluid of ALSP patients and may aid clinicians in formulating their diagnosis. | 42 | Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia |
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