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nord_42_6 | Therapies of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia | There are currently no FDA-approved treatments for ALSP. Researchers are further investigating underlying disease mechanisms and symptom progression to develop more effective treatment options. Current treatment options do not reverse brain damage but instead are meant to manage symptoms. For patients with ALSP who have seizures, anti-epileptic medications are useful for controlling seizures. Antibiotics may be prescribed to help control infections, such as pneumonia or urinary tract infections that may arise as patients grow progressively weaker. Muscle relaxers may be recommended to target spasticity. Anti-depressants are often prescribed to treat psychological symptoms of ALSP but are not especially effective. Anti-psychotic medications may be used to control aggression in ALSP but side effects are generally not well-tolerated. Nutritional supplements and physical therapy are often recommended to slow overall decline and maintain the most optimal overall health possible. Genetic counseling is recommended to help patients and families understand the genetics and progression of ALSP and to provide psychosocial support. | Therapies of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia. There are currently no FDA-approved treatments for ALSP. Researchers are further investigating underlying disease mechanisms and symptom progression to develop more effective treatment options. Current treatment options do not reverse brain damage but instead are meant to manage symptoms. For patients with ALSP who have seizures, anti-epileptic medications are useful for controlling seizures. Antibiotics may be prescribed to help control infections, such as pneumonia or urinary tract infections that may arise as patients grow progressively weaker. Muscle relaxers may be recommended to target spasticity. Anti-depressants are often prescribed to treat psychological symptoms of ALSP but are not especially effective. Anti-psychotic medications may be used to control aggression in ALSP but side effects are generally not well-tolerated. Nutritional supplements and physical therapy are often recommended to slow overall decline and maintain the most optimal overall health possible. Genetic counseling is recommended to help patients and families understand the genetics and progression of ALSP and to provide psychosocial support. | 42 | Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia |
nord_43_0 | Overview of Adult-Onset Still’s Disease | SummaryAdult-onset Still's disease (AOSD) is a rare inflammatory disorder that can affect the entire body (systemic disease). The cause of the disorder is unknown (idiopathic). Affected individuals may develop episodes of high, spiking fevers, a pink or salmon colored rash, joint pain, muscle pain, a sore throat and other symptoms associated with systemic inflammatory disease. The specific symptoms and frequency of episodes vary from one person to another and the progression of the disorder is difficult to predict. In some individuals, the disorder appears suddenly, disappears almost as quickly and may not return. In other people, AOSD is a chronic, potentially disabling condition. Various anti-inflammatory medications are used to treat individuals with AOSD, and affected individuals may respond to therapy differently. IntroductionAdult-onset Still's disease is the adult form of systemic juvenile idiopathic arthritis (juvenile Still's disease). These disorders are named after Sir George Frederic Still, a British physician who first described a form of childhood arthritis associated with fever in the medical literature in 1896. Adults with “Still’s disease” were first reported in the medial literature in 1971, but cases that fit the description of the disorder appear as early as the late 1800s. AOSD might be difficult to diagnose given its rarity and the fact that symptoms may overlap with other diseases. Making a timely and accurate diagnosis is important for appropriate patient care and counseling. Although the symptoms of AOSD can affect quality of life, especially if they are chronic, the disease is not usually life -threatening. | Overview of Adult-Onset Still’s Disease. SummaryAdult-onset Still's disease (AOSD) is a rare inflammatory disorder that can affect the entire body (systemic disease). The cause of the disorder is unknown (idiopathic). Affected individuals may develop episodes of high, spiking fevers, a pink or salmon colored rash, joint pain, muscle pain, a sore throat and other symptoms associated with systemic inflammatory disease. The specific symptoms and frequency of episodes vary from one person to another and the progression of the disorder is difficult to predict. In some individuals, the disorder appears suddenly, disappears almost as quickly and may not return. In other people, AOSD is a chronic, potentially disabling condition. Various anti-inflammatory medications are used to treat individuals with AOSD, and affected individuals may respond to therapy differently. IntroductionAdult-onset Still's disease is the adult form of systemic juvenile idiopathic arthritis (juvenile Still's disease). These disorders are named after Sir George Frederic Still, a British physician who first described a form of childhood arthritis associated with fever in the medical literature in 1896. Adults with “Still’s disease” were first reported in the medial literature in 1971, but cases that fit the description of the disorder appear as early as the late 1800s. AOSD might be difficult to diagnose given its rarity and the fact that symptoms may overlap with other diseases. Making a timely and accurate diagnosis is important for appropriate patient care and counseling. Although the symptoms of AOSD can affect quality of life, especially if they are chronic, the disease is not usually life -threatening. | 43 | Adult-Onset Still’s Disease |
nord_43_1 | Symptoms of Adult-Onset Still’s Disease | The symptoms, progression, and severity of AOSD are highly variable from one person to another, but three main patterns have been identified: Monophasic pattern: patients with monophasic AOSD have a single episode of symptoms that typically lasts weeks to months, but usually less than a year.Polyphasic (intermittent) pattern: patients with polyphasic AOSD develop more than one episode of symptoms. Affected individuals are usually symptom-free for weeks to years between episodes. In general, subsequent episodes tend to be less severe and shorter in duration compared to the initial one. Chronic pattern: patients with chronic AOSD have persistent symptoms over time. Most individuals with AOSD develop some combination of the symptoms normally associated with systemic inflammatory disease. These include a spiking fever, a skin rash, muscle pain (myalgia), and joint pain (arthralgia) and inflammation (arthritis). The fever seen in AOSD is typically greater than 102.2oF (39oC). In some patients, fever spikes occur once or twice a day, usually in the late afternoon or early evening. The rash of AOSD, which usually but not always develops during a fever episode, is pink or salmon colored. It mostly affects the chest and thighs, but can also affect the arms, legs and face. It may or may not be itchy (pruritic) and tends to disappear quickly (evanescent). Affected joints may become swollen, stiff and inflamed. The knees, wrists, ankles, and hips are most commonly affected. Muscle and joint pain can be intense and is often worse during a fever episode. If AOSD goes untreated, chronic inflammation of the joints can potentially result in destruction of the affected joints. Chronic joint inflammation leading to these complications is more common in chronic AOSD and can potentially cause long-term, severe and disabling complications. Other symptoms that can be seen in AOSD include a sore throat, abdominal pain, nausea, loss of appetite (anorexia), weight loss and enlargement of the spleen (splenomegaly), liver (hepatomegaly) and lymph nodes (lymphadenopathy).More rarely, AOSD can cause inflammation of internal organs. In some patients, the thin, sac-like membrane that surrounds the heart (pericardium) or the heart muscle (myocardium) may become inflamed (pericarditis or myocarditis, respectively). The membrane lining the lungs may also become inflamed (pleuritis) and may cause fluid to accumulate around the lungs (pleural effusion). Heart and lung involvement can cause difficulty breathing and chest pain, but in most patients it is usually not severe enough to be readily apparent and is often only detected by imaging. Another rare but potentially dangerous complication of AOSD is macrophage activation syndrome (MAS), also called secondary hemophagocytic lymphohystiocytosis (HLH), a condition characterized by an overactive and abnormal response of the immune system (for more information on this disorder, choose “HLH” as your search term in the Rare Disease Database). | Symptoms of Adult-Onset Still’s Disease. The symptoms, progression, and severity of AOSD are highly variable from one person to another, but three main patterns have been identified: Monophasic pattern: patients with monophasic AOSD have a single episode of symptoms that typically lasts weeks to months, but usually less than a year.Polyphasic (intermittent) pattern: patients with polyphasic AOSD develop more than one episode of symptoms. Affected individuals are usually symptom-free for weeks to years between episodes. In general, subsequent episodes tend to be less severe and shorter in duration compared to the initial one. Chronic pattern: patients with chronic AOSD have persistent symptoms over time. Most individuals with AOSD develop some combination of the symptoms normally associated with systemic inflammatory disease. These include a spiking fever, a skin rash, muscle pain (myalgia), and joint pain (arthralgia) and inflammation (arthritis). The fever seen in AOSD is typically greater than 102.2oF (39oC). In some patients, fever spikes occur once or twice a day, usually in the late afternoon or early evening. The rash of AOSD, which usually but not always develops during a fever episode, is pink or salmon colored. It mostly affects the chest and thighs, but can also affect the arms, legs and face. It may or may not be itchy (pruritic) and tends to disappear quickly (evanescent). Affected joints may become swollen, stiff and inflamed. The knees, wrists, ankles, and hips are most commonly affected. Muscle and joint pain can be intense and is often worse during a fever episode. If AOSD goes untreated, chronic inflammation of the joints can potentially result in destruction of the affected joints. Chronic joint inflammation leading to these complications is more common in chronic AOSD and can potentially cause long-term, severe and disabling complications. Other symptoms that can be seen in AOSD include a sore throat, abdominal pain, nausea, loss of appetite (anorexia), weight loss and enlargement of the spleen (splenomegaly), liver (hepatomegaly) and lymph nodes (lymphadenopathy).More rarely, AOSD can cause inflammation of internal organs. In some patients, the thin, sac-like membrane that surrounds the heart (pericardium) or the heart muscle (myocardium) may become inflamed (pericarditis or myocarditis, respectively). The membrane lining the lungs may also become inflamed (pleuritis) and may cause fluid to accumulate around the lungs (pleural effusion). Heart and lung involvement can cause difficulty breathing and chest pain, but in most patients it is usually not severe enough to be readily apparent and is often only detected by imaging. Another rare but potentially dangerous complication of AOSD is macrophage activation syndrome (MAS), also called secondary hemophagocytic lymphohystiocytosis (HLH), a condition characterized by an overactive and abnormal response of the immune system (for more information on this disorder, choose “HLH” as your search term in the Rare Disease Database). | 43 | Adult-Onset Still’s Disease |
nord_43_2 | Causes of Adult-Onset Still’s Disease | The cause of AOSD is unknown (idiopathic). Researchers believe that the disorder might be caused by a combination of genetic factors and an abnormal or exaggerated response to infections or other environmental exposures. AOSD is not a hereditary disease and usually does not run in families.Some researchers believe that AOSD is an autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system, which is the first line of defense of the immune system. They are not the same as autoimmune disorders, in which the adaptive immune system (the second line of defense of the immune system) malfunctions and mistakenly attacks healthy tissue. Researchers also believe that specialized proteins that modulate the immune system (cytokines) may also play a role in the development of AOSD. Interleukin-1 (IL-1), a cytokine that is known to mediate cell response to inflammation, may play a role in the development of the disease, as abnormal clinical findings involving IL-1 have been found in some individuals with AOSD. For this reason, therapy with a drug to block the activity of IL-1 is being explored (see Investigational Therapies below). Additional cytokines including interleukin-6 (IL-6), IL-18, and tumor necrosis factor-alpha (TNF-alpha) are also believed to play a role in the development of AOSD and could therefore potentially be targeted for treatment. | Causes of Adult-Onset Still’s Disease. The cause of AOSD is unknown (idiopathic). Researchers believe that the disorder might be caused by a combination of genetic factors and an abnormal or exaggerated response to infections or other environmental exposures. AOSD is not a hereditary disease and usually does not run in families.Some researchers believe that AOSD is an autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system, which is the first line of defense of the immune system. They are not the same as autoimmune disorders, in which the adaptive immune system (the second line of defense of the immune system) malfunctions and mistakenly attacks healthy tissue. Researchers also believe that specialized proteins that modulate the immune system (cytokines) may also play a role in the development of AOSD. Interleukin-1 (IL-1), a cytokine that is known to mediate cell response to inflammation, may play a role in the development of the disease, as abnormal clinical findings involving IL-1 have been found in some individuals with AOSD. For this reason, therapy with a drug to block the activity of IL-1 is being explored (see Investigational Therapies below). Additional cytokines including interleukin-6 (IL-6), IL-18, and tumor necrosis factor-alpha (TNF-alpha) are also believed to play a role in the development of AOSD and could therefore potentially be targeted for treatment. | 43 | Adult-Onset Still’s Disease |
nord_43_3 | Affects of Adult-Onset Still’s Disease | The exact incidence of AOSD is unknown, but it is thought to affect between 1 and 34 people per million, depending on the population studied. Because of the highly variable symptoms and rarity of the disorder, it often goes undiagnosed or misdiagnosed, making it difficult to determine its true frequency in the general population. AOSD seems to affect men and women in equal numbers, although some reports state that the disorder affects women slightly more often than men. It primarily affects young adults between the ages of 16-35 but can also occur in older individuals. | Affects of Adult-Onset Still’s Disease. The exact incidence of AOSD is unknown, but it is thought to affect between 1 and 34 people per million, depending on the population studied. Because of the highly variable symptoms and rarity of the disorder, it often goes undiagnosed or misdiagnosed, making it difficult to determine its true frequency in the general population. AOSD seems to affect men and women in equal numbers, although some reports state that the disorder affects women slightly more often than men. It primarily affects young adults between the ages of 16-35 but can also occur in older individuals. | 43 | Adult-Onset Still’s Disease |
nord_43_4 | Related disorders of Adult-Onset Still’s Disease | Symptoms of the following disorders can be similar to those of AOSD. Comparisons may be useful for a differential diagnosis.Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. Symptoms of these syndromes often include periodic fevers, rash, abdominal pain, joint pain, bone pain and other characteristic findings associated with chronic inflammation. These disorders include the cryopyrin-associated periodic syndromes (familial cold auto-inflammatory syndrome, CINCA/NOMID, and Muckle-Wells syndrome), hyperimmunoglobulin D syndrome (HIDS), familial Mediterranean fever (FMF), TRAPS, Schnitzler syndrome and mevalonate kinase deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Autoimmune disorders are a group of disorders in which the adaptive immune system mistakenly attacks healthy tissue. Symptoms common to many autoimmune disorders include repeated episodes of fever, rash, abdominal pain, joint pain and other symptoms associated with chronic inflammation. Autoimmune disorders that may resemble AOSD include systemic lupus erythematosus (SLE), dermatomyositis, and rheumatoid arthritis (RA). (For more information on dermatomyositis, choose the disorder name as your search term in the Rare Disease Database.)A wide variety of additional disorders can resemble AOSD including reactive arthritis, inflammatory bowel disease (IBD), Sweet syndrome, certain cancers such as lymphoma and leukemia, and certain infections such as tuberculosis, mononucleosis and toxoplasmosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Adult-Onset Still’s Disease. Symptoms of the following disorders can be similar to those of AOSD. Comparisons may be useful for a differential diagnosis.Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. Symptoms of these syndromes often include periodic fevers, rash, abdominal pain, joint pain, bone pain and other characteristic findings associated with chronic inflammation. These disorders include the cryopyrin-associated periodic syndromes (familial cold auto-inflammatory syndrome, CINCA/NOMID, and Muckle-Wells syndrome), hyperimmunoglobulin D syndrome (HIDS), familial Mediterranean fever (FMF), TRAPS, Schnitzler syndrome and mevalonate kinase deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Autoimmune disorders are a group of disorders in which the adaptive immune system mistakenly attacks healthy tissue. Symptoms common to many autoimmune disorders include repeated episodes of fever, rash, abdominal pain, joint pain and other symptoms associated with chronic inflammation. Autoimmune disorders that may resemble AOSD include systemic lupus erythematosus (SLE), dermatomyositis, and rheumatoid arthritis (RA). (For more information on dermatomyositis, choose the disorder name as your search term in the Rare Disease Database.)A wide variety of additional disorders can resemble AOSD including reactive arthritis, inflammatory bowel disease (IBD), Sweet syndrome, certain cancers such as lymphoma and leukemia, and certain infections such as tuberculosis, mononucleosis and toxoplasmosis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 43 | Adult-Onset Still’s Disease |
nord_43_5 | Diagnosis of Adult-Onset Still’s Disease | The diagnosis of AOSD is difficult to make because there is no specific test or distinguishing laboratory finding that clearly differentiates the disorder from similar disorders. A diagnosis of AOSD is usually made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and the exclusion of other possible disorders (diagnosis of exclusion). A variety of tests may be performed to aid in a diagnosis including blood tests as well as imaging studies that might reveal changes in the bones or joints or enlargement of the spleen or liver. An echocardiogram, which uses sound waves to create a picture of the heart, may reveal inflammation of the pericardium or myocardium.Blood tests may reveal characteristic changes to blood cell levels normally associated with AOSD. Affected individuals often have elevated levels of white blood cells (leukocytosis) and/or platelets (thrombocytosis) or low levels of red blood cells (anemia). However, this pattern of laboratory abnormalities is seen in many inflammatory disorders. Another common laboratory finding for individuals suspected of having an inflammatory disorder, including AOSD, is elevated inflammatory markers, namely the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Another blood test commonly used is serum ferritin, which is frequently disproportionally elevated in AOSD. Additionally, some patients have high blood levels of enzymes that are released by the liver, namely alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). To exclude other disorders, levels of certain antibodies such as antinuclear antibodies (ANA) and rheumatoid factor (RF) are usually measured. However, these antibodies are typically absent in patients with AOSD.Although they are not perfect, certain sets of criteria can also help with the diagnosis of AOSD. The most commonly used set of criteria are the Yamaguchi criteria. To be considered for a diagnosis of AOSD, affected individuals need to fulfil at least 5 criteria, including at least 2 major criteria. Conditions that can mimic AOSD also need to be excluded to make a diagnosis. The Yamaguchi criteria are the following:Major criteriaMinor criteria | Diagnosis of Adult-Onset Still’s Disease. The diagnosis of AOSD is difficult to make because there is no specific test or distinguishing laboratory finding that clearly differentiates the disorder from similar disorders. A diagnosis of AOSD is usually made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and the exclusion of other possible disorders (diagnosis of exclusion). A variety of tests may be performed to aid in a diagnosis including blood tests as well as imaging studies that might reveal changes in the bones or joints or enlargement of the spleen or liver. An echocardiogram, which uses sound waves to create a picture of the heart, may reveal inflammation of the pericardium or myocardium.Blood tests may reveal characteristic changes to blood cell levels normally associated with AOSD. Affected individuals often have elevated levels of white blood cells (leukocytosis) and/or platelets (thrombocytosis) or low levels of red blood cells (anemia). However, this pattern of laboratory abnormalities is seen in many inflammatory disorders. Another common laboratory finding for individuals suspected of having an inflammatory disorder, including AOSD, is elevated inflammatory markers, namely the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Another blood test commonly used is serum ferritin, which is frequently disproportionally elevated in AOSD. Additionally, some patients have high blood levels of enzymes that are released by the liver, namely alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). To exclude other disorders, levels of certain antibodies such as antinuclear antibodies (ANA) and rheumatoid factor (RF) are usually measured. However, these antibodies are typically absent in patients with AOSD.Although they are not perfect, certain sets of criteria can also help with the diagnosis of AOSD. The most commonly used set of criteria are the Yamaguchi criteria. To be considered for a diagnosis of AOSD, affected individuals need to fulfil at least 5 criteria, including at least 2 major criteria. Conditions that can mimic AOSD also need to be excluded to make a diagnosis. The Yamaguchi criteria are the following:Major criteriaMinor criteria | 43 | Adult-Onset Still’s Disease |
nord_43_6 | Therapies of Adult-Onset Still’s Disease | TreatmentMany different therapies have been tried for individuals with AOSD. No one treatment has proven consistently effective in all patients. In addition to symptomatic and supportive treatment, a variety of different drugs taken alone or in combination may be used to treat affected individuals.Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to treat symptoms of inflammation. Fever, joint pain and bone pain have responded to treatment with these drugs. Examples of NSAIDs include ibuprofen, naproxen, indomethacin and diclofenac. Other painkillers (analgesics) such as acetaminophen (Tylenol) may also be used. Corticosteroid drugs such as prednisone may be used to treat systemic symptoms. Corticosteroids have powerful anti-inflammatory properties. However, long-term use of corticosteroids is associated with many side effects. Affected individuals may therefore receive high doses of corticosteroids that will be progressively reduced over time. Researchers are also exploring medications that can replace corticosteroids or permit lower doses to be used (see Investigational Therapies below). One approved drug sometimes used in conjunction with corticosteroids to treat individuals with AOSD is the immunosuppressive drug methotrexate. Methotrexate is commonly used to treat arthritis and other conditions that affect joints (rheumatic diseases). When used for individuals with AOSD, methotrexate may be known as a “steroid-sparing agent” because it permits lower doses of corticosteroids to be used, thereby lowering the associated risk of side effects.In 2020, the U.S. Food and Drug Administration (FDA) approved canakinumab (Ilaris) to treat patients with active Still’s disease, including AOSD. Canakinumab blocks the cytokine IL-1. This medication is typically used if corticosteroids and methotrexate have not been successful. | Therapies of Adult-Onset Still’s Disease. TreatmentMany different therapies have been tried for individuals with AOSD. No one treatment has proven consistently effective in all patients. In addition to symptomatic and supportive treatment, a variety of different drugs taken alone or in combination may be used to treat affected individuals.Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to treat symptoms of inflammation. Fever, joint pain and bone pain have responded to treatment with these drugs. Examples of NSAIDs include ibuprofen, naproxen, indomethacin and diclofenac. Other painkillers (analgesics) such as acetaminophen (Tylenol) may also be used. Corticosteroid drugs such as prednisone may be used to treat systemic symptoms. Corticosteroids have powerful anti-inflammatory properties. However, long-term use of corticosteroids is associated with many side effects. Affected individuals may therefore receive high doses of corticosteroids that will be progressively reduced over time. Researchers are also exploring medications that can replace corticosteroids or permit lower doses to be used (see Investigational Therapies below). One approved drug sometimes used in conjunction with corticosteroids to treat individuals with AOSD is the immunosuppressive drug methotrexate. Methotrexate is commonly used to treat arthritis and other conditions that affect joints (rheumatic diseases). When used for individuals with AOSD, methotrexate may be known as a “steroid-sparing agent” because it permits lower doses of corticosteroids to be used, thereby lowering the associated risk of side effects.In 2020, the U.S. Food and Drug Administration (FDA) approved canakinumab (Ilaris) to treat patients with active Still’s disease, including AOSD. Canakinumab blocks the cytokine IL-1. This medication is typically used if corticosteroids and methotrexate have not been successful. | 43 | Adult-Onset Still’s Disease |
nord_44_0 | Overview of AEC Syndrome | SummaryAnkyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome, which is also known as Hay-Wells syndrome, is a rare disorder characterized by a wide variety of symptoms that can affect the skin, hair, nails, teeth, certain glands, and the hands and feet. Common symptoms include abnormal fibrous strands of tissue that can partially or completely fuse the upper and lower eyelids (ankyloblepharon), mild to severe skin erosions, abnormal hair, and cleft palate and/or cleft lip. Additional symptoms include malformation of the nails, abnormalities in skin color, limb malformations, and dental changes. Specific symptoms may vary greatly from one individual to another. AEC syndrome is caused by changes (mutations) in the TP63 gene and most cases are either new (spontaneous) mutations or are inherited in an autosomal dominant fashion. Another disorder that is caused by mutations in the TP63 gene, Rapp Hodgkin syndrome, is now considered to be part of the one disease spectrum that also includes AEC syndrome.IntroductionThere are at least three other syndromes caused by mutations in the TP63 gene including limb-mammary syndrome, ADULT syndrome, and ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome. In addition, TP63 mutations have also been reported as the cause of nonsyndromic split hand/foot malformation. There is considerable overlap among these disorders. Despite the overlap, the TP63-associated syndromes have their own characteristic physical findings, related in part, to the specific mutation in the TP63 gene present. These syndromes are further classified as forms of ectodermal dysplasia, a group of disorders characterized by abnormalities that occur during embryonic development. Ectodermal dysplasias typically affect the hair, teeth, nails, and/or skin. | Overview of AEC Syndrome. SummaryAnkyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome, which is also known as Hay-Wells syndrome, is a rare disorder characterized by a wide variety of symptoms that can affect the skin, hair, nails, teeth, certain glands, and the hands and feet. Common symptoms include abnormal fibrous strands of tissue that can partially or completely fuse the upper and lower eyelids (ankyloblepharon), mild to severe skin erosions, abnormal hair, and cleft palate and/or cleft lip. Additional symptoms include malformation of the nails, abnormalities in skin color, limb malformations, and dental changes. Specific symptoms may vary greatly from one individual to another. AEC syndrome is caused by changes (mutations) in the TP63 gene and most cases are either new (spontaneous) mutations or are inherited in an autosomal dominant fashion. Another disorder that is caused by mutations in the TP63 gene, Rapp Hodgkin syndrome, is now considered to be part of the one disease spectrum that also includes AEC syndrome.IntroductionThere are at least three other syndromes caused by mutations in the TP63 gene including limb-mammary syndrome, ADULT syndrome, and ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome. In addition, TP63 mutations have also been reported as the cause of nonsyndromic split hand/foot malformation. There is considerable overlap among these disorders. Despite the overlap, the TP63-associated syndromes have their own characteristic physical findings, related in part, to the specific mutation in the TP63 gene present. These syndromes are further classified as forms of ectodermal dysplasia, a group of disorders characterized by abnormalities that occur during embryonic development. Ectodermal dysplasias typically affect the hair, teeth, nails, and/or skin. | 44 | AEC Syndrome |
nord_44_1 | Symptoms of AEC Syndrome | The symptoms of AEC syndrome are highly variable, even among members of the same family. In addition, the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder prevent physicians from developing a completely accurate picture of associated symptoms and prognosis. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Many of the symptoms associated with AEC syndrome are present at birth (congenital). Many infants will have abnormal strands of tissue that connect the upper eyelids with the lower eyelids causing them to be fused together, a condition known as ankyloblepharon filiforme adnatum. Ankyloblepharon affects approximately 70% of individuals with AEC syndrome and is generally not seen in other TP63-related disorders.Most infants will have some degree of skin erosion, ranging from mild involvement of a specific area to severe, even life-threatening, involvement of the whole body. The scalp is commonly involved and is usually affected more severely than other areas. Severe scalp erosions can cause a generalized loss of hair (hypotrichosis) as well as patchy areas where hair loss is followed by the formation of scar tissue (scarring alopecia). Skin erosions may recur periodically throughout childhood and sometimes adulthood. The head and neck, palms and soles, and skin folds are most often affected. Skin erosions can be slow to heal and a considerable source of discomfort, pain and disability. In severe cases, these persistent skin erosions can lead to frequent infection and potentially life-threatening complications such as sepsis.Additional skin abnormalities may also be present. The characteristic skin erosions may be associated with a widespread (diffuse) reddish discoloration (erythroderma). The affected skin can also appear shiny and waxy (collodion membrane). Affected individuals may also develop areas of darkened or faded skin color (hyper- or hypo-pigmentation). Dry, scaly patches of skin may form on the palms and soles (palmar-plantar hyperkeratosis) as well as tiny, hardened bumps (punctate keratoderma). Increased numbers and depth of skin lines on the palms may also occur (hyperlinearity). Hyperkeratosis may also affect the knees and elbows.All affected individuals have oral clefting abnormalities. Some have only a cleft or groove on the roof of the mouth (palate), some have only a cleft lip, and others have both. A cleft palate or lip is usually obvious at birth. However, a cleft palate can vary in size and location and some small clefts can go unnoticed or undetected until later in life. Cleft palate occurs more frequently than cleft lip.AEC syndrome also causes decreased sweat production (hypohidrosis), which causes some affected individuals to be uncomfortable or feel “overheated” when the temperature rises (heat intolerance). Hypohidrosis is due, in part, to reduced number or absence of sweat glands.Additional common findings in AEC syndrome include sparse, wiry, brittle hair that is usually light colored. In some cases, flattened, twisted hair shafts (pili torti) may be present. Eyebrows and eyelashes are also sparse. Nail changes may also occur and can vary greatly among individuals. Such changes include misshapen or malformed fingernails and toenails, abnormally small nail plates (micronychia), frayed edges of the nails, and absent nails. Hair and nail abnormalities become more apparent as affected individuals grow older.Dental abnormalities are also common and can include one or more missing teeth (hypodontia), widely spaced teeth, and malformed or underdeveloped (hypoplastic) teeth. The lower jaw may also be small and underdeveloped (maxillary hypoplasia).Affected individuals may also have narrowing (atresia) or absence of the opening in the edge of each eyelid that is linked to the tear duct (lacrimal punctata). This can lead to obstruction of the tear ducts and predispose to recurrent eye crusting and conjunctivitis. Many individuals with AEC report chronic dry eyes. Chronic inflammation of the eyelids (blepharitis) has also been reported.Less often, certain limb anomalies have been associated with AEC syndrome including webbing of certain fingers or toes (syndactyly) and fingers that are stuck in a bent or flexed position (camptodactyly).Some children experience chronic middle ear infections (otitis media) and approximately 90% develop hearing loss due to the failure of sound waves to be sent (conducted) through the middle ear (conductive hearing loss). Hearing loss can cause delays in speech development.Poor weight gain, growth deficiencies and short stature can also occur. Additional findings that have been reported in individuals with AEC syndrome include abnormally small ears, a broad bridge of the nose, an abnormally short groove that runs from the top of the upper lip to the nose (philtrum), an abnormally small mouth (microstomia), and the inability to completely open the mouth (trismus). In affected males, the opening of the small tube that carries urine from the bladder to outside of the body (urethra) may be abnormally located on the underside of the penis (hypospadias). | Symptoms of AEC Syndrome. The symptoms of AEC syndrome are highly variable, even among members of the same family. In addition, the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder prevent physicians from developing a completely accurate picture of associated symptoms and prognosis. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Many of the symptoms associated with AEC syndrome are present at birth (congenital). Many infants will have abnormal strands of tissue that connect the upper eyelids with the lower eyelids causing them to be fused together, a condition known as ankyloblepharon filiforme adnatum. Ankyloblepharon affects approximately 70% of individuals with AEC syndrome and is generally not seen in other TP63-related disorders.Most infants will have some degree of skin erosion, ranging from mild involvement of a specific area to severe, even life-threatening, involvement of the whole body. The scalp is commonly involved and is usually affected more severely than other areas. Severe scalp erosions can cause a generalized loss of hair (hypotrichosis) as well as patchy areas where hair loss is followed by the formation of scar tissue (scarring alopecia). Skin erosions may recur periodically throughout childhood and sometimes adulthood. The head and neck, palms and soles, and skin folds are most often affected. Skin erosions can be slow to heal and a considerable source of discomfort, pain and disability. In severe cases, these persistent skin erosions can lead to frequent infection and potentially life-threatening complications such as sepsis.Additional skin abnormalities may also be present. The characteristic skin erosions may be associated with a widespread (diffuse) reddish discoloration (erythroderma). The affected skin can also appear shiny and waxy (collodion membrane). Affected individuals may also develop areas of darkened or faded skin color (hyper- or hypo-pigmentation). Dry, scaly patches of skin may form on the palms and soles (palmar-plantar hyperkeratosis) as well as tiny, hardened bumps (punctate keratoderma). Increased numbers and depth of skin lines on the palms may also occur (hyperlinearity). Hyperkeratosis may also affect the knees and elbows.All affected individuals have oral clefting abnormalities. Some have only a cleft or groove on the roof of the mouth (palate), some have only a cleft lip, and others have both. A cleft palate or lip is usually obvious at birth. However, a cleft palate can vary in size and location and some small clefts can go unnoticed or undetected until later in life. Cleft palate occurs more frequently than cleft lip.AEC syndrome also causes decreased sweat production (hypohidrosis), which causes some affected individuals to be uncomfortable or feel “overheated” when the temperature rises (heat intolerance). Hypohidrosis is due, in part, to reduced number or absence of sweat glands.Additional common findings in AEC syndrome include sparse, wiry, brittle hair that is usually light colored. In some cases, flattened, twisted hair shafts (pili torti) may be present. Eyebrows and eyelashes are also sparse. Nail changes may also occur and can vary greatly among individuals. Such changes include misshapen or malformed fingernails and toenails, abnormally small nail plates (micronychia), frayed edges of the nails, and absent nails. Hair and nail abnormalities become more apparent as affected individuals grow older.Dental abnormalities are also common and can include one or more missing teeth (hypodontia), widely spaced teeth, and malformed or underdeveloped (hypoplastic) teeth. The lower jaw may also be small and underdeveloped (maxillary hypoplasia).Affected individuals may also have narrowing (atresia) or absence of the opening in the edge of each eyelid that is linked to the tear duct (lacrimal punctata). This can lead to obstruction of the tear ducts and predispose to recurrent eye crusting and conjunctivitis. Many individuals with AEC report chronic dry eyes. Chronic inflammation of the eyelids (blepharitis) has also been reported.Less often, certain limb anomalies have been associated with AEC syndrome including webbing of certain fingers or toes (syndactyly) and fingers that are stuck in a bent or flexed position (camptodactyly).Some children experience chronic middle ear infections (otitis media) and approximately 90% develop hearing loss due to the failure of sound waves to be sent (conducted) through the middle ear (conductive hearing loss). Hearing loss can cause delays in speech development.Poor weight gain, growth deficiencies and short stature can also occur. Additional findings that have been reported in individuals with AEC syndrome include abnormally small ears, a broad bridge of the nose, an abnormally short groove that runs from the top of the upper lip to the nose (philtrum), an abnormally small mouth (microstomia), and the inability to completely open the mouth (trismus). In affected males, the opening of the small tube that carries urine from the bladder to outside of the body (urethra) may be abnormally located on the underside of the penis (hypospadias). | 44 | AEC Syndrome |
nord_44_2 | Causes of AEC Syndrome | AEC syndrome is caused by a mutation in the TP63 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. The official name of the gene mutated in AEC syndrome is tumor protein 63 (TP63).The TP63 gene contains instructions for synthesizing (encoding) a protein (p63) that is essential for the proper development of structures derived from the ectoderm. The ectoderm is the outermost germ layer of the developing embryo from which numerous structures of the body are derived, including the skin, hair, nails, glands of the skin, mucous membranes of the mouth, etc. Mutations in this gene lead to abnormal p63 protein function, which hinders the proper development of these structures.AEC syndrome is inherited in an autosomal dominant pattern. Seventy percent of cases of AEC syndrome occur sporadically with no previous family history (i.e., new or “de novo” mutation).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.The symptoms and physical findings of AEC syndrome can vary greatly in severity from one person to another (variable expressivity). In addition, individuals who inherited a defective gene for AEC syndrome may not develop all of the symptoms discussed above. Other factors such as additional genes that modify the expression of a disorder (modifier genes) may play a role in the variable findings of AEC syndrome. | Causes of AEC Syndrome. AEC syndrome is caused by a mutation in the TP63 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. The official name of the gene mutated in AEC syndrome is tumor protein 63 (TP63).The TP63 gene contains instructions for synthesizing (encoding) a protein (p63) that is essential for the proper development of structures derived from the ectoderm. The ectoderm is the outermost germ layer of the developing embryo from which numerous structures of the body are derived, including the skin, hair, nails, glands of the skin, mucous membranes of the mouth, etc. Mutations in this gene lead to abnormal p63 protein function, which hinders the proper development of these structures.AEC syndrome is inherited in an autosomal dominant pattern. Seventy percent of cases of AEC syndrome occur sporadically with no previous family history (i.e., new or “de novo” mutation).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.The symptoms and physical findings of AEC syndrome can vary greatly in severity from one person to another (variable expressivity). In addition, individuals who inherited a defective gene for AEC syndrome may not develop all of the symptoms discussed above. Other factors such as additional genes that modify the expression of a disorder (modifier genes) may play a role in the variable findings of AEC syndrome. | 44 | AEC Syndrome |
nord_44_3 | Affects of AEC Syndrome | AEC syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. AEC syndrome is a rare disorder and fewer than 100 affected individuals have been described in the medical literature. | Affects of AEC Syndrome. AEC syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder in the general population is unknown. AEC syndrome is a rare disorder and fewer than 100 affected individuals have been described in the medical literature. | 44 | AEC Syndrome |
nord_44_4 | Related disorders of AEC Syndrome | Several disorders in addition to AEC syndrome are caused by mutations in different parts of the TP63 gene.Ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome is a rare genetic disorder caused by mutations of the TP63 gene. (For more information choose “EEC” as your search term in the Rare Disease Database.) | Related disorders of AEC Syndrome. Several disorders in addition to AEC syndrome are caused by mutations in different parts of the TP63 gene.Ectrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome is a rare genetic disorder caused by mutations of the TP63 gene. (For more information choose “EEC” as your search term in the Rare Disease Database.) | 44 | AEC Syndrome |
nord_44_5 | Diagnosis of AEC Syndrome | A diagnosis of AEC syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A variety of specialized tests can aid in a diagnosis. For example, molecular examination of small samples of skin tissue (skin biopsy) may reveal specific features such as thinning (atrophy) of the outer layer of the skin (epidermis).Molecular genetic testing can confirm a diagnosis of AEC syndrome. Molecular genetic testing can detect mutations in the TP63 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.Prenatal diagnosis is available for families with a known risk for having a baby with AEC syndrome. | Diagnosis of AEC Syndrome. A diagnosis of AEC syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A variety of specialized tests can aid in a diagnosis. For example, molecular examination of small samples of skin tissue (skin biopsy) may reveal specific features such as thinning (atrophy) of the outer layer of the skin (epidermis).Molecular genetic testing can confirm a diagnosis of AEC syndrome. Molecular genetic testing can detect mutations in the TP63 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.Prenatal diagnosis is available for families with a known risk for having a baby with AEC syndrome. | 44 | AEC Syndrome |
nord_44_6 | Therapies of AEC Syndrome | Treatment
The treatment of AEC 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, ophthalmologists, orthopedic surgeons, dermatologists, dentists, audiologists, otolaryngologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Small ankyloblepharon may breakdown or disintegrate (autolyse) on their own without any treatment. Larger ones may require surgical removal. Surgery may also be necessary for cleft lip, cleft palate, limb malformations, and certain facial anomalies such as underdeveloped jaw.Dental surgery and corrective devices may be used to treat misshapen teeth. If teeth are missing, dentures may be necessary or dental implants may be considered during the teen-aged or early adult years. Affected individuals should pay particular attention to dental health to prevent tooth decay.Skin erosions are often difficult to treat and often do not respond to standard wound care options. Aggressive techniques such as debridement are not recommended and can worsen the condition. Gentle wound care options and periodic treatment with dilute bleach soaks are recommended. A dilute bleach soak involves using an antiseptic solution, such as the Dakins solution, to kill off germs that can grow in a wound. Limiting further trauma to the affected areas of skin is also important.Individuals with chronic skin erosions are at risk of developing secondary infection, which can be treated with topical or oral antibiotics. Anti-fungal medications can also be used in some cases.Myringotomy, a procedure in which a tiny incision is made in the eardrum and a small tube is placed to relieve pressure and drain fluid to treat hearing loss and ear infections. Artificial tears may be necessary for individuals with dry eyes. Hypohidrosis is mild and usually does not require treatment.A child’s weight should be monitored and proper caloric intake provided. If a child is failing to grow properly, consultation with the nutrition team is warranted.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | Therapies of AEC Syndrome. Treatment
The treatment of AEC 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, ophthalmologists, orthopedic surgeons, dermatologists, dentists, audiologists, otolaryngologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.Small ankyloblepharon may breakdown or disintegrate (autolyse) on their own without any treatment. Larger ones may require surgical removal. Surgery may also be necessary for cleft lip, cleft palate, limb malformations, and certain facial anomalies such as underdeveloped jaw.Dental surgery and corrective devices may be used to treat misshapen teeth. If teeth are missing, dentures may be necessary or dental implants may be considered during the teen-aged or early adult years. Affected individuals should pay particular attention to dental health to prevent tooth decay.Skin erosions are often difficult to treat and often do not respond to standard wound care options. Aggressive techniques such as debridement are not recommended and can worsen the condition. Gentle wound care options and periodic treatment with dilute bleach soaks are recommended. A dilute bleach soak involves using an antiseptic solution, such as the Dakins solution, to kill off germs that can grow in a wound. Limiting further trauma to the affected areas of skin is also important.Individuals with chronic skin erosions are at risk of developing secondary infection, which can be treated with topical or oral antibiotics. Anti-fungal medications can also be used in some cases.Myringotomy, a procedure in which a tiny incision is made in the eardrum and a small tube is placed to relieve pressure and drain fluid to treat hearing loss and ear infections. Artificial tears may be necessary for individuals with dry eyes. Hypohidrosis is mild and usually does not require treatment.A child’s weight should be monitored and proper caloric intake provided. If a child is failing to grow properly, consultation with the nutrition team is warranted.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well. | 44 | AEC Syndrome |
nord_45_0 | Overview of African Iron Overload | African iron overload is a rare disorder characterized abnormally elevated levels of iron in the body. The name originates from the initial description of this entity in sub-Saharan Africa, in communities where affected individuals drink a traditional, homemade beer that contains a high amount of iron. Symptoms may vary from case to case but can include the accumulation of fibrous tissue (fibrosis) in the liver and, eventually, scarring of the liver (cirrhosis). The exact cause of African iron overload is unknown, but researchers believe that a combination of dietary and genetic factors result in the development of the disorder.Researches originally believed that the popular, iron-rich beer caused cases of African iron overload. However, many individuals that drank the beer did not develop the disorder and some individuals that did not drink the beer did develop it. This led researchers to speculate that a mutation of a gene or genes involved in the transport or breakdown (metabolism) of iron must play a role in the development of African iron overload. Such a gene has not yet been identified. | Overview of African Iron Overload. African iron overload is a rare disorder characterized abnormally elevated levels of iron in the body. The name originates from the initial description of this entity in sub-Saharan Africa, in communities where affected individuals drink a traditional, homemade beer that contains a high amount of iron. Symptoms may vary from case to case but can include the accumulation of fibrous tissue (fibrosis) in the liver and, eventually, scarring of the liver (cirrhosis). The exact cause of African iron overload is unknown, but researchers believe that a combination of dietary and genetic factors result in the development of the disorder.Researches originally believed that the popular, iron-rich beer caused cases of African iron overload. However, many individuals that drank the beer did not develop the disorder and some individuals that did not drink the beer did develop it. This led researchers to speculate that a mutation of a gene or genes involved in the transport or breakdown (metabolism) of iron must play a role in the development of African iron overload. Such a gene has not yet been identified. | 45 | African Iron Overload |
nord_45_1 | Symptoms of African Iron Overload | The symptoms of African iron overload can vary from one person to another. The disorder usually develops in middle-aged or older adults. Affected individuals often develop abnormal enlargement of the liver (hepatomegaly). In more serious cases, the accumulation of fibrous tissue (fibrosis) in the main vein that supplies blood to the liver (portal vein) may result in high blood pressure in the this vein (portal hypertension). Abnormal fluid retention in the abdominal cavity can cause swelling (ascites). In some cases, scarring of the liver (cirrhosis) and, potentially, liver failure may eventually occur. Additional symptoms have been reported to occur in association with African iron overload depending upon the extent of and exact location of iron accumulation. For example, diabetes may occur because of iron accumulation in the pancreas, the small organ located behind the stomach that produces insulin. Diabetes is a common disorder in which the body does not produce enough or is unable to properly use insulin. Additional conditions that have been associated with African iron overload include bone thinning (osteoporosis), heart (cardiac) abnormalities, and an increased susceptibility to developing infections such as tuberculosis. Individuals with African iron overload are at a greater risk than the general population of developing esophageal cancer or a primary cancer of liver known as hepatocellular carcinoma. | Symptoms of African Iron Overload. The symptoms of African iron overload can vary from one person to another. The disorder usually develops in middle-aged or older adults. Affected individuals often develop abnormal enlargement of the liver (hepatomegaly). In more serious cases, the accumulation of fibrous tissue (fibrosis) in the main vein that supplies blood to the liver (portal vein) may result in high blood pressure in the this vein (portal hypertension). Abnormal fluid retention in the abdominal cavity can cause swelling (ascites). In some cases, scarring of the liver (cirrhosis) and, potentially, liver failure may eventually occur. Additional symptoms have been reported to occur in association with African iron overload depending upon the extent of and exact location of iron accumulation. For example, diabetes may occur because of iron accumulation in the pancreas, the small organ located behind the stomach that produces insulin. Diabetes is a common disorder in which the body does not produce enough or is unable to properly use insulin. Additional conditions that have been associated with African iron overload include bone thinning (osteoporosis), heart (cardiac) abnormalities, and an increased susceptibility to developing infections such as tuberculosis. Individuals with African iron overload are at a greater risk than the general population of developing esophageal cancer or a primary cancer of liver known as hepatocellular carcinoma. | 45 | African Iron Overload |
nord_45_2 | Causes of African Iron Overload | African iron overload was originally believed to be caused in individuals who had a diet high in iron, especially individuals in rural African communities that drank a homemade beer with high amounts of iron. However, many individuals in these regions who did not drink excessive amounts of this iron-rich beer also developed African iron overload. Researchers now believe that African iron overload is caused by mutations of an as yet unidentified gene or genes and can be worsened by a diet high in iron. The most common and best studied form of inherited iron overload is classical hereditary hemochromatosis, which is caused by mutations of the HFE gene. In the past few decades, researchers have identified separate forms of hemochromatosis and iron overload disorders that occur due to mutations of other iron-related genes. Studies have determined that African iron overload is not related to HFE mutations or to any of these other described mutations. More research is necessary to identify the genetic factors that may contribute to the development of this disorder. | Causes of African Iron Overload. African iron overload was originally believed to be caused in individuals who had a diet high in iron, especially individuals in rural African communities that drank a homemade beer with high amounts of iron. However, many individuals in these regions who did not drink excessive amounts of this iron-rich beer also developed African iron overload. Researchers now believe that African iron overload is caused by mutations of an as yet unidentified gene or genes and can be worsened by a diet high in iron. The most common and best studied form of inherited iron overload is classical hereditary hemochromatosis, which is caused by mutations of the HFE gene. In the past few decades, researchers have identified separate forms of hemochromatosis and iron overload disorders that occur due to mutations of other iron-related genes. Studies have determined that African iron overload is not related to HFE mutations or to any of these other described mutations. More research is necessary to identify the genetic factors that may contribute to the development of this disorder. | 45 | African Iron Overload |
nord_45_3 | Affects of African Iron Overload | African iron overload affects males and females in equal numbers. The exact incidence of the disorder is unknown. It has been reported in numerous countries in sub-Saharan Africa. Researchers believe that the disorder often goes unrecognized and is underdiagnosed, making it difficult to determine its true frequency in the general population. Some estimates suggest that iron overload affects more than 10 percent of the population in sub-Saharan Africa. Inherited forms of iron overload have been reported in natives of other countries who may be of African descent (e.g. African Americans). Whether this may represent the same disease as that seen in sub-Saharan Africa remains unknown. | Affects of African Iron Overload. African iron overload affects males and females in equal numbers. The exact incidence of the disorder is unknown. It has been reported in numerous countries in sub-Saharan Africa. Researchers believe that the disorder often goes unrecognized and is underdiagnosed, making it difficult to determine its true frequency in the general population. Some estimates suggest that iron overload affects more than 10 percent of the population in sub-Saharan Africa. Inherited forms of iron overload have been reported in natives of other countries who may be of African descent (e.g. African Americans). Whether this may represent the same disease as that seen in sub-Saharan Africa remains unknown. | 45 | African Iron Overload |
nord_45_4 | Related disorders of African Iron Overload | Symptoms of the following disorders can be similar to those of African iron overload. Comparisons may be useful for a differential diagnosis.Primary disorders of iron overload are a group of primarily rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, atransferrinemia, and neonatal hemochromatosis. Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis (which is not rare); hemochromatosis type 2 (juvenile hemochromatosis); hemochromatosis type 3, also known as TFR-related hemochromatosis; and hemochromatosis type 4, also known as ferroportin disease. The specific symptoms related to these disorders can vary depending upon the location and extent of iron accumulation. Common symptoms include fatigue, abdominal pain, lack of sex drive, joint pain, and heart abnormalities. If left untreated, iron can build up in various organs in the body causing serious, life-threatening complications. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of African Iron Overload. Symptoms of the following disorders can be similar to those of African iron overload. Comparisons may be useful for a differential diagnosis.Primary disorders of iron overload are a group of primarily rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, atransferrinemia, and neonatal hemochromatosis. Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis (which is not rare); hemochromatosis type 2 (juvenile hemochromatosis); hemochromatosis type 3, also known as TFR-related hemochromatosis; and hemochromatosis type 4, also known as ferroportin disease. The specific symptoms related to these disorders can vary depending upon the location and extent of iron accumulation. Common symptoms include fatigue, abdominal pain, lack of sex drive, joint pain, and heart abnormalities. If left untreated, iron can build up in various organs in the body causing serious, life-threatening complications. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 45 | African Iron Overload |
nord_45_5 | Diagnosis of African Iron Overload | A diagnosis of African iron overload is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as blood tests, which can reveal elevated levels of ferritin in the blood plasma. Ferritin is a protein that binds to iron and is used as an indicator of the body’s iron stores. Another test measures transferrin saturation. Transferrin is a protein involved in the transport of iron from the intestine into the bloodstream. | Diagnosis of African Iron Overload. A diagnosis of African iron overload is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as blood tests, which can reveal elevated levels of ferritin in the blood plasma. Ferritin is a protein that binds to iron and is used as an indicator of the body’s iron stores. Another test measures transferrin saturation. Transferrin is a protein involved in the transport of iron from the intestine into the bloodstream. | 45 | African Iron Overload |
nord_45_6 | Therapies of African Iron Overload | TreatmentTherapy involving the regular removal of blood via a vein (known as a venesection or phlebotomy) is a common therapy for disorders associated with excess iron in the blood and should be beneficial to individuals with African iron overload. Controlled clinical studies of therapeutic phlebotomy for individuals with African iron overload have not been done yet but phlebotomy, if tolerated, is considered by many to be the standard of care.Genetic counseling may be of benefit for affected individuals and their families. | Therapies of African Iron Overload. TreatmentTherapy involving the regular removal of blood via a vein (known as a venesection or phlebotomy) is a common therapy for disorders associated with excess iron in the blood and should be beneficial to individuals with African iron overload. Controlled clinical studies of therapeutic phlebotomy for individuals with African iron overload have not been done yet but phlebotomy, if tolerated, is considered by many to be the standard of care.Genetic counseling may be of benefit for affected individuals and their families. | 45 | African Iron Overload |
nord_46_0 | Overview of Agammaglobulinemia | Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes in the blood and lymph. Antibodies are proteins (immunoglobulins, (IgM), (IgG) etc) that are critical and key components of the immune system. They are essential if the immune system is to do its job of fighting off bacteria, viruses, and other foreign substances that threaten the body. The specialized precursor cells that produce gammaglobulins, fail to develop or function properly leading to the deficiency in the number of mature lymphocyte cells called B cells.The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia (ARAG). All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin in order to fight off infections. | Overview of Agammaglobulinemia. Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes in the blood and lymph. Antibodies are proteins (immunoglobulins, (IgM), (IgG) etc) that are critical and key components of the immune system. They are essential if the immune system is to do its job of fighting off bacteria, viruses, and other foreign substances that threaten the body. The specialized precursor cells that produce gammaglobulins, fail to develop or function properly leading to the deficiency in the number of mature lymphocyte cells called B cells.The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia (ARAG). All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin in order to fight off infections. | 46 | Agammaglobulinemia |
nord_46_1 | Symptoms of Agammaglobulinemia | The major symptoms of agammaglobulinemia are serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such infections only late in the first year of life, after the IgG antibodies from the mother have been depleted. Infections by almost any of the enterovirus family and the poliomyelitis virus can result in unusually severe illness in children with agammaglobulinemia. Echovirus infection can cause a group of symptoms that closely resembles dermatomyositis. These symptoms may include muscle weakness, often in the hip and shoulder areas, and difficulty swallowing. Areas of patchy, reddish skin may appear around the eyes, knuckles and elbows and occasionally on the knees and ankles. (For more information on this disorder, choose “dermatomyositis” as your search term in the Rare Disease Database.)Infections caused by mycoplasma bacteria can lead to severe arthritis including joint swelling and pain, in children with primary agammaglobulinemia. Hemophilus influenzae is the most common mucous- producing infection (pyogenic) that occurs in people with X-linked agammaglobulinemia. Children may also have repeated infections with pneumococci, streptococci, and staphylococci bacteria, and infrequently pseudomonas infections.Males with X-linked form of agammaglobulinemia have very low levels of IgA, IgG, and IgM antibodies circulating in their blood. Specialized white blood cells (neutrophils) are impaired in their ability to destroy bacteria, viruses, or other invading organisms (microbes). This occurs because neutrophils require antibodies from the immune system to begin to destroy invading bacteria (opsonization). The levels of circulating neutrophils in children with agammaglobulinemia may be persistently low, or may wax and wane (cyclic, transient neutropenia) in people with these disorders. The number of B-lymphocytes in children with X-linked agammaglobulinemia is less than one one-hundredth of the normal number. Only about 10 persons in 5 or 6 families have been diagnosed with X-linked agammaglobulinemia with growth hormone deficiency. The boys in these families have reduced or undetectable numbers of B-lymphocytes. Clinicians and geneticists speculate that a second mutation in the BTK gene, very close to the mutation in this gene that causes XLA, is responsible for the combination of agammaglobulinemia and very short stature. Autosomal recessive agammaglobulinemia has been reported to be due to genes that affect B cell development. | Symptoms of Agammaglobulinemia. The major symptoms of agammaglobulinemia are serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such infections only late in the first year of life, after the IgG antibodies from the mother have been depleted. Infections by almost any of the enterovirus family and the poliomyelitis virus can result in unusually severe illness in children with agammaglobulinemia. Echovirus infection can cause a group of symptoms that closely resembles dermatomyositis. These symptoms may include muscle weakness, often in the hip and shoulder areas, and difficulty swallowing. Areas of patchy, reddish skin may appear around the eyes, knuckles and elbows and occasionally on the knees and ankles. (For more information on this disorder, choose “dermatomyositis” as your search term in the Rare Disease Database.)Infections caused by mycoplasma bacteria can lead to severe arthritis including joint swelling and pain, in children with primary agammaglobulinemia. Hemophilus influenzae is the most common mucous- producing infection (pyogenic) that occurs in people with X-linked agammaglobulinemia. Children may also have repeated infections with pneumococci, streptococci, and staphylococci bacteria, and infrequently pseudomonas infections.Males with X-linked form of agammaglobulinemia have very low levels of IgA, IgG, and IgM antibodies circulating in their blood. Specialized white blood cells (neutrophils) are impaired in their ability to destroy bacteria, viruses, or other invading organisms (microbes). This occurs because neutrophils require antibodies from the immune system to begin to destroy invading bacteria (opsonization). The levels of circulating neutrophils in children with agammaglobulinemia may be persistently low, or may wax and wane (cyclic, transient neutropenia) in people with these disorders. The number of B-lymphocytes in children with X-linked agammaglobulinemia is less than one one-hundredth of the normal number. Only about 10 persons in 5 or 6 families have been diagnosed with X-linked agammaglobulinemia with growth hormone deficiency. The boys in these families have reduced or undetectable numbers of B-lymphocytes. Clinicians and geneticists speculate that a second mutation in the BTK gene, very close to the mutation in this gene that causes XLA, is responsible for the combination of agammaglobulinemia and very short stature. Autosomal recessive agammaglobulinemia has been reported to be due to genes that affect B cell development. | 46 | Agammaglobulinemia |
nord_46_2 | Causes of Agammaglobulinemia | X-linked agammaglobulinemia (B-lymphocyte defect) is inherited as an X-linked recessive genetic trait. The abnormal gene, named BTK, has been mapped to gene locus Xq21.3-q22. A different mutation in the BTK gene causes X-linked agammaglobulinemia with growth hormone deficiency. The genetic cause of ARAG is much more complex involving other genes that have been mapped to loci on different chromosomes: 22q11.21, 14q32.33, and 9q34.13. The genes at three sites are known as IGLL1, IGHM, and LCRR8 respectively. Chromosomes are located 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. 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 21q11.21” refers to band 11.21 on the long arm of chromosome 21. Similarly 14q32.33 refers to band 32.33 on the long arm of chromosome 14, and 9q34.13 refers to band 34.13 on the long arm of chromosome 9. The site described as Xq21.3-q22 refers to a region on the long arm of the X chromosome between bands 21.3 and 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome. 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. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. 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 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 defective 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Agammaglobulinemia. X-linked agammaglobulinemia (B-lymphocyte defect) is inherited as an X-linked recessive genetic trait. The abnormal gene, named BTK, has been mapped to gene locus Xq21.3-q22. A different mutation in the BTK gene causes X-linked agammaglobulinemia with growth hormone deficiency. The genetic cause of ARAG is much more complex involving other genes that have been mapped to loci on different chromosomes: 22q11.21, 14q32.33, and 9q34.13. The genes at three sites are known as IGLL1, IGHM, and LCRR8 respectively. Chromosomes are located 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. 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 21q11.21” refers to band 11.21 on the long arm of chromosome 21. Similarly 14q32.33 refers to band 32.33 on the long arm of chromosome 14, and 9q34.13 refers to band 34.13 on the long arm of chromosome 9. The site described as Xq21.3-q22 refers to a region on the long arm of the X chromosome between bands 21.3 and 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome. 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. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. 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 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 defective 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 46 | Agammaglobulinemia |
nord_46_3 | Affects of Agammaglobulinemia | Primary Agammaglobulinemia is a rare disorder that occurs almost exclusively in males although some females have been affected by certain types of this disorder. | Affects of Agammaglobulinemia. Primary Agammaglobulinemia is a rare disorder that occurs almost exclusively in males although some females have been affected by certain types of this disorder. | 46 | Agammaglobulinemia |
nord_46_4 | Related disorders of Agammaglobulinemia | Symptoms of the following disorders can be similar to those of primary agammaglobulinemias. Comparisons may be useful for a differential diagnosis:Common Variable Immunodeficiency (CVID) is rare immunodeficiency disorder characterized by recurrent infections in the lungs, sinuses or ears. The range and severity of symptoms and findings associated with CVI may vary from case to case. In some cases, individuals with CVID have an increased tendency to develop infections of the gastrointestinal system and may have a higher risk for some types of cancer such as non-Hodgkin lymphoma and stomach cancer. In addition, some individuals with CVID have an autoimmune disorder such as immune thrombocytopenia purpura that causes abnormal bruising and bleeding. The symptoms of CVI usually become apparent during the second to the fourth decade of life. CVID is thought to be caused by mutations in genes involved in the production of B cells that produce antibodies against infectious agents. CVID is likely to be caused by a combination of genetic and environmental factors in most cases, but autosomal recessive and autosomal dominant inheritance has been described in some families. (For more information on this disorder, choose “CVID” as your search term in the Rare Disease Database.) Hyper-IgM Syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white portion of the eyes, the skin, and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because approximately 70 percent of reported cases of HIGM are X-linked, the vast majority of affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose “Hyper IgM” as your search term in the Rare Disease Database.) Severe combined immunodeficiency (SCID) is the most grave of the primary immunodeficiency disorders. A person with SCID is subject to recurring infections because neither B nor T lymphocytes are present in sufficient numbers or they are malfunctioning. If untreated, this disorder may result in frequent, severe infections, growth retardation, and can be life-threatening. Other symptoms of this disorder may include weight loss, weakness, infections of the middle ear, and skin infections. (For more information on this disorder, choose “severe combined immunodeficiency” as your search term in the Rare Disease Database.)The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis, kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family. (For more information on this disorder, choose “WAS” as your search term in the Rare Disease Database.)IgA deficiency is an antibody deficiency that is related to agammaglobulinemia and is characterized by low levels of IgA in the blood in the presence of normal or increased levels of IgG and IgM. IgA deficiency is the most common primary immunodeficiency. Other deficiencies of immunoglobulin isotopes are IgM deficiency and IgG subclass deficiencies.Complement component 3 deficiency, is a rare inherited immune deficiency characterized by recurrent respiratory infections, skin infections, repeated middle ear infections, and sinusitis. The symptoms of this disorder are very similar to those of some of the agammaglobulinemia. Other symptoms may include pneumonia, bacterial infection of the blood (septicemia), and/or inflammation of the membranes that line the brain (meningitis). Other disorders may also be associated with complement component 3 deficiency including inflammation of blood vessels (vasculitis), joint pain (arthralgias), and autoimmune diseases such as lupus (systemic lupus erythematosus). | Related disorders of Agammaglobulinemia. Symptoms of the following disorders can be similar to those of primary agammaglobulinemias. Comparisons may be useful for a differential diagnosis:Common Variable Immunodeficiency (CVID) is rare immunodeficiency disorder characterized by recurrent infections in the lungs, sinuses or ears. The range and severity of symptoms and findings associated with CVI may vary from case to case. In some cases, individuals with CVID have an increased tendency to develop infections of the gastrointestinal system and may have a higher risk for some types of cancer such as non-Hodgkin lymphoma and stomach cancer. In addition, some individuals with CVID have an autoimmune disorder such as immune thrombocytopenia purpura that causes abnormal bruising and bleeding. The symptoms of CVI usually become apparent during the second to the fourth decade of life. CVID is thought to be caused by mutations in genes involved in the production of B cells that produce antibodies against infectious agents. CVID is likely to be caused by a combination of genetic and environmental factors in most cases, but autosomal recessive and autosomal dominant inheritance has been described in some families. (For more information on this disorder, choose “CVID” as your search term in the Rare Disease Database.) Hyper-IgM Syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white portion of the eyes, the skin, and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because approximately 70 percent of reported cases of HIGM are X-linked, the vast majority of affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose “Hyper IgM” as your search term in the Rare Disease Database.) Severe combined immunodeficiency (SCID) is the most grave of the primary immunodeficiency disorders. A person with SCID is subject to recurring infections because neither B nor T lymphocytes are present in sufficient numbers or they are malfunctioning. If untreated, this disorder may result in frequent, severe infections, growth retardation, and can be life-threatening. Other symptoms of this disorder may include weight loss, weakness, infections of the middle ear, and skin infections. (For more information on this disorder, choose “severe combined immunodeficiency” as your search term in the Rare Disease Database.)The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis, kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family. (For more information on this disorder, choose “WAS” as your search term in the Rare Disease Database.)IgA deficiency is an antibody deficiency that is related to agammaglobulinemia and is characterized by low levels of IgA in the blood in the presence of normal or increased levels of IgG and IgM. IgA deficiency is the most common primary immunodeficiency. Other deficiencies of immunoglobulin isotopes are IgM deficiency and IgG subclass deficiencies.Complement component 3 deficiency, is a rare inherited immune deficiency characterized by recurrent respiratory infections, skin infections, repeated middle ear infections, and sinusitis. The symptoms of this disorder are very similar to those of some of the agammaglobulinemia. Other symptoms may include pneumonia, bacterial infection of the blood (septicemia), and/or inflammation of the membranes that line the brain (meningitis). Other disorders may also be associated with complement component 3 deficiency including inflammation of blood vessels (vasculitis), joint pain (arthralgias), and autoimmune diseases such as lupus (systemic lupus erythematosus). | 46 | Agammaglobulinemia |
nord_46_5 | Diagnosis of Agammaglobulinemia | Diagnosis of Agammaglobulinemia. | 46 | Agammaglobulinemia |
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nord_46_6 | Therapies of Agammaglobulinemia | The administration of intravenous gammaglobulin replacement therapy is a standard treatment for agammaglobulinemia. Intravenous gammaglobulin or subcutaneou. is used to treat agammaglobulinemias and common variable immunodeficiency.Antibiotics are prescribed for people with agammaglobulinemia when bacterial infections occur. Some patients are treated with antibiotics as a preventive measure (prophylactically). All people who are immunodeficient should be protected as much as possible from exposure to infectious diseases. Corticosteroids or any drug that depresses the immune system (immunosuppressant drugs) should be avoided as much as possible, as well as physical activities such as rough contact sports that risk damage to the spleen.In people with immunodeficiency with elevated IgM, there is a tendency to bleed excessively associated with abnormally low levels of circulating platelets in the blood (thrombocytopenia). This may complicate any surgical procedure.Genetic counseling is recommended for people with agammaglobulinemias and their families. Other treatment is symptomatic and supportive. | Therapies of Agammaglobulinemia. The administration of intravenous gammaglobulin replacement therapy is a standard treatment for agammaglobulinemia. Intravenous gammaglobulin or subcutaneou. is used to treat agammaglobulinemias and common variable immunodeficiency.Antibiotics are prescribed for people with agammaglobulinemia when bacterial infections occur. Some patients are treated with antibiotics as a preventive measure (prophylactically). All people who are immunodeficient should be protected as much as possible from exposure to infectious diseases. Corticosteroids or any drug that depresses the immune system (immunosuppressant drugs) should be avoided as much as possible, as well as physical activities such as rough contact sports that risk damage to the spleen.In people with immunodeficiency with elevated IgM, there is a tendency to bleed excessively associated with abnormally low levels of circulating platelets in the blood (thrombocytopenia). This may complicate any surgical procedure.Genetic counseling is recommended for people with agammaglobulinemias and their families. Other treatment is symptomatic and supportive. | 46 | Agammaglobulinemia |
nord_47_0 | Overview of Agenesis of Corpus Callosum | Agenesis of corpus callosum (ACC) is a rare disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. This part of the brain is normally composed of transverse fibers. The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. It can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (Fetal alcohol syndrome) can also result in ACC. In some cases mental retardation may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.ACC is frequently diagnosed during the first two years of life. An epileptic seizure can be the first symptom indicating that a child should be tested for a brain dysfunction. The disorder can also be without apparent symptoms in the mildest cases for many years. | Overview of Agenesis of Corpus Callosum. Agenesis of corpus callosum (ACC) is a rare disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. This part of the brain is normally composed of transverse fibers. The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. It can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (Fetal alcohol syndrome) can also result in ACC. In some cases mental retardation may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.ACC is frequently diagnosed during the first two years of life. An epileptic seizure can be the first symptom indicating that a child should be tested for a brain dysfunction. The disorder can also be without apparent symptoms in the mildest cases for many years. | 47 | Agenesis of Corpus Callosum |
nord_47_1 | Symptoms of Agenesis of Corpus Callosum | Agenesis of corpus callosum (ACC) may initially become evident through the onset of epileptic seizures during the first weeks of life or within the first two years. However, not all individuals with ACC have seizures. (For more information on these types of seizures choose “epilepsy” as your search term in the Rare Disease Database).Other symptoms that may begin early in life are feeding problems and delays in holding the head erect. Sitting, standing and walking may also be delayed. Impairment of mental and physical development, and/or an accumulation of fluid in the skull (hydrocephalus) are also symptomatic of the early onset type of this disorder. (For more information, choose “hydrocephalus” as your search term in the Rare Disease Database.)Non-progressive mental retardation, impaired hand-eye coordination and visual or auditory (hearing) memory impairment can be diagnosed through neurological testing of patients with ACC.In some mild cases, symptoms may not appear for many years. Older patients are usually diagnosed during tests for symptoms such as seizures, monotonous or repetitive speech, or headaches. In mild cases it may be overlooked due to lack of obvious symptoms during childhood.Some patients may have deep-set eyes and a prominent forehead. An abnormally small head (microcephaly), or sometimes an unusually large head (macrocephaly), may be present. Tags of skin in front of the ears (pre-auricular skin tags), one or more bent fingers (camptodactyly), and delayed growth have also been associated with some cases of agenesis of corpus callosum. In other cases wide-set eyes (telecanthus), a small nose with upturned (anteverted) nostrils, abnormally shaped ears, excessive neck skin, short hands, diminished muscle tone (hypotonia), abnormalities of the larynx, heart defects, and symptoms of Pierre-Robin syndrome may be present. (For more information choose “Pierre-Robin” as your search term in the Rare Disease Database).Aicardi syndrome, thought to be inherited as an X-linked dominant disorder, consists of agenesis of corpus callosum, infantile spasms, and abnormal eye structure. This disorder is an extremely rare congenital disorder in which frequent seizures, striking abnormalities of the eye's middle coat (choroid) and retinal layers, and the absence of the structure linking the two cerebral hemispheres (the corpus callosum), accompany severe mental retardation. Only females are affected. (For more information on this disorder, choose “Aicardi” as your search term in the Rare Disease Database).Andermann syndrome, identified in 1972, is a genetic disorder characterized by a combination of agenesis of corpus callosum, mental retardation, and progressive sensorimotor nervous system disturbances (neuropathy). All known cases of this disorder originate from Charlevois County and the Saguenay-Lac St. Jean area of Quebec, Canada. The gene causing this rare form of ACC was recently identified and testing for this gene (SLC12A6) is currently available.XLAG (X linked lissencephaly with ambiguous genitalia is a rare genetic disorder in which males have small and smooth brains (lissencephaly), small penis, severe mental retardation and intractable epilepsy. This is caused by mutations in the ARX gene. In females, these same mutations can cause ACC alone, whereas less severe mutations in males can cause mental retardation. Testing for this disorder is also clinically available. | Symptoms of Agenesis of Corpus Callosum. Agenesis of corpus callosum (ACC) may initially become evident through the onset of epileptic seizures during the first weeks of life or within the first two years. However, not all individuals with ACC have seizures. (For more information on these types of seizures choose “epilepsy” as your search term in the Rare Disease Database).Other symptoms that may begin early in life are feeding problems and delays in holding the head erect. Sitting, standing and walking may also be delayed. Impairment of mental and physical development, and/or an accumulation of fluid in the skull (hydrocephalus) are also symptomatic of the early onset type of this disorder. (For more information, choose “hydrocephalus” as your search term in the Rare Disease Database.)Non-progressive mental retardation, impaired hand-eye coordination and visual or auditory (hearing) memory impairment can be diagnosed through neurological testing of patients with ACC.In some mild cases, symptoms may not appear for many years. Older patients are usually diagnosed during tests for symptoms such as seizures, monotonous or repetitive speech, or headaches. In mild cases it may be overlooked due to lack of obvious symptoms during childhood.Some patients may have deep-set eyes and a prominent forehead. An abnormally small head (microcephaly), or sometimes an unusually large head (macrocephaly), may be present. Tags of skin in front of the ears (pre-auricular skin tags), one or more bent fingers (camptodactyly), and delayed growth have also been associated with some cases of agenesis of corpus callosum. In other cases wide-set eyes (telecanthus), a small nose with upturned (anteverted) nostrils, abnormally shaped ears, excessive neck skin, short hands, diminished muscle tone (hypotonia), abnormalities of the larynx, heart defects, and symptoms of Pierre-Robin syndrome may be present. (For more information choose “Pierre-Robin” as your search term in the Rare Disease Database).Aicardi syndrome, thought to be inherited as an X-linked dominant disorder, consists of agenesis of corpus callosum, infantile spasms, and abnormal eye structure. This disorder is an extremely rare congenital disorder in which frequent seizures, striking abnormalities of the eye's middle coat (choroid) and retinal layers, and the absence of the structure linking the two cerebral hemispheres (the corpus callosum), accompany severe mental retardation. Only females are affected. (For more information on this disorder, choose “Aicardi” as your search term in the Rare Disease Database).Andermann syndrome, identified in 1972, is a genetic disorder characterized by a combination of agenesis of corpus callosum, mental retardation, and progressive sensorimotor nervous system disturbances (neuropathy). All known cases of this disorder originate from Charlevois County and the Saguenay-Lac St. Jean area of Quebec, Canada. The gene causing this rare form of ACC was recently identified and testing for this gene (SLC12A6) is currently available.XLAG (X linked lissencephaly with ambiguous genitalia is a rare genetic disorder in which males have small and smooth brains (lissencephaly), small penis, severe mental retardation and intractable epilepsy. This is caused by mutations in the ARX gene. In females, these same mutations can cause ACC alone, whereas less severe mutations in males can cause mental retardation. Testing for this disorder is also clinically available. | 47 | Agenesis of Corpus Callosum |
nord_47_2 | Causes of Agenesis of Corpus Callosum | In most cases, the cause of ACC is unknown. However, agenesis of corpus callosum can be inherited as an autosomal recessive trait or an X-linked dominant trait. This disorder may also be due in part to an infection during pregnancy (intrauterine) leading to abnormal development of the fetal brain.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.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 defective 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.In X-linked dominant disorders, a female with only one X chromosome with an abnormal gene will develop the disease. However, the affected male always has a more severe condition. Sometimes, affected males die before birth so that only female patients survive. This seems to be true for one form of agenesis of corpus callosum known as Aicardi syndrome. The majority of patients diagnosed so far have been females. Aicardi syndrome has been seen occasionally in males with an extra X chromosome. | Causes of Agenesis of Corpus Callosum. In most cases, the cause of ACC is unknown. However, agenesis of corpus callosum can be inherited as an autosomal recessive trait or an X-linked dominant trait. This disorder may also be due in part to an infection during pregnancy (intrauterine) leading to abnormal development of the fetal brain.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.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 defective 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.In X-linked dominant disorders, a female with only one X chromosome with an abnormal gene will develop the disease. However, the affected male always has a more severe condition. Sometimes, affected males die before birth so that only female patients survive. This seems to be true for one form of agenesis of corpus callosum known as Aicardi syndrome. The majority of patients diagnosed so far have been females. Aicardi syndrome has been seen occasionally in males with an extra X chromosome. | 47 | Agenesis of Corpus Callosum |
nord_47_3 | Affects of Agenesis of Corpus Callosum | Agenesis of Corpus Callosum produces symptoms during the first two years of life in approximately ninety percent of those affected. It has been thought to be a very rare condition but the increased use of neuro-imaging techniques, such as MRI, is resulting in an increased rate of diagnosis. This condition may also be identified during pregnancy through an ultrasound. Currently, the highest estimate of incidence is 7 in 1000 individuals. | Affects of Agenesis of Corpus Callosum. Agenesis of Corpus Callosum produces symptoms during the first two years of life in approximately ninety percent of those affected. It has been thought to be a very rare condition but the increased use of neuro-imaging techniques, such as MRI, is resulting in an increased rate of diagnosis. This condition may also be identified during pregnancy through an ultrasound. Currently, the highest estimate of incidence is 7 in 1000 individuals. | 47 | Agenesis of Corpus Callosum |
nord_47_4 | Related disorders of Agenesis of Corpus Callosum | Agenesis of corpus callosum can occur in conjunction with spina bifida. Spina bifida is a term meaning open (or non-fused) spine. In spina bifida, one or more of the individual bones of the spine fails to close completely, leaving a cleft or defect in the spinal canal. Part of the contents of the spine can protrude or herniate through this abnormal opening that produces a meningocele or meningomyelocele. (For more information on this disorder, choose “spina bifida” as your search term in the Rare Disease Database.) | Related disorders of Agenesis of Corpus Callosum. Agenesis of corpus callosum can occur in conjunction with spina bifida. Spina bifida is a term meaning open (or non-fused) spine. In spina bifida, one or more of the individual bones of the spine fails to close completely, leaving a cleft or defect in the spinal canal. Part of the contents of the spine can protrude or herniate through this abnormal opening that produces a meningocele or meningomyelocele. (For more information on this disorder, choose “spina bifida” as your search term in the Rare Disease Database.) | 47 | Agenesis of Corpus Callosum |
nord_47_5 | Diagnosis of Agenesis of Corpus Callosum | Ultrasound and magnetic resonance imaging (MRI) are imaging techniques that aid in diagnosis of agenesis of corpus callosum. | Diagnosis of Agenesis of Corpus Callosum. Ultrasound and magnetic resonance imaging (MRI) are imaging techniques that aid in diagnosis of agenesis of corpus callosum. | 47 | Agenesis of Corpus Callosum |
nord_47_6 | Therapies of Agenesis of Corpus Callosum | TreatmentTreatment is symptomatic and supportive. Anti-seizure medications, special education, physical therapy, and related services may be of benefit depending upon the range and severity of symptoms. When hydrocephalus is present it may be treated with a surgical shunt to drain the fluid from the brain cavity, thereby lowering the increased pressure on the brain. Genetic counseling may also be of benefit to families with this disorder. | Therapies of Agenesis of Corpus Callosum. TreatmentTreatment is symptomatic and supportive. Anti-seizure medications, special education, physical therapy, and related services may be of benefit depending upon the range and severity of symptoms. When hydrocephalus is present it may be treated with a surgical shunt to drain the fluid from the brain cavity, thereby lowering the increased pressure on the brain. Genetic counseling may also be of benefit to families with this disorder. | 47 | Agenesis of Corpus Callosum |
nord_48_0 | Overview of Agranulocytosis, Acquired | Acquired agranulocytosis is a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of white blood cells (granulocytes) in the circulating blood. The name granulocyte refers to grain-like bodies within the cell. Granulocytes include basophils, eosinophils, and neutrophils.Acquired agranulocytosis may be caused by a variety of drugs. However, among the drugs to which a patient may be sensitive are several used in the treatment of cancer (cancer chemotherapeutic agents) and others used as antipsychotic medications (e.g., clozapine). The symptoms of this disorder come about as the result of interference in the production of granulocytes in the bone marrow.People with acquired agranulocytosis are susceptible to a variety of bacterial infections, usually caused by otherwise benign bacteria found in the body. Not infrequently, painful ulcers also develop in mucous membranes that line the mouth and/or the gastrointestinal tract. | Overview of Agranulocytosis, Acquired. Acquired agranulocytosis is a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of white blood cells (granulocytes) in the circulating blood. The name granulocyte refers to grain-like bodies within the cell. Granulocytes include basophils, eosinophils, and neutrophils.Acquired agranulocytosis may be caused by a variety of drugs. However, among the drugs to which a patient may be sensitive are several used in the treatment of cancer (cancer chemotherapeutic agents) and others used as antipsychotic medications (e.g., clozapine). The symptoms of this disorder come about as the result of interference in the production of granulocytes in the bone marrow.People with acquired agranulocytosis are susceptible to a variety of bacterial infections, usually caused by otherwise benign bacteria found in the body. Not infrequently, painful ulcers also develop in mucous membranes that line the mouth and/or the gastrointestinal tract. | 48 | Agranulocytosis, Acquired |
nord_48_1 | Symptoms of Agranulocytosis, Acquired | The first symptoms of acquired agranulocytosis are usually those associated with a bacterial infection such as general weakness, chills, fever, and/or extreme exhaustion. Symptoms that are associated with rapidly falling white blood cell levels (granulocytopenia) may include the development of infected ulcers in the mucous membranes that line the mouth, throat, and/or intestinal tract. Some people with these ulcers may experience difficulty swallowing due to irritation and pain.Granulocytopenia causes a concurrent decrease in the number of neutrophils in the circulating blood (neutropenia). As neutrophil levels decrease, the susceptibility of patients with acquired agranulocytosis to bacterial infections becomes even greater. Fevers and abnormal enlargement of the spleen (splenomegaly) are characteristic features of neutropenia. If neutropenia is not treated, bacterial infections can lead to life-threatening complications such as bacterial shock or bacterial contamination of the blood (sepsis.) (For more information on this disorder, choose “Neutropenia” as your search term in the Rare Disease Database.)Chronic acquired agranulocytosis generally progresses more slowly than acquired agranulocytosis. Canker sores in the mouth and chronic inflammation of the gums (gingivitis) may be recurring symptoms. Other systemic infections may recur regularly. | Symptoms of Agranulocytosis, Acquired. The first symptoms of acquired agranulocytosis are usually those associated with a bacterial infection such as general weakness, chills, fever, and/or extreme exhaustion. Symptoms that are associated with rapidly falling white blood cell levels (granulocytopenia) may include the development of infected ulcers in the mucous membranes that line the mouth, throat, and/or intestinal tract. Some people with these ulcers may experience difficulty swallowing due to irritation and pain.Granulocytopenia causes a concurrent decrease in the number of neutrophils in the circulating blood (neutropenia). As neutrophil levels decrease, the susceptibility of patients with acquired agranulocytosis to bacterial infections becomes even greater. Fevers and abnormal enlargement of the spleen (splenomegaly) are characteristic features of neutropenia. If neutropenia is not treated, bacterial infections can lead to life-threatening complications such as bacterial shock or bacterial contamination of the blood (sepsis.) (For more information on this disorder, choose “Neutropenia” as your search term in the Rare Disease Database.)Chronic acquired agranulocytosis generally progresses more slowly than acquired agranulocytosis. Canker sores in the mouth and chronic inflammation of the gums (gingivitis) may be recurring symptoms. Other systemic infections may recur regularly. | 48 | Agranulocytosis, Acquired |
nord_48_2 | Causes of Agranulocytosis, Acquired | Acquired agranulocytosis is almost invariably caused by exposure to drugs and/or chemicals. Any chemical or drug that depresses the activity of the bone marrow may cause agranulocytosis. Some drugs cause this reaction in anyone given large enough doses. Other drugs may cause the reaction in one person but not in another (idiosyncratic). Clinicians do not understand why some people are susceptible to agranulocytosis and others are not.In some instances, the action of some drugs or chemicals suggests that the immune system is involved. In the case of gold, or anti-thyroid drugs, or quinidine, among others, antibodies are created that appear to break the granulocytes down. Other drugs that interfere with, or inhibit, granulocyte colony formation may induce agranulocytosis. Drugs with this characteristic include valproic acid, carbamazepine, and the beta-lactam antibiotics. A complicating factor is that several commonly used anti-cancer drugs are prone to cause agranulocytosis, thus interfering with treatment. The same may be said for several anti-psychotic medications.A variety of drugs can cause acquired agranulocytosis and neutropenia by destroying special cells in the bone marrow that later mature and become granulocytes (precursors). These drugs include phenytoin, pyrimethamine, methotrexate, and cytarabine. In rare cases of acute acquired agranulocytosis, destructive action of certain white blood cell antibodies (leukocyte isoantibodies) may be induced by certain drugs such as phenylbutazone, gold salts, sulfapyridine, aminopyrine, meralluride, and dipyrine. | Causes of Agranulocytosis, Acquired. Acquired agranulocytosis is almost invariably caused by exposure to drugs and/or chemicals. Any chemical or drug that depresses the activity of the bone marrow may cause agranulocytosis. Some drugs cause this reaction in anyone given large enough doses. Other drugs may cause the reaction in one person but not in another (idiosyncratic). Clinicians do not understand why some people are susceptible to agranulocytosis and others are not.In some instances, the action of some drugs or chemicals suggests that the immune system is involved. In the case of gold, or anti-thyroid drugs, or quinidine, among others, antibodies are created that appear to break the granulocytes down. Other drugs that interfere with, or inhibit, granulocyte colony formation may induce agranulocytosis. Drugs with this characteristic include valproic acid, carbamazepine, and the beta-lactam antibiotics. A complicating factor is that several commonly used anti-cancer drugs are prone to cause agranulocytosis, thus interfering with treatment. The same may be said for several anti-psychotic medications.A variety of drugs can cause acquired agranulocytosis and neutropenia by destroying special cells in the bone marrow that later mature and become granulocytes (precursors). These drugs include phenytoin, pyrimethamine, methotrexate, and cytarabine. In rare cases of acute acquired agranulocytosis, destructive action of certain white blood cell antibodies (leukocyte isoantibodies) may be induced by certain drugs such as phenylbutazone, gold salts, sulfapyridine, aminopyrine, meralluride, and dipyrine. | 48 | Agranulocytosis, Acquired |
nord_48_3 | Affects of Agranulocytosis, Acquired | Acquired Agranulocytosis is a rare blood disorder that affects males and females in equal numbers. People who are taking certain medications such as cancer drugs, alkylating agents, anti-thyroid drugs, dibenzepin compounds, or other drugs can be at risk for this disorder. | Affects of Agranulocytosis, Acquired. Acquired Agranulocytosis is a rare blood disorder that affects males and females in equal numbers. People who are taking certain medications such as cancer drugs, alkylating agents, anti-thyroid drugs, dibenzepin compounds, or other drugs can be at risk for this disorder. | 48 | Agranulocytosis, Acquired |
nord_48_4 | Related disorders of Agranulocytosis, Acquired | Symptoms of the following disorders can be similar to those of Acquired Agranulocytosis. Comparisons may be useful for a differential diagnosis:Chronic Granulomatous Disease is a very rare blood disorder that affects specialized white blood cells (i.e., neutrophils) and is characterized by widespread granular lesions in many areas of the body. People with this disorder have repeated infectious diseases, including abscesses of the liver; respiratory infections and pneumonia; and inflammation of the lymph nodes (suppurative lymphadenitis) and the spinal cord (osteomyelitis). Chronic infections may be evident in the liver, gastrointestinal tract, eyes, and/or brain. (For more information on this disorder, choose “Granulomatous Disease” as your search term in the Rare Disease Database.)Wegener's Granulomatosis is a rare multisystem disease that is characterized by inflammation and degenerative changes in the blood vessels that serve the lungs and upper respiratory tract. Acute inflammation may also occur in the blood vessels of the kidneys (glomerulonephritis). The symptoms vary greatly among affected individuals, and the disease can be limited to one or more systems of the body. The first symptoms of Wegener's Granulomatosis is usually those of an upper respiratory tract infection including nasal discharge, headache, and coughing accompanied by a mucous discharge. Other early symptoms may include fever, a general feeling of ill health, and weight loss. Symptoms that develop later in the course of the disease may affect the eyes, facial nerves, central nervous system, and/or heart. (For more information on this disorder, choose “Wegener's Granulomatosis” as your search term in the Rare Disease Database.)Sarcoidosis is a rare disorder that affects many systems of the body. It is characterized by small round lesions (tubercles) of granular material. Symptoms vary depending on the severity of the disease. They may be absent, slight, or severe. Organ function may be impaired by active granulomatous disease or by fibrous changes that are associated with acute inflammation. The initial symptoms may include fever, weight loss, and/or joint pain. Persistent fever is especially common with liver (hepatic) involvement. Enlargement of lymph glands is also common and usually without symptoms. The lungs and the lymph glands between the lungs are frequently affected, and symptoms may include coughing and difficulty breathing. (For more information on this disorder, choose “Sarcoidosis” as your search term in the Rare Disease Database.)Leukemia is a group of malignant blood diseases affecting the white blood cells (leukocytes). These leukocytes play an important part in the body's defenses against infection. Leukemia can affect both children and adults. Symptoms may include swollen lymph nodes, an enlarged spleen and liver, fevers, weight loss, paleness, fatigue, easy bruising, excessive bleeding, and/or repeated infections. (For more information on this disorder, choose “Leukemia” as your search term in the Rare Disease Database.)Myelofibrosis-Osteosclerosis is a rare disorder that is characterized by the growth of fibrous tissue in the bone marrow. This will result in anemia, generalized weakness, and fatigue due to low levels of red blood cells. Severe pain in the abdomen, bones, and joints may also occur. (For more information on this disorder, choose “Myelofibrosis” as your search term in the Rare Disease Database.) | Related disorders of Agranulocytosis, Acquired. Symptoms of the following disorders can be similar to those of Acquired Agranulocytosis. Comparisons may be useful for a differential diagnosis:Chronic Granulomatous Disease is a very rare blood disorder that affects specialized white blood cells (i.e., neutrophils) and is characterized by widespread granular lesions in many areas of the body. People with this disorder have repeated infectious diseases, including abscesses of the liver; respiratory infections and pneumonia; and inflammation of the lymph nodes (suppurative lymphadenitis) and the spinal cord (osteomyelitis). Chronic infections may be evident in the liver, gastrointestinal tract, eyes, and/or brain. (For more information on this disorder, choose “Granulomatous Disease” as your search term in the Rare Disease Database.)Wegener's Granulomatosis is a rare multisystem disease that is characterized by inflammation and degenerative changes in the blood vessels that serve the lungs and upper respiratory tract. Acute inflammation may also occur in the blood vessels of the kidneys (glomerulonephritis). The symptoms vary greatly among affected individuals, and the disease can be limited to one or more systems of the body. The first symptoms of Wegener's Granulomatosis is usually those of an upper respiratory tract infection including nasal discharge, headache, and coughing accompanied by a mucous discharge. Other early symptoms may include fever, a general feeling of ill health, and weight loss. Symptoms that develop later in the course of the disease may affect the eyes, facial nerves, central nervous system, and/or heart. (For more information on this disorder, choose “Wegener's Granulomatosis” as your search term in the Rare Disease Database.)Sarcoidosis is a rare disorder that affects many systems of the body. It is characterized by small round lesions (tubercles) of granular material. Symptoms vary depending on the severity of the disease. They may be absent, slight, or severe. Organ function may be impaired by active granulomatous disease or by fibrous changes that are associated with acute inflammation. The initial symptoms may include fever, weight loss, and/or joint pain. Persistent fever is especially common with liver (hepatic) involvement. Enlargement of lymph glands is also common and usually without symptoms. The lungs and the lymph glands between the lungs are frequently affected, and symptoms may include coughing and difficulty breathing. (For more information on this disorder, choose “Sarcoidosis” as your search term in the Rare Disease Database.)Leukemia is a group of malignant blood diseases affecting the white blood cells (leukocytes). These leukocytes play an important part in the body's defenses against infection. Leukemia can affect both children and adults. Symptoms may include swollen lymph nodes, an enlarged spleen and liver, fevers, weight loss, paleness, fatigue, easy bruising, excessive bleeding, and/or repeated infections. (For more information on this disorder, choose “Leukemia” as your search term in the Rare Disease Database.)Myelofibrosis-Osteosclerosis is a rare disorder that is characterized by the growth of fibrous tissue in the bone marrow. This will result in anemia, generalized weakness, and fatigue due to low levels of red blood cells. Severe pain in the abdomen, bones, and joints may also occur. (For more information on this disorder, choose “Myelofibrosis” as your search term in the Rare Disease Database.) | 48 | Agranulocytosis, Acquired |
nord_48_5 | Diagnosis of Agranulocytosis, Acquired | The diagnosis of acquired agranulocytosis is made by combining a thorough history with tests to confirm abnormally low levels of granulocytes in the circulating blood. Regular periodic blood testing is required for individuals who take drugs that place them at high risk for acquired agranulocytosis. In some cases (e.g., people who are taking clozapine), blood tests to monitor granulocyte levels are done on a weekly basis. | Diagnosis of Agranulocytosis, Acquired. The diagnosis of acquired agranulocytosis is made by combining a thorough history with tests to confirm abnormally low levels of granulocytes in the circulating blood. Regular periodic blood testing is required for individuals who take drugs that place them at high risk for acquired agranulocytosis. In some cases (e.g., people who are taking clozapine), blood tests to monitor granulocyte levels are done on a weekly basis. | 48 | Agranulocytosis, Acquired |
nord_48_6 | Therapies of Agranulocytosis, Acquired | TreatmentFilgrastim (Neupogen) has been designated an orphan drug and approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe, chronic neutropenia; and it has become a standard treatment for acquired agranulocytosis. Filgrastim is one of a class of colony-stimulating factors that does, indeed, stimulate the proliferation and differentiation of neutrophils. It is manufactured by Amgen, Inc., using recombinant DNA technology.The treatment of acquired agranulocytosis includes the identification and elimination of drugs or other agents that induce this disorder. Antibiotic medications may also be prescribed if there is a positive blood culture for the presence of bacteria or if a significant local infection develops.Treatment in adults with antibiotics should be limited to about 7-10 days since longer duration carries with it a greater risk of kidney (renal) complications and may set the stage for a new infection. When granulocyte levels return to a near normal range, fever and infections will generally subside.There is no definitive therapy that can stimulate bone marrow (myeloid) recovery. Corticosteroids are sometimes used to treat shock induced by overwhelming bacterial infection. However, these drugs are not recommended for the treatment of acute agranulocytopenia because they may mask other bacterial infections.People with abnormally low levels of immune factors in their blood (hypogammaglobulinemia) associated with acquired agranulocytosis are usually treated with infusions of gamma globulin.Mouth and throat ulcers associated with acquired agranulocytosis can be soothed with gargles of salt (saline) or hydrogen peroxide solutions. Anesthetic lozenges may also help to relieve irritation in the mouth and throat. Mouthwashes that contain the antifungal drug nystatin can be used to treat oral fungal infection (i.e., thrush or candida). A semi-solid or liquid diet may become necessary during episodes of acute oral and gastrointestinal inflammation. (For more information on this disorder, choose "Candidiasis" as your search term in the Rare Disease Database.)People with chronic granulocytopenia associated with acquired agranulocytosis need to be hospitalized during acute episodes of infection. These affected individuals should be taught to recognize the early symptoms and signs of acute infection and to seek immediate medical attention when necessary. The therapy for chronically affected individuals is similar to that for the acute form of the disease. People with chronic granulocytopenia, who take low-dose oral antibiotics on a rotating basis, must also be monitored for the infections caused by drug-resistant bacteria as well as infections with opportunistic organisms (e.g., fungi, cytomegalovirus). (For more information on this disorder, choose "Opportunistic Infections" as your search term in the Rare Disease Database.) | Therapies of Agranulocytosis, Acquired. TreatmentFilgrastim (Neupogen) has been designated an orphan drug and approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe, chronic neutropenia; and it has become a standard treatment for acquired agranulocytosis. Filgrastim is one of a class of colony-stimulating factors that does, indeed, stimulate the proliferation and differentiation of neutrophils. It is manufactured by Amgen, Inc., using recombinant DNA technology.The treatment of acquired agranulocytosis includes the identification and elimination of drugs or other agents that induce this disorder. Antibiotic medications may also be prescribed if there is a positive blood culture for the presence of bacteria or if a significant local infection develops.Treatment in adults with antibiotics should be limited to about 7-10 days since longer duration carries with it a greater risk of kidney (renal) complications and may set the stage for a new infection. When granulocyte levels return to a near normal range, fever and infections will generally subside.There is no definitive therapy that can stimulate bone marrow (myeloid) recovery. Corticosteroids are sometimes used to treat shock induced by overwhelming bacterial infection. However, these drugs are not recommended for the treatment of acute agranulocytopenia because they may mask other bacterial infections.People with abnormally low levels of immune factors in their blood (hypogammaglobulinemia) associated with acquired agranulocytosis are usually treated with infusions of gamma globulin.Mouth and throat ulcers associated with acquired agranulocytosis can be soothed with gargles of salt (saline) or hydrogen peroxide solutions. Anesthetic lozenges may also help to relieve irritation in the mouth and throat. Mouthwashes that contain the antifungal drug nystatin can be used to treat oral fungal infection (i.e., thrush or candida). A semi-solid or liquid diet may become necessary during episodes of acute oral and gastrointestinal inflammation. (For more information on this disorder, choose "Candidiasis" as your search term in the Rare Disease Database.)People with chronic granulocytopenia associated with acquired agranulocytosis need to be hospitalized during acute episodes of infection. These affected individuals should be taught to recognize the early symptoms and signs of acute infection and to seek immediate medical attention when necessary. The therapy for chronically affected individuals is similar to that for the acute form of the disease. People with chronic granulocytopenia, who take low-dose oral antibiotics on a rotating basis, must also be monitored for the infections caused by drug-resistant bacteria as well as infections with opportunistic organisms (e.g., fungi, cytomegalovirus). (For more information on this disorder, choose "Opportunistic Infections" as your search term in the Rare Disease Database.) | 48 | Agranulocytosis, Acquired |
nord_49_0 | Overview of Ahumada-Del Castillo Syndrome | Ahumada-Del Castillo is a rare endocrine disorder affecting adult females, which is characterized by impairment in the function of the pituitary and hypothalamus glands. Symptoms may include the production of breast milk (lactation) not associated with nursing and the absence of menstrual periods (amenorrhea) due to the lack of monthly ovulation (anovulation). | Overview of Ahumada-Del Castillo Syndrome. Ahumada-Del Castillo is a rare endocrine disorder affecting adult females, which is characterized by impairment in the function of the pituitary and hypothalamus glands. Symptoms may include the production of breast milk (lactation) not associated with nursing and the absence of menstrual periods (amenorrhea) due to the lack of monthly ovulation (anovulation). | 49 | Ahumada-Del Castillo Syndrome |
nord_49_1 | Symptoms of Ahumada-Del Castillo Syndrome | The symptoms of Ahumada-Del Castillo syndrome include the abnormal production of breast milk (galactorrhea) without childbirth and nursing, and the lack of regular menstrual periods (amenorrhea). Women with this disorder have breasts and nipples of normal size and appearance. Secondary female sexual characteristics, such as hair distribution and voice, are also normal. Since the ovaries do not produce eggs, affected females cannot become pregnant. | Symptoms of Ahumada-Del Castillo Syndrome. The symptoms of Ahumada-Del Castillo syndrome include the abnormal production of breast milk (galactorrhea) without childbirth and nursing, and the lack of regular menstrual periods (amenorrhea). Women with this disorder have breasts and nipples of normal size and appearance. Secondary female sexual characteristics, such as hair distribution and voice, are also normal. Since the ovaries do not produce eggs, affected females cannot become pregnant. | 49 | Ahumada-Del Castillo Syndrome |
nord_49_2 | Causes of Ahumada-Del Castillo Syndrome | The exact cause of Ahumada-Del Castillo syndrome is not known, although some research suggests that small tumors in the pituitary or hypothalamus glands may be responsible for some cases. These tumors are frequently microscopic and extremely difficult to detect. Rarer causes of Ahumada-Del Castillo syndrome may be associated with low levels of thyroid hormone (hypothyroidism), chronic use of drugs that inhibit dopamine (antagonistics) (e.g., chlorpromazine or thorazine), and discontinuation of oral contraceptives (birth control pills). In all cases, an over-secretion of the milk-producing hormone prolactin (hyperprolactinemia) results in the symptoms of Ahumada-Del Castillo. | Causes of Ahumada-Del Castillo Syndrome. The exact cause of Ahumada-Del Castillo syndrome is not known, although some research suggests that small tumors in the pituitary or hypothalamus glands may be responsible for some cases. These tumors are frequently microscopic and extremely difficult to detect. Rarer causes of Ahumada-Del Castillo syndrome may be associated with low levels of thyroid hormone (hypothyroidism), chronic use of drugs that inhibit dopamine (antagonistics) (e.g., chlorpromazine or thorazine), and discontinuation of oral contraceptives (birth control pills). In all cases, an over-secretion of the milk-producing hormone prolactin (hyperprolactinemia) results in the symptoms of Ahumada-Del Castillo. | 49 | Ahumada-Del Castillo Syndrome |
nord_49_3 | Affects of Ahumada-Del Castillo Syndrome | Ahumada-Del Castillo affects only females. The symptoms usually begin during adulthood. | Affects of Ahumada-Del Castillo Syndrome. Ahumada-Del Castillo affects only females. The symptoms usually begin during adulthood. | 49 | Ahumada-Del Castillo Syndrome |
nord_49_4 | Related disorders of Ahumada-Del Castillo Syndrome | Symptoms of the following disorders can be similar to those of Ahumada-Del Castillo syndrome. Comparisons may be useful for a differential diagnosis:Chiari-Frommel syndrome is a rare endocrine disorder that affects females who have recently had a baby (postpartum). It is characterized by the production of breast milk (lactation), lack of ovulation (anovulation), and the absence of regular menstrual periods (amenorrhea) for more than 6 months. Other symptoms may include emotional distress, anxiety, headaches, backaches, abdominal pain, impaired vision, and/or obesity. (For more information on this disorder, choose “Chiari-Frommel” as your search term in the Rare Disease Database.)Forbes-Albright syndrome is one in a group of rare endocrine disorders characterized by abnormally high levels of the hormone prolactin due to a tumor of the pituitary gland. Symptoms include the production and secretion of milk from the breasts (lactation) without associated childbirth or nursing (galactorrhea), and the absence of a regular menstrual period (amenorrhea). Women with Forbes-Albright syndrome generally have breasts and nipples of normal size and appearance, but the pattern of body hair and sexual drive may be reduced. (For more information on this disorder, choose “Forbes-Albright” as your search term in the Rare Disease Database.) | Related disorders of Ahumada-Del Castillo Syndrome. Symptoms of the following disorders can be similar to those of Ahumada-Del Castillo syndrome. Comparisons may be useful for a differential diagnosis:Chiari-Frommel syndrome is a rare endocrine disorder that affects females who have recently had a baby (postpartum). It is characterized by the production of breast milk (lactation), lack of ovulation (anovulation), and the absence of regular menstrual periods (amenorrhea) for more than 6 months. Other symptoms may include emotional distress, anxiety, headaches, backaches, abdominal pain, impaired vision, and/or obesity. (For more information on this disorder, choose “Chiari-Frommel” as your search term in the Rare Disease Database.)Forbes-Albright syndrome is one in a group of rare endocrine disorders characterized by abnormally high levels of the hormone prolactin due to a tumor of the pituitary gland. Symptoms include the production and secretion of milk from the breasts (lactation) without associated childbirth or nursing (galactorrhea), and the absence of a regular menstrual period (amenorrhea). Women with Forbes-Albright syndrome generally have breasts and nipples of normal size and appearance, but the pattern of body hair and sexual drive may be reduced. (For more information on this disorder, choose “Forbes-Albright” as your search term in the Rare Disease Database.) | 49 | Ahumada-Del Castillo Syndrome |
nord_49_5 | Diagnosis of Ahumada-Del Castillo Syndrome | Diagnosis of Ahumada-Del Castillo Syndrome. | 49 | Ahumada-Del Castillo Syndrome |
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nord_49_6 | Therapies of Ahumada-Del Castillo Syndrome | The diagnosis of Ahumada-Del Castillo Syndrome is usually made by specialized blood tests that detect abnormally elevated levels of the milk-producing hormone prolactin and low levels of the other hormones such as gonadotropins (e.g., follicle stimulating hormone or FSH).The treatment of Ahumada-Del Castillo syndrome involves the administration o. drugs that stimulate the production of dopamine (dopamine agonists) such as bromocriptine and perogolide. Two recently approved dopamine agonists, quinagolide and cabergoline, may be prescribed for women who do not respond to, or cannot tolerate, the commonly used bromocriptine.All of these drugs lower the levels of prolactin and may stop abnormal milk secretion and restore normal menstrual periods.The surgical removal of the small tumors of the pituitary and hypothalamus glands may be performed in some cases. In other patients, the tumors may respond to radiation therapy. When a disorder such as hypothyroidism causes Ahumada-Del Castillo syndrome, the symptoms are usually alleviated through the successful treatment of the underlying disorder. Other treatments may target specific symptoms. | Therapies of Ahumada-Del Castillo Syndrome. The diagnosis of Ahumada-Del Castillo Syndrome is usually made by specialized blood tests that detect abnormally elevated levels of the milk-producing hormone prolactin and low levels of the other hormones such as gonadotropins (e.g., follicle stimulating hormone or FSH).The treatment of Ahumada-Del Castillo syndrome involves the administration o. drugs that stimulate the production of dopamine (dopamine agonists) such as bromocriptine and perogolide. Two recently approved dopamine agonists, quinagolide and cabergoline, may be prescribed for women who do not respond to, or cannot tolerate, the commonly used bromocriptine.All of these drugs lower the levels of prolactin and may stop abnormal milk secretion and restore normal menstrual periods.The surgical removal of the small tumors of the pituitary and hypothalamus glands may be performed in some cases. In other patients, the tumors may respond to radiation therapy. When a disorder such as hypothyroidism causes Ahumada-Del Castillo syndrome, the symptoms are usually alleviated through the successful treatment of the underlying disorder. Other treatments may target specific symptoms. | 49 | Ahumada-Del Castillo Syndrome |
nord_50_0 | Overview of Aicardi Syndrome | SummaryAicardi syndrome is an extremely rare genetic disorder. Almost all people with Aicardi syndrome are females. Individuals with Aicardi syndrome have agenesis of the corpus callosum, chorioretinal lacunae and seizures. Agenesis of the corpus callosum means that the structure that connects the right half of the brain with the left half of the brain (corpus callosum) does not develop normally. Chorioretinal lacunae are small holes in the retina (back part of the eye). These are only visible to a doctor using a device to look into the back of the eye. It is very unusual (maybe impossible) to have Aicardi syndrome without having chorioretinal lacunae. The seizures can be of different types. Infants with Aicardi syndrome usually have a type of seizure known as “infantile spasms”. These are single jerks of the whole body. They may happen many times a day. Infants are usually awake during infantile spasms. These seizures look different from the more common type of seizures known as “generalized tonic-clonic” seizures. Generalized tonic-clonic seizures are rhythmic jerking of arms and legs. People often black out during this type of seizure. Children with Aicardi syndrome usually grow out of infantile spasms and then have generalized tonic-clonic or other types of seizures. Other parts of the brain also do not develop normally. These brain malformations cause frequent seizures and intellectual disability. | Overview of Aicardi Syndrome. SummaryAicardi syndrome is an extremely rare genetic disorder. Almost all people with Aicardi syndrome are females. Individuals with Aicardi syndrome have agenesis of the corpus callosum, chorioretinal lacunae and seizures. Agenesis of the corpus callosum means that the structure that connects the right half of the brain with the left half of the brain (corpus callosum) does not develop normally. Chorioretinal lacunae are small holes in the retina (back part of the eye). These are only visible to a doctor using a device to look into the back of the eye. It is very unusual (maybe impossible) to have Aicardi syndrome without having chorioretinal lacunae. The seizures can be of different types. Infants with Aicardi syndrome usually have a type of seizure known as “infantile spasms”. These are single jerks of the whole body. They may happen many times a day. Infants are usually awake during infantile spasms. These seizures look different from the more common type of seizures known as “generalized tonic-clonic” seizures. Generalized tonic-clonic seizures are rhythmic jerking of arms and legs. People often black out during this type of seizure. Children with Aicardi syndrome usually grow out of infantile spasms and then have generalized tonic-clonic or other types of seizures. Other parts of the brain also do not develop normally. These brain malformations cause frequent seizures and intellectual disability. | 50 | Aicardi Syndrome |
nord_50_1 | Symptoms of Aicardi Syndrome | Aicardi syndrome typically begins as involuntary muscle spasms between four months and four years of age. Other symptoms may include epilepsy, intellectual disability, profound muscle weakness (hypotonia), abnormally small eyes (microphthalmia), an incomplete development of the retina and nerve in the back of the eye (colobomas) and/or abnormalities of the ribs and/or spinal vertebral bones. In addition to the agenesis of the corpus callosum, imaging of the brain (by brain MRI) usually shows cysts in the brain as well as clumps of nerve cells that are in the wrong location (heterotopias). Children of all ages with Aicardi syndrome have significant delays in motor development. Aicardi syndrome can be life-threatening during childhood due to prolonged seizures and complications from upper respiratory infections. | Symptoms of Aicardi Syndrome. Aicardi syndrome typically begins as involuntary muscle spasms between four months and four years of age. Other symptoms may include epilepsy, intellectual disability, profound muscle weakness (hypotonia), abnormally small eyes (microphthalmia), an incomplete development of the retina and nerve in the back of the eye (colobomas) and/or abnormalities of the ribs and/or spinal vertebral bones. In addition to the agenesis of the corpus callosum, imaging of the brain (by brain MRI) usually shows cysts in the brain as well as clumps of nerve cells that are in the wrong location (heterotopias). Children of all ages with Aicardi syndrome have significant delays in motor development. Aicardi syndrome can be life-threatening during childhood due to prolonged seizures and complications from upper respiratory infections. | 50 | Aicardi Syndrome |
nord_50_2 | Causes of Aicardi Syndrome | Aicardi syndrome is likely caused by a new change (variant or mutation) in a gene located on the X chromosome. The gene that causes Aicardi syndrome is not known. A report describing changes in the genes TEAD1 and OCEL1 in two girls with Aicardi syndrome was not confirmed in a large cohort of other girls with Aicardi syndrome. Thus, these genes do not seem to be the cause of Aicardi syndrome. This condition is presumed to be lethal in males.The parents of a female with Aicardi syndrome are unaffected. Transmission of Aicardi syndrome from an affected mother to her child has not been reported. Other family members are also not usually at increased risk. | Causes of Aicardi Syndrome. Aicardi syndrome is likely caused by a new change (variant or mutation) in a gene located on the X chromosome. The gene that causes Aicardi syndrome is not known. A report describing changes in the genes TEAD1 and OCEL1 in two girls with Aicardi syndrome was not confirmed in a large cohort of other girls with Aicardi syndrome. Thus, these genes do not seem to be the cause of Aicardi syndrome. This condition is presumed to be lethal in males.The parents of a female with Aicardi syndrome are unaffected. Transmission of Aicardi syndrome from an affected mother to her child has not been reported. Other family members are also not usually at increased risk. | 50 | Aicardi Syndrome |
nord_50_3 | Affects of Aicardi Syndrome | Aicardi syndrome usually affects only females. In very rare cases, males with Klinefelter syndrome (47, XXY) may have Aicardi syndrome. It has been estimated that there are between 300 and 500 people reported to have Aicardi syndrome worldwide. There do not appear to be any differences based on race or ethnicity. | Affects of Aicardi Syndrome. Aicardi syndrome usually affects only females. In very rare cases, males with Klinefelter syndrome (47, XXY) may have Aicardi syndrome. It has been estimated that there are between 300 and 500 people reported to have Aicardi syndrome worldwide. There do not appear to be any differences based on race or ethnicity. | 50 | Aicardi Syndrome |
nord_50_4 | Related disorders of Aicardi Syndrome | Symptoms of the following disorders can be similar to those of Aicardi Syndrome. Comparisons may be useful for a differential diagnosis:Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR) can be confused with Aicardi syndrome. In MCLMR, the eye abnormalities are on the edges of the retinas, in contrast to Aicardi syndrome, where the lacunae are in the central part of the retina. Additionally, in MCLMR, the head size is very small (severe microcephaly) whereas in Aicardi syndrome the head size is usually normal. Additionally, individuals with MCLMR do not typically have agenesis of the corpus callosum or other developmental brain abnormalities typical of Aicardi syndrome.Agenesis of the corpus callosum is a rare birth defect involving a partial or complete absence of the fibers that connect the right and left sides of the brain. Sometimes intellectual disability may result, but some children may not have symptoms and have normal intelligence. The early symptoms of this disorder may be grand mal or Jacksonian epileptic seizures. These may occur during the first weeks or within the first 2 years of life. Other early symptoms may include abnormal accumulation of cerebrospinal fluid around the brain (hydrocephalus), impairment of mental development, and/or delays in physical development. (For more information on this disorder, choose “Agenesis of the Corpus Callosum” as your search term in the Rare Disease Database.) | Related disorders of Aicardi Syndrome. Symptoms of the following disorders can be similar to those of Aicardi Syndrome. Comparisons may be useful for a differential diagnosis:Microcephaly with or without chorioretinopathy, lymphedema, or impaired intellectual development (MCLMR) can be confused with Aicardi syndrome. In MCLMR, the eye abnormalities are on the edges of the retinas, in contrast to Aicardi syndrome, where the lacunae are in the central part of the retina. Additionally, in MCLMR, the head size is very small (severe microcephaly) whereas in Aicardi syndrome the head size is usually normal. Additionally, individuals with MCLMR do not typically have agenesis of the corpus callosum or other developmental brain abnormalities typical of Aicardi syndrome.Agenesis of the corpus callosum is a rare birth defect involving a partial or complete absence of the fibers that connect the right and left sides of the brain. Sometimes intellectual disability may result, but some children may not have symptoms and have normal intelligence. The early symptoms of this disorder may be grand mal or Jacksonian epileptic seizures. These may occur during the first weeks or within the first 2 years of life. Other early symptoms may include abnormal accumulation of cerebrospinal fluid around the brain (hydrocephalus), impairment of mental development, and/or delays in physical development. (For more information on this disorder, choose “Agenesis of the Corpus Callosum” as your search term in the Rare Disease Database.) | 50 | Aicardi Syndrome |
nord_50_5 | Diagnosis of Aicardi Syndrome | An MRI of the brain is usually the first step in diagnosing Aicardi syndrome. This study takes pictures of the brain to look for a small or missing corpus callosum and other problems with the formation of the brain. Individuals with Aicardi syndrome should have a test to look at the brain waves (EEG) to diagnose and treat seizures. An ophthalmologist should look into the eyes at the retina. In Aicardi syndrome, this almost always reveals small cream-colored cavities (lucunae) within the retina. | Diagnosis of Aicardi Syndrome. An MRI of the brain is usually the first step in diagnosing Aicardi syndrome. This study takes pictures of the brain to look for a small or missing corpus callosum and other problems with the formation of the brain. Individuals with Aicardi syndrome should have a test to look at the brain waves (EEG) to diagnose and treat seizures. An ophthalmologist should look into the eyes at the retina. In Aicardi syndrome, this almost always reveals small cream-colored cavities (lucunae) within the retina. | 50 | Aicardi Syndrome |
nord_50_6 | Therapies of Aicardi Syndrome | Treatment
Medications may be used to suppress the seizures caused by Aicardi syndrome. The seizures are often hard to treat, and no specific seizure medication works for all girls with Aicardi syndrome. The doctor may need to try several medicines to see which medication works best. | Therapies of Aicardi Syndrome. Treatment
Medications may be used to suppress the seizures caused by Aicardi syndrome. The seizures are often hard to treat, and no specific seizure medication works for all girls with Aicardi syndrome. The doctor may need to try several medicines to see which medication works best. | 50 | Aicardi Syndrome |
nord_51_0 | Overview of Aicardi-Goutières Syndrome | SummaryAicardi-Goutières syndrome (AGS) is a progressive disease of the brain (encephalopathy) that presents within the first year of life. Some of the signs of this syndrome are a small head (microcephaly), brain calcifications (basal ganglia and other locations), abnormalities in the white matter tracts of the brain, excess lymphocytes (a type of white blood cell) in the cerebrospinal fluid (CSF) and increased chemical messengers (interferon-alpha) made by the immune system in the CSF and the blood. The immune system does not function normally and excess interferon is produced. These problems are thought to lead to disease in AGS.Some children present as early as the first few weeks of life, but often children present in the first few years of life, after an initial period of normal development. As the disease progresses, infants may demonstrate skin sores or bumps (chilblains) on the toes, fingers and ears as well as with other rashes. Other organs, including the eyes (glaucoma), thyroid (hypothyroidism), lungs (pulmonary hypertension), heart (cardiomyopathy), liver (autoimmune hepatitis), muscle (myopathy) and joints (arthropathy) may become involved. Some infants presenting early in life may have an enlarged liver and spleen (hepatosplenomegaly), elevated liver enzymes and a low platelet count (thrombocytopenia) or other abnormalities of the blood cells, all of which may mimic a congenital infection.Changes (pathogenic variants or mutations) in several different genes are known to cause AGS. AGS is most commonly inherited in an autosomal recessive fashion (mother and father are both carriers for the harmful gene variant), but the disease can also result from a de novo (new) gene variant in the child or from autosomal dominant inheritance from one parent. | Overview of Aicardi-Goutières Syndrome. SummaryAicardi-Goutières syndrome (AGS) is a progressive disease of the brain (encephalopathy) that presents within the first year of life. Some of the signs of this syndrome are a small head (microcephaly), brain calcifications (basal ganglia and other locations), abnormalities in the white matter tracts of the brain, excess lymphocytes (a type of white blood cell) in the cerebrospinal fluid (CSF) and increased chemical messengers (interferon-alpha) made by the immune system in the CSF and the blood. The immune system does not function normally and excess interferon is produced. These problems are thought to lead to disease in AGS.Some children present as early as the first few weeks of life, but often children present in the first few years of life, after an initial period of normal development. As the disease progresses, infants may demonstrate skin sores or bumps (chilblains) on the toes, fingers and ears as well as with other rashes. Other organs, including the eyes (glaucoma), thyroid (hypothyroidism), lungs (pulmonary hypertension), heart (cardiomyopathy), liver (autoimmune hepatitis), muscle (myopathy) and joints (arthropathy) may become involved. Some infants presenting early in life may have an enlarged liver and spleen (hepatosplenomegaly), elevated liver enzymes and a low platelet count (thrombocytopenia) or other abnormalities of the blood cells, all of which may mimic a congenital infection.Changes (pathogenic variants or mutations) in several different genes are known to cause AGS. AGS is most commonly inherited in an autosomal recessive fashion (mother and father are both carriers for the harmful gene variant), but the disease can also result from a de novo (new) gene variant in the child or from autosomal dominant inheritance from one parent. | 51 | Aicardi-Goutières Syndrome |
nord_51_1 | Symptoms of Aicardi-Goutières Syndrome | AGS is a disease that affects the white matter of the brain (leukoencephalopathy) and may result in severe intellectual and physical disability. Some infants will present variably in the first few weeks of life with irritability, fever, abnormal muscle contractions (dystonia), microcephaly, basal ganglia calcifications, white matter tract abnormalities, CSF lymphocytosis and elevated CSF interferon-alpha. However, infants and young children may also present after a period of normal development, in some cases following a period of unexplained fever or rash due to inflammation. As the disease progresses, individuals with AGS may present with chilblain skin lesions, most commonly on the fingers, toes and ears, or with other atypical rashes. Some infants with AGS may present with symptoms resembling a congenital infection which should be ruled out prior to diagnosis. These signs include hepatosplenomegaly, elevated liver enzymes and thrombocytopenia (low platelets). Such infections include toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, HIV or Zika virus infections. Multiple organ systems may become involved including the eyes (glaucoma and uveitis), endocrine (hypothyroidism, diabetes, diabetes insipidus, growth delay), cardiovascular (cardiomyopathy, pulmonary hypertension and other abnormalities), gastrointestinal (autoimmune hepatitis, inflammatory bowel disease), musculoskeletal (myopathy, neuropathy, arthropathy), renal (renal insufficiency) and hematologic (thrombocytopenia, anemia, leukopenia). Due to the significant neurologic involvement of AGS, affected individuals typically display muscular spasticity and dystonia, decreased muscular tone of their trunk (truncal hypotonia), poor head control, and seizures.Two other clinical manifestations have been noted for specific subtypes of AGS. In patients who have a pathogenic variant of the SAMHD1 gene, intracranial large-vessel disease and aneurysms have been noted. This can lead to blood vessel narrowing (stenosis) in the brain, causing decreased blood flow to certain brain regions. It can also cause bulges (aneurysms) to form in vessels due to weakness in their walls, which can rupture and cause bleeding (hemorrhage) into the brain. In patients who have a pathogenic variant of the ADAR1 gene, refractory four-limb dystonia has been noted. This manifestation typically begins between the ages of eight months and five years and presents as abnormal postures or movements of all four limbs.Milder forms of AGS have also been described in patients with atypical pathogenic gene variants. | Symptoms of Aicardi-Goutières Syndrome. AGS is a disease that affects the white matter of the brain (leukoencephalopathy) and may result in severe intellectual and physical disability. Some infants will present variably in the first few weeks of life with irritability, fever, abnormal muscle contractions (dystonia), microcephaly, basal ganglia calcifications, white matter tract abnormalities, CSF lymphocytosis and elevated CSF interferon-alpha. However, infants and young children may also present after a period of normal development, in some cases following a period of unexplained fever or rash due to inflammation. As the disease progresses, individuals with AGS may present with chilblain skin lesions, most commonly on the fingers, toes and ears, or with other atypical rashes. Some infants with AGS may present with symptoms resembling a congenital infection which should be ruled out prior to diagnosis. These signs include hepatosplenomegaly, elevated liver enzymes and thrombocytopenia (low platelets). Such infections include toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, HIV or Zika virus infections. Multiple organ systems may become involved including the eyes (glaucoma and uveitis), endocrine (hypothyroidism, diabetes, diabetes insipidus, growth delay), cardiovascular (cardiomyopathy, pulmonary hypertension and other abnormalities), gastrointestinal (autoimmune hepatitis, inflammatory bowel disease), musculoskeletal (myopathy, neuropathy, arthropathy), renal (renal insufficiency) and hematologic (thrombocytopenia, anemia, leukopenia). Due to the significant neurologic involvement of AGS, affected individuals typically display muscular spasticity and dystonia, decreased muscular tone of their trunk (truncal hypotonia), poor head control, and seizures.Two other clinical manifestations have been noted for specific subtypes of AGS. In patients who have a pathogenic variant of the SAMHD1 gene, intracranial large-vessel disease and aneurysms have been noted. This can lead to blood vessel narrowing (stenosis) in the brain, causing decreased blood flow to certain brain regions. It can also cause bulges (aneurysms) to form in vessels due to weakness in their walls, which can rupture and cause bleeding (hemorrhage) into the brain. In patients who have a pathogenic variant of the ADAR1 gene, refractory four-limb dystonia has been noted. This manifestation typically begins between the ages of eight months and five years and presents as abnormal postures or movements of all four limbs.Milder forms of AGS have also been described in patients with atypical pathogenic gene variants. | 51 | Aicardi-Goutières Syndrome |
nord_51_2 | Causes of Aicardi-Goutières Syndrome | Aicardi-Goutières syndrome is caused by changes (pathogenic variants or mutations) in several different genes including TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1, IFIH, LSM11 and RNU7-1. These variants disrupt cellular signaling and production of immune-related molecules (interferons). AGS is characterized as an “interferonopathy,” meaning that it is a disease related to dysregulated or dysfunctional interferons (interferon alpha in this case).In certain forms of AGS, the inherited gene variants result in an inability to degrade old host RNA and DNA. The build-up of RNA and DNA leads to a response in the person’s body to attempt to clear the accumulation. Cellular proteins are activated by interferon alpha to engage cellular anti-viral defense mechanisms. The immune response that is activated then tries to clear a viral pathogen that does not exist in the person. The resulting inflammation leads to the characteristic signs and symptoms that were discussed earlier.Patients with variants in LSM11 and RNU7-1 have shown that histones, key parts of DNA, are essential in preventing the immune system from attacking its own DNA. In these forms of AGS, the variants lead to abnormalities in the processing and structure of histones, which then prevents them from performing one of their functions of suppressing the immune system from attacking its own DNA.Usually, AGS is inherited in an autosomal recessive fashion; however, certain subtypes have been found to be inherited in an autosomal dominant manner.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 have an affected child is 25% with each pregnancy. The risk of having 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.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause the disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. | Causes of Aicardi-Goutières Syndrome. Aicardi-Goutières syndrome is caused by changes (pathogenic variants or mutations) in several different genes including TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1, IFIH, LSM11 and RNU7-1. These variants disrupt cellular signaling and production of immune-related molecules (interferons). AGS is characterized as an “interferonopathy,” meaning that it is a disease related to dysregulated or dysfunctional interferons (interferon alpha in this case).In certain forms of AGS, the inherited gene variants result in an inability to degrade old host RNA and DNA. The build-up of RNA and DNA leads to a response in the person’s body to attempt to clear the accumulation. Cellular proteins are activated by interferon alpha to engage cellular anti-viral defense mechanisms. The immune response that is activated then tries to clear a viral pathogen that does not exist in the person. The resulting inflammation leads to the characteristic signs and symptoms that were discussed earlier.Patients with variants in LSM11 and RNU7-1 have shown that histones, key parts of DNA, are essential in preventing the immune system from attacking its own DNA. In these forms of AGS, the variants lead to abnormalities in the processing and structure of histones, which then prevents them from performing one of their functions of suppressing the immune system from attacking its own DNA.Usually, AGS is inherited in an autosomal recessive fashion; however, certain subtypes have been found to be inherited in an autosomal dominant manner.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 have an affected child is 25% with each pregnancy. The risk of having 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.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause the disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. | 51 | Aicardi-Goutières Syndrome |
nord_51_3 | Affects of Aicardi-Goutières Syndrome | The prevalence of AGS is unknown. Studies suggest that AGS is one of the most common genetic disorders affecting the white matter of the brain. | Affects of Aicardi-Goutières Syndrome. The prevalence of AGS is unknown. Studies suggest that AGS is one of the most common genetic disorders affecting the white matter of the brain. | 51 | Aicardi-Goutières Syndrome |
nord_51_4 | Related disorders of Aicardi-Goutières Syndrome | Since calcification of the basal ganglia can be seen in many disorders, it is important to rule out other potential causes of the clinical features. The following are a few conditions with similar symptoms | Related disorders of Aicardi-Goutières Syndrome. Since calcification of the basal ganglia can be seen in many disorders, it is important to rule out other potential causes of the clinical features. The following are a few conditions with similar symptoms | 51 | Aicardi-Goutières Syndrome |
nord_51_5 | Diagnosis of Aicardi-Goutières Syndrome | Aicardi-Goutières syndrome can be diagnosed when there is suspicion based on clinical features in addition to characteristic neuroimaging and laboratory findings. Neuroradiographic findings best visualized by CT scan or MRI include calcifications of the basal ganglia, particularly the putamen, globus pallidus and thalamus. Other neurologic findings include often diffuse white-matter changes and cerebral atrophy. Laboratory findings include characteristic features seen in the peripheral blood and cerebral spinal fluid (CSF). In the peripheral blood, abnormalities of the blood cells and elevated liver enzymes may be noted. In the CSF, leukocytosis (elevated white blood cell count), increased interferon-alpha and increased concentration of neopterin may all be found. Finally, the diagnosis can also be established through genetic and molecular testing. These tests include serial single-gene tests, a multigene panel and comprehensive genomic testing. These tests can search for pathogenic variants in genes known to cause AGS. | Diagnosis of Aicardi-Goutières Syndrome. Aicardi-Goutières syndrome can be diagnosed when there is suspicion based on clinical features in addition to characteristic neuroimaging and laboratory findings. Neuroradiographic findings best visualized by CT scan or MRI include calcifications of the basal ganglia, particularly the putamen, globus pallidus and thalamus. Other neurologic findings include often diffuse white-matter changes and cerebral atrophy. Laboratory findings include characteristic features seen in the peripheral blood and cerebral spinal fluid (CSF). In the peripheral blood, abnormalities of the blood cells and elevated liver enzymes may be noted. In the CSF, leukocytosis (elevated white blood cell count), increased interferon-alpha and increased concentration of neopterin may all be found. Finally, the diagnosis can also be established through genetic and molecular testing. These tests include serial single-gene tests, a multigene panel and comprehensive genomic testing. These tests can search for pathogenic variants in genes known to cause AGS. | 51 | Aicardi-Goutières Syndrome |
nord_51_6 | Therapies of Aicardi-Goutières Syndrome | TreatmentA multidisciplinary approach to the support and care of affected individuals is necessary.There are no definitive or curative treatments for Aicardi-Goutières syndrome. However, recent medical advances have shown janus kinase inhibitors to be useful in suppressing interferon activation in individuals with AGS. In particular, baricitinib has been shown to help individuals with AGS achieve new milestones and develop new skills. Further management of AGS involves diagnosing the extent of symptoms and assessing the individual needs of the affected infant. This involves evaluating nutritional status, initiating chest physiotherapy if respiratory complications arise and monitoring the various organ systems that may become affected.Genetic counseling is recommended for families with an affected child. | Therapies of Aicardi-Goutières Syndrome. TreatmentA multidisciplinary approach to the support and care of affected individuals is necessary.There are no definitive or curative treatments for Aicardi-Goutières syndrome. However, recent medical advances have shown janus kinase inhibitors to be useful in suppressing interferon activation in individuals with AGS. In particular, baricitinib has been shown to help individuals with AGS achieve new milestones and develop new skills. Further management of AGS involves diagnosing the extent of symptoms and assessing the individual needs of the affected infant. This involves evaluating nutritional status, initiating chest physiotherapy if respiratory complications arise and monitoring the various organ systems that may become affected.Genetic counseling is recommended for families with an affected child. | 51 | Aicardi-Goutières Syndrome |
nord_52_0 | Overview of AIDS Dysmorphic Syndrome | The term “AIDS dysmorphic syndrome” or “HIV embryopathy” has been used by some researchers to describe specific facial malformations (i.e., craniofacial dysmorphism), an unusually small head, and growth deficiency in some infants infected with HIV.* Such craniofacial abnormalities have included a prominent, boxlike forehead, large, wide eyes; a flattened nasal bridge, and an unusually pronounced philtrum, which is the vertical groove in the center of the upper lip.However, many investigators have since questioned the significance of these observations. Such researchers indicate that there is lack of evidence for characteristic craniofacial malformations in infants who acquired HIV infection from their mother before, during, or shortly after birth (i.e., perinatally).*HIV is the abbreviation for the human immunodeficiency virus, a retrovirus that infects certain white blood cells called helper T cells (CD4+ cells). HIV infection leads to progressive deterioration of the body's immune system and causes acquired immunodeficiency syndrome (AIDS). | Overview of AIDS Dysmorphic Syndrome. The term “AIDS dysmorphic syndrome” or “HIV embryopathy” has been used by some researchers to describe specific facial malformations (i.e., craniofacial dysmorphism), an unusually small head, and growth deficiency in some infants infected with HIV.* Such craniofacial abnormalities have included a prominent, boxlike forehead, large, wide eyes; a flattened nasal bridge, and an unusually pronounced philtrum, which is the vertical groove in the center of the upper lip.However, many investigators have since questioned the significance of these observations. Such researchers indicate that there is lack of evidence for characteristic craniofacial malformations in infants who acquired HIV infection from their mother before, during, or shortly after birth (i.e., perinatally).*HIV is the abbreviation for the human immunodeficiency virus, a retrovirus that infects certain white blood cells called helper T cells (CD4+ cells). HIV infection leads to progressive deterioration of the body's immune system and causes acquired immunodeficiency syndrome (AIDS). | 52 | AIDS Dysmorphic Syndrome |
nord_52_1 | Symptoms of AIDS Dysmorphic Syndrome | Some researchers have reported particular craniofacial abnormalities, described as “AIDS dysmorphic syndrome” or “HIV embryopathy”, in some infants who acquired HIV infection from their mother (perinatally). Such features have included a small head circumference (microcephaly); a prominent, boxlike forehead; a flattened nasal bridge and shortened nose; and/or an unusually pronounced vertical groove (philtrum) in the center of the upper lip. Various eye abnormalities have also been reported, such as unusually prominent and/or widely set eyes (ocular hypertelorism); slanting (obliquity) of the eyes; long eyelid folds (palpebral fissures); and/or an unusual bluish tint of the whites of the eyes (blue sclerae). Affected infants and children also typically had growth retardation, resulting in low weight and height as compared to others of the same age and sex. In some cases, growth failure began during fetal development (intrauterine growth retardation). Such features have varied in range and severity from case to case and have been noted prior to the development of symptoms associated with impaired functioning of the immune system (immunodeficiency).However, as noted above, investigators have since cited a lack of evidence for characteristic craniofacial abnormalities in infants with perinatal HIV infection. Rather, according to such researchers, evidence suggests that there is no significant difference in the incidence of such features in affected children compared with those in the general population. In addition, although a significant number may have microcephaly and growth failure after birth, such abnormalities could be associated with chronic illnesses and progressive neurologic dysfunction (see below) due to HIV infection. Investigators also note that the observed features in infants with perinatal HIV infection must be differentiated from findings that may be due to exposure to alcohol, certain drugs, or other factors during pregnancy.Symptoms of immunodeficiency due to perinatal HIV infection may become apparent during the first or second year of life or later during childhood. Common manifestations may include lung inflammation (lymphocytic interstitial pneumonitis); recurring bacterial infections; chronic fungal infection of the mouth (oral candidiasis); abnormal enlargement of the liver and spleen (hepatosplenomegaly); generalized swelling of lymph nodes (lymphadenopathy); swelling of certain salivary glands; rashes; persistent fever; chronic diarrhea; and severe weight loss (wasting). In addition, affected infants and children may develop chronic or recurrent infections with certain viruses, fungi, or other unusual opportunistic microorganisms. The term “opportunistic infections” refers to infections caused by microorganisms that usually do not cause disease in healthy individuals or to widespread (systemic) infection by microorganisms that typically cause only localized, mild infection. For example, affected infants and children may be prone to developing severe lung inflammation (pneumonia) due to infection with a microorganism known as Pneumocystis carinii, which may result in potentially life-threatening complications. Although uncommon, there may also be an increased risk of developing particular malignancies, such as certain cancers of the lymphatic system (e.g., non-Hodgkins B-cell lymphomas, brain lymphomas).As noted above, many affected infants and children may also develop progressive neurologic dysfunction, which may include delays in or loss of previously acquired developmental milestones; intellectual deterioration; microcephaly; and motor dysfunction. Various additional findings may also be present, including inflammation of the liver (hepatitis) and impaired functioning of the kidneys (renal failure) and the heart (heart failure). | Symptoms of AIDS Dysmorphic Syndrome. Some researchers have reported particular craniofacial abnormalities, described as “AIDS dysmorphic syndrome” or “HIV embryopathy”, in some infants who acquired HIV infection from their mother (perinatally). Such features have included a small head circumference (microcephaly); a prominent, boxlike forehead; a flattened nasal bridge and shortened nose; and/or an unusually pronounced vertical groove (philtrum) in the center of the upper lip. Various eye abnormalities have also been reported, such as unusually prominent and/or widely set eyes (ocular hypertelorism); slanting (obliquity) of the eyes; long eyelid folds (palpebral fissures); and/or an unusual bluish tint of the whites of the eyes (blue sclerae). Affected infants and children also typically had growth retardation, resulting in low weight and height as compared to others of the same age and sex. In some cases, growth failure began during fetal development (intrauterine growth retardation). Such features have varied in range and severity from case to case and have been noted prior to the development of symptoms associated with impaired functioning of the immune system (immunodeficiency).However, as noted above, investigators have since cited a lack of evidence for characteristic craniofacial abnormalities in infants with perinatal HIV infection. Rather, according to such researchers, evidence suggests that there is no significant difference in the incidence of such features in affected children compared with those in the general population. In addition, although a significant number may have microcephaly and growth failure after birth, such abnormalities could be associated with chronic illnesses and progressive neurologic dysfunction (see below) due to HIV infection. Investigators also note that the observed features in infants with perinatal HIV infection must be differentiated from findings that may be due to exposure to alcohol, certain drugs, or other factors during pregnancy.Symptoms of immunodeficiency due to perinatal HIV infection may become apparent during the first or second year of life or later during childhood. Common manifestations may include lung inflammation (lymphocytic interstitial pneumonitis); recurring bacterial infections; chronic fungal infection of the mouth (oral candidiasis); abnormal enlargement of the liver and spleen (hepatosplenomegaly); generalized swelling of lymph nodes (lymphadenopathy); swelling of certain salivary glands; rashes; persistent fever; chronic diarrhea; and severe weight loss (wasting). In addition, affected infants and children may develop chronic or recurrent infections with certain viruses, fungi, or other unusual opportunistic microorganisms. The term “opportunistic infections” refers to infections caused by microorganisms that usually do not cause disease in healthy individuals or to widespread (systemic) infection by microorganisms that typically cause only localized, mild infection. For example, affected infants and children may be prone to developing severe lung inflammation (pneumonia) due to infection with a microorganism known as Pneumocystis carinii, which may result in potentially life-threatening complications. Although uncommon, there may also be an increased risk of developing particular malignancies, such as certain cancers of the lymphatic system (e.g., non-Hodgkins B-cell lymphomas, brain lymphomas).As noted above, many affected infants and children may also develop progressive neurologic dysfunction, which may include delays in or loss of previously acquired developmental milestones; intellectual deterioration; microcephaly; and motor dysfunction. Various additional findings may also be present, including inflammation of the liver (hepatitis) and impaired functioning of the kidneys (renal failure) and the heart (heart failure). | 52 | AIDS Dysmorphic Syndrome |
nord_52_2 | Causes of AIDS Dysmorphic Syndrome | Most new cases of HIV infection in young children (pediatric HIV infection) are caused by transmission from the mother during pregnancy, labor and delivery, or breastfeeding (perinatal transmission). Estimates suggest that the transmission rate from untreated HIV-positive mothers in the United States is approximately 12 to 30 percent. (For further information, please see the “Standard Therapies” section of this report below.) Women with HIV infection are most often infected through heterosexual relations with an infected partner or injection drug use. | Causes of AIDS Dysmorphic Syndrome. Most new cases of HIV infection in young children (pediatric HIV infection) are caused by transmission from the mother during pregnancy, labor and delivery, or breastfeeding (perinatal transmission). Estimates suggest that the transmission rate from untreated HIV-positive mothers in the United States is approximately 12 to 30 percent. (For further information, please see the “Standard Therapies” section of this report below.) Women with HIV infection are most often infected through heterosexual relations with an infected partner or injection drug use. | 52 | AIDS Dysmorphic Syndrome |
nord_52_3 | Affects of AIDS Dysmorphic Syndrome | Perinatal HIV infection is thought to affect males and females in relatively equal numbers. As noted above, in some cases, certain dysmorphic features have been observed prior to the onset of symptoms associated with immunodeficiency. However, the significance of such observations has been questioned (see “Symptoms”). Symptoms and findings resulting from immunodeficiency may become apparent during the first or second year of life or later during childhood. | Affects of AIDS Dysmorphic Syndrome. Perinatal HIV infection is thought to affect males and females in relatively equal numbers. As noted above, in some cases, certain dysmorphic features have been observed prior to the onset of symptoms associated with immunodeficiency. However, the significance of such observations has been questioned (see “Symptoms”). Symptoms and findings resulting from immunodeficiency may become apparent during the first or second year of life or later during childhood. | 52 | AIDS Dysmorphic Syndrome |
nord_52_4 | Related disorders of AIDS Dysmorphic Syndrome | Related disorders of AIDS Dysmorphic Syndrome. | 52 | AIDS Dysmorphic Syndrome |
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nord_52_5 | Diagnosis of AIDS Dysmorphic Syndrome | Perinatal HIV infection is considered in infants of mothers known to be HIV-positive and/or in infants and children who have certain characteristic symptoms of HIV infection or immune system abnormalities. Infants who are born to mothers with HIV have antibodies against the virus in the bloodstream at birth (passively acquired maternal antibodies). In infants and children who are not infected with HIV, these passive antibodies eventually disappear, usually between six to 12 months, however, in some cases, they may be detectable for up to 18 months. Therefore, testing that detects the presence of HIV antibodies in the blood (serum antibody tests, e.g., enzyme immunoassay and confirmatory Western blot) in a child 18 months or older usually indicates infection; however, such testing is not conclusive in children younger than 18 months. In these children, HIV infection may be confirmed through the repeated use of various specialized viral detection laboratory tests (e.g., HIV viral cultures, a DNA-amplification and copying method known as polymerase chain reaction [PCR]). Additional laboratory tests may also be conducted to assess immune functioning in order to assist in diagnosis and to monitor disease progression and its treatment. Testing may include monitoring of helper T cell numbers (CD4+ cells), the ratio of helper T cells to certain other white blood cells (CD8+ cells), complete blood counts, and blood platelet levels. | Diagnosis of AIDS Dysmorphic Syndrome. Perinatal HIV infection is considered in infants of mothers known to be HIV-positive and/or in infants and children who have certain characteristic symptoms of HIV infection or immune system abnormalities. Infants who are born to mothers with HIV have antibodies against the virus in the bloodstream at birth (passively acquired maternal antibodies). In infants and children who are not infected with HIV, these passive antibodies eventually disappear, usually between six to 12 months, however, in some cases, they may be detectable for up to 18 months. Therefore, testing that detects the presence of HIV antibodies in the blood (serum antibody tests, e.g., enzyme immunoassay and confirmatory Western blot) in a child 18 months or older usually indicates infection; however, such testing is not conclusive in children younger than 18 months. In these children, HIV infection may be confirmed through the repeated use of various specialized viral detection laboratory tests (e.g., HIV viral cultures, a DNA-amplification and copying method known as polymerase chain reaction [PCR]). Additional laboratory tests may also be conducted to assess immune functioning in order to assist in diagnosis and to monitor disease progression and its treatment. Testing may include monitoring of helper T cell numbers (CD4+ cells), the ratio of helper T cells to certain other white blood cells (CD8+ cells), complete blood counts, and blood platelet levels. | 52 | AIDS Dysmorphic Syndrome |
nord_52_6 | Therapies of AIDS Dysmorphic Syndrome | TreatmentDisease management and treatment may require the coordinated efforts of a team of medical professionals, including obstetricians, pediatricians, specialists in HIV infection, and additional health care professionals.If pregnant women are infected with HIV, certain preventive measures may help to decrease the rate of transmission to their children. Such measures may include administration of the antiretroviral drug zidovudine (ZDV) by mouth (orally) during the second and third trimesters of pregnancy; intravenously during labor and delivery; and orally to the newborn during the first six weeks of life. Research has shown that, for selected HIV-infected pregnant women, this regimen may decrease the rate of perinatal HIV transmission by more than two-thirds. (ZDV is a nucleoside reverse transcriptase inhibitor.)HIV-infected women may have already been taking or may be offered standard antiretroviral combination therapy as currently recommended for non-pregnant adults (two nucleoside reverse transcriptase inhibitors and a protease inhibitor). Such therapy may be offered both to improve the mother's health and to potentially further reduce the risk of HIV transmission. Decisions concerning the use and choice of such medications during pregnancy should consider the potential benefits and risks to the mother and her child. However, as noted above, evidence indicates that therapy with the antiretroviral agent ZDV should be included to help prevent perinatal HIV transmission.Some research also shows that elective delivery by cesarean section may reduce the risk of HIV transmission to the newborn. However, the potential risks and benefits of cesarean section must be considered based on the specifics of each case. In addition, in the United States, HIV-infected mothers are advised not to breastfeed, since clean water and infant formulas are readily available.As noted above, the treatment of HIV-infected infants and children may require the coordinated efforts of a multidisciplinary team of medical professionals, including specialists in pediatric HIV infection. Recommended disease management may include combination therapy with various antiretroviral agents, such as two nucleoside reverse transcriptase inhibitors (e.g., ZDV with didanosine or lamivudine), possibly in combination with a third medication belonging to the class of drugs known as protease inhibitors. The specific combination therapies recommended may depend upon the child's age, symptoms, amount of virus in the blood (viral load), ability or inability to tolerate certain medications, possible drug interactions, and/or other factors. Children should be regularly monitored for evidence of disease progression, to assess the effectiveness of therapy, and to make any necessary therapy adjustments.Disease management may also include the administration of certain antibiotics to help prevent and/or aggressively treat particular infections (e.g., Pneumocystis carinii). In addition, certain corticosteroids may be prescribed. Intravenous immune globulin may also be recommended to help boost the ability of the immune system to fight certain infections. In addition, regular tuberculosis screening is advised.Most routine childhood vaccinations may be provided to most children with HIV infection. However, generally, live bacterial or viral vaccinations are not used (although there may be some exceptions, such as measles-mumps-rubella vaccine). In addition, when affected children are exposed to infectious diseases that are vaccine preventable, immune globulin may sometimes be indicated.Pediatricians may also provide parents of HIV-infected children with certain guidelines to help reduce the risk of potential infections. These may include avoiding raw or undercooked meat; understanding the importance of thorough handwashing; avoiding swimming in or drinking lake or river water; avoiding contact with farm animals; and understanding the potential risks of playing with pets.Additional therapies are under evaluation for the treatment of HIV infection in children. Other treatment for affected infants and children is symptomatic and supportive. | Therapies of AIDS Dysmorphic Syndrome. TreatmentDisease management and treatment may require the coordinated efforts of a team of medical professionals, including obstetricians, pediatricians, specialists in HIV infection, and additional health care professionals.If pregnant women are infected with HIV, certain preventive measures may help to decrease the rate of transmission to their children. Such measures may include administration of the antiretroviral drug zidovudine (ZDV) by mouth (orally) during the second and third trimesters of pregnancy; intravenously during labor and delivery; and orally to the newborn during the first six weeks of life. Research has shown that, for selected HIV-infected pregnant women, this regimen may decrease the rate of perinatal HIV transmission by more than two-thirds. (ZDV is a nucleoside reverse transcriptase inhibitor.)HIV-infected women may have already been taking or may be offered standard antiretroviral combination therapy as currently recommended for non-pregnant adults (two nucleoside reverse transcriptase inhibitors and a protease inhibitor). Such therapy may be offered both to improve the mother's health and to potentially further reduce the risk of HIV transmission. Decisions concerning the use and choice of such medications during pregnancy should consider the potential benefits and risks to the mother and her child. However, as noted above, evidence indicates that therapy with the antiretroviral agent ZDV should be included to help prevent perinatal HIV transmission.Some research also shows that elective delivery by cesarean section may reduce the risk of HIV transmission to the newborn. However, the potential risks and benefits of cesarean section must be considered based on the specifics of each case. In addition, in the United States, HIV-infected mothers are advised not to breastfeed, since clean water and infant formulas are readily available.As noted above, the treatment of HIV-infected infants and children may require the coordinated efforts of a multidisciplinary team of medical professionals, including specialists in pediatric HIV infection. Recommended disease management may include combination therapy with various antiretroviral agents, such as two nucleoside reverse transcriptase inhibitors (e.g., ZDV with didanosine or lamivudine), possibly in combination with a third medication belonging to the class of drugs known as protease inhibitors. The specific combination therapies recommended may depend upon the child's age, symptoms, amount of virus in the blood (viral load), ability or inability to tolerate certain medications, possible drug interactions, and/or other factors. Children should be regularly monitored for evidence of disease progression, to assess the effectiveness of therapy, and to make any necessary therapy adjustments.Disease management may also include the administration of certain antibiotics to help prevent and/or aggressively treat particular infections (e.g., Pneumocystis carinii). In addition, certain corticosteroids may be prescribed. Intravenous immune globulin may also be recommended to help boost the ability of the immune system to fight certain infections. In addition, regular tuberculosis screening is advised.Most routine childhood vaccinations may be provided to most children with HIV infection. However, generally, live bacterial or viral vaccinations are not used (although there may be some exceptions, such as measles-mumps-rubella vaccine). In addition, when affected children are exposed to infectious diseases that are vaccine preventable, immune globulin may sometimes be indicated.Pediatricians may also provide parents of HIV-infected children with certain guidelines to help reduce the risk of potential infections. These may include avoiding raw or undercooked meat; understanding the importance of thorough handwashing; avoiding swimming in or drinking lake or river water; avoiding contact with farm animals; and understanding the potential risks of playing with pets.Additional therapies are under evaluation for the treatment of HIV infection in children. Other treatment for affected infants and children is symptomatic and supportive. | 52 | AIDS Dysmorphic Syndrome |
nord_53_0 | Overview of ALAD Porphyria | SummaryALAD porphyria is a very rare genetic metabolic disease characterized by almost complete deficiency of the enzyme delta-aminolevulinic acid (ALA) dehydratase. Deficiency of this enzyme leads to the accumulation of the porphyrin precursor ALA, which can potentially result in a variety of symptoms. Symptoms vary from one person to another, but usually come from the neurological and gastrointestinal systems. This disease is inherited as an autosomal recessive disorder.IntroductionALAD porphyria is in the group of disorders known as the porphyrias. The porphyrias are characterized by abnormally high levels of porphyrins and porphyrin precursors in the body due to deficiencies of enzymes essential to the creation (synthesis) of heme, a part of hemoglobin. There are at least seven types of porphyria. The symptoms associated with the various types 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 related substances originate in excess amounts from the liver in the hepatic types, and mostly from the bone marrow in the erythropoietic types. ALAD porphyria is a hepatic form of porphyria. | Overview of ALAD Porphyria. SummaryALAD porphyria is a very rare genetic metabolic disease characterized by almost complete deficiency of the enzyme delta-aminolevulinic acid (ALA) dehydratase. Deficiency of this enzyme leads to the accumulation of the porphyrin precursor ALA, which can potentially result in a variety of symptoms. Symptoms vary from one person to another, but usually come from the neurological and gastrointestinal systems. This disease is inherited as an autosomal recessive disorder.IntroductionALAD porphyria is in the group of disorders known as the porphyrias. The porphyrias are characterized by abnormally high levels of porphyrins and porphyrin precursors in the body due to deficiencies of enzymes essential to the creation (synthesis) of heme, a part of hemoglobin. There are at least seven types of porphyria. The symptoms associated with the various types 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 related substances originate in excess amounts from the liver in the hepatic types, and mostly from the bone marrow in the erythropoietic types. ALAD porphyria is a hepatic form of porphyria. | 53 | ALAD Porphyria |
nord_53_1 | Symptoms of ALAD Porphyria | The onset, severity and type of symptoms can vary greatly in individuals with a specific type of porphyria. This variation may depend on, in part, the amount of residual enzyme activity in each individual. Individuals with more significant enzyme deficiency may have more severe symptoms and earlier onset. Individuals with partial deficiency will have milder symptoms, and some individuals will not develop any symptoms (asymptomatic). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their medical team about their specific case, associated symptoms and overall prognosis.Individuals with ALAD porphyria may have bouts or “attacks” when symptoms are intense, which are referred to as neurovisceral or acute attacks. An attack may last for several weeks. During an attack, affected individuals may experience severe abdominal cramping or pain accompanied by vomiting and constipation. During infancy, gastrointestinal abnormalities may cause an affected child to fail to grow and gain weight as expected.Several other neurological symptoms can occur during an acute attack due to problems with the nerves outside the central nervous system (peripheral neuropathy), resulting in numbness or tingling in the hands and feet, burning pain, sensitivity to touch, and a lack of coordination. In severe cases, the motor nerves are involved, resulting in loss or partial impairment of the ability to use voluntary muscles. ALAD porphyria can also be associated with psychological changes during an acute attack. In severe cases, loss of contact from reality (psychosis) has been reported.Additional symptoms that occur during acute attacks include a rapid heartbeat (tachycardia), high blood pressure (hypertension), seizures, and breathing (respiratory) impairment. | Symptoms of ALAD Porphyria. The onset, severity and type of symptoms can vary greatly in individuals with a specific type of porphyria. This variation may depend on, in part, the amount of residual enzyme activity in each individual. Individuals with more significant enzyme deficiency may have more severe symptoms and earlier onset. Individuals with partial deficiency will have milder symptoms, and some individuals will not develop any symptoms (asymptomatic). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their medical team about their specific case, associated symptoms and overall prognosis.Individuals with ALAD porphyria may have bouts or “attacks” when symptoms are intense, which are referred to as neurovisceral or acute attacks. An attack may last for several weeks. During an attack, affected individuals may experience severe abdominal cramping or pain accompanied by vomiting and constipation. During infancy, gastrointestinal abnormalities may cause an affected child to fail to grow and gain weight as expected.Several other neurological symptoms can occur during an acute attack due to problems with the nerves outside the central nervous system (peripheral neuropathy), resulting in numbness or tingling in the hands and feet, burning pain, sensitivity to touch, and a lack of coordination. In severe cases, the motor nerves are involved, resulting in loss or partial impairment of the ability to use voluntary muscles. ALAD porphyria can also be associated with psychological changes during an acute attack. In severe cases, loss of contact from reality (psychosis) has been reported.Additional symptoms that occur during acute attacks include a rapid heartbeat (tachycardia), high blood pressure (hypertension), seizures, and breathing (respiratory) impairment. | 53 | ALAD Porphyria |
nord_53_2 | Causes of ALAD Porphyria | ALAD porphyria is caused by mutations in the ALAD gene, and the disease is inherited as an autosomal recessive disorder. This means that both copies of the ALAD gene have a mutation. 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.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. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.The ALAD gene contains instructions for creating the enzyme aminolevulinate dehydratase (ALAD), which is necessary for the production of heme. Heme is part of hemoglobin, which is the oxygen-carrying component of red blood cells. Heme is mainly produced in the bone marrow and the liver. Eight different enzymes are necessary for the creation of heme.Mutations of the ALAD gene result in deficient levels ofporphobilinogen in the body, with accumulation of ALA, which causes the symptoms associated with ALAD porphyria.A variety of different triggers have been identified that can precipitatean acute attack in individuals with ALAD porphyria. These triggers include alcohol, certain drugs, physical and psychological stress, infection, fasting (reduced caloric intake) and dehydration. The use of estrogen or progesterone is also suspect of triggering an acute attack. | Causes of ALAD Porphyria. ALAD porphyria is caused by mutations in the ALAD gene, and the disease is inherited as an autosomal recessive disorder. This means that both copies of the ALAD gene have a mutation. 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.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. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.The ALAD gene contains instructions for creating the enzyme aminolevulinate dehydratase (ALAD), which is necessary for the production of heme. Heme is part of hemoglobin, which is the oxygen-carrying component of red blood cells. Heme is mainly produced in the bone marrow and the liver. Eight different enzymes are necessary for the creation of heme.Mutations of the ALAD gene result in deficient levels ofporphobilinogen in the body, with accumulation of ALA, which causes the symptoms associated with ALAD porphyria.A variety of different triggers have been identified that can precipitatean acute attack in individuals with ALAD porphyria. These triggers include alcohol, certain drugs, physical and psychological stress, infection, fasting (reduced caloric intake) and dehydration. The use of estrogen or progesterone is also suspect of triggering an acute attack. | 53 | ALAD Porphyria |
nord_53_3 | Affects of ALAD Porphyria | ALAD porphyria is an extremely rare disorder with few cases reported in the medical literature. Most cases have occurred in Europe. However, the disorder can potentially occur in any population. More males have been identified with ALAD porphyria than females in the medical literature, but the disorder affects probably males and females in equal numbers. Researchers suspect that some cases of ALAD porphyria go undiagnosed or misdiagnosed, making it difficult to estimate the true frequency of this disorder in the general population. The onset of ALAD porphyria is usually during infancy or childhood, but late-onset of the disorder (well into adult life) has also been reported. | Affects of ALAD Porphyria. ALAD porphyria is an extremely rare disorder with few cases reported in the medical literature. Most cases have occurred in Europe. However, the disorder can potentially occur in any population. More males have been identified with ALAD porphyria than females in the medical literature, but the disorder affects probably males and females in equal numbers. Researchers suspect that some cases of ALAD porphyria go undiagnosed or misdiagnosed, making it difficult to estimate the true frequency of this disorder in the general population. The onset of ALAD porphyria is usually during infancy or childhood, but late-onset of the disorder (well into adult life) has also been reported. | 53 | ALAD Porphyria |
nord_53_4 | Related disorders of ALAD Porphyria | Symptoms of the following disorders can be similar to those of ALAD porphyria. Comparisons may be useful for a differential diagnosis.Lead poisoning occurs when lead accumulates in the tissues of the body. This accumulation may occur slowly over months or years. The symptoms of lead poisoning vary depending upon the amount of lead exposure and the age of an affected individual. Lead poisoning can potentially cause behavioral changes such as irritability and sluggishness, and neurological abnormalities including poor coordination, convulsions, altered mental status, and disease of the nerves outside the central nervous system (peripheral neuropathy). Lead poisoning can also cause nonspecific symptoms including fever, joint pain, abdominal pain, nausea, vomiting and constipation. Lead inhibits the ALAD enzyme and can cause a clinical picture similar to ALAD porphyria. (For more information on this disorder, choose “heavy metal poisoning” as your search term in the Rare Disease Database.)Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder that is caused by lack of the enzyme fumaryl acetoacetate hydrolase, which is needed for the break-down of the amino acid tyrosine. Failure to break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. There is also accumulation of succinylacetone, which is a potent inhibitor of ALA dehydratase. 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 severe liver disease, cirrhosis, and hepatocellular carcinoma if left untreated. 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.)Acute intermittent porphyria (AIP) is a rare genetic metabolic disorder that is caused by deficiency of the enzyme porphobilinogen deaminase (PBG). This enzyme deficiency results in the accumulation of porphyrin precursors ALA and PBG in the body. The enzyme deficiency by itself is not sufficient to produce symptoms of the disease. Additional factors such as hormones, drugs and dietary changes trigger the appearance of symptoms. Symptoms of AIP may include severe abdominal pain, constipation, muscle weakness, rapid heartbeat (tachycardia), high blood pressure (hypertension), behavioral changes, seizures and disease of the nerves outside the central nervous system (peripheral neuropathy). Acute intermittent porphyria is inherited as an autosomal dominant trait. (For more information on this disorder, choose “acute intermittent porphyria” as your search term in the Rare Disease Database.)Variegate porphyria is a rare genetic metabolic disorder that is caused by deficiency of the enzyme protoporphyrinogen oxidase. This leads to the accumulation of porphyrins and porphyrin precursors in the body, which, can potentially result in a variety of symptoms. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Common skin (cutaneous) symptoms include hypersensitivity to sunlight with formation of blisters in sun-exposed areas. Common neurological symptoms include muscle weakness, muscle pain, convulsions, and behavioral issues. Affected individuals may also have gastrointestinal symptoms such as abdominal pain and vomiting. Variegate porphyria is caused by mutations in the PPOX gene. This genetic mutation is inherited as an autosomal dominant trait. Some individuals who inherit this mutation do not develop any symptoms. (For more information on this disorder, choose “variegate porphyria” as your search term in the Rare Disease Database.)An acquired form of ALAD porphyria has also been described in which six diabetic patients with advanced renal disease developed a syndrome similar to acute intermittent porphyria after initiation of treatment with erythropoietin. The symptoms varied but resolved in all patients when erythropoietin was stopped, and reappeared in four patients when erythropoietin was restarted. In all of the patients, the enzyme ALA dehydratase was low. (For more information on this disorder, see Hedger et al. Compr Ther. 2006 Fall; 32(3): 163-71. PMID:17435269) | Related disorders of ALAD Porphyria. Symptoms of the following disorders can be similar to those of ALAD porphyria. Comparisons may be useful for a differential diagnosis.Lead poisoning occurs when lead accumulates in the tissues of the body. This accumulation may occur slowly over months or years. The symptoms of lead poisoning vary depending upon the amount of lead exposure and the age of an affected individual. Lead poisoning can potentially cause behavioral changes such as irritability and sluggishness, and neurological abnormalities including poor coordination, convulsions, altered mental status, and disease of the nerves outside the central nervous system (peripheral neuropathy). Lead poisoning can also cause nonspecific symptoms including fever, joint pain, abdominal pain, nausea, vomiting and constipation. Lead inhibits the ALAD enzyme and can cause a clinical picture similar to ALAD porphyria. (For more information on this disorder, choose “heavy metal poisoning” as your search term in the Rare Disease Database.)Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder that is caused by lack of the enzyme fumaryl acetoacetate hydrolase, which is needed for the break-down of the amino acid tyrosine. Failure to break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. There is also accumulation of succinylacetone, which is a potent inhibitor of ALA dehydratase. 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 severe liver disease, cirrhosis, and hepatocellular carcinoma if left untreated. 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.)Acute intermittent porphyria (AIP) is a rare genetic metabolic disorder that is caused by deficiency of the enzyme porphobilinogen deaminase (PBG). This enzyme deficiency results in the accumulation of porphyrin precursors ALA and PBG in the body. The enzyme deficiency by itself is not sufficient to produce symptoms of the disease. Additional factors such as hormones, drugs and dietary changes trigger the appearance of symptoms. Symptoms of AIP may include severe abdominal pain, constipation, muscle weakness, rapid heartbeat (tachycardia), high blood pressure (hypertension), behavioral changes, seizures and disease of the nerves outside the central nervous system (peripheral neuropathy). Acute intermittent porphyria is inherited as an autosomal dominant trait. (For more information on this disorder, choose “acute intermittent porphyria” as your search term in the Rare Disease Database.)Variegate porphyria is a rare genetic metabolic disorder that is caused by deficiency of the enzyme protoporphyrinogen oxidase. This leads to the accumulation of porphyrins and porphyrin precursors in the body, which, can potentially result in a variety of symptoms. Some affected individuals present with skin symptoms, some with neurological symptoms and some with both. Common skin (cutaneous) symptoms include hypersensitivity to sunlight with formation of blisters in sun-exposed areas. Common neurological symptoms include muscle weakness, muscle pain, convulsions, and behavioral issues. Affected individuals may also have gastrointestinal symptoms such as abdominal pain and vomiting. Variegate porphyria is caused by mutations in the PPOX gene. This genetic mutation is inherited as an autosomal dominant trait. Some individuals who inherit this mutation do not develop any symptoms. (For more information on this disorder, choose “variegate porphyria” as your search term in the Rare Disease Database.)An acquired form of ALAD porphyria has also been described in which six diabetic patients with advanced renal disease developed a syndrome similar to acute intermittent porphyria after initiation of treatment with erythropoietin. The symptoms varied but resolved in all patients when erythropoietin was stopped, and reappeared in four patients when erythropoietin was restarted. In all of the patients, the enzyme ALA dehydratase was low. (For more information on this disorder, see Hedger et al. Compr Ther. 2006 Fall; 32(3): 163-71. PMID:17435269) | 53 | ALAD Porphyria |
nord_53_5 | Diagnosis of ALAD Porphyria | A diagnosis of ALAD porphyria is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation and of specialized tests that can detect delta-aminolevulinic acid in the urine.Molecular genetic testing can confirm a diagnosis of ALAD porphyria by identifying the characteristic genetic mutation that causes the disorder. | Diagnosis of ALAD Porphyria. A diagnosis of ALAD porphyria is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation and of specialized tests that can detect delta-aminolevulinic acid in the urine.Molecular genetic testing can confirm a diagnosis of ALAD porphyria by identifying the characteristic genetic mutation that causes the disorder. | 53 | ALAD Porphyria |
nord_53_6 | Therapies of ALAD Porphyria | TreatmentThe treatment of ALAD porphyria is directed toward the specific symptoms that are present in each individual. Because there have been so few cases of ALAD porphyria, there is only limited information on treatment for the disorder.Avoidance of triggering factors such as alcohol, certain drugs, fasting, and low carbohydrate diets is recommended for affected individuals. The specific drugs that may need to be avoided in one person can differ from the drugs that need to be avoided in another. More information on these preventive measures and a list of drugs that may potentially need to be avoided are available from the American Porphyria Foundation (see Resources section of this report).Two standard treatments for acute porphyrias in general are intravenous infusions of hemin and supplementation with glucose. However, these therapies have not been universally effective in treating individuals with ALAD porphyria.Hemin is an orphan drug that has been approved by the Food and Drug Administration (FDA) for the treatment of acute porphyria. The drug known as Panhematin® (hemin for injection) is usually given to treat an acute attack. The drug is manufactured by:Recordati Rare Diseases, Inc.
100 Corporate Drive
Lebanon, NJ 08833
Tel. 908-236-0888If hemin cannot be obtained quickly enough, glucose administration both orally and intravenously (which has similar effect to hemin) may be used to treat individuals with ALAD porphyria.Additional drugs may be used to treat affected individuals during an acute attack including pain medications such as opiates, beta-adrenergic blocking agents such as propranolol to treat a rapid heartbeat, sedatives to calm nerves, drugs that reduce nausea and vomiting (anti-emetics) and anti-seizure medications (anti-convulsants). In addition, intravenous fluid replacement may be necessary during an acute attack to ensure that proper fluid and electrolyte levels are maintained.Individuals with ALAD porphyria should carry Medic Alert bracelets or wallet cards. Genetic counseling may be of benefit for affected individuals and their families. | Therapies of ALAD Porphyria. TreatmentThe treatment of ALAD porphyria is directed toward the specific symptoms that are present in each individual. Because there have been so few cases of ALAD porphyria, there is only limited information on treatment for the disorder.Avoidance of triggering factors such as alcohol, certain drugs, fasting, and low carbohydrate diets is recommended for affected individuals. The specific drugs that may need to be avoided in one person can differ from the drugs that need to be avoided in another. More information on these preventive measures and a list of drugs that may potentially need to be avoided are available from the American Porphyria Foundation (see Resources section of this report).Two standard treatments for acute porphyrias in general are intravenous infusions of hemin and supplementation with glucose. However, these therapies have not been universally effective in treating individuals with ALAD porphyria.Hemin is an orphan drug that has been approved by the Food and Drug Administration (FDA) for the treatment of acute porphyria. The drug known as Panhematin® (hemin for injection) is usually given to treat an acute attack. The drug is manufactured by:Recordati Rare Diseases, Inc.
100 Corporate Drive
Lebanon, NJ 08833
Tel. 908-236-0888If hemin cannot be obtained quickly enough, glucose administration both orally and intravenously (which has similar effect to hemin) may be used to treat individuals with ALAD porphyria.Additional drugs may be used to treat affected individuals during an acute attack including pain medications such as opiates, beta-adrenergic blocking agents such as propranolol to treat a rapid heartbeat, sedatives to calm nerves, drugs that reduce nausea and vomiting (anti-emetics) and anti-seizure medications (anti-convulsants). In addition, intravenous fluid replacement may be necessary during an acute attack to ensure that proper fluid and electrolyte levels are maintained.Individuals with ALAD porphyria should carry Medic Alert bracelets or wallet cards. Genetic counseling may be of benefit for affected individuals and their families. | 53 | ALAD Porphyria |
nord_54_0 | Overview of Alagille Syndrome | Alagille syndrome (ALGS) is a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. The specific symptoms and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while others may have more serious forms. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth, and severe itching (pruritis). Additional symptoms include heart murmurs, congenital heart defects, vertebral (back bone) differences, thickening of the ring that normally lines the cornea in the eye (posterior embryotoxon) and distinctive facial features. Most people with Alagille syndrome have changes (mutations) in one copy of the JAG1 gene. A small percentage (2 percent) of patients has mutations of the NOTCH2 gene. These mutations can be inherited in an autosomal dominant pattern, but in about half of cases, the mutation occurs as a new change (“de novo”) in the individual and was not inherited from a parent. The current estimated incidence of ALGS is approximately 1/30,000 –1/45,000. | Overview of Alagille Syndrome. Alagille syndrome (ALGS) is a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. The specific symptoms and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while others may have more serious forms. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth, and severe itching (pruritis). Additional symptoms include heart murmurs, congenital heart defects, vertebral (back bone) differences, thickening of the ring that normally lines the cornea in the eye (posterior embryotoxon) and distinctive facial features. Most people with Alagille syndrome have changes (mutations) in one copy of the JAG1 gene. A small percentage (2 percent) of patients has mutations of the NOTCH2 gene. These mutations can be inherited in an autosomal dominant pattern, but in about half of cases, the mutation occurs as a new change (“de novo”) in the individual and was not inherited from a parent. The current estimated incidence of ALGS is approximately 1/30,000 –1/45,000. | 54 | Alagille Syndrome |
nord_54_1 | Symptoms of Alagille Syndrome | The symptoms and severity of Alagille syndrome can vary greatly from one person to another, even among members of the same family. Some individuals may have a mild form of the disorder that can virtually go unnoticed; other individuals may have a serious form of the disorder that can potentially cause life-threatening complications. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Alagille syndrome can be associated with abnormalities of the liver, heart, eyes, skeleton, kidneys and other organ systems of the body. A main finding of Alagille syndrome is liver disease that often becomes apparent within the first three months of life. However, individuals with mild liver involvement may not be diagnosed until later in life. Liver disease in Alagille syndrome, if present, may range in severity from jaundice or mild cholestasis to severe, progressive liver disease that can potentially result in liver failure.Approximately 90 percent of individuals with Alagille syndrome have a reduced number of bile ducts (bile duct paucity) within the liver. Bile ducts are small tube-like structures that carry bile from the liver to the small intestines. The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and helps eliminate excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.Because of the reduced number of bile ducts, individuals with Alagille syndrome can develop jaundice and cholestasis usually during the first four months of life. Cholestasis refers to reduced or obstructed flow of bile from the liver. Cholestasis can cause yellowing of the skin (jaundice) or whites of the eyes (icterus), itching (pruritus) that may be intense, pale-colored stools, dark urine, fatty bumps (xanthomas) just under the surface of the skin, and an abnormally enlarged liver (hepatomegaly) and/or enlarged spleen (splenomegaly). Because the body cannot properly absorb fats and fat-soluble vitamins (vitamins A, D, E, and K), affected children may also experience growth deficiencies and failure to thrive. Malabsorption of vital nutrients can also lead to rickets, a condition marked by softened, weakened bones (vitamin D deficiency), vision problems (vitamin A deficiency), poor coordination and developmental delays (vitamin E deficiency) and blood clotting problems (vitamin K deficiency).In approximately 15 percent of patients, progressive liver disease results in scarring of the liver (cirrhosis) and liver failure. There is no way to tell which children are at risk for serious, progressive liver disease in Alagille syndrome.Many individuals with Alagille syndrome have heart (cardiac) abnormalities that can range from benign heart murmurs to serious structural defects. A heart murmur is an extra sound that is heard during a heartbeat. Heart murmurs in children with Alagille syndrome are usually caused by narrowing of the blood vessels of the lungs (pulmonary artery stenosis). The most common heart abnormality is peripheral pulmonary stenosis in which some of the blood vessels carrying blood to the lungs (pulmonary arteries) are narrowed (stenosis). Some children with Alagille syndrome may have complex heart defects, the most common of which is tetralogy of Fallot. Tetralogy of Fallot is a rare form of cyanotic heart disease. Cyanosis is abnormal bluish discoloration of the skin and mucous membranes that occurs due to low levels of circulating oxygen in the blood.
Tetralogy of Fallot consists of a combination of four different heart defects: ventricular septal defect, obstructed outflow of blood from the right ventricle to the lungs due to an abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis), displaced aorta that causes blood to flow into the aorta from both the right and left ventricles, and abnormal enlargement of the right ventricle.Additional heart defects that can occur in Alagille syndrome include ventricular septal defects, atrial septal defects, patent ductus arteriosus, and coarctation of the aorta. Some studies have shown that in rare cases there is an association with Wolff-Parkinson-White syndrome, a condition characterized by electrical disturbances in the heart. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Some individuals with Alagille syndrome may have eye (ocular) abnormalities, especially posterior embryotoxon, a condition marked by thickening of the ring that normally lines the cornea in the eye. The cornea is the thin, transparent membrane that covers the eyeballs. In most cases, posterior embryotoxon is a benign finding that primarily helps to establish a clinical diagnosis and vision is usually unaffected, although mild decreases in the clarity of vision may occur. Less commonly, other eye abnormalities may occur such as Axenfeld anomaly, a condition in which strands of the iris are abnormally attached to the cornea, or progressive degeneration of the retina (pigmentary retinopathy). The retina is the thin layers of nerve cells that lines that inner surface of the back of the eyes and senses light and converts it to nerve signals, which are then relayed to the brain through the optic nerve.Individuals with Alagille syndrome usually have distinctive facial features including deeply-set and widely spaced (hypertelorism) eyes, a pointed chin, broad forehead, and low-set, malformed eyes. In older individuals and adults the chin may appear larger and more prominent (prognathia).Skeletal abnormalities may occur in some individuals with Alagille syndrome including butterfly vertebrae, a condition in which certain bones of the spinal column are irregularly-shaped. This condition is often noted on an x-ray, but usually does not cause any symptoms or problems (asymptomatic).Additional symptoms may occur in some individuals with Alagille syndrome including kidney (renal) abnormalities, pancreatic insufficiency, vascular anomalies, mild developmental delays and cognitive impairment. Kidney abnormalities may be more prevalent in individuals with Alagille syndrome caused by mutations in the NOTCH2 gene and include abnormally small kidneys, the presence of cysts on the kidneys and decreased or impaired kidney function. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps to break down sugar. Pancreatic insufficiency is when the pancreas cannot produce or transport enough enzymes to the intestines to aid in the breakdown and absorption of food and nutrients.Individuals with Alagille syndrome can also develop abnormalities of certain blood vessels (vascular anomalies) including those in the brain, liver, lungs, heart, and kidneys. Vascular anomalies in the brain can lead to bleeding inside the brain (intracranial bleeding) and stroke. Some individuals with Alagille syndrome have developed a condition known as Moyamoya syndrome. Moyamoya syndrome is a progressive disorder that is characterized by narrowing (stenosis) and/or closing (occlusion) inside the skull of the carotid artery, the major artery that delivers blood to the brain. Intracranial bleeding and other vascular anomalies are potentially life-threatening complications and account for a significant percentage of mortality and morbidity in Alagille syndrome. | Symptoms of Alagille Syndrome. The symptoms and severity of Alagille syndrome can vary greatly from one person to another, even among members of the same family. Some individuals may have a mild form of the disorder that can virtually go unnoticed; other individuals may have a serious form of the disorder that can potentially cause life-threatening complications. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Alagille syndrome can be associated with abnormalities of the liver, heart, eyes, skeleton, kidneys and other organ systems of the body. A main finding of Alagille syndrome is liver disease that often becomes apparent within the first three months of life. However, individuals with mild liver involvement may not be diagnosed until later in life. Liver disease in Alagille syndrome, if present, may range in severity from jaundice or mild cholestasis to severe, progressive liver disease that can potentially result in liver failure.Approximately 90 percent of individuals with Alagille syndrome have a reduced number of bile ducts (bile duct paucity) within the liver. Bile ducts are small tube-like structures that carry bile from the liver to the small intestines. The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and helps eliminate excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.Because of the reduced number of bile ducts, individuals with Alagille syndrome can develop jaundice and cholestasis usually during the first four months of life. Cholestasis refers to reduced or obstructed flow of bile from the liver. Cholestasis can cause yellowing of the skin (jaundice) or whites of the eyes (icterus), itching (pruritus) that may be intense, pale-colored stools, dark urine, fatty bumps (xanthomas) just under the surface of the skin, and an abnormally enlarged liver (hepatomegaly) and/or enlarged spleen (splenomegaly). Because the body cannot properly absorb fats and fat-soluble vitamins (vitamins A, D, E, and K), affected children may also experience growth deficiencies and failure to thrive. Malabsorption of vital nutrients can also lead to rickets, a condition marked by softened, weakened bones (vitamin D deficiency), vision problems (vitamin A deficiency), poor coordination and developmental delays (vitamin E deficiency) and blood clotting problems (vitamin K deficiency).In approximately 15 percent of patients, progressive liver disease results in scarring of the liver (cirrhosis) and liver failure. There is no way to tell which children are at risk for serious, progressive liver disease in Alagille syndrome.Many individuals with Alagille syndrome have heart (cardiac) abnormalities that can range from benign heart murmurs to serious structural defects. A heart murmur is an extra sound that is heard during a heartbeat. Heart murmurs in children with Alagille syndrome are usually caused by narrowing of the blood vessels of the lungs (pulmonary artery stenosis). The most common heart abnormality is peripheral pulmonary stenosis in which some of the blood vessels carrying blood to the lungs (pulmonary arteries) are narrowed (stenosis). Some children with Alagille syndrome may have complex heart defects, the most common of which is tetralogy of Fallot. Tetralogy of Fallot is a rare form of cyanotic heart disease. Cyanosis is abnormal bluish discoloration of the skin and mucous membranes that occurs due to low levels of circulating oxygen in the blood.
Tetralogy of Fallot consists of a combination of four different heart defects: ventricular septal defect, obstructed outflow of blood from the right ventricle to the lungs due to an abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis), displaced aorta that causes blood to flow into the aorta from both the right and left ventricles, and abnormal enlargement of the right ventricle.Additional heart defects that can occur in Alagille syndrome include ventricular septal defects, atrial septal defects, patent ductus arteriosus, and coarctation of the aorta. Some studies have shown that in rare cases there is an association with Wolff-Parkinson-White syndrome, a condition characterized by electrical disturbances in the heart. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Some individuals with Alagille syndrome may have eye (ocular) abnormalities, especially posterior embryotoxon, a condition marked by thickening of the ring that normally lines the cornea in the eye. The cornea is the thin, transparent membrane that covers the eyeballs. In most cases, posterior embryotoxon is a benign finding that primarily helps to establish a clinical diagnosis and vision is usually unaffected, although mild decreases in the clarity of vision may occur. Less commonly, other eye abnormalities may occur such as Axenfeld anomaly, a condition in which strands of the iris are abnormally attached to the cornea, or progressive degeneration of the retina (pigmentary retinopathy). The retina is the thin layers of nerve cells that lines that inner surface of the back of the eyes and senses light and converts it to nerve signals, which are then relayed to the brain through the optic nerve.Individuals with Alagille syndrome usually have distinctive facial features including deeply-set and widely spaced (hypertelorism) eyes, a pointed chin, broad forehead, and low-set, malformed eyes. In older individuals and adults the chin may appear larger and more prominent (prognathia).Skeletal abnormalities may occur in some individuals with Alagille syndrome including butterfly vertebrae, a condition in which certain bones of the spinal column are irregularly-shaped. This condition is often noted on an x-ray, but usually does not cause any symptoms or problems (asymptomatic).Additional symptoms may occur in some individuals with Alagille syndrome including kidney (renal) abnormalities, pancreatic insufficiency, vascular anomalies, mild developmental delays and cognitive impairment. Kidney abnormalities may be more prevalent in individuals with Alagille syndrome caused by mutations in the NOTCH2 gene and include abnormally small kidneys, the presence of cysts on the kidneys and decreased or impaired kidney function. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps to break down sugar. Pancreatic insufficiency is when the pancreas cannot produce or transport enough enzymes to the intestines to aid in the breakdown and absorption of food and nutrients.Individuals with Alagille syndrome can also develop abnormalities of certain blood vessels (vascular anomalies) including those in the brain, liver, lungs, heart, and kidneys. Vascular anomalies in the brain can lead to bleeding inside the brain (intracranial bleeding) and stroke. Some individuals with Alagille syndrome have developed a condition known as Moyamoya syndrome. Moyamoya syndrome is a progressive disorder that is characterized by narrowing (stenosis) and/or closing (occlusion) inside the skull of the carotid artery, the major artery that delivers blood to the brain. Intracranial bleeding and other vascular anomalies are potentially life-threatening complications and account for a significant percentage of mortality and morbidity in Alagille syndrome. | 54 | Alagille Syndrome |
nord_54_2 | Causes of Alagille Syndrome | Alagille syndrome is caused by mutations in one of two genes – the JAG1 gene or the NOTCH2 gene. Mutations of the JAG1 gene have been identified in more than 88 percent of cases. Mutations in the NOTCH2 gene account for less than 1 percent of cases. These mutations are inherited in an autosomal dominant pattern. In some cases, the mutations occur randomly due to a spontaneous genetic change (i.e., new mutation).Dominant genetic disorders occur when only a single copy of a gene with a mutation is necessary for the appearance of the disorder. The gene with the mutation can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. If carried by a parent, the risk of passing the gene with the mutation from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. | Causes of Alagille Syndrome. Alagille syndrome is caused by mutations in one of two genes – the JAG1 gene or the NOTCH2 gene. Mutations of the JAG1 gene have been identified in more than 88 percent of cases. Mutations in the NOTCH2 gene account for less than 1 percent of cases. These mutations are inherited in an autosomal dominant pattern. In some cases, the mutations occur randomly due to a spontaneous genetic change (i.e., new mutation).Dominant genetic disorders occur when only a single copy of a gene with a mutation is necessary for the appearance of the disorder. The gene with the mutation can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. If carried by a parent, the risk of passing the gene with the mutation from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. | 54 | Alagille Syndrome |
nord_54_3 | Affects of Alagille Syndrome | Alagille syndrome affects males and females in equal numbers. The incidence of Alagille syndrome has been estimated to be approximately 1 in 30,000-45,000 individuals in the general population. Some cases of Alagille syndrome may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of Alagille syndrome in the general population. | Affects of Alagille Syndrome. Alagille syndrome affects males and females in equal numbers. The incidence of Alagille syndrome has been estimated to be approximately 1 in 30,000-45,000 individuals in the general population. Some cases of Alagille syndrome may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of Alagille syndrome in the general population. | 54 | Alagille Syndrome |
nord_54_4 | Related disorders of Alagille Syndrome | Symptoms of the following disorders can be similar to those of Alagille syndrome. Comparisons may be useful for a differential diagnosis.Extrahepatic biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and breaking down fats in the small intestine. In extrahepatic biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants may have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (cirrhosis). Additional symptoms may include itching (pruritis), abnormal enlargement of the liver (hepatomegaly), pale or gray stools (acholic stools), and a swollen stomach. In some cases, additional abnormalities may be present, including heart defects and kidney and spleen malformations. The exact cause of extrahepatic biliary atresia is unknown. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.)Neonatal hepatitis refers to a group of liver disorders that affect newborns between the ages of about 1 and 2 months, and produce a typical yellow color to the infant’s skin (jaundice). In contrast to infants with Alagille syndrome, those with neonatal hepatitis have normal, intact bile ducts (biliary tracts). Symptoms may include an abnormal yellow discoloration of the skin and/or whites of the eyes (jaundice), pale stools, unusually dark urine, and/or abnormal enlargement of the liver (hepatomegaly). Infants with neonatal hepatitis may gain weight or grow at a slower than normal rate (failure to thrive). The infant may be irritable because of excessively itchy skin (pruritus). Additional symptoms may include abnormal enlargement of the spleen (splenomegaly) and the abnormal accumulation of body fluids within the abdomen (ascites). In many cases, the exact cause of neonatal hepatitis is unknown (idiopathic), although some cases seem to run in families. Some studies suggest an association with an infectious or viral disease. (For more information on this disorder, choose “idiopathic neonatal hepatitis” as your search term in the Rare Disease Database.)Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic disorders that affect the liver. The main symptom is the interruption or suppression of the flow of bile from the liver (cholestasis). Cholestasis occurs due to defects within the liver (intrahepatic). Additional symptoms may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, and severe itchiness (pruritus). The more severe forms of these disorders eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure.Velocardiofacial (VCFS) / DiGeorge syndrome is due to deletions of chromosome 22q11.2. Several clinical features that overlap with those seen in Alagille syndrome can be seen in individuals with this chromosome abnormality including congenital heart defects (pulmonic stenosis, tetralogy of Fallot, etc), posterior embryotoxon and other anterior chamber defects of the eyes and butterfly vertebrae. Liver (hepatic) involvement is not typically seen in individuals with the 22q11.2 deletion syndrome. (For more information on this disorder, choose “Chromosome 22q11.2 deletion syndrome” as your search term in the Rare Disease Database.)A wide variety of additional disorders and conditions can cause symptoms that are similar to those associated with Alagille syndrome. There are over 100 different causes of cholestasis in the newborn. Other disorders that can cause bile duct paucity including alpha-1-antitrypsin deficiency, cystic fibrosis, Zellweger spectrum disorders and various chromosomal, immunologic and infectious disorders. Most of these disorders have additional, distinctive symptoms or clinical findings that can distinguish them from Alagille syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Alagille Syndrome. Symptoms of the following disorders can be similar to those of Alagille syndrome. Comparisons may be useful for a differential diagnosis.Extrahepatic biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and breaking down fats in the small intestine. In extrahepatic biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants may have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (cirrhosis). Additional symptoms may include itching (pruritis), abnormal enlargement of the liver (hepatomegaly), pale or gray stools (acholic stools), and a swollen stomach. In some cases, additional abnormalities may be present, including heart defects and kidney and spleen malformations. The exact cause of extrahepatic biliary atresia is unknown. (For more information on this disorder, choose “biliary atresia” as your search term in the Rare Disease Database.)Neonatal hepatitis refers to a group of liver disorders that affect newborns between the ages of about 1 and 2 months, and produce a typical yellow color to the infant’s skin (jaundice). In contrast to infants with Alagille syndrome, those with neonatal hepatitis have normal, intact bile ducts (biliary tracts). Symptoms may include an abnormal yellow discoloration of the skin and/or whites of the eyes (jaundice), pale stools, unusually dark urine, and/or abnormal enlargement of the liver (hepatomegaly). Infants with neonatal hepatitis may gain weight or grow at a slower than normal rate (failure to thrive). The infant may be irritable because of excessively itchy skin (pruritus). Additional symptoms may include abnormal enlargement of the spleen (splenomegaly) and the abnormal accumulation of body fluids within the abdomen (ascites). In many cases, the exact cause of neonatal hepatitis is unknown (idiopathic), although some cases seem to run in families. Some studies suggest an association with an infectious or viral disease. (For more information on this disorder, choose “idiopathic neonatal hepatitis” as your search term in the Rare Disease Database.)Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic disorders that affect the liver. The main symptom is the interruption or suppression of the flow of bile from the liver (cholestasis). Cholestasis occurs due to defects within the liver (intrahepatic). Additional symptoms may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, and severe itchiness (pruritus). The more severe forms of these disorders eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure.Velocardiofacial (VCFS) / DiGeorge syndrome is due to deletions of chromosome 22q11.2. Several clinical features that overlap with those seen in Alagille syndrome can be seen in individuals with this chromosome abnormality including congenital heart defects (pulmonic stenosis, tetralogy of Fallot, etc), posterior embryotoxon and other anterior chamber defects of the eyes and butterfly vertebrae. Liver (hepatic) involvement is not typically seen in individuals with the 22q11.2 deletion syndrome. (For more information on this disorder, choose “Chromosome 22q11.2 deletion syndrome” as your search term in the Rare Disease Database.)A wide variety of additional disorders and conditions can cause symptoms that are similar to those associated with Alagille syndrome. There are over 100 different causes of cholestasis in the newborn. Other disorders that can cause bile duct paucity including alpha-1-antitrypsin deficiency, cystic fibrosis, Zellweger spectrum disorders and various chromosomal, immunologic and infectious disorders. Most of these disorders have additional, distinctive symptoms or clinical findings that can distinguish them from Alagille syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 54 | Alagille Syndrome |
nord_54_5 | Diagnosis of Alagille Syndrome | A diagnosis of Alagille syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Because the symptoms of Alagille syndrome are highly variable, obtaining a diagnosis can be difficult. Surgical removal and microscopic study of liver tissue (liver biopsy) can reveal bile duct paucity. Although bile duct paucity is considered a key characteristic of Alagille syndrome, this finding is not always present in infants with the disorder.A physician may suspect Alagille syndrome if an individual has three of the following five clinical findings in addition to bile duct paucity: symptoms of liver disease or cholestasis, heart defect, skeletal abnormality, eye (ophthalmologic) abnormality, and/or distinctive facial features.In addition to a liver biopsy, physicians may conduct other tests to aid in the diagnosis of Alagille syndrome. Such tests may include blood tests to determine liver function and detect fat-soluble vitamin deficiencies, an eye examination, x-rays of the spine to detect characteristic changes such as butterfly vertebrae, an abdominal ultrasound of the hepatobiliary tree (e.g., liver, pancreas, gall bladder and spleen) to detect abnormalities or rule out other conditions, and an examination of heart structure and function to detect potential heart abnormalities.The diagnosis of Alagille syndrome can be confirmed in many cases by molecular genetic testing, which reveals the presence of a JAG1 or NOTCH2 gene mutation. However, in some people with Alagille syndrome, genetic testing may not reveal a JAG1 or NOTCH2 mutation. | Diagnosis of Alagille Syndrome. A diagnosis of Alagille syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Because the symptoms of Alagille syndrome are highly variable, obtaining a diagnosis can be difficult. Surgical removal and microscopic study of liver tissue (liver biopsy) can reveal bile duct paucity. Although bile duct paucity is considered a key characteristic of Alagille syndrome, this finding is not always present in infants with the disorder.A physician may suspect Alagille syndrome if an individual has three of the following five clinical findings in addition to bile duct paucity: symptoms of liver disease or cholestasis, heart defect, skeletal abnormality, eye (ophthalmologic) abnormality, and/or distinctive facial features.In addition to a liver biopsy, physicians may conduct other tests to aid in the diagnosis of Alagille syndrome. Such tests may include blood tests to determine liver function and detect fat-soluble vitamin deficiencies, an eye examination, x-rays of the spine to detect characteristic changes such as butterfly vertebrae, an abdominal ultrasound of the hepatobiliary tree (e.g., liver, pancreas, gall bladder and spleen) to detect abnormalities or rule out other conditions, and an examination of heart structure and function to detect potential heart abnormalities.The diagnosis of Alagille syndrome can be confirmed in many cases by molecular genetic testing, which reveals the presence of a JAG1 or NOTCH2 gene mutation. However, in some people with Alagille syndrome, genetic testing may not reveal a JAG1 or NOTCH2 mutation. | 54 | Alagille Syndrome |
nord_54_6 | Therapies of Alagille Syndrome | The treatment of Alagille 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, gastroenterologists, cardiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Individuals with Alagille syndrome should have a baseline echocardiogram (ultrasound of the heart) to screen for heart involvement, ultrasound of the abdomen to screen for liver and kidney anomalies, and a screening eye (ophthalmology) exam, In addition, if not previously obtained for specific symptoms, a screening imaging study of the blood vessels of the head (MRI/MRA) is recommended for children who are old enough to sit through the study without need for anesthesia or sedation. Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E and K. Young children may be given formula with medium chain triglycerides because this form of fat is better absorbed by individuals with Alagille syndrome who have cholestasis. Some affected children may need to receive extra calories through a tube that runs from the nose to the stomach (nasogastric tube) or through a tube placed directly into the stomach through a small incision in the abdominal wall and stomach (gastrostomy tube).Specific treatment may be indicated for individuals with cholestatic liver disease. The drug ursodeoxycholic acid is given to help improve bile flow, which can lead to a reduction in some symptoms such as itching (pruritus) or cholesterol deposits (xanthomas). However, pruritus associated with Alagille syndrome often is resistant to therapy. In 2021, maralixibat (Livmarli) was approved by the U.S. Food and Drug Administration (FDA) to treat pruritus in patients with Alagille syndrome. In 2023, odevixibat (Bylvay) was approved by the FDA to treat pruritus in patients over 12 months of age with Alagille syndrome. Additional drugs that have been used to treat pruritus include antihistamines, rifampin, cholestyramine and naltrexone. Keeping the skin properly hydrated with moisturizers is also recommended. Cholestyramine may also be indicated for individuals with elevated cholesterol levels or xanthomas.Some affected infants and children with Alagille syndrome who do not respond to drug and dietary therapies may be treated by a surgical procedure known as partial biliary diversion. This surgical procedure is used to disrupt or divert recirculation of bile acids between the liver and the gastrointestinal tract. This therapy has demonstrated that, in some children, it can improve certain symptoms such as reducing itchiness or xanthoma formation.In severe cases of Alagille syndrome (i.e., cases that have progressed to cirrhosis or liver failure or in which other therapies were unsuccessful), liver transplantation may be required.Additional complications that can be associated with Alagille syndrome including heart, blood vessel and kidney abnormalities are treated in the standard manner. In some cases, this may include surgery. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Alagille Syndrome. The treatment of Alagille 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, gastroenterologists, cardiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Individuals with Alagille syndrome should have a baseline echocardiogram (ultrasound of the heart) to screen for heart involvement, ultrasound of the abdomen to screen for liver and kidney anomalies, and a screening eye (ophthalmology) exam, In addition, if not previously obtained for specific symptoms, a screening imaging study of the blood vessels of the head (MRI/MRA) is recommended for children who are old enough to sit through the study without need for anesthesia or sedation. Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E and K. Young children may be given formula with medium chain triglycerides because this form of fat is better absorbed by individuals with Alagille syndrome who have cholestasis. Some affected children may need to receive extra calories through a tube that runs from the nose to the stomach (nasogastric tube) or through a tube placed directly into the stomach through a small incision in the abdominal wall and stomach (gastrostomy tube).Specific treatment may be indicated for individuals with cholestatic liver disease. The drug ursodeoxycholic acid is given to help improve bile flow, which can lead to a reduction in some symptoms such as itching (pruritus) or cholesterol deposits (xanthomas). However, pruritus associated with Alagille syndrome often is resistant to therapy. In 2021, maralixibat (Livmarli) was approved by the U.S. Food and Drug Administration (FDA) to treat pruritus in patients with Alagille syndrome. In 2023, odevixibat (Bylvay) was approved by the FDA to treat pruritus in patients over 12 months of age with Alagille syndrome. Additional drugs that have been used to treat pruritus include antihistamines, rifampin, cholestyramine and naltrexone. Keeping the skin properly hydrated with moisturizers is also recommended. Cholestyramine may also be indicated for individuals with elevated cholesterol levels or xanthomas.Some affected infants and children with Alagille syndrome who do not respond to drug and dietary therapies may be treated by a surgical procedure known as partial biliary diversion. This surgical procedure is used to disrupt or divert recirculation of bile acids between the liver and the gastrointestinal tract. This therapy has demonstrated that, in some children, it can improve certain symptoms such as reducing itchiness or xanthoma formation.In severe cases of Alagille syndrome (i.e., cases that have progressed to cirrhosis or liver failure or in which other therapies were unsuccessful), liver transplantation may be required.Additional complications that can be associated with Alagille syndrome including heart, blood vessel and kidney abnormalities are treated in the standard manner. In some cases, this may include surgery. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 54 | Alagille Syndrome |
nord_55_0 | Overview of Alexander Disease | SummaryAlexander disease is an extremely rare, usually progressive and fatal, neurological disorder. Initially it was detected most often during infancy or early childhood, but as better diagnostic tools have become available has been found to occur with similar frequency at all stages of life. Alexander disease has historically been included among the leukodystrophies–diseases of the white matter of the brain. These diseases affect the fatty material (myelin) that forms an insulating wrapping (sheath) around certain nerve fibers (axons). Myelin enables the efficient transmission of nerve impulses and provides the “whitish” appearance of the so-called white matter of the brain. There is a marked deficit in myelin formation in most early onset patients with Alexander disease, and sometimes in later onset patients, particularly in the front (frontal lobes) of the brain's two hemispheres (cerebrum). However, white matter defects are sometimes not observed in later onset individuals. Instead, the unifying feature among all Alexander disease patients is the presence of abnormal protein aggregates known as “Rosenthal fibers” throughout certain regions of the brain and spinal cord (central nervous system [CNS]). These aggregates occur inside astrocytes, a common cell type in the CNS that helps maintain a normal CNS environment. Accordingly, it is more appropriate to consider Alexander disease a disease of astrocytes (an astrogliopathy) than a white matter disease (leukodystrophy).IntroductionAlexander disease is named after the physician who first described the condition in 1949 (WS Alexander). | Overview of Alexander Disease. SummaryAlexander disease is an extremely rare, usually progressive and fatal, neurological disorder. Initially it was detected most often during infancy or early childhood, but as better diagnostic tools have become available has been found to occur with similar frequency at all stages of life. Alexander disease has historically been included among the leukodystrophies–diseases of the white matter of the brain. These diseases affect the fatty material (myelin) that forms an insulating wrapping (sheath) around certain nerve fibers (axons). Myelin enables the efficient transmission of nerve impulses and provides the “whitish” appearance of the so-called white matter of the brain. There is a marked deficit in myelin formation in most early onset patients with Alexander disease, and sometimes in later onset patients, particularly in the front (frontal lobes) of the brain's two hemispheres (cerebrum). However, white matter defects are sometimes not observed in later onset individuals. Instead, the unifying feature among all Alexander disease patients is the presence of abnormal protein aggregates known as “Rosenthal fibers” throughout certain regions of the brain and spinal cord (central nervous system [CNS]). These aggregates occur inside astrocytes, a common cell type in the CNS that helps maintain a normal CNS environment. Accordingly, it is more appropriate to consider Alexander disease a disease of astrocytes (an astrogliopathy) than a white matter disease (leukodystrophy).IntroductionAlexander disease is named after the physician who first described the condition in 1949 (WS Alexander). | 55 | Alexander Disease |
nord_55_1 | Symptoms of Alexander Disease | Historically, three forms of Alexander disease have been described based on age of onset, Infantile, Juvenile and Adult; but an analysis of a large number of patients concluded that the disease is better described as having two forms, Type I, which generally has an onset by age 4, and Type II, which can have onset at any age, but primarily after age 4. Each type accounts for about half of the reported patients. Symptoms associated with the Type I form include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor impairment); and sudden episodes of uncontrolled electrical activity in the brain (seizures). Additional features typically include progressive enlargement of the head (macrocephaly); abnormally increased muscle stiffness and restriction of movement (spasticity); lack of coordination (ataxia); and vomiting and difficulty swallowing, coughing, breathing or talking (bulbar and pseudobulbar signs). Nearly 90% of infantile patients display developmental problems and seizures, and over 50% the other symptoms mentioned; however, no single symptom or combination of symptoms is always present.Patients with type II Alexander disease rarely show delay or regression of development, macrocephaly or seizures, and mental decline may develop slowly or not at all. Instead, about 50% display bulbar/pseudobulbar signs, about 75% have ataxia and about 33% spasticity. Because these symptoms are not specific, adult Alexander disease is sometimes confused with more common disorders such as multiple sclerosis or the presence of tumors. (For information on these diseases, see the related disorders section of this report.)The two different forms of Alexander disease are generalizations rather than defined entities. In actuality there is an overlapping continuum of presentations; a one year old could present with symptoms more typical of a 10 years old, and vice-versa. However, in all cases the symptoms almost always worsen with time and eventually lead to death, with the downhill course generally (but not always) being swifter the earlier the onset. | Symptoms of Alexander Disease. Historically, three forms of Alexander disease have been described based on age of onset, Infantile, Juvenile and Adult; but an analysis of a large number of patients concluded that the disease is better described as having two forms, Type I, which generally has an onset by age 4, and Type II, which can have onset at any age, but primarily after age 4. Each type accounts for about half of the reported patients. Symptoms associated with the Type I form include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor impairment); and sudden episodes of uncontrolled electrical activity in the brain (seizures). Additional features typically include progressive enlargement of the head (macrocephaly); abnormally increased muscle stiffness and restriction of movement (spasticity); lack of coordination (ataxia); and vomiting and difficulty swallowing, coughing, breathing or talking (bulbar and pseudobulbar signs). Nearly 90% of infantile patients display developmental problems and seizures, and over 50% the other symptoms mentioned; however, no single symptom or combination of symptoms is always present.Patients with type II Alexander disease rarely show delay or regression of development, macrocephaly or seizures, and mental decline may develop slowly or not at all. Instead, about 50% display bulbar/pseudobulbar signs, about 75% have ataxia and about 33% spasticity. Because these symptoms are not specific, adult Alexander disease is sometimes confused with more common disorders such as multiple sclerosis or the presence of tumors. (For information on these diseases, see the related disorders section of this report.)The two different forms of Alexander disease are generalizations rather than defined entities. In actuality there is an overlapping continuum of presentations; a one year old could present with symptoms more typical of a 10 years old, and vice-versa. However, in all cases the symptoms almost always worsen with time and eventually lead to death, with the downhill course generally (but not always) being swifter the earlier the onset. | 55 | Alexander Disease |
nord_55_2 | Causes of Alexander Disease | About 95% of Alexander disease cases are caused by mutations in a gene called GFAP for a structural protein called glial fibrillary acidic protein that is found exclusively in astrocytes in the CNS. The cause of the other 5% of cases is not known.The GFAP mutations are dominant. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Thus, Alexander patients have one mutant copy and one normal copy of the GFAP gene. The abnormal gene can be inherited from either parent or can be the result of a new mutation (change in the DNA of the gene). Most Alexander patients have a new mutation, indicating that neither of their parents has the mutation, but the mutation arose at some point during the development of sperm or ova or an embryo. As the disease becomes better diagnosed, familial cases, in which the disease is passed from one generation to the next, are being increasingly recognized. The risk of transmitting the disorder from an affected parent to an offspring is 50 percent for each pregnancy. The risk is the same for males and females.How the GFAP mutations produce Alexander disease is not known. The Rosenthal fibers, which contain GFAP, accumulate throughout the surfaces of the brain (cerebral cortex), in the white matter of the brain, and in the lower regions of the brain (brainstem), and the spinal cord, and primarily appear under the innermost of the protective membranes (meninges) surrounding the brain and spinal cord (pia mater); under the lining of the fluid-filled cavities (ventricles) of the brain (subependymal regions); and around blood vessels (perivascular regions). Studies in mice indicate that the mutations act by producing a new, toxic effect, rather than by interfering with the normal function of GFAP. This toxic effect may be due to the presence of the Rosenthal fibers, or to the very large, abnormal amounts of GFAP that accumulate in Alexander astrocytes, or both. Astrocytes perform many critical functions in the CNS, and several of these are affected by the GFAP mutations, but the importance of these changes to the disease is not yet known. | Causes of Alexander Disease. About 95% of Alexander disease cases are caused by mutations in a gene called GFAP for a structural protein called glial fibrillary acidic protein that is found exclusively in astrocytes in the CNS. The cause of the other 5% of cases is not known.The GFAP mutations are dominant. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Thus, Alexander patients have one mutant copy and one normal copy of the GFAP gene. The abnormal gene can be inherited from either parent or can be the result of a new mutation (change in the DNA of the gene). Most Alexander patients have a new mutation, indicating that neither of their parents has the mutation, but the mutation arose at some point during the development of sperm or ova or an embryo. As the disease becomes better diagnosed, familial cases, in which the disease is passed from one generation to the next, are being increasingly recognized. The risk of transmitting the disorder from an affected parent to an offspring is 50 percent for each pregnancy. The risk is the same for males and females.How the GFAP mutations produce Alexander disease is not known. The Rosenthal fibers, which contain GFAP, accumulate throughout the surfaces of the brain (cerebral cortex), in the white matter of the brain, and in the lower regions of the brain (brainstem), and the spinal cord, and primarily appear under the innermost of the protective membranes (meninges) surrounding the brain and spinal cord (pia mater); under the lining of the fluid-filled cavities (ventricles) of the brain (subependymal regions); and around blood vessels (perivascular regions). Studies in mice indicate that the mutations act by producing a new, toxic effect, rather than by interfering with the normal function of GFAP. This toxic effect may be due to the presence of the Rosenthal fibers, or to the very large, abnormal amounts of GFAP that accumulate in Alexander astrocytes, or both. Astrocytes perform many critical functions in the CNS, and several of these are affected by the GFAP mutations, but the importance of these changes to the disease is not yet known. | 55 | Alexander Disease |
nord_55_3 | Affects of Alexander Disease | Alexander disease has been estimated to occur at a frequency of about 1 in 1 million births. No racial, ethnic, geographic, or sex preference has been observed, nor is any expected given the de novo (new) nature of the mutations responsible for most cases. Although initially diagnosed primarily in young children, it is now being observed with similar frequency at all ages. | Affects of Alexander Disease. Alexander disease has been estimated to occur at a frequency of about 1 in 1 million births. No racial, ethnic, geographic, or sex preference has been observed, nor is any expected given the de novo (new) nature of the mutations responsible for most cases. Although initially diagnosed primarily in young children, it is now being observed with similar frequency at all ages. | 55 | Alexander Disease |
nord_55_4 | Related disorders of Alexander Disease | Symptoms of the following disorders can be similar to those of Alexander disease. Comparisons may be useful for a differential diagnosis:Hydrocephalus is a condition in which the normal flow of cerebrospinal fluid (CSF) is restricted and the spaces in the brain (ventricles) become abnormally enlarged. Fluid accumulates beneath the skull and puts pressure on the brain. Hydrocephalus is characterized in children by an abnormally enlarged head (megalencephaly). The scalp may be thin and transparent, and the forehead may bulge (frontal bossing). Other symptoms of hydrocephalus may include convulsions, abnormal reflexes, a slowed heartbeat, headache, vomiting, weakness and/or problems with vision. (For more information on this disorder, choose “Hydrocephalus” as your search term in the Rare Disease Database.)Multiple sclerosis is a chronic disorder of the CNS that causes the destruction of myelin, the fatty covering on axons (demyelination). The symptoms of this disease vary greatly and may include visual impairment, double vision and/or involuntary rhythmic movements of the eyes (nystagmus), impairment of speech, numbness or tingling sensations in the arms and legs, muscle weakness and/or difficulty walking, depending upon the area(s) of the CNS that Multiple Sclerosis affects. The symptoms of Multiple Sclerosis may be similar to those of Type II (late onset) Alexander disease. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)Astrocytomas are brain tumors that can be either slowly growing (low-grade) or rapidly growing (malignant or high-grade) and are composed of astrocytes. Symptoms may vary according to the size, location, and growth rate of the tumor. Frequently the first symptom is a recurrent headache that is typically a result of increased pressure within the skull due to the growth of the tumor. Headaches may be accompanied by vomiting and/or personality changes. Other symptoms of low-grade or high-grade astrocytomas may include irritability, emotional instability, memory loss, intellectual impairment, convulsions, paralysis, bulbar and pseudobulbar signs, and seizures. The tumor cells in some types of low-grade astrocytomas contain Rosenthal fibers. (For more information on this disorder, choose “Astrocytoma” as your search term in the Rare Disease Database.)Adrenoleukodystrophy is a form of leukodystrophy. It is a rare inherited metabolic disorder characterized by the accumulation of very long chain fatty acids in the brain that causes the progressive loss of myelin. This disorder also causes progressive degeneration of the adrenal gland (adrenal atrophy). Symptoms of the childhood form of adrenoleukodystrophy, which affects almost exclusively males and is inherited from the mother, may include loss of previously acquired intellectual skills, poor memory, loss of emotional control, a jerky uncoordinated walk (ataxia), and/or muscle weakness on one side of the body. Other symptoms may include difficulties with speech, hearing loss, and/or visual impairment. (For more information on this disorder, choose “Adrenoleukodystrophy” as your search term in the Rare Disease Database.)Canavan leukodystrophy is another rare, inherited form of leukodystrophy characterized by the progressive deterioration of the CNS. Symptoms of this disorder may include floppiness, the loss of previously acquired mental and motor skills, poor head control, an abnormally enlarged head (megalencephaly) and/or blindness. As Canavan leukodystrophy progresses, there may be spastic muscle contractions in the arms and legs and paralysis. This disorder is caused by a chemical imbalance in the brain and symptoms typically appear in early infancy. It is autosomal recessive, so that one mutated gene is inherited from each parent, and it is most common in individuals of Jewish background. (For more information on this disorder, choose “Canavan” as your search term in the Rare Disease Database.)Glutaricacidurias are rare, hereditary, metabolic disorders, caused by a deficiency or absence of an enzyme needed to break down certain chemicals in the body, resulting in the accumulation of several organic acids in the blood, urine, and organs. These disorders may have an extremely variable age of onset. Symptoms may include specific physical birth defects, a short life span, an enlarged head (macrocephaly), decreased muscle tone (hypotonia), nausea, vomiting, and low sugar (hypoglycemia) and excess acid in the blood. Affected individuals may also have involuntary movements of the trunk and limbs (dystonia or athetosis) and intellectual disability may also occur. (For more information on these disorders, choose “Glutaricaciduria I” and “Glutaricaciduria II” as your search terms in the Rare Disease Database.)Krabbe leukodystrophy is a rare, inherited, lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids, galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as intellectual disability, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe leukodystrophy is inherited as an autosomal recessive trait. (For more information on these disorders, choose “Leukodystrophy, Krabbe’s” as your search terms in the Rare Disease Database.)Leigh syndrome is a rare, genetic, neurometabolic disorder characterized by the degeneration of the CNS. The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. (For more information on this disorder, choose “Leigh syndrome” as your search term in the Rare Disease Database.)Metachromatic leukodystrophy is a rare, inherited, leukodystrophy characterized by the abnormal accumulation of a fatty-like substance (sphingolipid) in the brain and other tissues of the body. It affects both the central nervous system and the peripheral nervous system (peripheral nerves). Symptoms of this disorder may include muscle rigidity, visual impairment, and/or convulsions. Previously acquired physical and intellectual skills may be lost. This disorder may begin in infancy, adolescence, or adulthood. It is an autosomal recessive disorder. (For more information on this disorder, choose “Metachromatic Leukodystrophy” as your search term in the Rare Disease Database.)Pelizaeus-Merzbacher disease is a rare, inherited, leukodystrophy characterized by the degeneration of the brain caused by the loss of myelin (demyelination). This disorder may begin in infancy or, less commonly, at older ages. The first symptoms in an infant include failure to thrive, developmental delays, muscle spasms, unsteadiness, weakness, and/or visual impairment. Deformities of the joints and seizures are sometimes seen. It is much more common in males than females and is inherited from the mother. (For more information on this disorder, choose “Pelizaeus-Merzbacher” as your search term in the Rare Disease Database.)
Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in cells of the central nervous system. Nerve cells are particularly severely affected. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy; an adult form (late-onset Tay-Sachs disease) may occur anytime from adolescence to the mid 30’s. (For more information on this disorder, choose “Tay Sachs disease” as your search term in the Rare Disease Database.) | Related disorders of Alexander Disease. Symptoms of the following disorders can be similar to those of Alexander disease. Comparisons may be useful for a differential diagnosis:Hydrocephalus is a condition in which the normal flow of cerebrospinal fluid (CSF) is restricted and the spaces in the brain (ventricles) become abnormally enlarged. Fluid accumulates beneath the skull and puts pressure on the brain. Hydrocephalus is characterized in children by an abnormally enlarged head (megalencephaly). The scalp may be thin and transparent, and the forehead may bulge (frontal bossing). Other symptoms of hydrocephalus may include convulsions, abnormal reflexes, a slowed heartbeat, headache, vomiting, weakness and/or problems with vision. (For more information on this disorder, choose “Hydrocephalus” as your search term in the Rare Disease Database.)Multiple sclerosis is a chronic disorder of the CNS that causes the destruction of myelin, the fatty covering on axons (demyelination). The symptoms of this disease vary greatly and may include visual impairment, double vision and/or involuntary rhythmic movements of the eyes (nystagmus), impairment of speech, numbness or tingling sensations in the arms and legs, muscle weakness and/or difficulty walking, depending upon the area(s) of the CNS that Multiple Sclerosis affects. The symptoms of Multiple Sclerosis may be similar to those of Type II (late onset) Alexander disease. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)Astrocytomas are brain tumors that can be either slowly growing (low-grade) or rapidly growing (malignant or high-grade) and are composed of astrocytes. Symptoms may vary according to the size, location, and growth rate of the tumor. Frequently the first symptom is a recurrent headache that is typically a result of increased pressure within the skull due to the growth of the tumor. Headaches may be accompanied by vomiting and/or personality changes. Other symptoms of low-grade or high-grade astrocytomas may include irritability, emotional instability, memory loss, intellectual impairment, convulsions, paralysis, bulbar and pseudobulbar signs, and seizures. The tumor cells in some types of low-grade astrocytomas contain Rosenthal fibers. (For more information on this disorder, choose “Astrocytoma” as your search term in the Rare Disease Database.)Adrenoleukodystrophy is a form of leukodystrophy. It is a rare inherited metabolic disorder characterized by the accumulation of very long chain fatty acids in the brain that causes the progressive loss of myelin. This disorder also causes progressive degeneration of the adrenal gland (adrenal atrophy). Symptoms of the childhood form of adrenoleukodystrophy, which affects almost exclusively males and is inherited from the mother, may include loss of previously acquired intellectual skills, poor memory, loss of emotional control, a jerky uncoordinated walk (ataxia), and/or muscle weakness on one side of the body. Other symptoms may include difficulties with speech, hearing loss, and/or visual impairment. (For more information on this disorder, choose “Adrenoleukodystrophy” as your search term in the Rare Disease Database.)Canavan leukodystrophy is another rare, inherited form of leukodystrophy characterized by the progressive deterioration of the CNS. Symptoms of this disorder may include floppiness, the loss of previously acquired mental and motor skills, poor head control, an abnormally enlarged head (megalencephaly) and/or blindness. As Canavan leukodystrophy progresses, there may be spastic muscle contractions in the arms and legs and paralysis. This disorder is caused by a chemical imbalance in the brain and symptoms typically appear in early infancy. It is autosomal recessive, so that one mutated gene is inherited from each parent, and it is most common in individuals of Jewish background. (For more information on this disorder, choose “Canavan” as your search term in the Rare Disease Database.)Glutaricacidurias are rare, hereditary, metabolic disorders, caused by a deficiency or absence of an enzyme needed to break down certain chemicals in the body, resulting in the accumulation of several organic acids in the blood, urine, and organs. These disorders may have an extremely variable age of onset. Symptoms may include specific physical birth defects, a short life span, an enlarged head (macrocephaly), decreased muscle tone (hypotonia), nausea, vomiting, and low sugar (hypoglycemia) and excess acid in the blood. Affected individuals may also have involuntary movements of the trunk and limbs (dystonia or athetosis) and intellectual disability may also occur. (For more information on these disorders, choose “Glutaricaciduria I” and “Glutaricaciduria II” as your search terms in the Rare Disease Database.)Krabbe leukodystrophy is a rare, inherited, lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids, galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as intellectual disability, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe leukodystrophy is inherited as an autosomal recessive trait. (For more information on these disorders, choose “Leukodystrophy, Krabbe’s” as your search terms in the Rare Disease Database.)Leigh syndrome is a rare, genetic, neurometabolic disorder characterized by the degeneration of the CNS. The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. (For more information on this disorder, choose “Leigh syndrome” as your search term in the Rare Disease Database.)Metachromatic leukodystrophy is a rare, inherited, leukodystrophy characterized by the abnormal accumulation of a fatty-like substance (sphingolipid) in the brain and other tissues of the body. It affects both the central nervous system and the peripheral nervous system (peripheral nerves). Symptoms of this disorder may include muscle rigidity, visual impairment, and/or convulsions. Previously acquired physical and intellectual skills may be lost. This disorder may begin in infancy, adolescence, or adulthood. It is an autosomal recessive disorder. (For more information on this disorder, choose “Metachromatic Leukodystrophy” as your search term in the Rare Disease Database.)Pelizaeus-Merzbacher disease is a rare, inherited, leukodystrophy characterized by the degeneration of the brain caused by the loss of myelin (demyelination). This disorder may begin in infancy or, less commonly, at older ages. The first symptoms in an infant include failure to thrive, developmental delays, muscle spasms, unsteadiness, weakness, and/or visual impairment. Deformities of the joints and seizures are sometimes seen. It is much more common in males than females and is inherited from the mother. (For more information on this disorder, choose “Pelizaeus-Merzbacher” as your search term in the Rare Disease Database.)
Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in cells of the central nervous system. Nerve cells are particularly severely affected. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy; an adult form (late-onset Tay-Sachs disease) may occur anytime from adolescence to the mid 30’s. (For more information on this disorder, choose “Tay Sachs disease” as your search term in the Rare Disease Database.) | 55 | Alexander Disease |
nord_55_5 | Diagnosis of Alexander Disease | For many years a brain biopsy to determine the presence of Rosenthal fibers was required for the diagnosis of Alexander disease. However, even this procedure can be ambiguous, because Rosenthal fibers are also found in certain other disorders, such as tumors of astrocytes. More recently, MRI criteria have been developed that have a high degree of accuracy for diagnosing typical Type I (early onset) disease. These criteria have been less useful for some of the Type II cases, which have little or no white matter deficits in the brain, although abnormalities in the brainstem, cerebellum, and spinal cord can suggest the diagnosis. Accordingly, when making a diagnosis of Alexander disease, more common diseases that have similar symptoms for which tests are available should first be ruled out. These include adrenoleukodystrophy, Canavan's disease, glutaricacidurias, Krabbe leukodystrophy, Leigh syndrome, metachromic leukodystrophy, Pelizaeus-Merzbacher and Tay-Sachs disease. A definitive diagnosis of Alexander disease rests on the identification of a GFAP mutation in the patient's DNA, which can be obtained from a blood sample or a swab of the inside of the cheek. DNA analysis is provided by several commercial and research laboratories. However, since no GFAP mutation has been found in about 5% of known cases, a negative result does not completely rule out the disease. Presently, Alexander patients without a GFAP mutation can be definitively diagnosed only at autopsy by the presence of disseminated, large numbers of Rosenthal fibers. | Diagnosis of Alexander Disease. For many years a brain biopsy to determine the presence of Rosenthal fibers was required for the diagnosis of Alexander disease. However, even this procedure can be ambiguous, because Rosenthal fibers are also found in certain other disorders, such as tumors of astrocytes. More recently, MRI criteria have been developed that have a high degree of accuracy for diagnosing typical Type I (early onset) disease. These criteria have been less useful for some of the Type II cases, which have little or no white matter deficits in the brain, although abnormalities in the brainstem, cerebellum, and spinal cord can suggest the diagnosis. Accordingly, when making a diagnosis of Alexander disease, more common diseases that have similar symptoms for which tests are available should first be ruled out. These include adrenoleukodystrophy, Canavan's disease, glutaricacidurias, Krabbe leukodystrophy, Leigh syndrome, metachromic leukodystrophy, Pelizaeus-Merzbacher and Tay-Sachs disease. A definitive diagnosis of Alexander disease rests on the identification of a GFAP mutation in the patient's DNA, which can be obtained from a blood sample or a swab of the inside of the cheek. DNA analysis is provided by several commercial and research laboratories. However, since no GFAP mutation has been found in about 5% of known cases, a negative result does not completely rule out the disease. Presently, Alexander patients without a GFAP mutation can be definitively diagnosed only at autopsy by the presence of disseminated, large numbers of Rosenthal fibers. | 55 | Alexander Disease |
nord_55_6 | Therapies of Alexander Disease | TreatmentTreatment is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families. Fetal diagnosis is an option for a couple who have had a previously affected child. | Therapies of Alexander Disease. TreatmentTreatment is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families. Fetal diagnosis is an option for a couple who have had a previously affected child. | 55 | Alexander Disease |
nord_56_0 | Overview of Alkaptonuria | Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air. However, this change may not occur for several hours after urination and often goes unnoticed. Aside from dark urine that is present from infancy, affected individuals generally do not develop symptoms (asymptomatic) during infancy or childhood and often remain unaware of their condition until adulthood. Affected individuals eventually develop ochronosis, which is the bluish-black discoloration of connective and other tissue within the body. Affected individuals may develop discoloration of the skin overlying cartilage within the body such as over part of the outer ear. In some cases, the whites of the eyes (sclera) may also become discolored. In adulthood, affected individuals also develop progressive arthritis of the spine and large joints. The HGD gene codes for the enzyme required for the breakdown of homogentisic acid. Mutations in the HGD gene cause alkaptonuria. | Overview of Alkaptonuria. Alkaptonuria is a rare genetic metabolic disorder characterized by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of an enzyme required to breakdown homogentisic acid. Affected individuals may have dark urine or urine that turns black when exposed to air. However, this change may not occur for several hours after urination and often goes unnoticed. Aside from dark urine that is present from infancy, affected individuals generally do not develop symptoms (asymptomatic) during infancy or childhood and often remain unaware of their condition until adulthood. Affected individuals eventually develop ochronosis, which is the bluish-black discoloration of connective and other tissue within the body. Affected individuals may develop discoloration of the skin overlying cartilage within the body such as over part of the outer ear. In some cases, the whites of the eyes (sclera) may also become discolored. In adulthood, affected individuals also develop progressive arthritis of the spine and large joints. The HGD gene codes for the enzyme required for the breakdown of homogentisic acid. Mutations in the HGD gene cause alkaptonuria. | 56 | Alkaptonuria |
nord_56_1 | Symptoms of Alkaptonuria | Alkaptonuria is a genetic disorder, and urine that turns dark is present from birth. However, additional symptoms usually do not appear until adulthood. Symptoms are generally slowly progressive. The urine of individuals with alkaptonuria may be abnormally dark or it may turn black upon long-standing exposure to the air. However, since this change often takes several hours, it often goes unnoticed. During infancy, diapers may be stained black (from urine exposure to air), although this is often missed or ignored.The first noticeable signs and symptoms of alkaptonuria usually do not develop until approximately 30 years of age and are due to chronic accumulation of homogentisic acid in connective tissue, especially cartilage. Affected individuals develop a condition called ochronosis, in which connective tissue such as cartilage turns blue, grey or black due to the chronic accumulation of homogentisic acid. In many individuals, cartilage within the ear may become thickened, irregular and discolored blue, grey or black. Eventually, this discoloration may be apparent on the skin overlying the cartilage. In many cases, the whites of the eyes (sclera) also become discolored. However, this pigmentation does not interfere with vision.In addition to cartilage, homogentisic acid accumulates in other connective tissue including tendons and ligaments and even bone. Over time, affected tissue becomes discolored, brittle and weak. Affected individuals may develop abnormalities affecting the tendons including thickened Achilles tendons and inflammation of the tendons (tendonitis). Affected tendons and ligaments may be particularly susceptible to rupturing. Eventually, discoloration of tendons may become visible on the overlying skin.Long-standing alkaptonuria leads to chronic joint pain and inflammation (arthritis), especially in the spine and large joints (ochronotic arthropathy). Arthritis can be severe and disabling. Low back pain and stiffness are common symptoms and are sometimes seen before the age of 30. Discs between the vertebrae flatten and calcify. Eventually, vertebrae or other bones may fuse causing stiffening or immobility of affected joints (ankylosis). Spinal involvement may lead to abnormal outward curvature of the spine causing hunching of the back (kyphosis) and loss of height. The hip, knees and shoulders are commonly affected as well. Joint mobility is usually diminished and fluid buildup in affected joints (effusions) may also occur. Joint abnormalities are progressive and may eventually necessitate a joint replacement. Joint disease in alkaptonuria tends to begin earlier and progress more rapidly in males than females.Less often, additional symptoms may occur in alkaptonuria. Although these symptoms occur less often than the main symptoms of alkaptonuria, they occur with greater frequency than would be expected in the general population. Such symptoms include kidney stones, which develop in 50 percent of affected individuals over 64 years of age. Men with alkaptonuria may also develop prostate stones. Passage of these black stones can be extremely painful.In some individuals, heart disease may develop due to the accumulation of homogentisic acid within the aortic or mitral valves. This accumulation causes thickening of the valves and narrowing (stenosis) of the openings of the valves. Occasionally, the narrowing is severe enough that the aortic valve needs to be replaced. The aortic valve connects the lower left chamber (main pumping chamber) of the heart with the aorta (the main artery of the body). The mitral valve is located between the left upper and left lower chambers of the heart. Affected individuals may develop calcification of the valves and/or backflow of blood back through the affected valves (regurgitation), which can lead to reduced blood flow throughout the body. Widening (dilation) of the aorta may also occur. In some cases, calcification of the small blood vessels that supply blood and oxygen to the heart (coronary blood vessels) may also occur.Alkaptonuria does not cause developmental delays or cognitive impairment and does not appear to affect life span. However, chronic pain and mobility issues can develop. | Symptoms of Alkaptonuria. Alkaptonuria is a genetic disorder, and urine that turns dark is present from birth. However, additional symptoms usually do not appear until adulthood. Symptoms are generally slowly progressive. The urine of individuals with alkaptonuria may be abnormally dark or it may turn black upon long-standing exposure to the air. However, since this change often takes several hours, it often goes unnoticed. During infancy, diapers may be stained black (from urine exposure to air), although this is often missed or ignored.The first noticeable signs and symptoms of alkaptonuria usually do not develop until approximately 30 years of age and are due to chronic accumulation of homogentisic acid in connective tissue, especially cartilage. Affected individuals develop a condition called ochronosis, in which connective tissue such as cartilage turns blue, grey or black due to the chronic accumulation of homogentisic acid. In many individuals, cartilage within the ear may become thickened, irregular and discolored blue, grey or black. Eventually, this discoloration may be apparent on the skin overlying the cartilage. In many cases, the whites of the eyes (sclera) also become discolored. However, this pigmentation does not interfere with vision.In addition to cartilage, homogentisic acid accumulates in other connective tissue including tendons and ligaments and even bone. Over time, affected tissue becomes discolored, brittle and weak. Affected individuals may develop abnormalities affecting the tendons including thickened Achilles tendons and inflammation of the tendons (tendonitis). Affected tendons and ligaments may be particularly susceptible to rupturing. Eventually, discoloration of tendons may become visible on the overlying skin.Long-standing alkaptonuria leads to chronic joint pain and inflammation (arthritis), especially in the spine and large joints (ochronotic arthropathy). Arthritis can be severe and disabling. Low back pain and stiffness are common symptoms and are sometimes seen before the age of 30. Discs between the vertebrae flatten and calcify. Eventually, vertebrae or other bones may fuse causing stiffening or immobility of affected joints (ankylosis). Spinal involvement may lead to abnormal outward curvature of the spine causing hunching of the back (kyphosis) and loss of height. The hip, knees and shoulders are commonly affected as well. Joint mobility is usually diminished and fluid buildup in affected joints (effusions) may also occur. Joint abnormalities are progressive and may eventually necessitate a joint replacement. Joint disease in alkaptonuria tends to begin earlier and progress more rapidly in males than females.Less often, additional symptoms may occur in alkaptonuria. Although these symptoms occur less often than the main symptoms of alkaptonuria, they occur with greater frequency than would be expected in the general population. Such symptoms include kidney stones, which develop in 50 percent of affected individuals over 64 years of age. Men with alkaptonuria may also develop prostate stones. Passage of these black stones can be extremely painful.In some individuals, heart disease may develop due to the accumulation of homogentisic acid within the aortic or mitral valves. This accumulation causes thickening of the valves and narrowing (stenosis) of the openings of the valves. Occasionally, the narrowing is severe enough that the aortic valve needs to be replaced. The aortic valve connects the lower left chamber (main pumping chamber) of the heart with the aorta (the main artery of the body). The mitral valve is located between the left upper and left lower chambers of the heart. Affected individuals may develop calcification of the valves and/or backflow of blood back through the affected valves (regurgitation), which can lead to reduced blood flow throughout the body. Widening (dilation) of the aorta may also occur. In some cases, calcification of the small blood vessels that supply blood and oxygen to the heart (coronary blood vessels) may also occur.Alkaptonuria does not cause developmental delays or cognitive impairment and does not appear to affect life span. However, chronic pain and mobility issues can develop. | 56 | Alkaptonuria |
nord_56_2 | Causes of Alkaptonuria | Alkaptonuria is caused by mutation of the homogentisate 1,2-dioxygenase (HGD) gene. The HGD gene contains instructions for creating (encoding) an enzyme known as homogentisate 1,2-dioxygenase. This enzyme is essential for the breakdown of homogentisic acid. Mutations of the HGD gene result in deficient levels of functional homogentisate 1,2-dioxygenase, which, in turn, leads to excess levels of homogentisic acid. Although homogentisic acid is rapidly cleared from the body by the kidneys, it also slowly accumulates in the various tissues of the body, especially connective tissue such as cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to a slate blue or black. Long-term, chronic accumulation of homogentisic acid eventually weakens and damages affected tissue and leads to many of the characteristic symptoms of alkaptonuria.Alkaptonuria is inherited as an autosomal recessive trait. 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females. | Causes of Alkaptonuria. Alkaptonuria is caused by mutation of the homogentisate 1,2-dioxygenase (HGD) gene. The HGD gene contains instructions for creating (encoding) an enzyme known as homogentisate 1,2-dioxygenase. This enzyme is essential for the breakdown of homogentisic acid. Mutations of the HGD gene result in deficient levels of functional homogentisate 1,2-dioxygenase, which, in turn, leads to excess levels of homogentisic acid. Although homogentisic acid is rapidly cleared from the body by the kidneys, it also slowly accumulates in the various tissues of the body, especially connective tissue such as cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to a slate blue or black. Long-term, chronic accumulation of homogentisic acid eventually weakens and damages affected tissue and leads to many of the characteristic symptoms of alkaptonuria.Alkaptonuria is inherited as an autosomal recessive trait. 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females. | 56 | Alkaptonuria |
nord_56_3 | Affects of Alkaptonuria | Alkaptonuria affects males and females in equal numbers, although symptoms tend to develop sooner and become more severe in males. More than 1,000 affected individuals have been reported in the medical literature. The exact incidence of alkaptonuria is unknown. In the United States it is estimated to occur in 1 in 250,000-1,000,000 live births. Alkaptonuria has been reported in all ethnic groups. Areas with increased frequencies of the disorder have been identified in Slovakia, the Dominican Republic and Germany. | Affects of Alkaptonuria. Alkaptonuria affects males and females in equal numbers, although symptoms tend to develop sooner and become more severe in males. More than 1,000 affected individuals have been reported in the medical literature. The exact incidence of alkaptonuria is unknown. In the United States it is estimated to occur in 1 in 250,000-1,000,000 live births. Alkaptonuria has been reported in all ethnic groups. Areas with increased frequencies of the disorder have been identified in Slovakia, the Dominican Republic and Germany. | 56 | Alkaptonuria |
nord_56_4 | Related disorders of Alkaptonuria | Symptoms of the following disorders can be similar to those of alkaptonuria. Comparisons may be useful for a differential diagnosis.Ochronosis can also occur as a reversible, acquired condition that is unrelated to alkaptonuria. In such cases, ochronosis occurs secondary to exposure to a variety of substances including benzene, phenol and trinitrophenol. Individuals have also developed ochronosis following long-term use of certain medications including the antimalarial drug Atabrine®, the skin-lightening agent hydroquinone, or the antibiotic minocycline. Prolonged use of carbolic acid dressings, which may be used to treat chronic skin ulcers, can also cause ochronotic skin changes.The joint and spinal symptoms associated with alkaptonuria can resemble symptoms associated with other disorders such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Alkaptonuria. Symptoms of the following disorders can be similar to those of alkaptonuria. Comparisons may be useful for a differential diagnosis.Ochronosis can also occur as a reversible, acquired condition that is unrelated to alkaptonuria. In such cases, ochronosis occurs secondary to exposure to a variety of substances including benzene, phenol and trinitrophenol. Individuals have also developed ochronosis following long-term use of certain medications including the antimalarial drug Atabrine®, the skin-lightening agent hydroquinone, or the antibiotic minocycline. Prolonged use of carbolic acid dressings, which may be used to treat chronic skin ulcers, can also cause ochronotic skin changes.The joint and spinal symptoms associated with alkaptonuria can resemble symptoms associated with other disorders such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 56 | Alkaptonuria |
nord_56_5 | Diagnosis of Alkaptonuria | The diagnosis of alkaptonuria is made upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Identification of vastly elevated levels of homogentisic acid in the urine is indicative of alkaptonuria. Alkaptonuria should be suspected in individuals with dark urine. However, since some individuals with alkaptonuria do not have dark urine, it may be advisable to rule out the disorder for all individuals with osteoarthritis, especially those with an early onset of symptoms.Clinical Testing and Work-upElevated amounts of homogentisic acid in the urine can be detected by gas chromatography-mass spectrometry analysis. Various imaging techniques can be used to determine the presence and extent of joint and spinal disease or the involvement of the aortic or mitral valves.Molecular genetic testing, which can detect mutations in the HGD gene, is available on a clinical basis. However, this testing is not required to confirm the diagnosis.In individuals over 40, echocardiography may be recommended to detect potential cardiac complications such as aortic dilation or calcification or regurgitation of the aortic or mitral valves. With echocardiography, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and motion.Computed tomography (CT) scan may be recommended to detect coronary artery calcification. | Diagnosis of Alkaptonuria. The diagnosis of alkaptonuria is made upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Identification of vastly elevated levels of homogentisic acid in the urine is indicative of alkaptonuria. Alkaptonuria should be suspected in individuals with dark urine. However, since some individuals with alkaptonuria do not have dark urine, it may be advisable to rule out the disorder for all individuals with osteoarthritis, especially those with an early onset of symptoms.Clinical Testing and Work-upElevated amounts of homogentisic acid in the urine can be detected by gas chromatography-mass spectrometry analysis. Various imaging techniques can be used to determine the presence and extent of joint and spinal disease or the involvement of the aortic or mitral valves.Molecular genetic testing, which can detect mutations in the HGD gene, is available on a clinical basis. However, this testing is not required to confirm the diagnosis.In individuals over 40, echocardiography may be recommended to detect potential cardiac complications such as aortic dilation or calcification or regurgitation of the aortic or mitral valves. With echocardiography, sound waves are bounced off the heart (echoes), enabling physicians to study cardiac function and motion.Computed tomography (CT) scan may be recommended to detect coronary artery calcification. | 56 | Alkaptonuria |
nord_56_6 | Therapies of Alkaptonuria | TreatmentThe treatment of alkaptonuria is aimed at the specific symptoms that are present in each individual. Individuals with alkaptonuria often receive anti-inflammatory medications to treat joint pain. In severe cases, stronger medications such as narcotics may be recommended. Pain management is tailored to each individual’s specific case and requires long-term follow up and adjustment.Some individuals with alkaptonuria will benefit from physical and occupational therapy, which can help maintain the strength and flexibility of muscles and joints. Genetic counseling may be of benefit for affected individuals and their families.Some individuals with alkaptonuria require surgical intervention. Approximately half of individuals with alkaptonuria will require hip, knee or shoulder joint replacement, often by 50-60 years of age. Infrequently, individuals require spinal surgery, including fusion and/or removal of the lumber discs. Surgery to replace the aortic or mitral valves may also be necessary. In some cases, chronic and painful kidney or prostate stones may require surgical intervention or preventive (prophylactic) therapy.Dietary restrictions have generally proven ineffective. Severe restriction of protein intake is required and has proven difficult for individuals to maintain over a long period of time. In addition, long-term, severe restriction of protein intake can be associated with complications.In older children and adults, high-doses of vitamin C have also been used to treat alkaptonuria because it hinders the accumulation and deposition of homogentisic acid. However, long-term use of vitamin C has generally proven ineffective and definite clinical studies on its efficacy are lacking.Activities that place significant physical stress to the spine and joints such as high impact sports or heavy manual labor should be avoided. | Therapies of Alkaptonuria. TreatmentThe treatment of alkaptonuria is aimed at the specific symptoms that are present in each individual. Individuals with alkaptonuria often receive anti-inflammatory medications to treat joint pain. In severe cases, stronger medications such as narcotics may be recommended. Pain management is tailored to each individual’s specific case and requires long-term follow up and adjustment.Some individuals with alkaptonuria will benefit from physical and occupational therapy, which can help maintain the strength and flexibility of muscles and joints. Genetic counseling may be of benefit for affected individuals and their families.Some individuals with alkaptonuria require surgical intervention. Approximately half of individuals with alkaptonuria will require hip, knee or shoulder joint replacement, often by 50-60 years of age. Infrequently, individuals require spinal surgery, including fusion and/or removal of the lumber discs. Surgery to replace the aortic or mitral valves may also be necessary. In some cases, chronic and painful kidney or prostate stones may require surgical intervention or preventive (prophylactic) therapy.Dietary restrictions have generally proven ineffective. Severe restriction of protein intake is required and has proven difficult for individuals to maintain over a long period of time. In addition, long-term, severe restriction of protein intake can be associated with complications.In older children and adults, high-doses of vitamin C have also been used to treat alkaptonuria because it hinders the accumulation and deposition of homogentisic acid. However, long-term use of vitamin C has generally proven ineffective and definite clinical studies on its efficacy are lacking.Activities that place significant physical stress to the spine and joints such as high impact sports or heavy manual labor should be avoided. | 56 | Alkaptonuria |
nord_57_0 | Overview of Alopecia Areata | Alopecia areata is a disorder characterized by loss of hair. Sometimes, this means simply a few bare patches on the scalp. In other cases, hair loss is more extensive. Although the exact cause is not known, this is thought to be an autoimmune disorder in which the immune system, the body's own defense system, mistakenly attacks the hair follicles, the tiny structures from which hairs grow. Unpredictable hair loss is the only noticeable symptom of this disorder. Regrowth of hair may or may not occur. Hair loss is usually confined to the head and face, although the entire body may be involved. | Overview of Alopecia Areata. Alopecia areata is a disorder characterized by loss of hair. Sometimes, this means simply a few bare patches on the scalp. In other cases, hair loss is more extensive. Although the exact cause is not known, this is thought to be an autoimmune disorder in which the immune system, the body's own defense system, mistakenly attacks the hair follicles, the tiny structures from which hairs grow. Unpredictable hair loss is the only noticeable symptom of this disorder. Regrowth of hair may or may not occur. Hair loss is usually confined to the head and face, although the entire body may be involved. | 57 | Alopecia Areata |
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