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nord_114_2 | Causes of ASXL3-Related Disorder | ASXL3-related disorder is caused by pathogenic or likely pathogenic variants in the ASXL3 gene. The majority of variants are new mutations that result in a shortened protein product that does not function properly.ASXL3-related disorder follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. | Causes of ASXL3-Related Disorder. ASXL3-related disorder is caused by pathogenic or likely pathogenic variants in the ASXL3 gene. The majority of variants are new mutations that result in a shortened protein product that does not function properly.ASXL3-related disorder follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. | 114 | ASXL3-Related Disorder |
nord_114_3 | Affects of ASXL3-Related Disorder | ASXL3-related disorder has been described all over the world and is not population specific. | Affects of ASXL3-Related Disorder. ASXL3-related disorder has been described all over the world and is not population specific. | 114 | ASXL3-Related Disorder |
nord_114_4 | Related disorders of ASXL3-Related Disorder | The characteristics of ASXL-related disorder can be similar to other disorders including ASXL1-Bohring-Opitz syndrome and ASXL2-Shashi-Pena syndrome.There is also overlap in terms of clinical presentation with other rare neurodevelopmental disorders (RNDD) which is an ever-increasing group of conditions characterized by developmental delay, intellectual disability with or without seizures caused by pathogenic variants in several different genes. | Related disorders of ASXL3-Related Disorder. The characteristics of ASXL-related disorder can be similar to other disorders including ASXL1-Bohring-Opitz syndrome and ASXL2-Shashi-Pena syndrome.There is also overlap in terms of clinical presentation with other rare neurodevelopmental disorders (RNDD) which is an ever-increasing group of conditions characterized by developmental delay, intellectual disability with or without seizures caused by pathogenic variants in several different genes. | 114 | ASXL3-Related Disorder |
nord_114_5 | Diagnosis of ASXL3-Related Disorder | ASXL-related disorder may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with genomic testing that shows a pathogenic variant in the ASXL3 gene. | Diagnosis of ASXL3-Related Disorder. ASXL-related disorder may be suspected based on the signs and symptoms associated with the disorder. The diagnosis is confirmed with genomic testing that shows a pathogenic variant in the ASXL3 gene. | 114 | ASXL3-Related Disorder |
nord_114_6 | Therapies of ASXL3-Related Disorder | Multidisciplinary care is recommended and includes management of multiple subspecialty appointments, equipment, medications and supplies. Ongoing assessment for palliative care involvement and/or home nursing is needed.Developmental delay and intellectual disability should be managed by a developmental pediatrician. Speech and language delay should be managed by appropriate healthcare professionals. Epilepsy should be treated with antiepileptic drugs (AEDs) by an experienced neurologist. Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.Poor weight gain and failure to thrive may require feeding therapy and gastrostomy tube placement for persistent feeding issues. | Therapies of ASXL3-Related Disorder. Multidisciplinary care is recommended and includes management of multiple subspecialty appointments, equipment, medications and supplies. Ongoing assessment for palliative care involvement and/or home nursing is needed.Developmental delay and intellectual disability should be managed by a developmental pediatrician. Speech and language delay should be managed by appropriate healthcare professionals. Epilepsy should be treated with antiepileptic drugs (AEDs) by an experienced neurologist. Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.Poor weight gain and failure to thrive may require feeding therapy and gastrostomy tube placement for persistent feeding issues. | 114 | ASXL3-Related Disorder |
nord_115_0 | Overview of Ataxia Telangiectasia | Ataxia telangiectasia (AT) is a complex neurodegenerative disorder. Symptoms associated with AT usually present during the preschool years between one and four years of age. An unsteady gait (ataxia) is often the first sign of AT. Symptoms that distinguish AT from other disorders include an impaired ability to coordinate eye movements (oculomotor apraxia) and episodes of involuntary movements (choreoathetosis). Progression of ataxia is associated with cerebellar degeneration, and many school-age children with AT are dependent on wheelchair assistance.Telangiectasias, which are dilated blood vessels, may be present in the eye, skin or mucous membranes of children with AT. Ocular telangiectasias are the most common type of telangiectasias and usually present between 4 and 6 years of age. Impaired functioning of the immune system (i.e., cellular and humoral immunodeficiency) is present in many people with AT and many affected individuals have an increased risk of developing infections in the sinuses and lungs. People with AT are also at increased risk for certain cancers, particularly lymphomas and leukemias during the first two decades of life and cancers in solid organs during early adulthood. AT is caused by changes (mutations) in the ataxia telangiectasia mutated (ATM) gene and is inherited in an autosomal recessive pattern. | Overview of Ataxia Telangiectasia. Ataxia telangiectasia (AT) is a complex neurodegenerative disorder. Symptoms associated with AT usually present during the preschool years between one and four years of age. An unsteady gait (ataxia) is often the first sign of AT. Symptoms that distinguish AT from other disorders include an impaired ability to coordinate eye movements (oculomotor apraxia) and episodes of involuntary movements (choreoathetosis). Progression of ataxia is associated with cerebellar degeneration, and many school-age children with AT are dependent on wheelchair assistance.Telangiectasias, which are dilated blood vessels, may be present in the eye, skin or mucous membranes of children with AT. Ocular telangiectasias are the most common type of telangiectasias and usually present between 4 and 6 years of age. Impaired functioning of the immune system (i.e., cellular and humoral immunodeficiency) is present in many people with AT and many affected individuals have an increased risk of developing infections in the sinuses and lungs. People with AT are also at increased risk for certain cancers, particularly lymphomas and leukemias during the first two decades of life and cancers in solid organs during early adulthood. AT is caused by changes (mutations) in the ataxia telangiectasia mutated (ATM) gene and is inherited in an autosomal recessive pattern. | 115 | Ataxia Telangiectasia |
nord_115_1 | Symptoms of Ataxia Telangiectasia | The name ataxia telangiectasia refers to two major symptoms associated with AT. One major symptom is diminished muscle coordination and voluntary muscle control (ataxia). Another is the development of red or purple clusters of dilated blood vessels (telangiectasias) on mucous membranes and the sun-exposed areas of the skin, often visible by age six. The severity of symptoms can vary, but AT usually affects coordination of muscle control and immune and pulmonary responses to infection and stress. The symptoms are discussed below. Muscle SystemImpairment of muscle coordination begins in the head and neck, which can affect swallowing and breathing and lead to drooling and choking. An early and defining symptom of AT is reduced ability to control voluntary eye movements (oculomotor apraxia). Eye movement abnormalities are typically present in most patients. Slurred speech (dysarthria) is another early symptom, often resulting in speech that is monotonous, slow and unstable. Shortly after learning to walk, affected children will begin to stagger and require wheelchair assistance by 10-12 years of age. Most affected individuals exhibit episodes of involuntary movements (choreoathetosis) and tremors. Other common muscle impairment symptoms include involuntary, rapid, rhythmic eye movements (nystagmus), muscle stiffness and contractions and/or shortening and hardening (contractures) of fingers and toes. Muscle impairment also reduces ability to read and write, even though most individuals with AT have normal intelligence. Non-classical forms of AT present with milder symptoms and later onset ataxia. Immune System About 60-80% of affected individuals have abnormal functioning of the immune system (immunodeficiencies). Affected individuals have a high risk of infection due to low levels of antibodies (immunoglobulins) including white blood cells (lymphocytes). Respiratory SystemIndividuals with AT have an increased risk of sinus and pulmonary infections, including pneumonia and chronic bronchitis. Causes for respiratory symptoms are multifactorial and may include an impaired cough preventing clearance of airway secretions, swallowing abnormalities increasing the risk for aspiration and abnormal immune responses to respiratory infections and stress. Lung (pulmonary) failure is one of the greatest health risks for individuals with AT. DevelopmentShort height and delayed puberty are common symptoms. Other symptoms include underdeveloped adenoids, tonsils, peripheral lymph nodes and sexual organs. Affected females may experience loss of ovarian function. Affected individuals may also demonstrate premature aging of the hair and skin as teenagers.Other Health RisksIndividuals with AT are at a high risk of cancer, especially cancer in the lymphatic system (lymphomas) or in the blood (leukemia) as well as abnormal tissue growth (neoplasm). During the first 20 years, affected individuals have an increased risk of cancers (malignancies) in the blood. Affected young adults are at an increased risk of cancers/tumors in the solid organs (ex. liver, spleen). People with one ATM gene mutation do not have AT but have a four times higher risk of cancer than the general population, as well as a higher risk for coronary artery disease. In some people with AT, type II diabetes mellitus may occur. Diabetes mellitus is a condition characterized by insulin resistance (type II) or insufficient secretion of insulin (type I). Primary symptoms may include abnormally increased thirst and urination (polydipsia and polyuria), weight loss, lack of appetite and fatigue. Recent research suggests that diabetes develops during puberty in individuals with AT. Often type II diabetes in people with AT is associated with metabolic syndrome (a constellation of symptoms including type II diabetes, elevated cholesterol and systemic hypertension). AT is also characterized by cerebellar degeneration, chromosomal instability and sensitivity to radiation. People with AT should minimize exposure to ionizing radiation (i.e., x-rays) due to their sensitivity to radiation. | Symptoms of Ataxia Telangiectasia. The name ataxia telangiectasia refers to two major symptoms associated with AT. One major symptom is diminished muscle coordination and voluntary muscle control (ataxia). Another is the development of red or purple clusters of dilated blood vessels (telangiectasias) on mucous membranes and the sun-exposed areas of the skin, often visible by age six. The severity of symptoms can vary, but AT usually affects coordination of muscle control and immune and pulmonary responses to infection and stress. The symptoms are discussed below. Muscle SystemImpairment of muscle coordination begins in the head and neck, which can affect swallowing and breathing and lead to drooling and choking. An early and defining symptom of AT is reduced ability to control voluntary eye movements (oculomotor apraxia). Eye movement abnormalities are typically present in most patients. Slurred speech (dysarthria) is another early symptom, often resulting in speech that is monotonous, slow and unstable. Shortly after learning to walk, affected children will begin to stagger and require wheelchair assistance by 10-12 years of age. Most affected individuals exhibit episodes of involuntary movements (choreoathetosis) and tremors. Other common muscle impairment symptoms include involuntary, rapid, rhythmic eye movements (nystagmus), muscle stiffness and contractions and/or shortening and hardening (contractures) of fingers and toes. Muscle impairment also reduces ability to read and write, even though most individuals with AT have normal intelligence. Non-classical forms of AT present with milder symptoms and later onset ataxia. Immune System About 60-80% of affected individuals have abnormal functioning of the immune system (immunodeficiencies). Affected individuals have a high risk of infection due to low levels of antibodies (immunoglobulins) including white blood cells (lymphocytes). Respiratory SystemIndividuals with AT have an increased risk of sinus and pulmonary infections, including pneumonia and chronic bronchitis. Causes for respiratory symptoms are multifactorial and may include an impaired cough preventing clearance of airway secretions, swallowing abnormalities increasing the risk for aspiration and abnormal immune responses to respiratory infections and stress. Lung (pulmonary) failure is one of the greatest health risks for individuals with AT. DevelopmentShort height and delayed puberty are common symptoms. Other symptoms include underdeveloped adenoids, tonsils, peripheral lymph nodes and sexual organs. Affected females may experience loss of ovarian function. Affected individuals may also demonstrate premature aging of the hair and skin as teenagers.Other Health RisksIndividuals with AT are at a high risk of cancer, especially cancer in the lymphatic system (lymphomas) or in the blood (leukemia) as well as abnormal tissue growth (neoplasm). During the first 20 years, affected individuals have an increased risk of cancers (malignancies) in the blood. Affected young adults are at an increased risk of cancers/tumors in the solid organs (ex. liver, spleen). People with one ATM gene mutation do not have AT but have a four times higher risk of cancer than the general population, as well as a higher risk for coronary artery disease. In some people with AT, type II diabetes mellitus may occur. Diabetes mellitus is a condition characterized by insulin resistance (type II) or insufficient secretion of insulin (type I). Primary symptoms may include abnormally increased thirst and urination (polydipsia and polyuria), weight loss, lack of appetite and fatigue. Recent research suggests that diabetes develops during puberty in individuals with AT. Often type II diabetes in people with AT is associated with metabolic syndrome (a constellation of symptoms including type II diabetes, elevated cholesterol and systemic hypertension). AT is also characterized by cerebellar degeneration, chromosomal instability and sensitivity to radiation. People with AT should minimize exposure to ionizing radiation (i.e., x-rays) due to their sensitivity to radiation. | 115 | Ataxia Telangiectasia |
nord_115_2 | Causes of Ataxia Telangiectasia | AT is caused by pathogenic variants (mutations) in the ATM gene. The ATM gene codes for a serine/threonine protein kinase. A kinase is a biological catalyst (enzyme) that speeds up the addition of phosphate groups to other molecules. The serine/threonine protein kinase belongs to the PI3 kinase-like kinases (PIKKs) family. It is primarily located in the cell nucleus. The ATM kinase activates and interacts with multiple different molecules. Currently, the best-known function of the ATM protein is to coordinate the repair of double strand breaks in DNA, the hereditary material that carries the genetic code. Double strand breaks in DNA can damage the cell. The ATM protein can activate certain enzymes to fix broken strands of DNA. This repair is essential to maintain the stability of the cell’s genetic information. The ATM protein can also be activated in response to oxidative stress within the cell. In individuals with AT, the ATM gene is mutated in a way that affects the function of the ATM protein and its kinase activity. Therefore, the signaling networks that respond to double strand breaks in the DNA or the reduction of oxidative stress are defective. The mutations in the ATM gene that produce a defective ATM protein cause some of the symptoms associated with AT. For example, without the ATM protein, a cell cannot repair double strand breaks in the DNA. Thus, the cell may die or replicate with damaged DNA, and this can lead to cancer. Cell death in the cerebellum (particularly the Purkinje cells and to a lesser extent the granule neurons), can cause ataxia resulting in difficulties coordinating voluntary movements. The majority of ATM mutations introduce an early halt (stop codon) to the process of creating the ATM protein (truncating mutation). This results in the shortening of the ATM gene sequence, which creates unstable ATM protein fragments. Truncating mutations correspond to more severe symptoms of AT because the ATM protein is not detected in the body, or it lacks enzymatic activity. ATM mutations can also occur when a base pair is accidentally changed in the DNA (missense mutation) or there is an insertion or deletion of a nucleotide that shifts the reading frame of the DNA (frameshift mutation). With these mutations, the ATM protein is detected and may have some enzymatic activity. Individuals with missense mutations in the ATM gene may experience less severe symptoms.AT is inherited as an autosomal recessive disorder. Generally, an individual receives two copies of a single gene, one from each parent. Since AT is a recessive disorder, an individual must carry two copies of the abnormal gene to develop the disease. People who have one mutated gene and one normal gene do not develop AT. These individuals are known as carriers. It is estimated that one in 100 persons may be a carrier for an ATM mutation. Although carriers do not have AT, they are more likely to develop cancer and heart disease compared to those without any ATM gene mutations. Carriers of AT typically do not display any symptoms of the disease; however, they can pass down the altered gene to children. The inheritance pattern for two carrier parents is explained as follows. These individuals have a 25% chance (per pregnancy) of having a child with AT if they both contribute a mutated gene to their offspring. They also have a 25% chance (per pregnancy) of having a child with two normal genes and no AT. Lastly, they have a 50% chance of having a carrier child with one normal gene and one mutated gene who does not develop AT. | Causes of Ataxia Telangiectasia. AT is caused by pathogenic variants (mutations) in the ATM gene. The ATM gene codes for a serine/threonine protein kinase. A kinase is a biological catalyst (enzyme) that speeds up the addition of phosphate groups to other molecules. The serine/threonine protein kinase belongs to the PI3 kinase-like kinases (PIKKs) family. It is primarily located in the cell nucleus. The ATM kinase activates and interacts with multiple different molecules. Currently, the best-known function of the ATM protein is to coordinate the repair of double strand breaks in DNA, the hereditary material that carries the genetic code. Double strand breaks in DNA can damage the cell. The ATM protein can activate certain enzymes to fix broken strands of DNA. This repair is essential to maintain the stability of the cell’s genetic information. The ATM protein can also be activated in response to oxidative stress within the cell. In individuals with AT, the ATM gene is mutated in a way that affects the function of the ATM protein and its kinase activity. Therefore, the signaling networks that respond to double strand breaks in the DNA or the reduction of oxidative stress are defective. The mutations in the ATM gene that produce a defective ATM protein cause some of the symptoms associated with AT. For example, without the ATM protein, a cell cannot repair double strand breaks in the DNA. Thus, the cell may die or replicate with damaged DNA, and this can lead to cancer. Cell death in the cerebellum (particularly the Purkinje cells and to a lesser extent the granule neurons), can cause ataxia resulting in difficulties coordinating voluntary movements. The majority of ATM mutations introduce an early halt (stop codon) to the process of creating the ATM protein (truncating mutation). This results in the shortening of the ATM gene sequence, which creates unstable ATM protein fragments. Truncating mutations correspond to more severe symptoms of AT because the ATM protein is not detected in the body, or it lacks enzymatic activity. ATM mutations can also occur when a base pair is accidentally changed in the DNA (missense mutation) or there is an insertion or deletion of a nucleotide that shifts the reading frame of the DNA (frameshift mutation). With these mutations, the ATM protein is detected and may have some enzymatic activity. Individuals with missense mutations in the ATM gene may experience less severe symptoms.AT is inherited as an autosomal recessive disorder. Generally, an individual receives two copies of a single gene, one from each parent. Since AT is a recessive disorder, an individual must carry two copies of the abnormal gene to develop the disease. People who have one mutated gene and one normal gene do not develop AT. These individuals are known as carriers. It is estimated that one in 100 persons may be a carrier for an ATM mutation. Although carriers do not have AT, they are more likely to develop cancer and heart disease compared to those without any ATM gene mutations. Carriers of AT typically do not display any symptoms of the disease; however, they can pass down the altered gene to children. The inheritance pattern for two carrier parents is explained as follows. These individuals have a 25% chance (per pregnancy) of having a child with AT if they both contribute a mutated gene to their offspring. They also have a 25% chance (per pregnancy) of having a child with two normal genes and no AT. Lastly, they have a 50% chance of having a carrier child with one normal gene and one mutated gene who does not develop AT. | 115 | Ataxia Telangiectasia |
nord_115_3 | Affects of Ataxia Telangiectasia | In the United States, the prevalence of AT is approximately 1:40,000 to 1:100,000 live births. Males and females are affected in equal numbers. Certain ethnic groups may have a higher prevalence of AT due to a founder effect. | Affects of Ataxia Telangiectasia. In the United States, the prevalence of AT is approximately 1:40,000 to 1:100,000 live births. Males and females are affected in equal numbers. Certain ethnic groups may have a higher prevalence of AT due to a founder effect. | 115 | Ataxia Telangiectasia |
nord_115_4 | Related disorders of Ataxia Telangiectasia | There are several disorders that present similar symptoms or laboratory findings to AT. These symptoms are typically related to the loss of motor functions. Information is provided below about such disorders. Comparisons may be useful for a differential diagnosis.Cerebral palsy (CP) is a group of movement disorders that affect muscle tone and posture. CP is caused by damage or malformation to the brain. The signs and symptoms of CP appear during infancy or childhood, similar to AT. It is common for children to develop an unsteady gait, an unusual posture or abnormal muscle tightness (spasticity). Visual impairments are also observed related to tracking, fixations or quick eye movements (saccades). A crucial difference between CP and AT is that neurological functions accomplished with CP do not deteriorate overtime. However, this is not the case with AT affected children. Moreover, the spasticity patterns seen in CP are not consistent with AT. Lastly, children with CP that experience a lack of muscle control or difficulties with voluntary movement coordination (ataxia) will not exhibit the laboratory irregularities associated with AT. Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia. AOA1 is similar to AT in that it is diagnosed in early childhood and is followed by oculomotor apraxia. Symptoms of this disorder include a progressive gait imbalance and muscle weakness. Individuals may also have short limbs and involuntary muscle contractions (dystonia). AOA1 is associated with the APTX gene, which is one major difference between this disorder and AT. The APTX gene is responsible for creating parataxis, a protein that modifies the broken ends of DNA strands. Moreover, individuals with AOA1 do not develop telangiectasias or immunodeficiency, two of the common symptoms in AT.Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder. It is characterized by the onset of ataxia around three years old, oculomotor apraxia, cerebellar ataxia and elevated alpha-fetoprotein (AFP). Some individuals with AOA2 have mild cognitive impairments related to memory loss and sequence learning. Unlike with AT, patients with AOA2 typically do not develop telangiectasias, cancers or immunodeficiency. AOA2 is also associated with the SETX gene, a different gene than AT. The SETX gene is involved in the production of proteins from genes (transcription), DNA repair and RNA processing. Ataxia-telangiectasia-like disorder (ATLD) is an autosomal disorder that develops during childhood. Patients typically have cerebellar atrophy, dysarthria and difficulties walking. They also experience oculomotor apraxia and sensitivity to radiation. The gene mutation responsible for ATLD occurs in the human Mre11 gene. The human Mre11 gene codes for the human Mre11 protein that is likely involved in DNA damage response pathways. Symptomatically, ATLD is similar to AT. However, the progression of ATLD is slower and less severe than with AT. Moreover, patients with ATLD do not report common symptoms of AT, such as telangiectasias, high AFP levels, immunodeficiency or lymphoid tumors. Friedreich’s ataxia (FRDA) is an inherited neurological disorder that causes difficulties with movement and progressive damage to the nervous system. The age of onset for FRDA is between 10 and 15 years old, which is slightly older than that for AT. Initial symptoms may include unsteady posture, frequent falling and progressive difficulties with walking due to ataxia. Affected individuals may also develop abnormalities of certain reflexes; characteristic foot deformities; scoliosis; increasing incoordination of the arms and hands; slurred speech (dysarthria) and rapid, involuntary eye movements (nystagmus). FRDA is caused by mutations to the FXN gene. The FXN gene codes for frataxin, a protein that is necessary for other proteins to carry out their functions. FRDA differs from AT in that affected individuals do not have telangiectasias or oculomotor apraxia. They may also have normal AFP levels which are typically high in AT affected populations. (For more information on this disorder, choose “Friedreich’s ataxia” as your search term in the Rare Disease Database.) | Related disorders of Ataxia Telangiectasia. There are several disorders that present similar symptoms or laboratory findings to AT. These symptoms are typically related to the loss of motor functions. Information is provided below about such disorders. Comparisons may be useful for a differential diagnosis.Cerebral palsy (CP) is a group of movement disorders that affect muscle tone and posture. CP is caused by damage or malformation to the brain. The signs and symptoms of CP appear during infancy or childhood, similar to AT. It is common for children to develop an unsteady gait, an unusual posture or abnormal muscle tightness (spasticity). Visual impairments are also observed related to tracking, fixations or quick eye movements (saccades). A crucial difference between CP and AT is that neurological functions accomplished with CP do not deteriorate overtime. However, this is not the case with AT affected children. Moreover, the spasticity patterns seen in CP are not consistent with AT. Lastly, children with CP that experience a lack of muscle control or difficulties with voluntary movement coordination (ataxia) will not exhibit the laboratory irregularities associated with AT. Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia. AOA1 is similar to AT in that it is diagnosed in early childhood and is followed by oculomotor apraxia. Symptoms of this disorder include a progressive gait imbalance and muscle weakness. Individuals may also have short limbs and involuntary muscle contractions (dystonia). AOA1 is associated with the APTX gene, which is one major difference between this disorder and AT. The APTX gene is responsible for creating parataxis, a protein that modifies the broken ends of DNA strands. Moreover, individuals with AOA1 do not develop telangiectasias or immunodeficiency, two of the common symptoms in AT.Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder. It is characterized by the onset of ataxia around three years old, oculomotor apraxia, cerebellar ataxia and elevated alpha-fetoprotein (AFP). Some individuals with AOA2 have mild cognitive impairments related to memory loss and sequence learning. Unlike with AT, patients with AOA2 typically do not develop telangiectasias, cancers or immunodeficiency. AOA2 is also associated with the SETX gene, a different gene than AT. The SETX gene is involved in the production of proteins from genes (transcription), DNA repair and RNA processing. Ataxia-telangiectasia-like disorder (ATLD) is an autosomal disorder that develops during childhood. Patients typically have cerebellar atrophy, dysarthria and difficulties walking. They also experience oculomotor apraxia and sensitivity to radiation. The gene mutation responsible for ATLD occurs in the human Mre11 gene. The human Mre11 gene codes for the human Mre11 protein that is likely involved in DNA damage response pathways. Symptomatically, ATLD is similar to AT. However, the progression of ATLD is slower and less severe than with AT. Moreover, patients with ATLD do not report common symptoms of AT, such as telangiectasias, high AFP levels, immunodeficiency or lymphoid tumors. Friedreich’s ataxia (FRDA) is an inherited neurological disorder that causes difficulties with movement and progressive damage to the nervous system. The age of onset for FRDA is between 10 and 15 years old, which is slightly older than that for AT. Initial symptoms may include unsteady posture, frequent falling and progressive difficulties with walking due to ataxia. Affected individuals may also develop abnormalities of certain reflexes; characteristic foot deformities; scoliosis; increasing incoordination of the arms and hands; slurred speech (dysarthria) and rapid, involuntary eye movements (nystagmus). FRDA is caused by mutations to the FXN gene. The FXN gene codes for frataxin, a protein that is necessary for other proteins to carry out their functions. FRDA differs from AT in that affected individuals do not have telangiectasias or oculomotor apraxia. They may also have normal AFP levels which are typically high in AT affected populations. (For more information on this disorder, choose “Friedreich’s ataxia” as your search term in the Rare Disease Database.) | 115 | Ataxia Telangiectasia |
nord_115_5 | Diagnosis of Ataxia Telangiectasia | A diagnosis of ataxia telangiectasia is made based upon a detailed patient history, thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized tests including genetic testing, blood tests and magnetic resonance imaging (MRI).If AT is suspected, then genetic testing should be performed. Genetic testing can be used to show a mutation or duplication/deletion of the ATM gene. When there is a family history of AT, genetic testing may be used to detect ATM gene mutations in a child before the onset of symptoms. Further testing, referred to as protein assays, can detect the amount of ATM protein. Protein assay tests can be revealing because 90% of individuals with diagnosed AT have no detectable amounts of ATM protein. However, some patients have activity of the ATM gene, which can be associated with milder symptoms.If there is no family history, the diagnosis of AT may be delayed. Recently however, newborn screening for severe combined immunodeficiency (SCID) has resulted in earlier detection of infants with AT before symptoms are present. Similar to neonates with SCID, some newborns with AT may have low levels of T-cell receptor excision circles (TRECs).During a brain examination called magnetic resonance imaging (MRI), magnetic fields and radio waves are used to create cross-sectional images of the brain. These images can be helpful in diagnosis because affected individuals often show shrinkage (atrophy) in the cerebellum, the part of the brain responsible for coordinating movement. However, the shrinkage is not always detectable in the MRI scans of young children. While there is limited access to the technology, diffusion weighted MRIs have been able to detect shrinkage in children as young as three years old. Inability to control voluntary eye movement (oculomotor apraxia) is a very specific symptom of AT and can be used to differentiate AT from other related diseases. | Diagnosis of Ataxia Telangiectasia. A diagnosis of ataxia telangiectasia is made based upon a detailed patient history, thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized tests including genetic testing, blood tests and magnetic resonance imaging (MRI).If AT is suspected, then genetic testing should be performed. Genetic testing can be used to show a mutation or duplication/deletion of the ATM gene. When there is a family history of AT, genetic testing may be used to detect ATM gene mutations in a child before the onset of symptoms. Further testing, referred to as protein assays, can detect the amount of ATM protein. Protein assay tests can be revealing because 90% of individuals with diagnosed AT have no detectable amounts of ATM protein. However, some patients have activity of the ATM gene, which can be associated with milder symptoms.If there is no family history, the diagnosis of AT may be delayed. Recently however, newborn screening for severe combined immunodeficiency (SCID) has resulted in earlier detection of infants with AT before symptoms are present. Similar to neonates with SCID, some newborns with AT may have low levels of T-cell receptor excision circles (TRECs).During a brain examination called magnetic resonance imaging (MRI), magnetic fields and radio waves are used to create cross-sectional images of the brain. These images can be helpful in diagnosis because affected individuals often show shrinkage (atrophy) in the cerebellum, the part of the brain responsible for coordinating movement. However, the shrinkage is not always detectable in the MRI scans of young children. While there is limited access to the technology, diffusion weighted MRIs have been able to detect shrinkage in children as young as three years old. Inability to control voluntary eye movement (oculomotor apraxia) is a very specific symptom of AT and can be used to differentiate AT from other related diseases. | 115 | Ataxia Telangiectasia |
nord_115_6 | Therapies of Ataxia Telangiectasia | TreatmentTreatment for AT is directed toward the control of symptoms as there is no current cure for the disease. It is recommended that patients diagnosed with AT be treated by physicians with knowledge about the individual’s clinical needs. Optimally, patients should also be seen in a multidisciplinary hospital. For respiratory infections, some effective treatment options include therapy with an antibiotic when clinically indicated and chest physiotherapy. Some children will benefit from bronchodilator therapy and routine use of a cough assist device to help bring up airway secretions. IVIG replacement therapy is often used to treat chronic infections and/or low IgG levels. IgG levels refer to antibodies in the blood that function to fend off infections. Low levels increase risk of infection. The goal of IVIG replacement therapy is to reduce the risk of infection. Gastrostomy tube (G-tube) feedings are often recommended for affected individuals due to their difficulty swallowing to prevent choking (asphyxiation). Other common treatments include immunoglobulin replacement therapy, antioxidant usage and anti-inflammatory hormone therapy.Treatments for secondary symptoms of AT, such as cancer, require careful monitoring. Individuals with AT have an increased sensitivity to radiation and chemotherapy. Improper use of these treatments can potentially be lethal or toxic to patients with AT. Doses of chemotherapy can be reduced by 25-50% with longer recovery periods to accommodate the increased sensitivity. Affected individuals can be adversely affected by anesthesia, so careful monitoring during surgery is required, especially in breathing and swallowing. Careful monitoring for cancer or tumor growth signs is necessary, including signs of weight loss, bruising and/or pain or swelling in a particular area of the body.
Avoidance of undue exposure to sunlight may help control spread and severity of dilated blood vessels (telangiectasias). Other treatments are symptomatic and supportive. Since recent research suggests that diabetes develops during puberty and early adulthood for individuals with AT, an annual diabetes screening starting from age 12 is recommended. Genetic counseling is recommended for people with AT and their families. | Therapies of Ataxia Telangiectasia. TreatmentTreatment for AT is directed toward the control of symptoms as there is no current cure for the disease. It is recommended that patients diagnosed with AT be treated by physicians with knowledge about the individual’s clinical needs. Optimally, patients should also be seen in a multidisciplinary hospital. For respiratory infections, some effective treatment options include therapy with an antibiotic when clinically indicated and chest physiotherapy. Some children will benefit from bronchodilator therapy and routine use of a cough assist device to help bring up airway secretions. IVIG replacement therapy is often used to treat chronic infections and/or low IgG levels. IgG levels refer to antibodies in the blood that function to fend off infections. Low levels increase risk of infection. The goal of IVIG replacement therapy is to reduce the risk of infection. Gastrostomy tube (G-tube) feedings are often recommended for affected individuals due to their difficulty swallowing to prevent choking (asphyxiation). Other common treatments include immunoglobulin replacement therapy, antioxidant usage and anti-inflammatory hormone therapy.Treatments for secondary symptoms of AT, such as cancer, require careful monitoring. Individuals with AT have an increased sensitivity to radiation and chemotherapy. Improper use of these treatments can potentially be lethal or toxic to patients with AT. Doses of chemotherapy can be reduced by 25-50% with longer recovery periods to accommodate the increased sensitivity. Affected individuals can be adversely affected by anesthesia, so careful monitoring during surgery is required, especially in breathing and swallowing. Careful monitoring for cancer or tumor growth signs is necessary, including signs of weight loss, bruising and/or pain or swelling in a particular area of the body.
Avoidance of undue exposure to sunlight may help control spread and severity of dilated blood vessels (telangiectasias). Other treatments are symptomatic and supportive. Since recent research suggests that diabetes develops during puberty and early adulthood for individuals with AT, an annual diabetes screening starting from age 12 is recommended. Genetic counseling is recommended for people with AT and their families. | 115 | Ataxia Telangiectasia |
nord_116_0 | Overview of Ataxia with Vitamin E Deficiency | SummaryAtaxia with vitamin E deficiency (AVED) is a rare progressive neurodegenerative disorder affecting movement and motor control caused by very low vitamin E levels in the blood. Vitamin E is found in food sources and is necessary for proper health, as it acts as an important antioxidant that protects cells in the body from damaging molecules called free radicals. Individuals with AVED are unable to retain and use vitamin E from the diet. AVED can affect many different systems of the body such as the central nervous system (brain and spinal cord), eyes and heart. Without adequate levels of vitamin E, individuals with AVED have neurological issues like trouble coordinating movements (ataxia) and speech (dysarthria), loss of reflexes in the legs (lower limb areflexia) and a loss of sensation in the limbs (peripheral neuropathy). Additionally, an individual with AVED may experience eye abnormalities (retinitis pigmentosa), disorders affecting the heart muscles (cardiomyopathy) and abnormal curvature of the spine (scoliosis). AVED is very similar to Friedreich’s ataxia, which is a more common disorder. AVED is inherited in an autosomal recessive pattern and caused by a changes (mutations or pathogenic variants) in the alpha-tocopherol transfer protein (TTPA) gene. | Overview of Ataxia with Vitamin E Deficiency. SummaryAtaxia with vitamin E deficiency (AVED) is a rare progressive neurodegenerative disorder affecting movement and motor control caused by very low vitamin E levels in the blood. Vitamin E is found in food sources and is necessary for proper health, as it acts as an important antioxidant that protects cells in the body from damaging molecules called free radicals. Individuals with AVED are unable to retain and use vitamin E from the diet. AVED can affect many different systems of the body such as the central nervous system (brain and spinal cord), eyes and heart. Without adequate levels of vitamin E, individuals with AVED have neurological issues like trouble coordinating movements (ataxia) and speech (dysarthria), loss of reflexes in the legs (lower limb areflexia) and a loss of sensation in the limbs (peripheral neuropathy). Additionally, an individual with AVED may experience eye abnormalities (retinitis pigmentosa), disorders affecting the heart muscles (cardiomyopathy) and abnormal curvature of the spine (scoliosis). AVED is very similar to Friedreich’s ataxia, which is a more common disorder. AVED is inherited in an autosomal recessive pattern and caused by a changes (mutations or pathogenic variants) in the alpha-tocopherol transfer protein (TTPA) gene. | 116 | Ataxia with Vitamin E Deficiency |
nord_116_1 | Symptoms of Ataxia with Vitamin E Deficiency | Individuals usually show symptoms between 5 and 20 years of age. Symptoms and the severity of AVED may be different from person to person. Without treatment, symptoms may get worse as the person grows older.AVED affects the brain and spinal cord (central nervous system or CNS) as well as the motor and sensory nerves that connect the CNS to the rest of the body (peripheral nervous system). This results in ataxia, which is difficulty controlling body movements and numbness of the hands and feet (peripheral neuropathy). Individuals with AVED develop increasing weakness of the legs, which may appear as an unsteady or staggering way of walking (gait) or trembling when standing still. If symptoms become very severe, an individual with AVED may require a wheelchair if they cannot walk.Additional symptoms related to the CNS include loss of proprioception, which is an awareness of joint position in relation to other parts of the body. With time, reflexes in the legs may slow down or be absent (areflexia). Involvement of the throat muscles may lead to impaired swallowing or choking and may cause difficulty in eating. Slurred speech or difficulty speaking (dysarthria) may also be present. Some affected individuals may develop a tremor or shaking of the head (titubation). Intellect and emotions are rarely affected.In addition to neurological symptoms, individuals with AVED may develop symptoms affecting other systems of the body including the eyes. Retinitis pigmentosa (RP) is a large group of rare eye diseases that cause progressive degeneration of the membrane lining the eyes (retina). This results in visual impairment or decreased vision. Some affected individuals may have yellow “fatty” deposits (xanthelasma) in the retina.Affected individuals may also develop sideways curvature of the spine (scoliosis), degenerative changes of the heart muscle (cardiomyopathy) or “fatty” deposits (xanthomas) affecting the Achilles tendon around the ankle. Some individuals with AVED may experience a form of dystonia. Dystonia is the name for a group of movement disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). | Symptoms of Ataxia with Vitamin E Deficiency. Individuals usually show symptoms between 5 and 20 years of age. Symptoms and the severity of AVED may be different from person to person. Without treatment, symptoms may get worse as the person grows older.AVED affects the brain and spinal cord (central nervous system or CNS) as well as the motor and sensory nerves that connect the CNS to the rest of the body (peripheral nervous system). This results in ataxia, which is difficulty controlling body movements and numbness of the hands and feet (peripheral neuropathy). Individuals with AVED develop increasing weakness of the legs, which may appear as an unsteady or staggering way of walking (gait) or trembling when standing still. If symptoms become very severe, an individual with AVED may require a wheelchair if they cannot walk.Additional symptoms related to the CNS include loss of proprioception, which is an awareness of joint position in relation to other parts of the body. With time, reflexes in the legs may slow down or be absent (areflexia). Involvement of the throat muscles may lead to impaired swallowing or choking and may cause difficulty in eating. Slurred speech or difficulty speaking (dysarthria) may also be present. Some affected individuals may develop a tremor or shaking of the head (titubation). Intellect and emotions are rarely affected.In addition to neurological symptoms, individuals with AVED may develop symptoms affecting other systems of the body including the eyes. Retinitis pigmentosa (RP) is a large group of rare eye diseases that cause progressive degeneration of the membrane lining the eyes (retina). This results in visual impairment or decreased vision. Some affected individuals may have yellow “fatty” deposits (xanthelasma) in the retina.Affected individuals may also develop sideways curvature of the spine (scoliosis), degenerative changes of the heart muscle (cardiomyopathy) or “fatty” deposits (xanthomas) affecting the Achilles tendon around the ankle. Some individuals with AVED may experience a form of dystonia. Dystonia is the name for a group of movement disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). | 116 | Ataxia with Vitamin E Deficiency |
nord_116_2 | Causes of Ataxia with Vitamin E Deficiency | AVED is caused by changes (mutations or pathogenic variants) in the TTPA gene, which provides instructions to synthesize the alpha-tocopherol transfer protein (αTTP) . This protein controls the distribution and transportation of vitamin E from the liver to other cells and tissues throughout the body, including the brain. Individuals with AVED have non-working genes for TTPA and therefore, vitamin E cannot be properly distributed throughout the body especially to the brain where it is necessary for proper function. AVED is characterized by very low levels of vitamin E in the blood and tissues in the brain. Without normal levels of vitamin E in the tissues, an individual with AVED experiences damage to the body from lack of protection from damaging free radicals.Vitamin E deficiency often occurs secondary to disorders that impair the absorption of vitamin E from fat including liver disorders, disorders of fat metabolism and disorders of bile secretion. These disorders include choleostasis (a syndrome of various causes characterized by impaired bile secretion), cystic fibrosis (primarily a lung disorder that results in choleostasis), primary biliary cirrhosis (a liver disorder that results in choleostasis) and abetalipoproteinemia (a digestive disorder characterized by fat malabsorption). Premature infants may have low vitamin E levels due to small amounts of vitamin E cross the placenta. In rare cases vitamin E deficiency may be caused due to poor diet. (For more information on the above disorders, choose the specific disorder name as your search term in the Rare Disease Database.)AVED is inherited, or passed down from parent to child, in an autosomal recessive 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, therefore, have a child with AVED 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. | Causes of Ataxia with Vitamin E Deficiency. AVED is caused by changes (mutations or pathogenic variants) in the TTPA gene, which provides instructions to synthesize the alpha-tocopherol transfer protein (αTTP) . This protein controls the distribution and transportation of vitamin E from the liver to other cells and tissues throughout the body, including the brain. Individuals with AVED have non-working genes for TTPA and therefore, vitamin E cannot be properly distributed throughout the body especially to the brain where it is necessary for proper function. AVED is characterized by very low levels of vitamin E in the blood and tissues in the brain. Without normal levels of vitamin E in the tissues, an individual with AVED experiences damage to the body from lack of protection from damaging free radicals.Vitamin E deficiency often occurs secondary to disorders that impair the absorption of vitamin E from fat including liver disorders, disorders of fat metabolism and disorders of bile secretion. These disorders include choleostasis (a syndrome of various causes characterized by impaired bile secretion), cystic fibrosis (primarily a lung disorder that results in choleostasis), primary biliary cirrhosis (a liver disorder that results in choleostasis) and abetalipoproteinemia (a digestive disorder characterized by fat malabsorption). Premature infants may have low vitamin E levels due to small amounts of vitamin E cross the placenta. In rare cases vitamin E deficiency may be caused due to poor diet. (For more information on the above disorders, choose the specific disorder name as your search term in the Rare Disease Database.)AVED is inherited, or passed down from parent to child, in an autosomal recessive 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, therefore, have a child with AVED 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. | 116 | Ataxia with Vitamin E Deficiency |
nord_116_3 | Affects of Ataxia with Vitamin E Deficiency | AVED affects both males and females equally. The disorder is estimated to occur in fewer than 1 in 1,000,000 people. North African populations are most affected with AVED. Other cases have been reported in the Mediterranean region and Northern European countries. There have been cases in Asian countries such as Japan, China and the Philippines. The onset of AVED can occur during childhood or adulthood with cases reported ranging in children as young as 2 and adults as old as 52. Typically, the disease presents in individuals between ages 5 and 20 years. The disorder was first described in the medical literature in 1981. | Affects of Ataxia with Vitamin E Deficiency. AVED affects both males and females equally. The disorder is estimated to occur in fewer than 1 in 1,000,000 people. North African populations are most affected with AVED. Other cases have been reported in the Mediterranean region and Northern European countries. There have been cases in Asian countries such as Japan, China and the Philippines. The onset of AVED can occur during childhood or adulthood with cases reported ranging in children as young as 2 and adults as old as 52. Typically, the disease presents in individuals between ages 5 and 20 years. The disorder was first described in the medical literature in 1981. | 116 | Ataxia with Vitamin E Deficiency |
nord_116_4 | Related disorders of Ataxia with Vitamin E Deficiency | The following disorders present with symptoms that can be similar to those of AVED. Comparisons of these disorders may be useful for a differential diagnosis:Friedreich’s ataxia is a genetic, progressive, neurologic movement disorder that typically shows symptoms before adolescence. AVED and Friedreich’s ataxia share many similar symptoms, however Friedreich’s ataxia is not associated with any vitamin E deficiency. In Friedreich’s ataxia, the nerves in the spinal cord and the peripheral nerves gradually become thinner, causing symptoms to worsen over time. Symptoms in the beginning may include unsteady posture, frequent falling and progressive difficulties walking due to an impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop abnormalities of certain reflexes; characteristic foot deformities; increasing incoordination of the arms and hands; slurred speech (dysarthria), and an irregular curvature of the spine (scoliosis). Friedreich’s ataxia may also be associated with cardiomyopathy, a disease of cardiac muscle that may be characterized by shortness of breath upon exertion (dyspnea), chest pain and irregularities in heart rhythm (cardiac arrhythmias). Friedreich’s ataxia is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Friedreich’s ataxia” as your search term in the Rare Disease Database.)Refsum disease is a rare lipid metabolic disorder inherited in an autosomal recessive pattern. Symptoms may include weakness or unsteadiness of the arms and legs (cerebellar ataxia), retinitis pigmentosa (a progressive vision disorder), a loss of smell (anosmia), rough, scaly skin (ichthyosis) and deafness. This disorder is believed to be due to the absence of phytanic acid hydroxylase in the blood, an enzyme needed for the metabolism of phytanic acid (found in dairy products, beef, lamb and some seafood). Refsum disease is characterized by a marked accumulation of phytanic acid in the plasma and tissues. Prolonged treatment with a diet deficient in phytanic acid can be beneficial. This slowly progressive disorder is most common in children and young adults of Scandinavian heritage. Phytanic acid is a derivative of phytol, a component of chlorophyll. (For more information on this disorder, choose “Refsum” as your search term in the Rare Disease Database.)Abetalipoproteinemia is a rare autosomal recessive inherited disorder affecting fat absorption. Abnormalities in fat metabolism result in an inability to absorb fat and vitamin E from food sources. Affected individuals experience increasing neurological deterioration, muscle weakness, difficulty walking and blood abnormalities including a condition where the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision (retinitis pigmentosa). (For more information on this disorder, choose “Abetalipoproteinemia” as your search term in the Rare Disease Database.) | Related disorders of Ataxia with Vitamin E Deficiency. The following disorders present with symptoms that can be similar to those of AVED. Comparisons of these disorders may be useful for a differential diagnosis:Friedreich’s ataxia is a genetic, progressive, neurologic movement disorder that typically shows symptoms before adolescence. AVED and Friedreich’s ataxia share many similar symptoms, however Friedreich’s ataxia is not associated with any vitamin E deficiency. In Friedreich’s ataxia, the nerves in the spinal cord and the peripheral nerves gradually become thinner, causing symptoms to worsen over time. Symptoms in the beginning may include unsteady posture, frequent falling and progressive difficulties walking due to an impaired ability to coordinate voluntary movements (ataxia). Affected individuals may also develop abnormalities of certain reflexes; characteristic foot deformities; increasing incoordination of the arms and hands; slurred speech (dysarthria), and an irregular curvature of the spine (scoliosis). Friedreich’s ataxia may also be associated with cardiomyopathy, a disease of cardiac muscle that may be characterized by shortness of breath upon exertion (dyspnea), chest pain and irregularities in heart rhythm (cardiac arrhythmias). Friedreich’s ataxia is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Friedreich’s ataxia” as your search term in the Rare Disease Database.)Refsum disease is a rare lipid metabolic disorder inherited in an autosomal recessive pattern. Symptoms may include weakness or unsteadiness of the arms and legs (cerebellar ataxia), retinitis pigmentosa (a progressive vision disorder), a loss of smell (anosmia), rough, scaly skin (ichthyosis) and deafness. This disorder is believed to be due to the absence of phytanic acid hydroxylase in the blood, an enzyme needed for the metabolism of phytanic acid (found in dairy products, beef, lamb and some seafood). Refsum disease is characterized by a marked accumulation of phytanic acid in the plasma and tissues. Prolonged treatment with a diet deficient in phytanic acid can be beneficial. This slowly progressive disorder is most common in children and young adults of Scandinavian heritage. Phytanic acid is a derivative of phytol, a component of chlorophyll. (For more information on this disorder, choose “Refsum” as your search term in the Rare Disease Database.)Abetalipoproteinemia is a rare autosomal recessive inherited disorder affecting fat absorption. Abnormalities in fat metabolism result in an inability to absorb fat and vitamin E from food sources. Affected individuals experience increasing neurological deterioration, muscle weakness, difficulty walking and blood abnormalities including a condition where the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision (retinitis pigmentosa). (For more information on this disorder, choose “Abetalipoproteinemia” as your search term in the Rare Disease Database.) | 116 | Ataxia with Vitamin E Deficiency |
nord_116_5 | Diagnosis of Ataxia with Vitamin E Deficiency | A diagnosis of AVED is made upon a thorough clinical evaluation, a detailed patient history, and a variety of tests and characteristic findings (e.g., low levels of vitamin E with normal levels of lipoproteins and lipids with no evidence of fat malabsorption and abnormalities in the TTPA gene). | Diagnosis of Ataxia with Vitamin E Deficiency. A diagnosis of AVED is made upon a thorough clinical evaluation, a detailed patient history, and a variety of tests and characteristic findings (e.g., low levels of vitamin E with normal levels of lipoproteins and lipids with no evidence of fat malabsorption and abnormalities in the TTPA gene). | 116 | Ataxia with Vitamin E Deficiency |
nord_116_6 | Therapies of Ataxia with Vitamin E Deficiency | TreatmentIndividuals with AVED are treated with high doses of vitamin E supplements. Early diagnosis and treatment can slow down or stop the progression of the disorder and in some people, even improve existing symptoms. Lifelong treatment with vitamin E will be needed.Genetic counseling is recommended for affected individuals and their families. | Therapies of Ataxia with Vitamin E Deficiency. TreatmentIndividuals with AVED are treated with high doses of vitamin E supplements. Early diagnosis and treatment can slow down or stop the progression of the disorder and in some people, even improve existing symptoms. Lifelong treatment with vitamin E will be needed.Genetic counseling is recommended for affected individuals and their families. | 116 | Ataxia with Vitamin E Deficiency |
nord_117_0 | Overview of ATR-16 Syndrome | SummaryATR-16 syndrome is an extremely rare genetic disorder in which affected individuals have a large loss of genetic material (monosomy) on chromosome 16 in which several adjacent genes are lost. Symptoms include intellectual disability, clubfoot, head circumference that is smaller than would be expected based upon an infant’s age and gender (microcephaly), and alpha thalassemia, a blood disorder characterized in this disorder by reduced levels of functional hemoglobin. Hemoglobin, a protein that is found in red blood cells, is responsible for carrying oxygen throughout the body via the blood. Some affected infants have distinctive facial features including eyes that are spaced apart farther than usual (hypertelorism), a broad, prominent bridge of the nose, small ears, and a short neck. ATR-16 syndrome is a contiguous gene syndrome, in which the loss of genetic material on chromosome 16 causes the loss of function of several adjacent genes. ATR-16 syndrome occurs as a spontaneous (de novo) event with no previous family history or in parents with a balanced chromosomal translocation that is inherited in an unbalanced manner.IntroductionThe uncommon combination of alpha thalassemia and intellectual disability was first reported in the medical literature in 1981 by Dr. Weatherall, et al. Since that original description, two distinct syndromes have been defined through additional case reports in the medical literature. One is alpha thalassemia X-linked intellectual disability or ATR-X syndrome. NORD has a separate report on this disorder in the Rare Disease Database. The other is ATR-16 syndrome, the subject of this report. | Overview of ATR-16 Syndrome. SummaryATR-16 syndrome is an extremely rare genetic disorder in which affected individuals have a large loss of genetic material (monosomy) on chromosome 16 in which several adjacent genes are lost. Symptoms include intellectual disability, clubfoot, head circumference that is smaller than would be expected based upon an infant’s age and gender (microcephaly), and alpha thalassemia, a blood disorder characterized in this disorder by reduced levels of functional hemoglobin. Hemoglobin, a protein that is found in red blood cells, is responsible for carrying oxygen throughout the body via the blood. Some affected infants have distinctive facial features including eyes that are spaced apart farther than usual (hypertelorism), a broad, prominent bridge of the nose, small ears, and a short neck. ATR-16 syndrome is a contiguous gene syndrome, in which the loss of genetic material on chromosome 16 causes the loss of function of several adjacent genes. ATR-16 syndrome occurs as a spontaneous (de novo) event with no previous family history or in parents with a balanced chromosomal translocation that is inherited in an unbalanced manner.IntroductionThe uncommon combination of alpha thalassemia and intellectual disability was first reported in the medical literature in 1981 by Dr. Weatherall, et al. Since that original description, two distinct syndromes have been defined through additional case reports in the medical literature. One is alpha thalassemia X-linked intellectual disability or ATR-X syndrome. NORD has a separate report on this disorder in the Rare Disease Database. The other is ATR-16 syndrome, the subject of this report. | 117 | ATR-16 Syndrome |
nord_117_1 | Symptoms of ATR-16 Syndrome | Researchers have experienced difficulty establishing a clear syndrome with characteristic or “core” symptoms and much about the disorder is not fully understood. In many cases, there are other chromosomal abnormalities (in addition to the deletion on chromosome 16) and it is difficult to determine what symptoms are associated with what chromosomal abnormality. In addition, the small overall number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Not surprisingly, the specific symptoms and severity of ATR-16 syndrome can vary greatly from one individual to another. But it is clear that the larger the loss of genetic material from chromosome 16 the more severe the consequences. Infants with ATR-16 syndrome have alpha thalassemia a form of anemia associated with abnormally small (microcytic) red blood cells which do not contain enough functional hemoglobin. Although anemia from various causes can be associated with symptoms for example fatigue, weakness and shortness of breath, in ATR-16 syndrome the anemia is usually mild, asymptomatic and commonly, an incidental finding.Alpha thalassemia is caused by mutations in two different genes, the HBA1 and the HBA2 genes, which are located on the chromosome 16. All individuals have two copies of each of these genes (for a total of four). Infants with ATR-16 syndrome will have a condition called alpha thalassemia minor or trait because the loss of genetic material on chromosome 16 includes one copy of each of these genes. If they receive a mutation in one of these genes on the other chromosome 16, they will develop a form of alpha thalassemia known as hemoglobin H (HbH) disease. Such individuals usually have mild HbH disease. (NORD has a separate report on alpha thalassemia. For more information, choose “alpha thalassemia” as your search term in the Rare Disease Database.)Intellectual disability, which often ranges from mild to moderate, also occurs in children with ATR-16 syndrome who have loss of at least 1 Mb of genetic material including 55 genes. Developmental and speech delays become apparent as an affected child ages. Less commonly, seizures have been reported. Head circumference may be smaller than would be expected based upon an infant’s age and gender (microcephaly). Growth delays can result in short stature, in which children are shorter than would be expected based upon age and gender.Infants with ATR-16 syndrome who have larger deletions of genetic material may also have distinctive facial features including eyes that are spaced apart farther than usual (hypertelorism), downward-slanting palpebral fissures (which means the openings between the eyelids slant downward), a broad, prominent bridge of the nose, small ears, receding chin (retrognathia), and a short neck.Skeletal malformations may occur in some cases including clubfoot (talipes equinovarus) and pinkies that are fixed or “locked” in a bent position. In males certain genital abnormalities may be present such as failure of the testes to descend (cryptorchidism) and the abnormal placement of the urinary opening on the underside of the penis (hypospadias).In one individual with a deletion of at least 2Mb of genetic information associated with an unbalanced chromosomal translocation, the clinical picture is dominated by more severe intellectual disability, tuberous sclerosis (associated with the loss of the gene TSC2) and polycystic kidney disease (associated with loss of the gene PKD1).Tumor development has been described in two cases with ATR-16; osteosarcoma (bone cancer) was identified one child and a neurocytoma (brain tumor) was identified in a fetus. It is unclear at present whether the tumor development was directly related to the ATR-16. | Symptoms of ATR-16 Syndrome. Researchers have experienced difficulty establishing a clear syndrome with characteristic or “core” symptoms and much about the disorder is not fully understood. In many cases, there are other chromosomal abnormalities (in addition to the deletion on chromosome 16) and it is difficult to determine what symptoms are associated with what chromosomal abnormality. In addition, the small overall number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Not surprisingly, the specific symptoms and severity of ATR-16 syndrome can vary greatly from one individual to another. But it is clear that the larger the loss of genetic material from chromosome 16 the more severe the consequences. Infants with ATR-16 syndrome have alpha thalassemia a form of anemia associated with abnormally small (microcytic) red blood cells which do not contain enough functional hemoglobin. Although anemia from various causes can be associated with symptoms for example fatigue, weakness and shortness of breath, in ATR-16 syndrome the anemia is usually mild, asymptomatic and commonly, an incidental finding.Alpha thalassemia is caused by mutations in two different genes, the HBA1 and the HBA2 genes, which are located on the chromosome 16. All individuals have two copies of each of these genes (for a total of four). Infants with ATR-16 syndrome will have a condition called alpha thalassemia minor or trait because the loss of genetic material on chromosome 16 includes one copy of each of these genes. If they receive a mutation in one of these genes on the other chromosome 16, they will develop a form of alpha thalassemia known as hemoglobin H (HbH) disease. Such individuals usually have mild HbH disease. (NORD has a separate report on alpha thalassemia. For more information, choose “alpha thalassemia” as your search term in the Rare Disease Database.)Intellectual disability, which often ranges from mild to moderate, also occurs in children with ATR-16 syndrome who have loss of at least 1 Mb of genetic material including 55 genes. Developmental and speech delays become apparent as an affected child ages. Less commonly, seizures have been reported. Head circumference may be smaller than would be expected based upon an infant’s age and gender (microcephaly). Growth delays can result in short stature, in which children are shorter than would be expected based upon age and gender.Infants with ATR-16 syndrome who have larger deletions of genetic material may also have distinctive facial features including eyes that are spaced apart farther than usual (hypertelorism), downward-slanting palpebral fissures (which means the openings between the eyelids slant downward), a broad, prominent bridge of the nose, small ears, receding chin (retrognathia), and a short neck.Skeletal malformations may occur in some cases including clubfoot (talipes equinovarus) and pinkies that are fixed or “locked” in a bent position. In males certain genital abnormalities may be present such as failure of the testes to descend (cryptorchidism) and the abnormal placement of the urinary opening on the underside of the penis (hypospadias).In one individual with a deletion of at least 2Mb of genetic information associated with an unbalanced chromosomal translocation, the clinical picture is dominated by more severe intellectual disability, tuberous sclerosis (associated with the loss of the gene TSC2) and polycystic kidney disease (associated with loss of the gene PKD1).Tumor development has been described in two cases with ATR-16; osteosarcoma (bone cancer) was identified one child and a neurocytoma (brain tumor) was identified in a fetus. It is unclear at present whether the tumor development was directly related to the ATR-16. | 117 | ATR-16 Syndrome |
nord_117_2 | Causes of ATR-16 Syndrome | ATR-16 syndrome is caused by the loss or deletion of genetic material affecting multiple genes that are next to (adjacent) to one another on chromosome 16, specifically from band 13.3 on the short arm (p) to the end (terminus) of the chromosome.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 16p13.3-pter” refers to the region on the short arm of chromosome 16 encompassing band 13.3 to the end or terminus.The loss of genetic material on chromosome 16 includes the loss of multiple genes. Genes provides 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 specific functions of the particular protein, this can affect many organ systems of the body, including the brain.Alpha thalassemia is caused by the loss of the HBA1 and HBA2 genes. The other genes in this chromosome region and their specific functions have not yet been identified, although the loss of one of these as-yet-unidentified genes most likely causes the intellectual disability associated with the disorder. A pure loss of genetic material (isolated monosomy) on chromosome 16p unassociated with another chromosomal abnormality is extremely rare. Many individuals have an additional chromosomal abnormality or abnormalities, which results in the wide variety of reported symptoms and prevents ATR-16 syndrome from being clearly defined.In many cases, the deleted section of chromosome 16 appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). In such de novo cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.In other cases, ATR-16 syndrome may be due to a balanced chromosomal rearrangement in one of the parents. In most cases, the parental rearrangement is described as a “balanced translocation.” Translocations occur when portions of a chromosome break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. However, no genetic material is gained or lost, only rearranged. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes; it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring. Such children may inherit an unaltered set of chromosomes, the same balanced translocation as the parent, or an unbalanced translocation, in which a chromosome has extra (trisomic) or missing (monosomic) genetic material. | Causes of ATR-16 Syndrome. ATR-16 syndrome is caused by the loss or deletion of genetic material affecting multiple genes that are next to (adjacent) to one another on chromosome 16, specifically from band 13.3 on the short arm (p) to the end (terminus) of the chromosome.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 16p13.3-pter” refers to the region on the short arm of chromosome 16 encompassing band 13.3 to the end or terminus.The loss of genetic material on chromosome 16 includes the loss of multiple genes. Genes provides 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 specific functions of the particular protein, this can affect many organ systems of the body, including the brain.Alpha thalassemia is caused by the loss of the HBA1 and HBA2 genes. The other genes in this chromosome region and their specific functions have not yet been identified, although the loss of one of these as-yet-unidentified genes most likely causes the intellectual disability associated with the disorder. A pure loss of genetic material (isolated monosomy) on chromosome 16p unassociated with another chromosomal abnormality is extremely rare. Many individuals have an additional chromosomal abnormality or abnormalities, which results in the wide variety of reported symptoms and prevents ATR-16 syndrome from being clearly defined.In many cases, the deleted section of chromosome 16 appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). In such de novo cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.In other cases, ATR-16 syndrome may be due to a balanced chromosomal rearrangement in one of the parents. In most cases, the parental rearrangement is described as a “balanced translocation.” Translocations occur when portions of a chromosome break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. However, no genetic material is gained or lost, only rearranged. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes; it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring. Such children may inherit an unaltered set of chromosomes, the same balanced translocation as the parent, or an unbalanced translocation, in which a chromosome has extra (trisomic) or missing (monosomic) genetic material. | 117 | ATR-16 Syndrome |
nord_117_3 | Affects of ATR-16 Syndrome | ATR-16 syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. More than 20 cases have been reported in the medical literature. | Affects of ATR-16 Syndrome. ATR-16 syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. More than 20 cases have been reported in the medical literature. | 117 | ATR-16 Syndrome |
nord_117_4 | Related disorders of ATR-16 Syndrome | Symptoms of the following disorders can be similar to those of ATR-16 syndrome. Comparisons may be useful for a differential diagnosis.Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder affecting multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, developmental delays, diminished muscle tone (hypotonia), distinctive facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia is not seen in every case. Distinctive facial features include an abnormally large space between the eyes (hypertelorism), vertical skin folds (epicanthal folds) that may cover the inner corners of the eyes, underdevelopment of the middle portion of the face (midface hypoplasia), an abnormally flat nasal bridge, and a small, triangular nose. Most infants also have microcephaly. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition and occurs due to mutations of the ATRX gene on the X chromosome. (For more information on this disorder, choose “ATR-X syndrome” as your search term in the Rare Disease Database.)Alpha thalassemia is the one of the most common autosomal recessive disorders in the world. Individuals with alpha thalassemia can, coincidentally, develop intellectual disability because of a different underlying reason, unrelated to chromosome 16. | Related disorders of ATR-16 Syndrome. Symptoms of the following disorders can be similar to those of ATR-16 syndrome. Comparisons may be useful for a differential diagnosis.Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder affecting multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, developmental delays, diminished muscle tone (hypotonia), distinctive facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia is not seen in every case. Distinctive facial features include an abnormally large space between the eyes (hypertelorism), vertical skin folds (epicanthal folds) that may cover the inner corners of the eyes, underdevelopment of the middle portion of the face (midface hypoplasia), an abnormally flat nasal bridge, and a small, triangular nose. Most infants also have microcephaly. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition and occurs due to mutations of the ATRX gene on the X chromosome. (For more information on this disorder, choose “ATR-X syndrome” as your search term in the Rare Disease Database.)Alpha thalassemia is the one of the most common autosomal recessive disorders in the world. Individuals with alpha thalassemia can, coincidentally, develop intellectual disability because of a different underlying reason, unrelated to chromosome 16. | 117 | ATR-16 Syndrome |
nord_117_5 | Diagnosis of ATR-16 Syndrome | A diagnosis of ATR-16 syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
Routine cytogenetic studies can be performed to diagnose ATR-16 syndrome when it is associated with a chromosomal abnormality such as a translocation but in the case of deletions and subtelomeric translocations such high resolution cytogenetic analysis appears entirely normal. A specific chromosomal study known as G-band analysis, which demonstrates rearranged chromosomal material, can be used to help obtain a diagnosis. Chromosomes may be obtained from a blood sample. During this test the chromosomes are stained so that they can be more easily seen and then are examined under a microscope where the rearranged chromosomes can be detected (karyotyping). To determine the precise breakpoint or to look for a suspected deletion not detected by G-band analysis, a more sensitive test known as fluorescent in situ hybridization (FISH) may be necessary. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view that specific region of the chromosome.As a first line investigation these technologies are being superseded by newer techniques. One is known as array comparative genome hybridization (array CGH). During this exam, a person’s DNA is compared to the DNA of a person without a chromosomal abnormality (‘control’ person). A chromosome abnormality is noted when a difference is found between the DNA samples. Analysis by array CGH or a related approach, SNParray, allow for the detection of very small changes or alterations. An alternative approach is multiple ligation-dependent probe amplification (MLPA). | Diagnosis of ATR-16 Syndrome. A diagnosis of ATR-16 syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
Routine cytogenetic studies can be performed to diagnose ATR-16 syndrome when it is associated with a chromosomal abnormality such as a translocation but in the case of deletions and subtelomeric translocations such high resolution cytogenetic analysis appears entirely normal. A specific chromosomal study known as G-band analysis, which demonstrates rearranged chromosomal material, can be used to help obtain a diagnosis. Chromosomes may be obtained from a blood sample. During this test the chromosomes are stained so that they can be more easily seen and then are examined under a microscope where the rearranged chromosomes can be detected (karyotyping). To determine the precise breakpoint or to look for a suspected deletion not detected by G-band analysis, a more sensitive test known as fluorescent in situ hybridization (FISH) may be necessary. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view that specific region of the chromosome.As a first line investigation these technologies are being superseded by newer techniques. One is known as array comparative genome hybridization (array CGH). During this exam, a person’s DNA is compared to the DNA of a person without a chromosomal abnormality (‘control’ person). A chromosome abnormality is noted when a difference is found between the DNA samples. Analysis by array CGH or a related approach, SNParray, allow for the detection of very small changes or alterations. An alternative approach is multiple ligation-dependent probe amplification (MLPA). | 117 | ATR-16 Syndrome |
nord_117_6 | Therapies of ATR-16 Syndrome | TreatmentThe treatment of ATR-16 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, neurologists, hematologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Psychosocial support for the entire family is essential as well. Early intervention services during infancy and toddlerhood (before the age of three) are important in ensuring that affected children reach their potential. Special services that may be beneficial during childhood include special remedial education, speech therapy and/or other medical, and social services. An Individualized Family Support Plan (IFSP) may be developed to guide the early intervention process for infants and toddlers with disabilities. An individual education plan (IEP) may be developed to assist children in school if special services are required, or a 504 plan which can ensure that the child receives access to an equal education through accommodations in their learning environment. Such planning is individualized, especially because the degree of intellectual disability is highly variable.Alpha thalassemia and HbH disease do not require treatment in most cases. It is conceivable with a more severe expression of the disorder, affected individuals may require occasional blood transfusions and/or medications that remove excess iron from the blood (chelators). Additional therapies for ATR-16 syndrome depend upon the specific abnormalities present and generally follow standard guidelines.Genetic counseling is recommended for affected individuals and their families. | Therapies of ATR-16 Syndrome. TreatmentThe treatment of ATR-16 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, neurologists, hematologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Psychosocial support for the entire family is essential as well. Early intervention services during infancy and toddlerhood (before the age of three) are important in ensuring that affected children reach their potential. Special services that may be beneficial during childhood include special remedial education, speech therapy and/or other medical, and social services. An Individualized Family Support Plan (IFSP) may be developed to guide the early intervention process for infants and toddlers with disabilities. An individual education plan (IEP) may be developed to assist children in school if special services are required, or a 504 plan which can ensure that the child receives access to an equal education through accommodations in their learning environment. Such planning is individualized, especially because the degree of intellectual disability is highly variable.Alpha thalassemia and HbH disease do not require treatment in most cases. It is conceivable with a more severe expression of the disorder, affected individuals may require occasional blood transfusions and/or medications that remove excess iron from the blood (chelators). Additional therapies for ATR-16 syndrome depend upon the specific abnormalities present and generally follow standard guidelines.Genetic counseling is recommended for affected individuals and their families. | 117 | ATR-16 Syndrome |
nord_118_0 | Overview of Atransferrinemia | Atransferrinemia is an extremely rare genetic disorder characterized by low levels of healthy, functional red cells in the blood (hypochromic, microcytic anemia) and by the accumulation of excess iron in the body (hemosiderosis). Symptoms may vary based upon the severity of anemia and upon the extent of iron accumulation in the body and the specific organs affected. Common symptoms include recurrent infections and growth delays. Atransferrinemia is principally caused by mutations of the transferrin (TF) gene and is inherited as an autosomal recessive trait. Atransferrinemia is classified as an iron overload disorder. A milder form of atransferrinemia, known as hypotransferrinemia, is caused by mutations in the same gene. | Overview of Atransferrinemia. Atransferrinemia is an extremely rare genetic disorder characterized by low levels of healthy, functional red cells in the blood (hypochromic, microcytic anemia) and by the accumulation of excess iron in the body (hemosiderosis). Symptoms may vary based upon the severity of anemia and upon the extent of iron accumulation in the body and the specific organs affected. Common symptoms include recurrent infections and growth delays. Atransferrinemia is principally caused by mutations of the transferrin (TF) gene and is inherited as an autosomal recessive trait. Atransferrinemia is classified as an iron overload disorder. A milder form of atransferrinemia, known as hypotransferrinemia, is caused by mutations in the same gene. | 118 | Atransferrinemia |
nord_118_1 | Symptoms of Atransferrinemia | The symptoms and severity of atransferrinemia vary from one person to another depending upon the specific location and extent of iron accumulation in the body. Some individuals may develop mild symptoms, others may develop serious, life-threatening complications.Affected individuals often develop severe microcytic hypochromic anemia, a condition characterized by abnormally small red cells (erythrocytes) that are insufficiently filled with hemoglobin. Red cells are blood cells that deliver oxygen throughout the body. Hemoglobin is the iron-rich, oxygen-bearing protein in blood. Microcytic hypochromic anemia may be associated with pallor and fatigue. Some affected individuals may have a slightly enlarged liver (hepatomegaly).Atransferrinemia is also often associated with growth delays and recurrent infections. Additional symptoms depend upon the location and extent of iron accumulation in the body. Atransferrinemia can potentially affect the liver, heart, joints, pancreas, kidneys and thyroid. Iron accumulation can damage affected organs and can cause scarring (cirrhosis) of the liver, arthritis, an underactive thyroid (hypothyroidism) and heart abnormalities. In severe cases, affected individuals can develop life-threatening complications such as pneumonia or an impaired ability to circulate blood to the lungs and the rest of the body, resulting in fluid buildup in the heart, lungs and various body tissues (congestive heart failure). | Symptoms of Atransferrinemia. The symptoms and severity of atransferrinemia vary from one person to another depending upon the specific location and extent of iron accumulation in the body. Some individuals may develop mild symptoms, others may develop serious, life-threatening complications.Affected individuals often develop severe microcytic hypochromic anemia, a condition characterized by abnormally small red cells (erythrocytes) that are insufficiently filled with hemoglobin. Red cells are blood cells that deliver oxygen throughout the body. Hemoglobin is the iron-rich, oxygen-bearing protein in blood. Microcytic hypochromic anemia may be associated with pallor and fatigue. Some affected individuals may have a slightly enlarged liver (hepatomegaly).Atransferrinemia is also often associated with growth delays and recurrent infections. Additional symptoms depend upon the location and extent of iron accumulation in the body. Atransferrinemia can potentially affect the liver, heart, joints, pancreas, kidneys and thyroid. Iron accumulation can damage affected organs and can cause scarring (cirrhosis) of the liver, arthritis, an underactive thyroid (hypothyroidism) and heart abnormalities. In severe cases, affected individuals can develop life-threatening complications such as pneumonia or an impaired ability to circulate blood to the lungs and the rest of the body, resulting in fluid buildup in the heart, lungs and various body tissues (congestive heart failure). | 118 | Atransferrinemia |
nord_118_2 | Causes of Atransferrinemia | Atransferrinemia / hypotransferrinemia is principally caused by mutations of the transferrin (TF) gene. It is inherited as an autosomal recessive trait. 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 both to pass the defective gene and, therefore, to 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.Investigators have determined that the transferrin (TF) gene is located at band 21 on the long arm (q) of chromosome 3 (3q21). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q21” refers to band 21 on the long arm of chromosome 3. The numbered bands help to specify the location of the thousands of genes that are present on each chromosome.The TF gene contains instructions for producing a protein called transferrin. This protein is essential for the proper transport of iron within the body. Mutations of the TF gene result in deficient levels of functional transferrin, which ultimately results in the accumulation of excess iron in various organs of the body. Iron accumulation damages the tissue of affected organs, causing the characteristic symptoms of atransferrinemia.Researchers have determined that the absence of transferrin results in an inability of the body to deliver iron to immature red cells in the bone marrow. The lack of delivery of iron to these immature cells causes the body to increase the absorption of iron in the intestines significantly, resulting in the iron overload that characterizes atransferrinemia. | Causes of Atransferrinemia. Atransferrinemia / hypotransferrinemia is principally caused by mutations of the transferrin (TF) gene. It is inherited as an autosomal recessive trait. 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 both to pass the defective gene and, therefore, to 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.Investigators have determined that the transferrin (TF) gene is located at band 21 on the long arm (q) of chromosome 3 (3q21). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q21” refers to band 21 on the long arm of chromosome 3. The numbered bands help to specify the location of the thousands of genes that are present on each chromosome.The TF gene contains instructions for producing a protein called transferrin. This protein is essential for the proper transport of iron within the body. Mutations of the TF gene result in deficient levels of functional transferrin, which ultimately results in the accumulation of excess iron in various organs of the body. Iron accumulation damages the tissue of affected organs, causing the characteristic symptoms of atransferrinemia.Researchers have determined that the absence of transferrin results in an inability of the body to deliver iron to immature red cells in the bone marrow. The lack of delivery of iron to these immature cells causes the body to increase the absorption of iron in the intestines significantly, resulting in the iron overload that characterizes atransferrinemia. | 118 | Atransferrinemia |
nord_118_3 | Affects of Atransferrinemia | Atransferrinemia is an extremely rare disorder. Approximately 10 cases in 8 families have been reported in the medical literature. Because atransferrinemia may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Atransferrinemia affects males and females in equal numbers. Atransferrinemia was first described in the medical literature in 1961. | Affects of Atransferrinemia. Atransferrinemia is an extremely rare disorder. Approximately 10 cases in 8 families have been reported in the medical literature. Because atransferrinemia may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Atransferrinemia affects males and females in equal numbers. Atransferrinemia was first described in the medical literature in 1961. | 118 | Atransferrinemia |
nord_118_4 | Related disorders of Atransferrinemia | Symptoms of the following disorders can be similar to those of hereditary atransferrinemia/hypotransferrinemia. Comparisons may be useful for a differential diagnosis.Acquired hypotransferrinemia is a condition characterized by low levels of the protein transferrin in the body, which results in the accumulation of iron in various organs of the body. Unlike, congenital or hereditary atransferrinemia, this condition is acquired and not genetic. Acquired hypotransferrinemia may develop in individuals with liver or kidney disease, cancer, or inflammatory disease (including autoimmunity).Dysfunction or deficiency of the cell-surface protein, the transferrin receptor, that binds to transferrin and that makes it possible for the iron carried by transferrin to enter the cell is known in humans and in mice. Like atransferrinemia / hypotransferrinemia, transferrin-receptor disease leads to hypochromic, microcytic anemia. Tissue iron stores are not increased, however, and concentrations of transferrin in circulation are normal.Primary disorders of iron overload are a group of rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, neonatal hemochromatosis, and African iron overload disease. (“Neonatal hemochromatosis” is thought to be a consequence of immune-mediated fetal liver disease rather than of iron overload in utero.) Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis; hemochromatosis type 2 (juvenile hemochromatosis), known as hemojuvelin disease; 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 of 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 Atransferrinemia. Symptoms of the following disorders can be similar to those of hereditary atransferrinemia/hypotransferrinemia. Comparisons may be useful for a differential diagnosis.Acquired hypotransferrinemia is a condition characterized by low levels of the protein transferrin in the body, which results in the accumulation of iron in various organs of the body. Unlike, congenital or hereditary atransferrinemia, this condition is acquired and not genetic. Acquired hypotransferrinemia may develop in individuals with liver or kidney disease, cancer, or inflammatory disease (including autoimmunity).Dysfunction or deficiency of the cell-surface protein, the transferrin receptor, that binds to transferrin and that makes it possible for the iron carried by transferrin to enter the cell is known in humans and in mice. Like atransferrinemia / hypotransferrinemia, transferrin-receptor disease leads to hypochromic, microcytic anemia. Tissue iron stores are not increased, however, and concentrations of transferrin in circulation are normal.Primary disorders of iron overload are a group of rare disorders characterized by iron accumulation in the body. This group includes hemochromatosis, neonatal hemochromatosis, and African iron overload disease. (“Neonatal hemochromatosis” is thought to be a consequence of immune-mediated fetal liver disease rather than of iron overload in utero.) Hemochromatosis has been separated into four distinct disorders – hereditary (classic) hemochromatosis, also known as HFE-related hemochromatosis; hemochromatosis type 2 (juvenile hemochromatosis), known as hemojuvelin disease; 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 of 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.) | 118 | Atransferrinemia |
nord_118_5 | Diagnosis of Atransferrinemia | A diagnosis of atransferrinemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Laboratory tests can reveal low or undetectable levels of transferrin in the blood. | Diagnosis of Atransferrinemia. A diagnosis of atransferrinemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Laboratory tests can reveal low or undetectable levels of transferrin in the blood. | 118 | Atransferrinemia |
nord_118_6 | Therapies of Atransferrinemia | TreatmentThe treatment of atransferrinemia is directed toward the specific symptoms that are apparent in each individual. Affected individuals have been treated with infusions of plasma or of a urified form of transferrin (apotransferrin) that may correct certain symptoms (e.g., anemia, growth deficiencies) associated with the disorder. As the liver synthesizes most transferrin, liver transplantation theoretically could supply a cure; its use has not been reported. In long-term survival with atransferrinemia, iron toxicity to tissues, rather than anemia, is the principal cause of illness. Approaches to off-loading excess body iron stores are not well worked out (see below).Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Atransferrinemia. TreatmentThe treatment of atransferrinemia is directed toward the specific symptoms that are apparent in each individual. Affected individuals have been treated with infusions of plasma or of a urified form of transferrin (apotransferrin) that may correct certain symptoms (e.g., anemia, growth deficiencies) associated with the disorder. As the liver synthesizes most transferrin, liver transplantation theoretically could supply a cure; its use has not been reported. In long-term survival with atransferrinemia, iron toxicity to tissues, rather than anemia, is the principal cause of illness. Approaches to off-loading excess body iron stores are not well worked out (see below).Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 118 | Atransferrinemia |
nord_119_0 | Overview of Atrial Septal Defects | Atrial septal defects (ASDs) are a group of rare disorders of the heart that are present at birth (congenital) and involve a hole in the wall (septum) that separates the two upper-chambers (atria) of the heart.Normally the heart has four chambers: two upper chambers known as atria that are separated from each other by a fibrous partition known as the atrial septum and two lower chambers known as ventricles that are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. A small opening between the two atria (foramen ovale) is present at birth. Shortly after birth, the atrial septum gradually grows and seals this opening. In infants with atrial septal defects, the atrial septum may not close properly or may be malformed during fetal development. In these disorders, the opening (called patent foramen ovale) between the atria persists long after it should be closed, resulting in an increase in the workload on the right side of the heart and excessive blood flow to the lungs.Initially, the symptoms associated with atrial septal defects may be absent or so mild that they may go unnoticed. Frequently this disorder is not recognized until school age or even adulthood. In adults with undetected atrial septal defects, various respiratory problems and/or heart failure may develop.Several forms of atrial septal defects are recognized. They are classified according to their location in the septum. The term primum refers to defects that are in the lower part of the septum. The term secundum refers to defects that are located in the middle of the septum, and the term sinus venosus refers to defects in the upper part of the septum. | Overview of Atrial Septal Defects. Atrial septal defects (ASDs) are a group of rare disorders of the heart that are present at birth (congenital) and involve a hole in the wall (septum) that separates the two upper-chambers (atria) of the heart.Normally the heart has four chambers: two upper chambers known as atria that are separated from each other by a fibrous partition known as the atrial septum and two lower chambers known as ventricles that are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. A small opening between the two atria (foramen ovale) is present at birth. Shortly after birth, the atrial septum gradually grows and seals this opening. In infants with atrial septal defects, the atrial septum may not close properly or may be malformed during fetal development. In these disorders, the opening (called patent foramen ovale) between the atria persists long after it should be closed, resulting in an increase in the workload on the right side of the heart and excessive blood flow to the lungs.Initially, the symptoms associated with atrial septal defects may be absent or so mild that they may go unnoticed. Frequently this disorder is not recognized until school age or even adulthood. In adults with undetected atrial septal defects, various respiratory problems and/or heart failure may develop.Several forms of atrial septal defects are recognized. They are classified according to their location in the septum. The term primum refers to defects that are in the lower part of the septum. The term secundum refers to defects that are located in the middle of the septum, and the term sinus venosus refers to defects in the upper part of the septum. | 119 | Atrial Septal Defects |
nord_119_1 | Symptoms of Atrial Septal Defects | Ostium secundum atrial septal defect is the most common form of this group of heart defects. The middle portion of the atrial septum in the region of the foramen ovale fails to close during fetal development. The size of the opening may vary, along with the severity of the symptoms.Ostium primum atrial septal defect is less common. The lower part of the atrial septum fails to develop normally, leaving an opening between the atria. Frequently, the valves that separate the atria from their respective ventricles (tricuspid and mitral) are also malformed, and the septum that divides the ventricles may also be deficient or malformed (atrioventricular septal defect). Another defect may have occurred during embryonic development in the tissue that forms the septum that divides the heart into atria and ventricles (endocardial cushion defect).Sinus venosus, the least common form of atrial septal defect, occurs when there is an opening on the upper portion of the atrial septum. This defect is often associated with malformations of the vein that leads from the lungs into the heart (right pulmonary vein). One of the major veins of the body that returns blood to the heart (superior vena cava) may also be malformed.Most children with atrial septal defects have no symptoms. A few affected individuals may be abnormally thin and experience mild growth delays as well as an increased susceptibility to respiratory infections. Other very severely affected children, especially those with ostium primum defects, may experience breathlessness, easy fatigability with exercise, and/or irregular heartbeats (arrhythmias).A heart murmur is the most common sign and usually the only sign of ASD in children. There may also be a change in heart sounds that represents the closing of the valves of the heart. Around the age of 40 years, people with atrial septal defects may experience symptoms related to an increase in pressure in the blood vessels of the lungs (pulmonary hypertension). Increased pressure in these vessels causes the blood to be propelled or “shunted” through the abnormal opening in the heart. Symptoms may include a bluish discoloration of the skin (cyanosis), clubbing of the fingertips, exercise intolerance, and/or an abnormal increase in the number of circulating red blood cells (polycythemia). Abscesses may also develop in the brain. Other symptoms may include swelling of the arms and legs and/or difficulty breathing.Severe cases of atrial septal defects may lead to life-threatening complications such as chest pain, irregular heartbeats (arrhythmias), abnormal enlargement of the heart, a “fluttering” of the heart (atrial fibrillation), and/or heart failure. Females with atrial septal defects who become pregnant may be at risk for episodes of blood clot formation. These clots may detach from the walls of the blood vessels and travel through the systemic circulation (embolism). | Symptoms of Atrial Septal Defects. Ostium secundum atrial septal defect is the most common form of this group of heart defects. The middle portion of the atrial septum in the region of the foramen ovale fails to close during fetal development. The size of the opening may vary, along with the severity of the symptoms.Ostium primum atrial septal defect is less common. The lower part of the atrial septum fails to develop normally, leaving an opening between the atria. Frequently, the valves that separate the atria from their respective ventricles (tricuspid and mitral) are also malformed, and the septum that divides the ventricles may also be deficient or malformed (atrioventricular septal defect). Another defect may have occurred during embryonic development in the tissue that forms the septum that divides the heart into atria and ventricles (endocardial cushion defect).Sinus venosus, the least common form of atrial septal defect, occurs when there is an opening on the upper portion of the atrial septum. This defect is often associated with malformations of the vein that leads from the lungs into the heart (right pulmonary vein). One of the major veins of the body that returns blood to the heart (superior vena cava) may also be malformed.Most children with atrial septal defects have no symptoms. A few affected individuals may be abnormally thin and experience mild growth delays as well as an increased susceptibility to respiratory infections. Other very severely affected children, especially those with ostium primum defects, may experience breathlessness, easy fatigability with exercise, and/or irregular heartbeats (arrhythmias).A heart murmur is the most common sign and usually the only sign of ASD in children. There may also be a change in heart sounds that represents the closing of the valves of the heart. Around the age of 40 years, people with atrial septal defects may experience symptoms related to an increase in pressure in the blood vessels of the lungs (pulmonary hypertension). Increased pressure in these vessels causes the blood to be propelled or “shunted” through the abnormal opening in the heart. Symptoms may include a bluish discoloration of the skin (cyanosis), clubbing of the fingertips, exercise intolerance, and/or an abnormal increase in the number of circulating red blood cells (polycythemia). Abscesses may also develop in the brain. Other symptoms may include swelling of the arms and legs and/or difficulty breathing.Severe cases of atrial septal defects may lead to life-threatening complications such as chest pain, irregular heartbeats (arrhythmias), abnormal enlargement of the heart, a “fluttering” of the heart (atrial fibrillation), and/or heart failure. Females with atrial septal defects who become pregnant may be at risk for episodes of blood clot formation. These clots may detach from the walls of the blood vessels and travel through the systemic circulation (embolism). | 119 | Atrial Septal Defects |
nord_119_2 | Causes of Atrial Septal Defects | Most cases of atrial septal defects occur on their own for no apparent reason (sporadically). The exact nature of the developmental defect or defects that may occur during embryonic development (embryogenesis) remain unclear.Some cases of ASD appear to run in families. In such rare cases, the two forms, ostium primum and ostium secundum defects seem to be inherited as autosomal dominant genetic traits. To complicate matters further, genetic analysis suggests that there are at least two different genetic disorders involving ASD that are linked to mutations in a gene called NKX2-5.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 6p21.3” refers to band 21.3 on the short arm of chromosome 6. Similarly “chromosome 8p23.1-p22” refers to a region between bands 22 and 23.1 on the short arm of chromosome 8. 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. 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 regardless of the sex of the resulting child.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. 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. Atrial septal defects may also occur in association with a variety of other congenital heart defects, or in newborns that are relatively small or premature. Ostium primum defects occur frequently in individuals with Down syndrome or Ellis van-Creveld syndrome. (For more information on this disorder, choose “Down” or “Ellis van-Creveld” as your search term in the Rare Disease Database.) | Causes of Atrial Septal Defects. Most cases of atrial septal defects occur on their own for no apparent reason (sporadically). The exact nature of the developmental defect or defects that may occur during embryonic development (embryogenesis) remain unclear.Some cases of ASD appear to run in families. In such rare cases, the two forms, ostium primum and ostium secundum defects seem to be inherited as autosomal dominant genetic traits. To complicate matters further, genetic analysis suggests that there are at least two different genetic disorders involving ASD that are linked to mutations in a gene called NKX2-5.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 6p21.3” refers to band 21.3 on the short arm of chromosome 6. Similarly “chromosome 8p23.1-p22” refers to a region between bands 22 and 23.1 on the short arm of chromosome 8. 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. 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 regardless of the sex of the resulting child.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. 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. Atrial septal defects may also occur in association with a variety of other congenital heart defects, or in newborns that are relatively small or premature. Ostium primum defects occur frequently in individuals with Down syndrome or Ellis van-Creveld syndrome. (For more information on this disorder, choose “Down” or “Ellis van-Creveld” as your search term in the Rare Disease Database.) | 119 | Atrial Septal Defects |
nord_119_3 | Affects of Atrial Septal Defects | Atrial septal defects are rare congenital heart defects that affect more females than males (2 or 3:1). Approximately 1 percent of all infants in the United States are born with a form of congenital heart defect. About 10 percent of these infants have atrial septal defects.Although atrial septal defects can be diagnosed during infancy or in children between the ages of 6 months and 3 years, the disorder is usually diagnosed after the age of 40 years, when symptoms frequently appear. Symptoms may be noticed at an earlier age if the defects are very severe or if affected individuals live at high elevations (i.e., in the mountains). This is due to the slight narrowing of the arteries of the heart and lungs at higher altitudes.Ostium primum atrial septal defects may occur in individuals with Down syndrome or in over 50 percent of people with Ellis van-Creveld syndrome. These defects may also occur in association with a variety of other disorders. | Affects of Atrial Septal Defects. Atrial septal defects are rare congenital heart defects that affect more females than males (2 or 3:1). Approximately 1 percent of all infants in the United States are born with a form of congenital heart defect. About 10 percent of these infants have atrial septal defects.Although atrial septal defects can be diagnosed during infancy or in children between the ages of 6 months and 3 years, the disorder is usually diagnosed after the age of 40 years, when symptoms frequently appear. Symptoms may be noticed at an earlier age if the defects are very severe or if affected individuals live at high elevations (i.e., in the mountains). This is due to the slight narrowing of the arteries of the heart and lungs at higher altitudes.Ostium primum atrial septal defects may occur in individuals with Down syndrome or in over 50 percent of people with Ellis van-Creveld syndrome. These defects may also occur in association with a variety of other disorders. | 119 | Atrial Septal Defects |
nord_119_4 | Related disorders of Atrial Septal Defects | Symptoms of the following disorders may be similar to those of atrial septal defects. Comparisons may be useful for a differential diagnosis:Atrioventricular septal defect is a rare heart defect that is present at birth (congenital) and is characterized by the improper development of the septa and valves of the heart. Infants with the complete form of the defect usually develop congestive heart failure. Excessive fluid accumulates in other areas of the body, especially the lungs. This pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin (cyanosis), poor feeding habits, abnormally rapid breathing (tachypnea) and heart rate (tachycardia), and/or excessive sweating (hyperhidrosis). Adults with atrioventricular septal defect may experience abnormally low blood pressure, irregular heartbeats, and/or a rapid heartbeat. (For more information on this disorder, choose “atrioventricular septal defect” as your search term in the Rare Disease Database.)Ventricular septal defects (cor triloculare biventricularis) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with these defects may have 2 atria and 1 large ventricle. Symptoms of these conditions are similar to atrioventricular septal defect and may include an abnormally rapid rate of breathing (tachypnea), wheezing, a rapid heart beat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). Ventricular septal defects can also cause the excessive accumulation of fluid around the heart, leading to congestive heart failure. (For more information on this disorder, choose “ventricular septal defects” as your search term in the Rare Disease Database.)Cor triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of cor triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor triloculare biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of atrial septal defect and include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. It is characterized by the abnormal narrowing of the opening of the mitral value. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness.Atrial septal defects may occur in association with a variety of other disorders including Down syndrome, Ellis van-Creveld syndrome, Opitz syndrome, Costello syndrome, Chondroectodermal dysplasia, fetal effects of Rubella, Holt-Oram syndrome, Hurler syndrome, and others. (For more information on these disorders, choose “Down,” “Opitz,” “Ellis van-Creveld,” “Rubella,” “Holt-Oram,” and “Hurler” as your search terms in the Rare Disease Database.) | Related disorders of Atrial Septal Defects. Symptoms of the following disorders may be similar to those of atrial septal defects. Comparisons may be useful for a differential diagnosis:Atrioventricular septal defect is a rare heart defect that is present at birth (congenital) and is characterized by the improper development of the septa and valves of the heart. Infants with the complete form of the defect usually develop congestive heart failure. Excessive fluid accumulates in other areas of the body, especially the lungs. This pulmonary congestion may lead to difficulty breathing (dyspnea). Other symptoms may include a bluish discoloration of the skin (cyanosis), poor feeding habits, abnormally rapid breathing (tachypnea) and heart rate (tachycardia), and/or excessive sweating (hyperhidrosis). Adults with atrioventricular septal defect may experience abnormally low blood pressure, irregular heartbeats, and/or a rapid heartbeat. (For more information on this disorder, choose “atrioventricular septal defect” as your search term in the Rare Disease Database.)Ventricular septal defects (cor triloculare biventricularis) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with these defects may have 2 atria and 1 large ventricle. Symptoms of these conditions are similar to atrioventricular septal defect and may include an abnormally rapid rate of breathing (tachypnea), wheezing, a rapid heart beat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). Ventricular septal defects can also cause the excessive accumulation of fluid around the heart, leading to congestive heart failure. (For more information on this disorder, choose “ventricular septal defects” as your search term in the Rare Disease Database.)Cor triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of cor triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor triloculare biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of atrial septal defect and include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. It is characterized by the abnormal narrowing of the opening of the mitral value. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness.Atrial septal defects may occur in association with a variety of other disorders including Down syndrome, Ellis van-Creveld syndrome, Opitz syndrome, Costello syndrome, Chondroectodermal dysplasia, fetal effects of Rubella, Holt-Oram syndrome, Hurler syndrome, and others. (For more information on these disorders, choose “Down,” “Opitz,” “Ellis van-Creveld,” “Rubella,” “Holt-Oram,” and “Hurler” as your search terms in the Rare Disease Database.) | 119 | Atrial Septal Defects |
nord_119_5 | Diagnosis of Atrial Septal Defects | The diagnosis of atrial septal defects is confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart. These tests may include an X-ray study, electrocardiogram (EKG), echocardiogram, and cardiac catheterization. X-ray studies may reveal abnormal enlargement of the heart or malformation of other heart structures. During an echocardiogram, ultrasonic waves are directed toward the heart, enabling physicians to study the motion and function of the heart. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities. | Diagnosis of Atrial Septal Defects. The diagnosis of atrial septal defects is confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart. These tests may include an X-ray study, electrocardiogram (EKG), echocardiogram, and cardiac catheterization. X-ray studies may reveal abnormal enlargement of the heart or malformation of other heart structures. During an echocardiogram, ultrasonic waves are directed toward the heart, enabling physicians to study the motion and function of the heart. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities. | 119 | Atrial Septal Defects |
nord_119_6 | Therapies of Atrial Septal Defects | TreatmentTreatment is usually surgical with the use of medications limited to the period during which the patient waits for a surgical procedure. In the case of the youngest patients "watchful waiting" is often sufficient as the opening closes while the child grows.SurgicalSurgery to close the opening of the heart was, until recently, the favored form of treatment. Open-heart surgery was designed to sew edges of the hole together (sutured) and close it. In some cases the hole might be patched and closed with a graft or prosthetic patch. The success rate is high for these surgical procedures. For ostium primum septal defects, surgery may be performed to repair or replace the atrioventricular valves. The success rate for this complex procedure is considerably lower. Surgery is optimally performed between the ages of 3 and 6 years.In recent years a less traumatic way of closing the septal opening has been developed involving the use of catheters to which is attached a special device designed to close the opening(s) (septal occluder). A catheter is inserted into the heart through the groin and the surgeon "threads" a special fabric-covered wire frame to the heart. Half of the frame is positioned on each of the left and right side of the septal atrium. The surgeon then "wedges" the ASD between the two parts of the occluder. Over the next 6-8 weeks normal tissue grows around the device forming a stable and solid patch over the hole. The use of a catheter-closing device works best for those defects located in the middle of the dividing wall (secundum). There must be enough tissue left in other cases for the closure to take place.Genetic counseling may be of benefit for some affected patients and their families. Other treatment is symptomatic and supportive. | Therapies of Atrial Septal Defects. TreatmentTreatment is usually surgical with the use of medications limited to the period during which the patient waits for a surgical procedure. In the case of the youngest patients "watchful waiting" is often sufficient as the opening closes while the child grows.SurgicalSurgery to close the opening of the heart was, until recently, the favored form of treatment. Open-heart surgery was designed to sew edges of the hole together (sutured) and close it. In some cases the hole might be patched and closed with a graft or prosthetic patch. The success rate is high for these surgical procedures. For ostium primum septal defects, surgery may be performed to repair or replace the atrioventricular valves. The success rate for this complex procedure is considerably lower. Surgery is optimally performed between the ages of 3 and 6 years.In recent years a less traumatic way of closing the septal opening has been developed involving the use of catheters to which is attached a special device designed to close the opening(s) (septal occluder). A catheter is inserted into the heart through the groin and the surgeon "threads" a special fabric-covered wire frame to the heart. Half of the frame is positioned on each of the left and right side of the septal atrium. The surgeon then "wedges" the ASD between the two parts of the occluder. Over the next 6-8 weeks normal tissue grows around the device forming a stable and solid patch over the hole. The use of a catheter-closing device works best for those defects located in the middle of the dividing wall (secundum). There must be enough tissue left in other cases for the closure to take place.Genetic counseling may be of benefit for some affected patients and their families. Other treatment is symptomatic and supportive. | 119 | Atrial Septal Defects |
nord_120_0 | Overview of Atrioventricular Septal Defect | Atrioventricular septal defect (AVSD) is a general term for a group of rare heart defects that are present at birth (congenital). Infants with AVSDs have improperly developed atrial and ventricular septa and adjoining valves.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition called the atrial septum. The two lower chambers, known as ventricles, are separated from each other by the ventricular septum. Valves (e.g., mitral and tricuspid) connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.The parts of the heart described above are formed from an embryonic structure called the endocardial cushions. In individuals with AVSD there is some combination of malformation of these parts of the heart. They may include a hole in the atrial septum, a hole in the ventricular septum, and/or abnormalities of the mitral and triscupid valves. AVSD may be classified as one of three forms: an incomplete (or partial) AVSD (atrial septal defect primum); a transitional form (atrial septal defect and small ventricular septal defect); or a more severe or complete form (large atrial and ventricular defects).The symptoms of AVSD vary greatly and depend on the severity of the malformations (e.g., valve leakage between ventricles and ventricular size). About half the cases of AVSD occur in children with Down syndrome. | Overview of Atrioventricular Septal Defect. Atrioventricular septal defect (AVSD) is a general term for a group of rare heart defects that are present at birth (congenital). Infants with AVSDs have improperly developed atrial and ventricular septa and adjoining valves.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition called the atrial septum. The two lower chambers, known as ventricles, are separated from each other by the ventricular septum. Valves (e.g., mitral and tricuspid) connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.The parts of the heart described above are formed from an embryonic structure called the endocardial cushions. In individuals with AVSD there is some combination of malformation of these parts of the heart. They may include a hole in the atrial septum, a hole in the ventricular septum, and/or abnormalities of the mitral and triscupid valves. AVSD may be classified as one of three forms: an incomplete (or partial) AVSD (atrial septal defect primum); a transitional form (atrial septal defect and small ventricular septal defect); or a more severe or complete form (large atrial and ventricular defects).The symptoms of AVSD vary greatly and depend on the severity of the malformations (e.g., valve leakage between ventricles and ventricular size). About half the cases of AVSD occur in children with Down syndrome. | 120 | Atrioventricular Septal Defect |
nord_120_1 | Symptoms of Atrioventricular Septal Defect | Infants with the complete form of atrioventricular septal defect usually develop a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid buildup in the heart, lung and various body tissues (congestive heart failure). Pulmonary congestion may lead to difficulty breathing (dyspnea) and fatigue. Infants with complete atrioventricular septal defect often have a bluish discoloration of the skin and mucous membranes (cyanosis) due to insufficient oxygen supply to these tissues.Other symptoms that may occur in all forms of AVSD include poor feeding, abnormally rapid breathing (tachypnea), excessive sweating, and/or an abnormally rapid heartbeat (tachycardia).Frequent episodes of acute inflammation of the lungs (pneumonia) and bronchial tubes (bronchitis) are common in children with all forms of AVSD. Abnormally high pressure within the artery that leads to the heart from the lungs (pulmonary artery) may impair lung function and result in permanent pulmonary vascular disease before the age of 1 year. Some more severely affected infants may have congestive heart failure as a direct result of these serious complications.Older children with untreated AVSD may be at risk for brain abscesses, the development of blood clots (thrombosis) that may travel and lodge in the arteries (embolism), and/or acute inflammation of the inner membranes that line the heart (bacterial endocarditis).Adults with AVSD who have not had surgery to correct this heart defect may develop Eisenmenger syndrome. This is a rare disorder characterized by restricted blood flow between the lungs and the heart that occurs because of a ventricular septal defect. Symptoms of this condition may include abnormally low blood pressure, irregular heartbeats, and/or rapid heart rate. (For more information on this disorder, choose “Eisenmenger” as your search term in the Rare Disease Database.) | Symptoms of Atrioventricular Septal Defect. Infants with the complete form of atrioventricular septal defect usually develop a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid buildup in the heart, lung and various body tissues (congestive heart failure). Pulmonary congestion may lead to difficulty breathing (dyspnea) and fatigue. Infants with complete atrioventricular septal defect often have a bluish discoloration of the skin and mucous membranes (cyanosis) due to insufficient oxygen supply to these tissues.Other symptoms that may occur in all forms of AVSD include poor feeding, abnormally rapid breathing (tachypnea), excessive sweating, and/or an abnormally rapid heartbeat (tachycardia).Frequent episodes of acute inflammation of the lungs (pneumonia) and bronchial tubes (bronchitis) are common in children with all forms of AVSD. Abnormally high pressure within the artery that leads to the heart from the lungs (pulmonary artery) may impair lung function and result in permanent pulmonary vascular disease before the age of 1 year. Some more severely affected infants may have congestive heart failure as a direct result of these serious complications.Older children with untreated AVSD may be at risk for brain abscesses, the development of blood clots (thrombosis) that may travel and lodge in the arteries (embolism), and/or acute inflammation of the inner membranes that line the heart (bacterial endocarditis).Adults with AVSD who have not had surgery to correct this heart defect may develop Eisenmenger syndrome. This is a rare disorder characterized by restricted blood flow between the lungs and the heart that occurs because of a ventricular septal defect. Symptoms of this condition may include abnormally low blood pressure, irregular heartbeats, and/or rapid heart rate. (For more information on this disorder, choose “Eisenmenger” as your search term in the Rare Disease Database.) | 120 | Atrioventricular Septal Defect |
nord_120_2 | Causes of Atrioventricular Septal Defect | The exact cause of atrioventricular septal defect is not known (idiopathic). This birth defect can occur alone with no apparent cause (sporadically), or it can occur in association with other disorders such as Down syndrome. Researchers believe that, in cases of isolated AVSD, environmental, genetic, and/or other factors (multifactorial) may be involved in some way. | Causes of Atrioventricular Septal Defect. The exact cause of atrioventricular septal defect is not known (idiopathic). This birth defect can occur alone with no apparent cause (sporadically), or it can occur in association with other disorders such as Down syndrome. Researchers believe that, in cases of isolated AVSD, environmental, genetic, and/or other factors (multifactorial) may be involved in some way. | 120 | Atrioventricular Septal Defect |
nord_120_3 | Affects of Atrioventricular Septal Defect | Atrioventricular septal defect affects males and females in equal numbers. Approximately 50 percent of cases occur in association with other disorders, especially Down syndrome. AVSD may also occur with other congenital heart defects, in 10 percent of cases it occurs in association with patent ductus arteriosus or tetralogy of Fallot. (For more information on these disorders, choose the exact disorder name as your search term in the Rare Disease Database.)The exact incidence of AVSD in the general population is unknown. The complete form of AVSD occurs more often than the partial or transitional forms. Approximately 75 percent of cases of complete AVSD occur in individuals with Down syndrome. Most cases of partial AVSD do not occur in individuals with Down syndrome. | Affects of Atrioventricular Septal Defect. Atrioventricular septal defect affects males and females in equal numbers. Approximately 50 percent of cases occur in association with other disorders, especially Down syndrome. AVSD may also occur with other congenital heart defects, in 10 percent of cases it occurs in association with patent ductus arteriosus or tetralogy of Fallot. (For more information on these disorders, choose the exact disorder name as your search term in the Rare Disease Database.)The exact incidence of AVSD in the general population is unknown. The complete form of AVSD occurs more often than the partial or transitional forms. Approximately 75 percent of cases of complete AVSD occur in individuals with Down syndrome. Most cases of partial AVSD do not occur in individuals with Down syndrome. | 120 | Atrioventricular Septal Defect |
nord_120_4 | Related disorders of Atrioventricular Septal Defect | Symptoms of the following disorders can be similar to those of atrioventricular septal defect. Comparisons may be useful for a differential diagnosis:Atrial septal defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. This defect leads to an increase in the workload on the right heart, and excessive blood flow to the lungs. The symptoms, which may become apparent during infancy, childhood, or adulthood, can vary greatly and depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis). Some people with atrial septal defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism) blocking blood circulation. (For more information on this disorder, choose “atrial septal defect” as your search term in the Rare Disease Database.)Ventricular septal defects (Cor Triloculare Biventricularis) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with this defect have 2 atria and 1 large ventricle. Symptoms of these defects are similar to atrioventricular septal defect and may include an abnormal rapid rate of breathing (tachypnea), wheezing, a rapid heartbeat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). Ventricular septal defects can also cause the excessive accumulation of fluid around the heart leading to congestive heart failure. (For more information on this disorder, choose “ventricular septal defect” as your search term in the Rare Disease Database.)Cor Triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of Cor Triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor Triloculare Biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of Atrioventricular Septal Defect and include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness. | Related disorders of Atrioventricular Septal Defect. Symptoms of the following disorders can be similar to those of atrioventricular septal defect. Comparisons may be useful for a differential diagnosis:Atrial septal defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart. This defect leads to an increase in the workload on the right heart, and excessive blood flow to the lungs. The symptoms, which may become apparent during infancy, childhood, or adulthood, can vary greatly and depend on the severity of the defect. The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis). Some people with atrial septal defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism) blocking blood circulation. (For more information on this disorder, choose “atrial septal defect” as your search term in the Rare Disease Database.)Ventricular septal defects (Cor Triloculare Biventricularis) are a group of common congenital heart defects characterized by the absence of one ventricle. Infants with this defect have 2 atria and 1 large ventricle. Symptoms of these defects are similar to atrioventricular septal defect and may include an abnormal rapid rate of breathing (tachypnea), wheezing, a rapid heartbeat (tachycardia), and/or an abnormally enlarged liver (hepatomegaly). Ventricular septal defects can also cause the excessive accumulation of fluid around the heart leading to congestive heart failure. (For more information on this disorder, choose “ventricular septal defect” as your search term in the Rare Disease Database.)Cor Triatriatum is an extremely rare congenital heart defect characterized by the presence of an extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra “third atrium.” The symptoms of Cor Triatriatum vary greatly and depend on the size of the opening between the chambers. Symptoms may include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion). (For more information on this disorder, choose “Cor Triatriatum” as your search term in the Rare Disease Database.)Cor Triloculare Biatriatum is an extremely rare congenital heart defect characterized by the absence of one ventricle. Infants with this defect have two atria and one large ventricle. The symptoms are similar to those of Atrioventricular Septal Defect and include breathing difficulties (dyspnea), excessive accumulation of fluid in the lungs and around the heart (pulmonary edema), and/or a bluish discoloration of the skin and mucous membranes (cyanosis). Other symptoms may include poor feeding habits, abnormally rapid breathing (tachypnea), and/or an abnormally rapid heartbeat (tachycardia).Mitral valve stenosis is a rare heart defect that may be present at birth (congenital) or acquired. In the congenital form, the symptoms vary greatly and may include coughing, difficulty breathing, heart palpitations, and/or frequent respiratory infections. In acquired mitral valve stenosis, the symptoms may also include weakness, abdominal discomfort, chest pain (angina), and/or periodic loss of consciousness. | 120 | Atrioventricular Septal Defect |
nord_120_5 | Diagnosis of Atrioventricular Septal Defect | The diagnosis of atrioventricular septal defect can be made by imaging techniques of the heart such as magnetic resonance imaging (MRI) and echocardiogram (EC). In another procedure known as a cardiac catheterization, a long fine tube (catheter) is inserted into a large vein and then channeled directly into the heart. This allows the physician to determine the extent of the defect (i.e., complete, transitional, or incomplete) and to determine the rate of blood flow through the heart. Angiography is another useful diagnostic procedure and allows the physician to view an enhanced x-ray of the heart. Children with AVSD typically have an abnormal EKG reading. | Diagnosis of Atrioventricular Septal Defect. The diagnosis of atrioventricular septal defect can be made by imaging techniques of the heart such as magnetic resonance imaging (MRI) and echocardiogram (EC). In another procedure known as a cardiac catheterization, a long fine tube (catheter) is inserted into a large vein and then channeled directly into the heart. This allows the physician to determine the extent of the defect (i.e., complete, transitional, or incomplete) and to determine the rate of blood flow through the heart. Angiography is another useful diagnostic procedure and allows the physician to view an enhanced x-ray of the heart. Children with AVSD typically have an abnormal EKG reading. | 120 | Atrioventricular Septal Defect |
nord_120_6 | Therapies of Atrioventricular Septal Defect | TreatmentInfants with AVSD should be referred to a hospital that can perform sophisticated diagnostic procedures and cardiovascular surgery. Infants with AVSD generally require surgery at a young age, usually before the age of 6 to 12 months.Prior to surgery, congestive heart failure associated with AVSD may be managed by reducing fluid volume with diuretic drugs and, if necessary, the dietary restriction of fluids and salt. The drug digoxin may also be administered to decrease the heart rate and increase the strength of the heart's contractions. Oxygen therapy and adequate nutrition may also prove beneficial.Because children with AVSD are susceptible to bacterial infection of the membranes that surround the heart (endocarditis), any respiratory infection should be treated vigorously and early. Affected individuals should also be given antibiotics before invasive dental procedures (e.g., root canal or extractions) or other surgical procedures to help prevent potentially life-threatening infections. | Therapies of Atrioventricular Septal Defect. TreatmentInfants with AVSD should be referred to a hospital that can perform sophisticated diagnostic procedures and cardiovascular surgery. Infants with AVSD generally require surgery at a young age, usually before the age of 6 to 12 months.Prior to surgery, congestive heart failure associated with AVSD may be managed by reducing fluid volume with diuretic drugs and, if necessary, the dietary restriction of fluids and salt. The drug digoxin may also be administered to decrease the heart rate and increase the strength of the heart's contractions. Oxygen therapy and adequate nutrition may also prove beneficial.Because children with AVSD are susceptible to bacterial infection of the membranes that surround the heart (endocarditis), any respiratory infection should be treated vigorously and early. Affected individuals should also be given antibiotics before invasive dental procedures (e.g., root canal or extractions) or other surgical procedures to help prevent potentially life-threatening infections. | 120 | Atrioventricular Septal Defect |
nord_121_0 | Overview of Atypical Hemolytic Uremic Syndrome | SummaryAtypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterized by low levels of circulating red blood cells due to their destruction (hemolytic anemia), low platelet count (thrombocytopenia) due to their consumption and inability of the kidneys to process waste products from the blood and excrete them into the urine (acute kidney failure), a condition known as uremia. It is a distinctly different illness from the more common disorder known as typical hemolytic uremic syndrome, which is caused by E.coli-producing Shiga toxins (Stx HUS) and is generally foodborne. Most cases of aHUS are genetic, although some may be acquired due to autoantibodies or occur for unknown reasons (idiopathic). aHUS may become chronic, and affected individuals may experience repeated episodes of the disorder. Unlike individuals with typical HUS, who usually recover from the life-threatening initial episode and usually respond well to supportive treatment, individuals with aHUS are much more likely to develop chronic serious complications such as severe high blood pressure (hypertension) and kidney (renal) failure. The signs and symptoms of aHUS result from the formation of tiny blood clots (microthrombi) in various small blood vessels of the body. These clots reduce or prevent proper blood flow to various organs of the body, especially the kidneys. aHUS is a complex disorder and multiple factors, including certain genetic, environmental and immunologic factors, all play a role in its development.
Introduction
The nomenclature and terminology surrounding this disorder can be confusing. aHUS is considered a form of thrombotic microangiopathy (TMA). TMA is broken down into two main forms – thrombotic thrombocytopenia purpura and hemolytic uremic syndrome. Generally, hemolytic uremic syndrome is also broken down into two main forms – aHUS and Stx HUS. More than 90% of individuals with hemolytic uremic syndrome have Stx HUS. aHUS is extremely rare and for many years was used to describe any form that was not Stx HUS. aHUS is now used specifically for instances of the disorder associated with excess activation or dysregulation of the alternate pathway of complement, which is part of the innate immune system. This excludes instances of secondary HUS, in which hemolytic uremic syndrome occurs as a secondary finding of a different disorder or condition. Causes of secondary HUS include malignancy, HIV infection, solid organ transplants, hematopoietic stem cell transplants, autoimmune disorders and the use of certain drugs or medications. | Overview of Atypical Hemolytic Uremic Syndrome. SummaryAtypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterized by low levels of circulating red blood cells due to their destruction (hemolytic anemia), low platelet count (thrombocytopenia) due to their consumption and inability of the kidneys to process waste products from the blood and excrete them into the urine (acute kidney failure), a condition known as uremia. It is a distinctly different illness from the more common disorder known as typical hemolytic uremic syndrome, which is caused by E.coli-producing Shiga toxins (Stx HUS) and is generally foodborne. Most cases of aHUS are genetic, although some may be acquired due to autoantibodies or occur for unknown reasons (idiopathic). aHUS may become chronic, and affected individuals may experience repeated episodes of the disorder. Unlike individuals with typical HUS, who usually recover from the life-threatening initial episode and usually respond well to supportive treatment, individuals with aHUS are much more likely to develop chronic serious complications such as severe high blood pressure (hypertension) and kidney (renal) failure. The signs and symptoms of aHUS result from the formation of tiny blood clots (microthrombi) in various small blood vessels of the body. These clots reduce or prevent proper blood flow to various organs of the body, especially the kidneys. aHUS is a complex disorder and multiple factors, including certain genetic, environmental and immunologic factors, all play a role in its development.
Introduction
The nomenclature and terminology surrounding this disorder can be confusing. aHUS is considered a form of thrombotic microangiopathy (TMA). TMA is broken down into two main forms – thrombotic thrombocytopenia purpura and hemolytic uremic syndrome. Generally, hemolytic uremic syndrome is also broken down into two main forms – aHUS and Stx HUS. More than 90% of individuals with hemolytic uremic syndrome have Stx HUS. aHUS is extremely rare and for many years was used to describe any form that was not Stx HUS. aHUS is now used specifically for instances of the disorder associated with excess activation or dysregulation of the alternate pathway of complement, which is part of the innate immune system. This excludes instances of secondary HUS, in which hemolytic uremic syndrome occurs as a secondary finding of a different disorder or condition. Causes of secondary HUS include malignancy, HIV infection, solid organ transplants, hematopoietic stem cell transplants, autoimmune disorders and the use of certain drugs or medications. | 121 | Atypical Hemolytic Uremic Syndrome |
nord_121_1 | Symptoms of Atypical Hemolytic Uremic Syndrome | The onset of atypical hemolytic uremic syndrome ranges from before birth (prenatally) to adulthood. In young children, the disorder often develops suddenly and usually follows an infection, particularly an upper respiratory infection or gastroenteritis. When it follows an episode of gastroenteritis it can more easily be confused with Stx HUS which almost always is preceded by diarrhea. The disease has different causes and can be unpredictable in how it will progress in one individual as opposed to another.Many affected individuals present with vague feelings of illness, fatigue, irritability, and lethargy that can potentially lead to hospitalization. The early phases may be difficult to diagnose, and the condition tends to be progressive. Because complications and relapse are common, it is critical that aHUS be recognized at this stage.The three main findings of aHUS are hemolytic anemia, thrombocytopenia, and acute kidney failure. Although most affected individuals develop these three conditions, some individuals will not. Hemolytic anemia is a condition in which there is a premature destruction (hemolysis) of red blood cells. Thrombocytopenia is a condition in which there are low levels of platelets, a blood cell that is involved in clotting.Kidney disease can be mild or severe. Kidney damage tends to worsen with each subsequent episode. Blood and protein in the urine (hematuria and proteinuria), frequent indicators of kidney disease, are common, especially during acute episodes. Kidney disease is progressive and can potentially progress to cause end stage renal failure, necessitating chronic dialysis or a kidney transplant.High blood pressure (hypertension) is common and can result from kidney disease or because of lack of blood flow (ischemia) due to the formation small blood clots (microthrombi). Hypertension can be severe and may be associated with headaches and seizures.Because small blood clots can potentially form in blood vessels serving other organs of the body, organ damage and failure can occur elsewhere besides the kidneys (which is the organ that is most commonly affected). The brain, gastrointestinal tract, liver, lungs, and heart can also be affected. Specific symptoms can vary based upon the specific organ system involved. Cardiovascular complications can include disease of the heart muscle (cardiomyopathy) or heart attack (myocardial infarction). Neurological complications can include headaches, double vision (diplopia), irritability, drowsiness, facial paralysis, seizures, transient ischemic attacks, stroke, and coma. Gastrointestinal bleeding may also occur. The lungs can be affected and bleeding or fluid accumulation in the lungs (pulmonary edema) can occur. | Symptoms of Atypical Hemolytic Uremic Syndrome. The onset of atypical hemolytic uremic syndrome ranges from before birth (prenatally) to adulthood. In young children, the disorder often develops suddenly and usually follows an infection, particularly an upper respiratory infection or gastroenteritis. When it follows an episode of gastroenteritis it can more easily be confused with Stx HUS which almost always is preceded by diarrhea. The disease has different causes and can be unpredictable in how it will progress in one individual as opposed to another.Many affected individuals present with vague feelings of illness, fatigue, irritability, and lethargy that can potentially lead to hospitalization. The early phases may be difficult to diagnose, and the condition tends to be progressive. Because complications and relapse are common, it is critical that aHUS be recognized at this stage.The three main findings of aHUS are hemolytic anemia, thrombocytopenia, and acute kidney failure. Although most affected individuals develop these three conditions, some individuals will not. Hemolytic anemia is a condition in which there is a premature destruction (hemolysis) of red blood cells. Thrombocytopenia is a condition in which there are low levels of platelets, a blood cell that is involved in clotting.Kidney disease can be mild or severe. Kidney damage tends to worsen with each subsequent episode. Blood and protein in the urine (hematuria and proteinuria), frequent indicators of kidney disease, are common, especially during acute episodes. Kidney disease is progressive and can potentially progress to cause end stage renal failure, necessitating chronic dialysis or a kidney transplant.High blood pressure (hypertension) is common and can result from kidney disease or because of lack of blood flow (ischemia) due to the formation small blood clots (microthrombi). Hypertension can be severe and may be associated with headaches and seizures.Because small blood clots can potentially form in blood vessels serving other organs of the body, organ damage and failure can occur elsewhere besides the kidneys (which is the organ that is most commonly affected). The brain, gastrointestinal tract, liver, lungs, and heart can also be affected. Specific symptoms can vary based upon the specific organ system involved. Cardiovascular complications can include disease of the heart muscle (cardiomyopathy) or heart attack (myocardial infarction). Neurological complications can include headaches, double vision (diplopia), irritability, drowsiness, facial paralysis, seizures, transient ischemic attacks, stroke, and coma. Gastrointestinal bleeding may also occur. The lungs can be affected and bleeding or fluid accumulation in the lungs (pulmonary edema) can occur. | 121 | Atypical Hemolytic Uremic Syndrome |
nord_121_2 | Causes of Atypical Hemolytic Uremic Syndrome | Most cases of aHUS are associated with mutations amongst the multiple genes that produce (encode) proteins involved in the alternate pathway of complement, which is part of the complement system of the innate immune system. The complement system is a complex group of proteins that work together to fight infection in the body. Complement proteins respond to bacteria, viruses or other foreign substances in the body and ultimately produce a large multi-protein complex that directly attacks these foreign invaders. Other complement proteins regulate the formation of this attack complex in order to protect the body’s own cells from being damaged. Most individuals with aHUS have a mutation in one or more of the genes that encode these regulatory proteins.A mutation in one of these genes is not enough to cause aHUS on its own. These genes most likely convey a genetic predisposition to developing aHUS rather than causing the disorder outright. A genetic predisposition means that a person carries a gene (or genes) for a disorder, but it may not be expressed unless it is triggered or “activated” under certain circumstances such as because of particular environmental factors or because of an another illness.In most individuals, there is a triggering occurrence or event such as an acute infection. Other triggers have included chicken pox (varicella) or H1N1 influenza. In women, pregnancy is a common trigger. In addition to an environmental trigger, affected individuals may require a mutation in a second complement gene or a second genetic variant such as single nucleotide polymorphisms (SNP) for the development the disorder. SNPs are the most common genetic variation in humans and occur frequently in a person’s DNA. Most SNPs have no effect on a person’s health.At least six different genes have been identified to be associated with aHUS. About 30% of the time, aHUS is associated with malfunctions in the gene (CFH) responsible for the production of a blood protein known as factor H. This is the most common gene mutation associated with aHUS. Factor H is one of the regulatory proteins of the complement system that protect blood vessels from injury. When factor H is deficient or inactive, there is the potential for damage to the small vessels in the kidneys with secondary injury to red blood cells and platelets.Other cases are associated with loss-of-function mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (MCP) and factor I, or with gain-of-function mutations in genes encoding the key complement proteins complement factor B and C3. Finally, mutations in the gene encoding thrombomodulin (THBD), an endothelial anticoagulant glycoprotein with complement regulatory properties, have been found in 3-5% of individuals with aHUS.A seventh gene known as DGKE has been identified as being associated with aHUS. Some researchers believe DGKE-associated aHUS is a similar, but distinct disorder. The protein produced by the DGKE gene is not associated with the alternate pathway of complement and instead appears to be involved in the coagulation process.The specific genetic mutation present may be more likely to be associated with specific symptoms or severity of the disorder. This is known as genotype-phenotype correlation. The response to treatment can also be influenced by the specific underlying genetic mutation. For example, MCP mutations have a lower risk of permanent kidney failure and a low risk of disease recurrence following a kidney transplant. Individuals with mutations in the CFH or THBD genes are more likely to present during childhood.Some individuals develop aHUS because of autoantibodies that target proteins encoded by complement genes. Antibodies are specialized proteins that react against foreign materials in the body, bringing about their destruction. When antibodies react against healthy tissue, they are known as autoantibodies. Anti-factor H autoantibodies have been reported in 6-10% of cases, mainly children. Less often, autoantibodies that target other complement proteins have been identified. The reason why these autoantibodies develop is unknown.In approximately 30%-50% of individuals with aHUS, no mutation in a complement gene and no autoantibodies can be detected. These individuals may be referred to as having idiopathic aHUS. However, many researchers believe these individuals most likely have yet unidentified mutations in complement genes.The genetic mutations in complement genes that predispose individuals to aHUS usually occur sporadically, meaning that there is no previous family history of the disorder. The disorder has run in families only about 20% of the time. In such instances, these mutations are transmitted (inherited) as an autosomal dominant trait or, less often, as an autosomal recessive trait. The dominant form affects adults more often than children.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.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. | Causes of Atypical Hemolytic Uremic Syndrome. Most cases of aHUS are associated with mutations amongst the multiple genes that produce (encode) proteins involved in the alternate pathway of complement, which is part of the complement system of the innate immune system. The complement system is a complex group of proteins that work together to fight infection in the body. Complement proteins respond to bacteria, viruses or other foreign substances in the body and ultimately produce a large multi-protein complex that directly attacks these foreign invaders. Other complement proteins regulate the formation of this attack complex in order to protect the body’s own cells from being damaged. Most individuals with aHUS have a mutation in one or more of the genes that encode these regulatory proteins.A mutation in one of these genes is not enough to cause aHUS on its own. These genes most likely convey a genetic predisposition to developing aHUS rather than causing the disorder outright. A genetic predisposition means that a person carries a gene (or genes) for a disorder, but it may not be expressed unless it is triggered or “activated” under certain circumstances such as because of particular environmental factors or because of an another illness.In most individuals, there is a triggering occurrence or event such as an acute infection. Other triggers have included chicken pox (varicella) or H1N1 influenza. In women, pregnancy is a common trigger. In addition to an environmental trigger, affected individuals may require a mutation in a second complement gene or a second genetic variant such as single nucleotide polymorphisms (SNP) for the development the disorder. SNPs are the most common genetic variation in humans and occur frequently in a person’s DNA. Most SNPs have no effect on a person’s health.At least six different genes have been identified to be associated with aHUS. About 30% of the time, aHUS is associated with malfunctions in the gene (CFH) responsible for the production of a blood protein known as factor H. This is the most common gene mutation associated with aHUS. Factor H is one of the regulatory proteins of the complement system that protect blood vessels from injury. When factor H is deficient or inactive, there is the potential for damage to the small vessels in the kidneys with secondary injury to red blood cells and platelets.Other cases are associated with loss-of-function mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (MCP) and factor I, or with gain-of-function mutations in genes encoding the key complement proteins complement factor B and C3. Finally, mutations in the gene encoding thrombomodulin (THBD), an endothelial anticoagulant glycoprotein with complement regulatory properties, have been found in 3-5% of individuals with aHUS.A seventh gene known as DGKE has been identified as being associated with aHUS. Some researchers believe DGKE-associated aHUS is a similar, but distinct disorder. The protein produced by the DGKE gene is not associated with the alternate pathway of complement and instead appears to be involved in the coagulation process.The specific genetic mutation present may be more likely to be associated with specific symptoms or severity of the disorder. This is known as genotype-phenotype correlation. The response to treatment can also be influenced by the specific underlying genetic mutation. For example, MCP mutations have a lower risk of permanent kidney failure and a low risk of disease recurrence following a kidney transplant. Individuals with mutations in the CFH or THBD genes are more likely to present during childhood.Some individuals develop aHUS because of autoantibodies that target proteins encoded by complement genes. Antibodies are specialized proteins that react against foreign materials in the body, bringing about their destruction. When antibodies react against healthy tissue, they are known as autoantibodies. Anti-factor H autoantibodies have been reported in 6-10% of cases, mainly children. Less often, autoantibodies that target other complement proteins have been identified. The reason why these autoantibodies develop is unknown.In approximately 30%-50% of individuals with aHUS, no mutation in a complement gene and no autoantibodies can be detected. These individuals may be referred to as having idiopathic aHUS. However, many researchers believe these individuals most likely have yet unidentified mutations in complement genes.The genetic mutations in complement genes that predispose individuals to aHUS usually occur sporadically, meaning that there is no previous family history of the disorder. The disorder has run in families only about 20% of the time. In such instances, these mutations are transmitted (inherited) as an autosomal dominant trait or, less often, as an autosomal recessive trait. The dominant form affects adults more often than children.Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.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. | 121 | Atypical Hemolytic Uremic Syndrome |
nord_121_3 | Affects of Atypical Hemolytic Uremic Syndrome | In childhood, aHUS affects males and females in equal numbers. In adulthood, females are affected more often than males, most likely because pregnancy is a triggering event. The exact overall incidence and prevalence is unknown. One study placed the incidence in the United States at 2 individuals per 1 million in the general population. In Europe, the disorder is estimated to affect approximately .11 per 1 million individuals between the ages of 0-18. aHUS accounts for approximately 5-10% of all cases of hemolytic uremic syndrome. | Affects of Atypical Hemolytic Uremic Syndrome. In childhood, aHUS affects males and females in equal numbers. In adulthood, females are affected more often than males, most likely because pregnancy is a triggering event. The exact overall incidence and prevalence is unknown. One study placed the incidence in the United States at 2 individuals per 1 million in the general population. In Europe, the disorder is estimated to affect approximately .11 per 1 million individuals between the ages of 0-18. aHUS accounts for approximately 5-10% of all cases of hemolytic uremic syndrome. | 121 | Atypical Hemolytic Uremic Syndrome |
nord_121_4 | Related disorders of Atypical Hemolytic Uremic Syndrome | Symptoms of the following disorders can be similar to those of aHUS. Comparisons may be useful for a differential diagnosis.Shiga toxin-associated hemolytic-uremic syndrome (Stx HUS) is an uncommon disorder that primarily affects young children between the ages of one and 10 years, with a peak incidence around three years of age. Onset of the disorder is usually preceded by a gastroenteritis characterized by vomiting, abdominal pain, fever, and diarrhea that becomes bloody. Symptoms usually become apparent three to 10 days after the development of gastroenteritis, and include sudden paleness (pallor), irritability, weakness, lack of energy (lethargy), and/or excretion of diminished amounts of urine (oliguria). The disease typically progresses to include inability of the kidneys to process waste products from the blood and excrete them into the urine (acute kidney failure), a decrease in circulating red blood cells (microangiopathic hemolytic anemia), a decrease in circulating blood platelets (thrombocytopenia); and the abnormal accumulation of platelets within certain blood vessels (microthrombi), reducing the blood flow to several organs (kidneys, pancreas, brain). This potentially leads to multiple organ dysfunction or failure. In some instances, neurological problems may be present at the onset of Stx HUS or may occur at any time during the illness. Neurological symptoms are uncommon and may include dizziness, seizures (partial or generalized), disorientation or confusion, and/or loss of consciousness (coma). The cause of Stx HUS most frequently is infection by a particular strain (0157:H7) of Escherichia coli (E. coli) bacterium. Occasionally, adults may be affected by Stx HUS. (For more information on this disorder, choose “Typical Hemolytic Uremic Syndrome” as your search term in the Rare Disease Database.)Thrombotic thrombocytopenia purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). TTP occurs most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. Some individuals with TTP may have acute kidney injury, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); and an abnormal accumulation of fluid between layers of tissue under the skin (edema). In some instances, acute kidney failure may lead to life-threatening complications. TTP is caused by a failure to break up the large proteins in the blood that form the scaffolding for the formation of blood clots. This failure is due to the absence or functional inactivation of the enzyme responsible for the break-down of this structure. (For more information on this disorder, choose “Thrombotic Thrombocytopenia Purpura” as your search term in the Rare Disease Database.)Streptococcal pneumoniae associated HUS [SpHUS] is the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in the setting of a Streptococcal pneumoniae (S. pneumoniae) infection. SpHUS accounts for 5-15% of all cases of HUS. The majority of cases have pneumonia with a low mortality rate in contrast to those with meningitis who have a more severe clinical course with a mortality rate of 2-12%. SpHUS is often not diagnosed because of overlapping features with disseminated intravascular coagulation (DIC), which can result from any serious bacterial infection, and the lack of strict diagnostic criteria. The epidemiology of SpHUS has changed with the emergence of different pneumococcal serotypes as newer vaccines are introduced. | Related disorders of Atypical Hemolytic Uremic Syndrome. Symptoms of the following disorders can be similar to those of aHUS. Comparisons may be useful for a differential diagnosis.Shiga toxin-associated hemolytic-uremic syndrome (Stx HUS) is an uncommon disorder that primarily affects young children between the ages of one and 10 years, with a peak incidence around three years of age. Onset of the disorder is usually preceded by a gastroenteritis characterized by vomiting, abdominal pain, fever, and diarrhea that becomes bloody. Symptoms usually become apparent three to 10 days after the development of gastroenteritis, and include sudden paleness (pallor), irritability, weakness, lack of energy (lethargy), and/or excretion of diminished amounts of urine (oliguria). The disease typically progresses to include inability of the kidneys to process waste products from the blood and excrete them into the urine (acute kidney failure), a decrease in circulating red blood cells (microangiopathic hemolytic anemia), a decrease in circulating blood platelets (thrombocytopenia); and the abnormal accumulation of platelets within certain blood vessels (microthrombi), reducing the blood flow to several organs (kidneys, pancreas, brain). This potentially leads to multiple organ dysfunction or failure. In some instances, neurological problems may be present at the onset of Stx HUS or may occur at any time during the illness. Neurological symptoms are uncommon and may include dizziness, seizures (partial or generalized), disorientation or confusion, and/or loss of consciousness (coma). The cause of Stx HUS most frequently is infection by a particular strain (0157:H7) of Escherichia coli (E. coli) bacterium. Occasionally, adults may be affected by Stx HUS. (For more information on this disorder, choose “Typical Hemolytic Uremic Syndrome” as your search term in the Rare Disease Database.)Thrombotic thrombocytopenia purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). TTP occurs most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. Some individuals with TTP may have acute kidney injury, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); and an abnormal accumulation of fluid between layers of tissue under the skin (edema). In some instances, acute kidney failure may lead to life-threatening complications. TTP is caused by a failure to break up the large proteins in the blood that form the scaffolding for the formation of blood clots. This failure is due to the absence or functional inactivation of the enzyme responsible for the break-down of this structure. (For more information on this disorder, choose “Thrombotic Thrombocytopenia Purpura” as your search term in the Rare Disease Database.)Streptococcal pneumoniae associated HUS [SpHUS] is the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in the setting of a Streptococcal pneumoniae (S. pneumoniae) infection. SpHUS accounts for 5-15% of all cases of HUS. The majority of cases have pneumonia with a low mortality rate in contrast to those with meningitis who have a more severe clinical course with a mortality rate of 2-12%. SpHUS is often not diagnosed because of overlapping features with disseminated intravascular coagulation (DIC), which can result from any serious bacterial infection, and the lack of strict diagnostic criteria. The epidemiology of SpHUS has changed with the emergence of different pneumococcal serotypes as newer vaccines are introduced. | 121 | Atypical Hemolytic Uremic Syndrome |
nord_121_5 | Diagnosis of Atypical Hemolytic Uremic Syndrome | Diagnosing aHUS is complicated by the fact that it is more difficult to establish without a family history of the disorder. The diagnostic criteria associated with aHUS are hemolytic anemia (anemia in the presence of broken red blood cells), low platelet count (thrombocytopenia) and kidney dysfunction. aHUS is considered genetic when two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded, or when a disease-causing mutation(s) is identified in one of the genes known to be associated with aHUS, irrespective of familial history.Individuals with aHUS do not present with the aggressive and bloody diarrhea that characterize the onset of Stx HUS, although 30-50% of children with aHUS may have diarrhea. The absence of bloody diarrhea, negative stool cultures for Shiga toxin producing-E. coli (most frequently E. coli 0157:H7) associated with HUS, a progressive course, and prior manifestations of nephrotic syndrome, such as swelling from the accumulation of fluid (edema), presence of blood in the urine (hematuria), excessive protein in the urine (proteinuria), and reduced albumin in the serum (hypoalbuminemia), with marked elevation in blood pressure are features that alert pediatricians and kidney specialists (nephrologists) to the possible diagnosis of aHUS. | Diagnosis of Atypical Hemolytic Uremic Syndrome. Diagnosing aHUS is complicated by the fact that it is more difficult to establish without a family history of the disorder. The diagnostic criteria associated with aHUS are hemolytic anemia (anemia in the presence of broken red blood cells), low platelet count (thrombocytopenia) and kidney dysfunction. aHUS is considered genetic when two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded, or when a disease-causing mutation(s) is identified in one of the genes known to be associated with aHUS, irrespective of familial history.Individuals with aHUS do not present with the aggressive and bloody diarrhea that characterize the onset of Stx HUS, although 30-50% of children with aHUS may have diarrhea. The absence of bloody diarrhea, negative stool cultures for Shiga toxin producing-E. coli (most frequently E. coli 0157:H7) associated with HUS, a progressive course, and prior manifestations of nephrotic syndrome, such as swelling from the accumulation of fluid (edema), presence of blood in the urine (hematuria), excessive protein in the urine (proteinuria), and reduced albumin in the serum (hypoalbuminemia), with marked elevation in blood pressure are features that alert pediatricians and kidney specialists (nephrologists) to the possible diagnosis of aHUS. | 121 | Atypical Hemolytic Uremic Syndrome |
nord_121_6 | Therapies of Atypical Hemolytic Uremic Syndrome | TreatmentTreatment by a medical team familiar with the unique challenges of aHUS is recommended and can include pediatricians or general internists, kidney specialists (nephrologists), intensive care physicians, nurses, nutritionists and social workers.Initially, affected individuals may receive supportive care including maintaining proper nutrition and electrolyte and fluid balance through intravenous feeding (parenteral) when and if necessary. Blood transfusions are administered when the hemoglobin level is below 7 g/dl. Platelet transfusions are avoided if at all possible. Drugs that expand the blood vessels (vasodilators) are used to control blood pressure (hypertension). In some instances, individuals are diagnosed with aHUS when they already have kidney damage and may initially require supportive measures such as peritoneal dialysis or hemodialysis.In 2011, the U.S Food and Drug Administration (FDA) approved the use of the humanized anti-C5 monoclonal antibody eculizumab as a treatment for acute hemolytic uremic syndrome. This drug is used to block excessive complement activation in individuals with aHUS. Eculizumab has led to improvement with the blood abnormalities (reduced hemolysis and stabilized platelet counts) and reversed acute kidney injury. Eculizumab is now recommended as first-line therapy in both children and adults with a confirmed or strongly suspected diagnosis of aHUS.In 2019, the FDA approved Ultomiris (ravulizumab-cwvz), a long-acting C5 complement inhibitor, for the treatment of adults and pediatric patients one month of age and older with aHUS to inhibit TMA.For years, plasma therapy was the standard treatment for individuals with aHUS. Both infusions of fresh frozen plasma (plasma infusion) as well as plasma exchange (plasmapheresis) were utilized. Fresh frozen plasma is a blood derivative that is obtained from donors. Plasma exchange is a method for removing potentially harmful substances (e.g. toxins, metabolic substances, and plasma parts) from the blood. Blood is removed from the affected individual and blood cells are separated from the plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individuals. Plasma exchange can also remove mutant factors and autoantibodies.Plasma therapy has led to a remission in a subset of individuals. However, many of these individuals experience relapses if they don’t receive long term maintenance therapy. Other individuals, while seeing an improvement in the blood complications (e.g. hemolysis and thrombocytopenia), still experience progressive kidney damage, ultimately progressing to end stage renal disease. Plasma therapy has not been studied as a treatment for aHUS in a controlled fashion.Individuals who fail to recover kidney function after treatment may require a kidney (renal) transplant. Renal transplantation had been a controversial option for aHUS because an estimated 50% of affected individuals who underwent this procedure had a recurrence of the disease in the newly grafted organ. Molecular genetic tests could help to define graft prognosis; thus, all patients should undergo such testing prior to transplantation. Molecular genetic testing should be particularly recommended before live related donation to avoid the risk of triggering disease in the donors. Eculizumab has been shown to be effective in preventing and treating post-transplant aHUS recurrences.Plasmapheresis in conjunction with drugs that suppress the immune system (immunosuppressive therapy) can be used to treat individuals with aHUS due to autoantibodies to factor H.The optimal treatment strategy for individuals with aHUS due to mutations in the DGKE gene has not been established. The effectiveness of eculizumab for these individuals has not been established presumably because the underlying defect does not involve complement proteins. Several affected individuals received a kidney transplant with no reported recurrence of the disorder. | Therapies of Atypical Hemolytic Uremic Syndrome. TreatmentTreatment by a medical team familiar with the unique challenges of aHUS is recommended and can include pediatricians or general internists, kidney specialists (nephrologists), intensive care physicians, nurses, nutritionists and social workers.Initially, affected individuals may receive supportive care including maintaining proper nutrition and electrolyte and fluid balance through intravenous feeding (parenteral) when and if necessary. Blood transfusions are administered when the hemoglobin level is below 7 g/dl. Platelet transfusions are avoided if at all possible. Drugs that expand the blood vessels (vasodilators) are used to control blood pressure (hypertension). In some instances, individuals are diagnosed with aHUS when they already have kidney damage and may initially require supportive measures such as peritoneal dialysis or hemodialysis.In 2011, the U.S Food and Drug Administration (FDA) approved the use of the humanized anti-C5 monoclonal antibody eculizumab as a treatment for acute hemolytic uremic syndrome. This drug is used to block excessive complement activation in individuals with aHUS. Eculizumab has led to improvement with the blood abnormalities (reduced hemolysis and stabilized platelet counts) and reversed acute kidney injury. Eculizumab is now recommended as first-line therapy in both children and adults with a confirmed or strongly suspected diagnosis of aHUS.In 2019, the FDA approved Ultomiris (ravulizumab-cwvz), a long-acting C5 complement inhibitor, for the treatment of adults and pediatric patients one month of age and older with aHUS to inhibit TMA.For years, plasma therapy was the standard treatment for individuals with aHUS. Both infusions of fresh frozen plasma (plasma infusion) as well as plasma exchange (plasmapheresis) were utilized. Fresh frozen plasma is a blood derivative that is obtained from donors. Plasma exchange is a method for removing potentially harmful substances (e.g. toxins, metabolic substances, and plasma parts) from the blood. Blood is removed from the affected individual and blood cells are separated from the plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individuals. Plasma exchange can also remove mutant factors and autoantibodies.Plasma therapy has led to a remission in a subset of individuals. However, many of these individuals experience relapses if they don’t receive long term maintenance therapy. Other individuals, while seeing an improvement in the blood complications (e.g. hemolysis and thrombocytopenia), still experience progressive kidney damage, ultimately progressing to end stage renal disease. Plasma therapy has not been studied as a treatment for aHUS in a controlled fashion.Individuals who fail to recover kidney function after treatment may require a kidney (renal) transplant. Renal transplantation had been a controversial option for aHUS because an estimated 50% of affected individuals who underwent this procedure had a recurrence of the disease in the newly grafted organ. Molecular genetic tests could help to define graft prognosis; thus, all patients should undergo such testing prior to transplantation. Molecular genetic testing should be particularly recommended before live related donation to avoid the risk of triggering disease in the donors. Eculizumab has been shown to be effective in preventing and treating post-transplant aHUS recurrences.Plasmapheresis in conjunction with drugs that suppress the immune system (immunosuppressive therapy) can be used to treat individuals with aHUS due to autoantibodies to factor H.The optimal treatment strategy for individuals with aHUS due to mutations in the DGKE gene has not been established. The effectiveness of eculizumab for these individuals has not been established presumably because the underlying defect does not involve complement proteins. Several affected individuals received a kidney transplant with no reported recurrence of the disorder. | 121 | Atypical Hemolytic Uremic Syndrome |
nord_122_0 | Overview of Auditory Neuropathy Spectrum Disorder | SummaryAuditory neuropathy spectrum disorder (ANSD) is a newly described condition defined as a sensorineural hearing loss that affects a person’s ability to hear or understand speech. Sensorineural means that this disorder is due to a lesion or defect in the inner ear, auditory nerve or the connection between the nerve and brain. As a result, sound enters through the ear but doesn't get adequately transmitted to the brain. The hearing loss varies from normal to severe while speech is generally perceived as distorted and hard to understand. ANSD is characterized by an abnormal speech perception that does not necessarily correlate with the patient's hearing abilities. It is a disease that primarily affects children. Most people are affected from birth and are diagnosed early on in life. However, some adults may be affected but are undiagnosed. The general population incidence varies between study reports, but approximatively 1 to 3 children per 10,000 births are affected by ANSD. With a proper follow-up, medical devices and therapies, a child with ANSD can develop good language, communication and hearing skills.IntroductionThe term “auditory neuropathy” was first proposed by Arnold Starr, MD and colleagues in 1996 as hearing impairments due to a defect in the eighth cranial nerve (or auditory nerve that allows us to hear). This definition was later expanded to include loss of inner hair cells in the ear or damage between the nerve and brain. According to the affected site in that pathway, a patient can have a presentation ranging from mild hearing loss to functionally deaf. This is why this disorder has been subsequently renamed “auditory neuropathy spectrum disorder”. Hearing ability and speech perception may vary. When a child is suspected of having hearing problems, a proper diagnosis and early intervention are crucial for a better outcome. | Overview of Auditory Neuropathy Spectrum Disorder. SummaryAuditory neuropathy spectrum disorder (ANSD) is a newly described condition defined as a sensorineural hearing loss that affects a person’s ability to hear or understand speech. Sensorineural means that this disorder is due to a lesion or defect in the inner ear, auditory nerve or the connection between the nerve and brain. As a result, sound enters through the ear but doesn't get adequately transmitted to the brain. The hearing loss varies from normal to severe while speech is generally perceived as distorted and hard to understand. ANSD is characterized by an abnormal speech perception that does not necessarily correlate with the patient's hearing abilities. It is a disease that primarily affects children. Most people are affected from birth and are diagnosed early on in life. However, some adults may be affected but are undiagnosed. The general population incidence varies between study reports, but approximatively 1 to 3 children per 10,000 births are affected by ANSD. With a proper follow-up, medical devices and therapies, a child with ANSD can develop good language, communication and hearing skills.IntroductionThe term “auditory neuropathy” was first proposed by Arnold Starr, MD and colleagues in 1996 as hearing impairments due to a defect in the eighth cranial nerve (or auditory nerve that allows us to hear). This definition was later expanded to include loss of inner hair cells in the ear or damage between the nerve and brain. According to the affected site in that pathway, a patient can have a presentation ranging from mild hearing loss to functionally deaf. This is why this disorder has been subsequently renamed “auditory neuropathy spectrum disorder”. Hearing ability and speech perception may vary. When a child is suspected of having hearing problems, a proper diagnosis and early intervention are crucial for a better outcome. | 122 | Auditory Neuropathy Spectrum Disorder |
nord_122_1 | Symptoms of Auditory Neuropathy Spectrum Disorder | If you are a parent and notice any or all of the following, it's essential to consult a doctor.If a hearing problem is suspected, you will be referred to an audiologist, a healthcare professional who can diagnose and treat hearing loss or an otolaryngologist (ENT = ear, nose and throat doctor).If you are an adult and notice that you cannot hear well on the phone and have difficulty understanding speech, it’s important to talk about this with your general practitioner.Symptoms of auditory neuropathy may present in various ways, depending on the affected site in the auditory pathway. They can also fluctuate day to day. For some patients, symptoms may improve with time, and for others, they might stay the same or get worse. A patient can present with one or more of the following:Newborn hearing screening protocols are not the same everywhere. Thus, sometimes ANSD is not detected in the early stages and symptoms can only be noticed over time. In children, speech may develop naturally or be delayed. Speech discrimination can range from no difficulty distinguishing sounds to difficulty discriminating sounds in a quiet environment. When a child is followed over time, spontaneous improvement is possible clinically by 12 months, and stabilization may happen around 18 months. However, improvement depends on the severity of the impairments, the underlying cause and the treatment's efficacy. | Symptoms of Auditory Neuropathy Spectrum Disorder. If you are a parent and notice any or all of the following, it's essential to consult a doctor.If a hearing problem is suspected, you will be referred to an audiologist, a healthcare professional who can diagnose and treat hearing loss or an otolaryngologist (ENT = ear, nose and throat doctor).If you are an adult and notice that you cannot hear well on the phone and have difficulty understanding speech, it’s important to talk about this with your general practitioner.Symptoms of auditory neuropathy may present in various ways, depending on the affected site in the auditory pathway. They can also fluctuate day to day. For some patients, symptoms may improve with time, and for others, they might stay the same or get worse. A patient can present with one or more of the following:Newborn hearing screening protocols are not the same everywhere. Thus, sometimes ANSD is not detected in the early stages and symptoms can only be noticed over time. In children, speech may develop naturally or be delayed. Speech discrimination can range from no difficulty distinguishing sounds to difficulty discriminating sounds in a quiet environment. When a child is followed over time, spontaneous improvement is possible clinically by 12 months, and stabilization may happen around 18 months. However, improvement depends on the severity of the impairments, the underlying cause and the treatment's efficacy. | 122 | Auditory Neuropathy Spectrum Disorder |
nord_122_2 | Causes of Auditory Neuropathy Spectrum Disorder | Sound waves usually enter thought the outer ear and travel via the ear canal. When they arrive at the eardrum, it vibrates. Those vibrations are then transmitted via a series of bones to the cochlea, a fluid-filled structure with a membrane that contains two types of cells: outer and inner hair cells. The inner ones are responsible for 95% of the information sent to the brain via the auditory nerve, while the outer cells amplify the sound stimulus. Damage to any of these sites may lead to hearing loss. A defect in the inner hair cells, the auditory nerve, the connection between them or the connection between the nerve and brain can lead to ANSD. If any or all are affected, the brain will receive a disorganized signal (hard to understand) or no signal at all (functionally deaf). Most of the time, ANSD affects both ears, but in some patients it can affect only one ear. A head injury can cause a lesion in the auditory nerve and lead to ANSD. However, this cause is rare and auditory neuropathy is most often due to health problems before or during birth, especially in children.Acquired ANSD can be due to many factors present either immediately before or after birth, such as:ANSD has also been associated with infections due to various viruses such as measles, mumps, cytomegalovirus (CMV) and HIV, seizure disorders and high fever. For some patients, the cause remains unknown.Congenital ANSD may be due to genetic causes. More than 15 genetic mutations have been linked to ANSD. Some can present alone (non-syndromic) or with other symptoms (syndromic). Researchers continue to investigate the role of genetic mutations in ANSD and their variations in different populations. An OTOF gene mutation is the most common non-syndromic cause of ANSD. This gene is essential for the inner hair cell function and might also be necessary for the outer hair cells. It's inherited in an autosomal recessive pattern, which means that an individual will develop the disorder only if they receive one non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Various non-syndromic mutations can affect different parts of the auditory pathway and contribute to the variable presentation of ANSD.Syndromic auditory neuropathies are abnormalities linked to other syndromes such as:Auditory neuropathy can also be caused by a mitochondrial mutation associated with mitochondrial syndromes. Genes for mitochondria (mtDNA) are inherited from the mother. If a mother has a non-working mtDNA, she will pass these genes to all her children and only daughters will pass them on to future generations. Leber hereditary optic neuropathy (LHON) is a disorder inherited in this way that causes bilateral, painless loss of vision in teenagers or young adults. Rarely, it can cause ANSD. | Causes of Auditory Neuropathy Spectrum Disorder. Sound waves usually enter thought the outer ear and travel via the ear canal. When they arrive at the eardrum, it vibrates. Those vibrations are then transmitted via a series of bones to the cochlea, a fluid-filled structure with a membrane that contains two types of cells: outer and inner hair cells. The inner ones are responsible for 95% of the information sent to the brain via the auditory nerve, while the outer cells amplify the sound stimulus. Damage to any of these sites may lead to hearing loss. A defect in the inner hair cells, the auditory nerve, the connection between them or the connection between the nerve and brain can lead to ANSD. If any or all are affected, the brain will receive a disorganized signal (hard to understand) or no signal at all (functionally deaf). Most of the time, ANSD affects both ears, but in some patients it can affect only one ear. A head injury can cause a lesion in the auditory nerve and lead to ANSD. However, this cause is rare and auditory neuropathy is most often due to health problems before or during birth, especially in children.Acquired ANSD can be due to many factors present either immediately before or after birth, such as:ANSD has also been associated with infections due to various viruses such as measles, mumps, cytomegalovirus (CMV) and HIV, seizure disorders and high fever. For some patients, the cause remains unknown.Congenital ANSD may be due to genetic causes. More than 15 genetic mutations have been linked to ANSD. Some can present alone (non-syndromic) or with other symptoms (syndromic). Researchers continue to investigate the role of genetic mutations in ANSD and their variations in different populations. An OTOF gene mutation is the most common non-syndromic cause of ANSD. This gene is essential for the inner hair cell function and might also be necessary for the outer hair cells. It's inherited in an autosomal recessive pattern, which means that an individual will develop the disorder only if they receive one non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Various non-syndromic mutations can affect different parts of the auditory pathway and contribute to the variable presentation of ANSD.Syndromic auditory neuropathies are abnormalities linked to other syndromes such as:Auditory neuropathy can also be caused by a mitochondrial mutation associated with mitochondrial syndromes. Genes for mitochondria (mtDNA) are inherited from the mother. If a mother has a non-working mtDNA, she will pass these genes to all her children and only daughters will pass them on to future generations. Leber hereditary optic neuropathy (LHON) is a disorder inherited in this way that causes bilateral, painless loss of vision in teenagers or young adults. Rarely, it can cause ANSD. | 122 | Auditory Neuropathy Spectrum Disorder |
nord_122_3 | Affects of Auditory Neuropathy Spectrum Disorder | Auditory neuropathy occurs equally in males and females with a slightly higher frequency in males. Prevalence and incidence remain uncertain as many studies report different figures due to the variability of clinical presentations in ANSD patients. Overall, it is estimated that 1 to 3 children per 10,000 births are affected by this disorder. It can occur at any stage of life. Children, adults and seniors can be affected. However, in most cases, it's detected in newborns, particularly those admitted to the neonatal intensive care units (NICU). In the NICU, 10 to 15% of the babies are diagnosed with a sensorineural hearing loss (SNHL). | Affects of Auditory Neuropathy Spectrum Disorder. Auditory neuropathy occurs equally in males and females with a slightly higher frequency in males. Prevalence and incidence remain uncertain as many studies report different figures due to the variability of clinical presentations in ANSD patients. Overall, it is estimated that 1 to 3 children per 10,000 births are affected by this disorder. It can occur at any stage of life. Children, adults and seniors can be affected. However, in most cases, it's detected in newborns, particularly those admitted to the neonatal intensive care units (NICU). In the NICU, 10 to 15% of the babies are diagnosed with a sensorineural hearing loss (SNHL). | 122 | Auditory Neuropathy Spectrum Disorder |
nord_122_4 | Related disorders of Auditory Neuropathy Spectrum Disorder | There are other disorders that result in hearing loss due to damage to outer hair cells that are different from ANSD. These include acquired hearing loss related to aging or noise exposure, hearing loss at birth from infections (rubella, herpes simplex) and genetic conditions such as Usher syndrome.Usher syndrome is a rare genetic disorder characterized by deafness due to an abnormality of the inner ear hair cells leading to sensorineural hearing loss accompanied by retinitis pigmentosa, a disorder that affects the retina of the eyes and causes progressive loss of vision. The age of onset and the severity of symptoms are determined by the underlying genetic cause. Usher syndrome is inherited in an autosomal recessive pattern. | Related disorders of Auditory Neuropathy Spectrum Disorder. There are other disorders that result in hearing loss due to damage to outer hair cells that are different from ANSD. These include acquired hearing loss related to aging or noise exposure, hearing loss at birth from infections (rubella, herpes simplex) and genetic conditions such as Usher syndrome.Usher syndrome is a rare genetic disorder characterized by deafness due to an abnormality of the inner ear hair cells leading to sensorineural hearing loss accompanied by retinitis pigmentosa, a disorder that affects the retina of the eyes and causes progressive loss of vision. The age of onset and the severity of symptoms are determined by the underlying genetic cause. Usher syndrome is inherited in an autosomal recessive pattern. | 122 | Auditory Neuropathy Spectrum Disorder |
nord_122_5 | Diagnosis of Auditory Neuropathy Spectrum Disorder | There are several tests that may be performed when someone is suspected of having hearing problems. In most screening programs, only the otoacoustic emission (OAE) is used, which is insufficient to detect ANSD. ANSD is classically characterized by normal OAE with an abnormal auditory brainstem response (ABR) test. Measuring the middle ear muscle reflex (MEMR) test or cochlear microphonic (CM) tests can be helpful in the diagnosis of ANSD. The following tests may be ordered:Otoacoustic emission (OAE) testCochlear microphonic (CM) testAuditory brainstem response (ABR) testMiddle ear muscle reflex (MEMR) testFor ANSD screening, most universal newborn hearing screening (UNHS) programs recommend screening newborns by one month, not only with OAE but also with an ABR test since OAE alone cannot diagnose ANSD. If the baby fails the first test, a second ABR test should be performed to confirm ANSD diagnosis. Ideally, the diagnosis should be verified by three months of age, and interventions should begin by six months.To diagnose ANSD, all of the following criteria must be present:Additional tests can be performed when suspecting ANSD in older children and adults:Pure tone audiogram testingSpeech audiometryOnce diagnostic tests show that a person has ANSD, other tests are needed to determine severity. Some of these tests, such as imaging tests, cannot be performed in the newborn period. Children may need to be at least one-year-old to receive these tests. | Diagnosis of Auditory Neuropathy Spectrum Disorder. There are several tests that may be performed when someone is suspected of having hearing problems. In most screening programs, only the otoacoustic emission (OAE) is used, which is insufficient to detect ANSD. ANSD is classically characterized by normal OAE with an abnormal auditory brainstem response (ABR) test. Measuring the middle ear muscle reflex (MEMR) test or cochlear microphonic (CM) tests can be helpful in the diagnosis of ANSD. The following tests may be ordered:Otoacoustic emission (OAE) testCochlear microphonic (CM) testAuditory brainstem response (ABR) testMiddle ear muscle reflex (MEMR) testFor ANSD screening, most universal newborn hearing screening (UNHS) programs recommend screening newborns by one month, not only with OAE but also with an ABR test since OAE alone cannot diagnose ANSD. If the baby fails the first test, a second ABR test should be performed to confirm ANSD diagnosis. Ideally, the diagnosis should be verified by three months of age, and interventions should begin by six months.To diagnose ANSD, all of the following criteria must be present:Additional tests can be performed when suspecting ANSD in older children and adults:Pure tone audiogram testingSpeech audiometryOnce diagnostic tests show that a person has ANSD, other tests are needed to determine severity. Some of these tests, such as imaging tests, cannot be performed in the newborn period. Children may need to be at least one-year-old to receive these tests. | 122 | Auditory Neuropathy Spectrum Disorder |
nord_122_6 | Therapies of Auditory Neuropathy Spectrum Disorder | Treatment Since the clinical presentation of ANSD varies, treatments are chosen according to the site in the auditory pathway affected, the severity of the ANSD and clinical deficits. A multidisciplinary approach is necessary to ensure adequate follow-up and to optimize treatment choice. Genetic evaluation can help the clinician understand the cause of ANSD in some cases. Ongoing therapy with a speech-language (SLP) is recommended to optimize language skills development. Even if improvements are observed in most cases, many children continue to have some or many abnormal hearing tests results that require a lifelong follow-up with several health care professionals (e.g. audiologist, otolaryngologist, neurologist, SLP, genetic counselor, etc.). No cure has been found for ANSD. However, many assistive listening devices (ALDs), like the ones listed below, can help with hearing deficits and acquiring language skills.Frequency modulation (FM) systemHearing aids (HA)Cochlear implant (CI) | Therapies of Auditory Neuropathy Spectrum Disorder. Treatment Since the clinical presentation of ANSD varies, treatments are chosen according to the site in the auditory pathway affected, the severity of the ANSD and clinical deficits. A multidisciplinary approach is necessary to ensure adequate follow-up and to optimize treatment choice. Genetic evaluation can help the clinician understand the cause of ANSD in some cases. Ongoing therapy with a speech-language (SLP) is recommended to optimize language skills development. Even if improvements are observed in most cases, many children continue to have some or many abnormal hearing tests results that require a lifelong follow-up with several health care professionals (e.g. audiologist, otolaryngologist, neurologist, SLP, genetic counselor, etc.). No cure has been found for ANSD. However, many assistive listening devices (ALDs), like the ones listed below, can help with hearing deficits and acquiring language skills.Frequency modulation (FM) systemHearing aids (HA)Cochlear implant (CI) | 122 | Auditory Neuropathy Spectrum Disorder |
nord_123_0 | Overview of Autoimmune Blistering Diseases | Autoimmune blistering diseases are a group of disorders in which the body mistakenly attacks healthy tissue, causing blistering lesions that primarily affect the skin and mucous and membranes. In autoimmune blistering diseases, antibodies erroneously attack proteins that are essential for the layers of skin to stick (adhere) together. The specific symptoms and severity of blistering diseases vary from one person to another, even among individuals with the same disorder. In some people, blistering lesions can cover a significant portion of the skin. Although there is no cure for autoimmune blistering diseases, they can often be controlled with treatment. In other cases, autoimmune blistering diseases if left untreated can eventually cause life-threatening complications. In recent years, new insight into the causes and development of these disorders has led to research into new therapies such as the development of drugs that target the specific antibodies which cause the symptoms of these diseases. NORD has individual reports on many of the specific disorders classified as autoimmune blistering diseases. For more information, choose the specific disease name as your search term in the Rare Disease Database. | Overview of Autoimmune Blistering Diseases. Autoimmune blistering diseases are a group of disorders in which the body mistakenly attacks healthy tissue, causing blistering lesions that primarily affect the skin and mucous and membranes. In autoimmune blistering diseases, antibodies erroneously attack proteins that are essential for the layers of skin to stick (adhere) together. The specific symptoms and severity of blistering diseases vary from one person to another, even among individuals with the same disorder. In some people, blistering lesions can cover a significant portion of the skin. Although there is no cure for autoimmune blistering diseases, they can often be controlled with treatment. In other cases, autoimmune blistering diseases if left untreated can eventually cause life-threatening complications. In recent years, new insight into the causes and development of these disorders has led to research into new therapies such as the development of drugs that target the specific antibodies which cause the symptoms of these diseases. NORD has individual reports on many of the specific disorders classified as autoimmune blistering diseases. For more information, choose the specific disease name as your search term in the Rare Disease Database. | 123 | Autoimmune Blistering Diseases |
nord_123_1 | Symptoms of Autoimmune Blistering Diseases | The skin is the largest organ of the body. In addition to serving as a protective barrier, the skin is involved in many additional functions of the body such as regulating internal body temperature. Five distinct layers make up the skin; each layer is filled with specialized cells. The two main structural layers of the skin are the epidermis – the outermost, protective layer of skin – and the dermis – an underlying layer that contains numerous specialized cells, tissues and structures. Specialized proteins and structures are required for the dermis and epidermis to stick together. When the epidermis separates from the dermis a blister (bulla) may form.A blister can be either tiny or large and consists of a fluid-filled bubble that forms underneath the surface of damaged or dead skin. Most blisters develop in response to irritation or injury of the skin. In autoimmune blistering diseases, blisters form because the body creates antibodies that attack certain proteins required for the proper health and function of the skin. In many cases, blisters can rupture, becoming open sores or wounds.In some autoimmune blistering diseases, blisters or lesions can also form on the mucous membranes, the thin, moist coverings of many of the body’s internal surfaces. Mucous membranes line the esophagus and anus, the inside of the mouth, the nasal passageways, the genitals and the throat. Associated symptoms depend on the location of blister formation, but can include gastrointestinal bleeding, difficulty swallowing or difficulty breathing.There are several different categories of autoimmune blistering diseases including pemphigus, pemphigoid, IgA-mediated dermatoses and epidermolysis bullosa acquista. Pemphigus, pemphigoid and IgA-mediated dermatoses can be further broken down into additional subtypes.Pemphigus
The term pemphigus is a general term for a group of related autoimmune blistering diseases. The two main types of pemphigus are pemphigus vulgaris and pemphigus foliaceus. Each type has additional subtypes.
Pemphigus vulgaris is the most common form of pemphigus. It is characterized by blisters that rupture easily and cause painful erosions. In most people, pemphigus vulgaris first develops in the mouth, followed by blistering of the skin. Any area may potentially be affected. The blisters are usually not itchy.Pemphigus foliaceus is characterized by multiple small blisters that quickly break apart to form itchy (pruritic), scaly, crusted lesions that affect the uppermost layer of the skin. The scalp and face are usually affected first. Eventually, the chest and upper back may become involved. The lesions are usually not painful. The mucous membranes are usually not affected.Additional disorders are sometimes classified as subtypes of pemphigus including paraneoplastic pemphigus and pemphigus IgA. Some physicians consider these disorders similar, yet distinct, autoimmune blistering diseases.Paraneoplastic pemphigus is a rare disease that occurs in individuals who have cancer, especially blood (hematologic) cancers such as leukemia or lymphoma. Paraneoplastic pemphigus is characterized by painful lesions affecting the mucous membranes, especially those found in the mouth and the lips. The mucous membrane lining the inside of the eyelids (conjunctiva) is also frequently affected. In other cases, the lesions can affect the linings of the gastrointestinal or respiratory tracts and potentially cause life-threatening complications. In some cases, lesions affecting the skin may develop. These lesions may vary from case to case and may appear as small, reddened bumps (erythematous macules), non-firm (flaccid) blisters, scaly plaques, pustules, or erosions.Pemphigus IgA, also known as intraepidermal neutrophilic IgA dermatosis, is characterized by the development of fluid-filled blisters on the skin. The mucous membranes are usually not affected. In most cases, the trunk and the upper arms or legs are affected. The scalp can be extensively affected in some people.Pemphigoid
Pemphigoid is a general term for a group of related diseases characterized by blistering skin eruptions. The main forms of pemphigoid are bullous pemphigoid, mucous membrane pemphigoid, and pemphigoid gestationis.Bullous pemphigoid is a chronic skin disease usually affecting the elderly that is characterized by firm, large blisters that develop on normal-appearing or reddened skin on the trunk or skin folds, sometimes around cuts or scars. Within weeks, blisters often spread to the groin, armpit, abdomen, and the skin where muscle contracts or flexes (flexor muscles). In some people, the lesions may become widespread covering a significant portion of the skin and blisters may form inside the mouth. In most people, the mucous membranes are not affected and, when they are, they tend to heal quickly. The lesions of bullous pemphigoid are often associated with intense itching.Mucous membrane pemphigoid (MMP) is a rare group of chronic autoimmune diseases characterized by blistering lesions that primarily affect the various mucous membranes of the body. The mucous membranes of the mouth and eyes are most often affected. The mucous membranes of the nose, throat, genitalia and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat. In some people, blistering lesions also form on the skin, especially in the head and neck area. Mucous membrane pemphigoid has been known by many different names within the medical literature including benign mucous membrane pemphigoid, cicatricial (scarring) pemphigoid, and ocular cicatricial pemphigoid.Pemphigoid gestationis occurs in women during pregnancy or shortly after birth (postpartum period). Affected individuals develop reddish bumps or hives usually around the navel (umbilicus) and the arms and legs. The rash may spread to affect other areas of the body and may be extremely itchy. Eventually, the skin lesions progress to form blisters. Pemphigoid gestationis usually resolves within three months without treatment (spontaneously).IgA Mediated Bullous Dermatoses
IgA-mediated bullous dermatoses are disorders characterized by elevated levels within the body of a specialized protein known as immunoglobulin A (IgA). In these disorders, IgA has a particular tendency to accumulate in the skin. Dermatitis herpetiformis and linear IgA disease are IgA-mediated bullous dermatoses. When liner IgA disease affects children, it may be known as chronic bullous disease of childhood.Dermatitis herpetiformis, also known as Duhring disease, is characterized by red clusters of extremely itchy (pruritic) blisters. The elbows, knees, scalp and buttocks are most often affected. The mucous membranes are rarely involved. The symptoms of dermatitis herpetiformis tend to come and go. Most cases of dermatitis herpetiformis are associated with celiac disease, a digestive disorder characterized by intolerance to dietary gluten, which is a protein found in wheat, rye and barley.Linear IgA disease is characterized by blistering eruptions on the skin. The elbows, knees and buttocks are most often affected. New blisters may arise in areas where older blisters are – a finding that creates a small group of blisters that may be described as a “cluster of jewels”. In some cases, itching (pruritis) may develop and may occur before the development of skin lesions. In approximately 50 percent of cases the mucous membranes are affected as well, especially the mucous membranes of the mouth and eyes. Eye involved can cause blurred vision, irritation, light sensitivity and corneal scarring.Epidermolysis Bullosa Acquista
Epidermolysis bullosa acquista is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. The skin of affected individuals is extremely fragile. Trauma to the skin can cause blisters to form. The elbows, knees, pelvis, buttocks and/or scalp are most often affected. Increased levels of a specialized protein known as immunoglobulin G are usually found around the blisters. After the blisters heal, scars and small white bumps or cysts (milia) may remain. The mucous membranes are rarely involved. A subset of patients with epidermolysis bullosa acquista has a widespread, inflammatory form of the disorder that develops rapidly and often involves the mucous membranes. | Symptoms of Autoimmune Blistering Diseases. The skin is the largest organ of the body. In addition to serving as a protective barrier, the skin is involved in many additional functions of the body such as regulating internal body temperature. Five distinct layers make up the skin; each layer is filled with specialized cells. The two main structural layers of the skin are the epidermis – the outermost, protective layer of skin – and the dermis – an underlying layer that contains numerous specialized cells, tissues and structures. Specialized proteins and structures are required for the dermis and epidermis to stick together. When the epidermis separates from the dermis a blister (bulla) may form.A blister can be either tiny or large and consists of a fluid-filled bubble that forms underneath the surface of damaged or dead skin. Most blisters develop in response to irritation or injury of the skin. In autoimmune blistering diseases, blisters form because the body creates antibodies that attack certain proteins required for the proper health and function of the skin. In many cases, blisters can rupture, becoming open sores or wounds.In some autoimmune blistering diseases, blisters or lesions can also form on the mucous membranes, the thin, moist coverings of many of the body’s internal surfaces. Mucous membranes line the esophagus and anus, the inside of the mouth, the nasal passageways, the genitals and the throat. Associated symptoms depend on the location of blister formation, but can include gastrointestinal bleeding, difficulty swallowing or difficulty breathing.There are several different categories of autoimmune blistering diseases including pemphigus, pemphigoid, IgA-mediated dermatoses and epidermolysis bullosa acquista. Pemphigus, pemphigoid and IgA-mediated dermatoses can be further broken down into additional subtypes.Pemphigus
The term pemphigus is a general term for a group of related autoimmune blistering diseases. The two main types of pemphigus are pemphigus vulgaris and pemphigus foliaceus. Each type has additional subtypes.
Pemphigus vulgaris is the most common form of pemphigus. It is characterized by blisters that rupture easily and cause painful erosions. In most people, pemphigus vulgaris first develops in the mouth, followed by blistering of the skin. Any area may potentially be affected. The blisters are usually not itchy.Pemphigus foliaceus is characterized by multiple small blisters that quickly break apart to form itchy (pruritic), scaly, crusted lesions that affect the uppermost layer of the skin. The scalp and face are usually affected first. Eventually, the chest and upper back may become involved. The lesions are usually not painful. The mucous membranes are usually not affected.Additional disorders are sometimes classified as subtypes of pemphigus including paraneoplastic pemphigus and pemphigus IgA. Some physicians consider these disorders similar, yet distinct, autoimmune blistering diseases.Paraneoplastic pemphigus is a rare disease that occurs in individuals who have cancer, especially blood (hematologic) cancers such as leukemia or lymphoma. Paraneoplastic pemphigus is characterized by painful lesions affecting the mucous membranes, especially those found in the mouth and the lips. The mucous membrane lining the inside of the eyelids (conjunctiva) is also frequently affected. In other cases, the lesions can affect the linings of the gastrointestinal or respiratory tracts and potentially cause life-threatening complications. In some cases, lesions affecting the skin may develop. These lesions may vary from case to case and may appear as small, reddened bumps (erythematous macules), non-firm (flaccid) blisters, scaly plaques, pustules, or erosions.Pemphigus IgA, also known as intraepidermal neutrophilic IgA dermatosis, is characterized by the development of fluid-filled blisters on the skin. The mucous membranes are usually not affected. In most cases, the trunk and the upper arms or legs are affected. The scalp can be extensively affected in some people.Pemphigoid
Pemphigoid is a general term for a group of related diseases characterized by blistering skin eruptions. The main forms of pemphigoid are bullous pemphigoid, mucous membrane pemphigoid, and pemphigoid gestationis.Bullous pemphigoid is a chronic skin disease usually affecting the elderly that is characterized by firm, large blisters that develop on normal-appearing or reddened skin on the trunk or skin folds, sometimes around cuts or scars. Within weeks, blisters often spread to the groin, armpit, abdomen, and the skin where muscle contracts or flexes (flexor muscles). In some people, the lesions may become widespread covering a significant portion of the skin and blisters may form inside the mouth. In most people, the mucous membranes are not affected and, when they are, they tend to heal quickly. The lesions of bullous pemphigoid are often associated with intense itching.Mucous membrane pemphigoid (MMP) is a rare group of chronic autoimmune diseases characterized by blistering lesions that primarily affect the various mucous membranes of the body. The mucous membranes of the mouth and eyes are most often affected. The mucous membranes of the nose, throat, genitalia and anus may also be affected. The symptoms of MMP vary among affected individuals depending upon the specific site(s) involved and the progression of the disease. Blistering lesions eventually heal, sometimes with scarring. Progressive scarring may potentially lead to serious complications affecting the eyes and throat. In some people, blistering lesions also form on the skin, especially in the head and neck area. Mucous membrane pemphigoid has been known by many different names within the medical literature including benign mucous membrane pemphigoid, cicatricial (scarring) pemphigoid, and ocular cicatricial pemphigoid.Pemphigoid gestationis occurs in women during pregnancy or shortly after birth (postpartum period). Affected individuals develop reddish bumps or hives usually around the navel (umbilicus) and the arms and legs. The rash may spread to affect other areas of the body and may be extremely itchy. Eventually, the skin lesions progress to form blisters. Pemphigoid gestationis usually resolves within three months without treatment (spontaneously).IgA Mediated Bullous Dermatoses
IgA-mediated bullous dermatoses are disorders characterized by elevated levels within the body of a specialized protein known as immunoglobulin A (IgA). In these disorders, IgA has a particular tendency to accumulate in the skin. Dermatitis herpetiformis and linear IgA disease are IgA-mediated bullous dermatoses. When liner IgA disease affects children, it may be known as chronic bullous disease of childhood.Dermatitis herpetiformis, also known as Duhring disease, is characterized by red clusters of extremely itchy (pruritic) blisters. The elbows, knees, scalp and buttocks are most often affected. The mucous membranes are rarely involved. The symptoms of dermatitis herpetiformis tend to come and go. Most cases of dermatitis herpetiformis are associated with celiac disease, a digestive disorder characterized by intolerance to dietary gluten, which is a protein found in wheat, rye and barley.Linear IgA disease is characterized by blistering eruptions on the skin. The elbows, knees and buttocks are most often affected. New blisters may arise in areas where older blisters are – a finding that creates a small group of blisters that may be described as a “cluster of jewels”. In some cases, itching (pruritis) may develop and may occur before the development of skin lesions. In approximately 50 percent of cases the mucous membranes are affected as well, especially the mucous membranes of the mouth and eyes. Eye involved can cause blurred vision, irritation, light sensitivity and corneal scarring.Epidermolysis Bullosa Acquista
Epidermolysis bullosa acquista is a rare autoimmune disorder of the skin that typically affects middle-aged and elderly people. The skin of affected individuals is extremely fragile. Trauma to the skin can cause blisters to form. The elbows, knees, pelvis, buttocks and/or scalp are most often affected. Increased levels of a specialized protein known as immunoglobulin G are usually found around the blisters. After the blisters heal, scars and small white bumps or cysts (milia) may remain. The mucous membranes are rarely involved. A subset of patients with epidermolysis bullosa acquista has a widespread, inflammatory form of the disorder that develops rapidly and often involves the mucous membranes. | 123 | Autoimmune Blistering Diseases |
nord_123_2 | Causes of Autoimmune Blistering Diseases | Autoimmune blistering diseases occur when the body’s immune system mistakenly attacks healthy tissue. The immune system normally produces specialized proteins called antibodies. Antibodies react against foreign materials (e.g., bacteria, virus, toxins) in the body bringing about their destruction. Antibodies can directly kill microorganisms or coat them, so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen. Antibodies are also known as immunoglobulins. There are four major classes of immunoglobulins known as IgM, IgG, IgA and IgE. When antibodies react against healthy tissue, they are known as autoantibodies.In autoimmune blistering diseases, autoantibodies attack proteins that are essential to the proper function of the basement membrane zone, a network of proteins that acts as a “glue” that holds the epidermis to the underlying tissues of the dermis. In autoimmune blistering disease, the connection (adhesion) of the epidermis and dermis is damaged because autoantibodies attack specific structures or proteins, causing the epidermis and dermis to separate and blisters to form.In pemphigus, autoantibodies react to antigens found on the surface of certain skin cells (keratinocytes). Keratinocytes are the major cell of the epidermis, and they stick (adhere) together to form the barrier that is the epidermis, and they serve as an anchor to the underlying skin layer (the dermis).In pemphigoid, autoantibodies react against proteins found at the junction where the epidermis and dermis meet, known as the dermal-epidermal junction (DEJ). The DEJ is part of the basement membrane zone.
In linear IgA disease, autoantibodies react against structures found at the dermal-epidermal junction causing the epidermis and dermis to separate.In dermatitis herpetiformis, it is believed that circulating IgA reacts against substances in the skin that ultimately results in damage to and the separation of the dermal-epidermal junction. However, in this disorder gluten sensitivity in combination with elevated levels of immunoglobulin A causes an immune system response, which may also contribute to the development of symptoms.
In epidermolysis bullosa acquista, autoantibodies react to collagen VII, a protein that is essential in anchoring the basement membrane to the dermis.The exact, underlying reason why the immune system malfunctions in individuals with autoimmune blistering diseases is unknown. A variety of factors have been speculated to trigger or worsen autoimmune blistering diseases. Such factors include exposure to ultraviolent light, exposure to certain pesticides, hormones, several infectious agents and certain foods. Certain drugs are also known to play a role in the development or aggravation of these disorders. Stress may also aggravate some types of autoimmune blistering diseases.
Researchers believe that some individuals may have a genetic predisposition to developing certain autoimmune blistering diseases such as pemphigoid and dermatitis herpetiformis. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance). | Causes of Autoimmune Blistering Diseases. Autoimmune blistering diseases occur when the body’s immune system mistakenly attacks healthy tissue. The immune system normally produces specialized proteins called antibodies. Antibodies react against foreign materials (e.g., bacteria, virus, toxins) in the body bringing about their destruction. Antibodies can directly kill microorganisms or coat them, so they are more easily destroyed by white blood cells. Specific antibodies are created in response to specific materials or substances. A substance that stimulates an antibody to be produced is called an antigen. Antibodies are also known as immunoglobulins. There are four major classes of immunoglobulins known as IgM, IgG, IgA and IgE. When antibodies react against healthy tissue, they are known as autoantibodies.In autoimmune blistering diseases, autoantibodies attack proteins that are essential to the proper function of the basement membrane zone, a network of proteins that acts as a “glue” that holds the epidermis to the underlying tissues of the dermis. In autoimmune blistering disease, the connection (adhesion) of the epidermis and dermis is damaged because autoantibodies attack specific structures or proteins, causing the epidermis and dermis to separate and blisters to form.In pemphigus, autoantibodies react to antigens found on the surface of certain skin cells (keratinocytes). Keratinocytes are the major cell of the epidermis, and they stick (adhere) together to form the barrier that is the epidermis, and they serve as an anchor to the underlying skin layer (the dermis).In pemphigoid, autoantibodies react against proteins found at the junction where the epidermis and dermis meet, known as the dermal-epidermal junction (DEJ). The DEJ is part of the basement membrane zone.
In linear IgA disease, autoantibodies react against structures found at the dermal-epidermal junction causing the epidermis and dermis to separate.In dermatitis herpetiformis, it is believed that circulating IgA reacts against substances in the skin that ultimately results in damage to and the separation of the dermal-epidermal junction. However, in this disorder gluten sensitivity in combination with elevated levels of immunoglobulin A causes an immune system response, which may also contribute to the development of symptoms.
In epidermolysis bullosa acquista, autoantibodies react to collagen VII, a protein that is essential in anchoring the basement membrane to the dermis.The exact, underlying reason why the immune system malfunctions in individuals with autoimmune blistering diseases is unknown. A variety of factors have been speculated to trigger or worsen autoimmune blistering diseases. Such factors include exposure to ultraviolent light, exposure to certain pesticides, hormones, several infectious agents and certain foods. Certain drugs are also known to play a role in the development or aggravation of these disorders. Stress may also aggravate some types of autoimmune blistering diseases.
Researchers believe that some individuals may have a genetic predisposition to developing certain autoimmune blistering diseases such as pemphigoid and dermatitis herpetiformis. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance). | 123 | Autoimmune Blistering Diseases |
nord_123_3 | Affects of Autoimmune Blistering Diseases | Autoimmune blistering diseases affect males and females in equal numbers. Most forms occur in middle-aged individuals, usually people in their 50s and 60s. However, autoimmune blistering diseases can affect individuals of any age including children. The overall incidence and prevalence of pemphigus varies depending upon the specific population studied. Pemphigus is estimated to affect anywhere from 0.7-5 people per 1,000,000 per year in the general population (Israel has the highest incidence at 16 per 1,000,000 per year). The incidence of dermatitis herpetiformis has been estimated at 10 in 100,000. The exact incidence of epidermolysis bullosa acquista and the pemphigoid disorders is unknown. | Affects of Autoimmune Blistering Diseases. Autoimmune blistering diseases affect males and females in equal numbers. Most forms occur in middle-aged individuals, usually people in their 50s and 60s. However, autoimmune blistering diseases can affect individuals of any age including children. The overall incidence and prevalence of pemphigus varies depending upon the specific population studied. Pemphigus is estimated to affect anywhere from 0.7-5 people per 1,000,000 per year in the general population (Israel has the highest incidence at 16 per 1,000,000 per year). The incidence of dermatitis herpetiformis has been estimated at 10 in 100,000. The exact incidence of epidermolysis bullosa acquista and the pemphigoid disorders is unknown. | 123 | Autoimmune Blistering Diseases |
nord_123_4 | Related disorders of Autoimmune Blistering Diseases | Symptoms of the following disorders can be similar to those of autoimmune blistering diseases. Comparisons may be useful for a differential diagnosis.Genetic blistering disease is a group of rare disorders that are characterized by blistering lesions that primarily affect the skin and mucous membranes. These disorders are caused by a variant in a gene that creates proteins necessary for the proper health and function of the skin. This group of disorders includes Hailey-Hailey disease and the various forms of epidermolysis bullosa. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)Grover’s disease, also known as transient acantholytic dermatosis, is a rare skin disorder characterized by the sudden appearance of small, firm, raised red lesions, most often on the skin of the chest and back. Diagnosis of this disorder becomes apparent under microscopic examination when a loss of “cement” that holds the cells of the skin together is observed. Over time, as the skin loses the “cement,” the cells separate (lysis). Small blisters containing a watery liquid are present. These blisters tend to group and have a swollen red border around them. The skin lesions may itch (pruritis). The lesions usually disappear after a period of six to 12 months. Grover’s disease is mainly seen in males older than forty or fifty. The cause is unknown, but it is thought to be related to trauma to sun damaged skin. (For more information on this disorder, choose “Grover’s disease” as your search term in the Rare Disease Database.)Additional skin disorders can cause blisters including erythema multiforme, porphyria cutanea tarda, staphylococcal scalded skin syndrome and impetigo. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Autoimmune Blistering Diseases. Symptoms of the following disorders can be similar to those of autoimmune blistering diseases. Comparisons may be useful for a differential diagnosis.Genetic blistering disease is a group of rare disorders that are characterized by blistering lesions that primarily affect the skin and mucous membranes. These disorders are caused by a variant in a gene that creates proteins necessary for the proper health and function of the skin. This group of disorders includes Hailey-Hailey disease and the various forms of epidermolysis bullosa. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)Grover’s disease, also known as transient acantholytic dermatosis, is a rare skin disorder characterized by the sudden appearance of small, firm, raised red lesions, most often on the skin of the chest and back. Diagnosis of this disorder becomes apparent under microscopic examination when a loss of “cement” that holds the cells of the skin together is observed. Over time, as the skin loses the “cement,” the cells separate (lysis). Small blisters containing a watery liquid are present. These blisters tend to group and have a swollen red border around them. The skin lesions may itch (pruritis). The lesions usually disappear after a period of six to 12 months. Grover’s disease is mainly seen in males older than forty or fifty. The cause is unknown, but it is thought to be related to trauma to sun damaged skin. (For more information on this disorder, choose “Grover’s disease” as your search term in the Rare Disease Database.)Additional skin disorders can cause blisters including erythema multiforme, porphyria cutanea tarda, staphylococcal scalded skin syndrome and impetigo. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.) | 123 | Autoimmune Blistering Diseases |
nord_123_5 | Diagnosis of Autoimmune Blistering Diseases | A diagnosis of an autoimmune blistering disease is suspected based upon identification of characteristic findings, a thorough clinical evaluation and a detailed patient history. A diagnosis may be confirmed based upon a variety of specialized tests including blood tests or skin biopsy. Blood tests can reveal the characteristic antibodies associated with specific autoimmune blistering diseases. A skin biopsy is a small sample of affected tissue that is taken and examined under a microscope, which may reveal characteristic findings. Physicians also perform direct immunofluorescence (DIF) on a skin biopsy sample that presents a gold standard in the assessment of patients with bullous disorder. This is a test in which the sample is stained with special dyes that allow antibodies to be seen under a special microscope.Determining the specific antibody present confirms a diagnosis of a specific autoimmune blistering disease. | Diagnosis of Autoimmune Blistering Diseases. A diagnosis of an autoimmune blistering disease is suspected based upon identification of characteristic findings, a thorough clinical evaluation and a detailed patient history. A diagnosis may be confirmed based upon a variety of specialized tests including blood tests or skin biopsy. Blood tests can reveal the characteristic antibodies associated with specific autoimmune blistering diseases. A skin biopsy is a small sample of affected tissue that is taken and examined under a microscope, which may reveal characteristic findings. Physicians also perform direct immunofluorescence (DIF) on a skin biopsy sample that presents a gold standard in the assessment of patients with bullous disorder. This is a test in which the sample is stained with special dyes that allow antibodies to be seen under a special microscope.Determining the specific antibody present confirms a diagnosis of a specific autoimmune blistering disease. | 123 | Autoimmune Blistering Diseases |
nord_123_6 | Therapies of Autoimmune Blistering Diseases | Treatment
The treatment of autoimmune blistering diseases is directed toward the specific symptoms that are apparent in each individual and preventing complications potentially associated with these diseases. Although there is no cure for these disorders, they can be controlled medically. Generally, the less widespread an autoimmune blistering disease is, the easier it is to control.The development, severity and progression of autoimmune blistering diseases are not uniform and the response to therapies can vary among individuals. Consequently, physicians will take several different factors into account when planning an individual’s treatment, which will be tailored to the individual’s specific needs and situation.The mainstay of treatment for autoimmune blistering diseases is treatment with corticosteroids such as prednisone. Corticosteroid therapy is not effective in all cases and long-term treatment with high doses of corticosteroids can cause serious side effects.Additional drugs have been used to treat individuals with autoimmune blistering diseases, either alone or in combination with corticosteroids. These drugs include drugs that suppress the immune system (immunosuppressive drugs) such as mycophenolate, azathioprine or cyclophosphamide, immunosuppressive biological therapies such as rituximab and intravenous immunoglobulin G (IVIG). Plasmapheresis also is a well-established form of treatment for severe cases of autoimmune blistering diseases. | Therapies of Autoimmune Blistering Diseases. Treatment
The treatment of autoimmune blistering diseases is directed toward the specific symptoms that are apparent in each individual and preventing complications potentially associated with these diseases. Although there is no cure for these disorders, they can be controlled medically. Generally, the less widespread an autoimmune blistering disease is, the easier it is to control.The development, severity and progression of autoimmune blistering diseases are not uniform and the response to therapies can vary among individuals. Consequently, physicians will take several different factors into account when planning an individual’s treatment, which will be tailored to the individual’s specific needs and situation.The mainstay of treatment for autoimmune blistering diseases is treatment with corticosteroids such as prednisone. Corticosteroid therapy is not effective in all cases and long-term treatment with high doses of corticosteroids can cause serious side effects.Additional drugs have been used to treat individuals with autoimmune blistering diseases, either alone or in combination with corticosteroids. These drugs include drugs that suppress the immune system (immunosuppressive drugs) such as mycophenolate, azathioprine or cyclophosphamide, immunosuppressive biological therapies such as rituximab and intravenous immunoglobulin G (IVIG). Plasmapheresis also is a well-established form of treatment for severe cases of autoimmune blistering diseases. | 123 | Autoimmune Blistering Diseases |
nord_124_0 | Overview of Autoimmune Hepatitis | SummaryAutoimmune hepatitis (AIH) is a non-contagious, chronic, inflammatory, autoimmune disease in which one’s own immune system attacks healthy, normal liver cells. The cause of liver cell destruction in this disease is unclear, but may be related to an imbalance in some of the immune system cells (effector and regulatory). The persistent inflammation within the liver observed in AIH can result in scarring, ultimately leading to cirrhosis, liver failure requiring a liver transplant, and even death. AIH is about 4 times more common in females than males and is commonly associated with other autoimmune conditions including type 1 diabetes, Hashimoto's thyroiditis, and celiac disease. In fact, 25-50% of AIH patients will develop another concurrent autoimmune disease in their lifetime.There are two clinically relevant types of AIH, including type 1and type 2. Type 1 AIH, also referred to as the classic type, is typically diagnosed in adulthood, whereas type 2 is diagnosed during childhood. Both types are treated similarly; however, type 2 AIH can be more severe and more difficult to control. Symptoms associated with AIH include fatigue, itching (pruritus), yellowing of the skin and whites of the eyes (jaundice), nausea, vomiting, abdominal pain, weight loss, light colored stools, dark colored urine, joint pain, rashes, and loss of menstruation in women. AIH is commonly diagnosed via a combination of the patient’s symptoms, blood work, and a liver biopsy. Although there is no cure for AIH, it can often be controlled with medication including steroids and other agents which suppress the immune system. Those with AIH often follow with either a gastroenterologist or hepatologist to manage their condition.IntroductionIn the 1950’s, an internal medicine doctor named Dr. Waldenström, first described this condition after observing a cohort of young women with elevated liver tests and an elevated component of the immune system called gamma globulin. This was eventually termed “lupoid hepatitis” by Dr. Mackay until the 1960s when the name was changed to autoimmune hepatitis. AIH was the first chronic liver disease to have a dedicated treatment. In the 1960s-1970s, therapy with glucocorticoids and azathioprine revealed successful disease control for many. Since these sentinel observations, there has been limited advancement in novel drug therapies. Early detection of AIH is key, as early and effective treatment is associated with better patient outcomes. | Overview of Autoimmune Hepatitis. SummaryAutoimmune hepatitis (AIH) is a non-contagious, chronic, inflammatory, autoimmune disease in which one’s own immune system attacks healthy, normal liver cells. The cause of liver cell destruction in this disease is unclear, but may be related to an imbalance in some of the immune system cells (effector and regulatory). The persistent inflammation within the liver observed in AIH can result in scarring, ultimately leading to cirrhosis, liver failure requiring a liver transplant, and even death. AIH is about 4 times more common in females than males and is commonly associated with other autoimmune conditions including type 1 diabetes, Hashimoto's thyroiditis, and celiac disease. In fact, 25-50% of AIH patients will develop another concurrent autoimmune disease in their lifetime.There are two clinically relevant types of AIH, including type 1and type 2. Type 1 AIH, also referred to as the classic type, is typically diagnosed in adulthood, whereas type 2 is diagnosed during childhood. Both types are treated similarly; however, type 2 AIH can be more severe and more difficult to control. Symptoms associated with AIH include fatigue, itching (pruritus), yellowing of the skin and whites of the eyes (jaundice), nausea, vomiting, abdominal pain, weight loss, light colored stools, dark colored urine, joint pain, rashes, and loss of menstruation in women. AIH is commonly diagnosed via a combination of the patient’s symptoms, blood work, and a liver biopsy. Although there is no cure for AIH, it can often be controlled with medication including steroids and other agents which suppress the immune system. Those with AIH often follow with either a gastroenterologist or hepatologist to manage their condition.IntroductionIn the 1950’s, an internal medicine doctor named Dr. Waldenström, first described this condition after observing a cohort of young women with elevated liver tests and an elevated component of the immune system called gamma globulin. This was eventually termed “lupoid hepatitis” by Dr. Mackay until the 1960s when the name was changed to autoimmune hepatitis. AIH was the first chronic liver disease to have a dedicated treatment. In the 1960s-1970s, therapy with glucocorticoids and azathioprine revealed successful disease control for many. Since these sentinel observations, there has been limited advancement in novel drug therapies. Early detection of AIH is key, as early and effective treatment is associated with better patient outcomes. | 124 | Autoimmune Hepatitis |
nord_124_1 | Symptoms of Autoimmune Hepatitis | Symptoms can vary from person to person with AIH; some may not even have any symptoms. Common initial symptoms can include fatigue, nausea, vomiting, abdominal pain, weight loss, light colored stools, dark colored urine, joint pain, rashes, and loss of menstruation in women. Some may develop an enlarged liver (hepatomegaly) and/or spleen (splenomegaly).Without adequate therapy, there is risk of disease progression in the form of liver fibrosis. With time, one may develop liver scaring (cirrhosis) that can increase risk of liver failure, development of fluid in the abdomen (ascites), gastrointestinal bleeding from abnormal blood flow in the esophagus and stomach, confusion associated with a poorly functioning liver, and even liver cancer. | Symptoms of Autoimmune Hepatitis. Symptoms can vary from person to person with AIH; some may not even have any symptoms. Common initial symptoms can include fatigue, nausea, vomiting, abdominal pain, weight loss, light colored stools, dark colored urine, joint pain, rashes, and loss of menstruation in women. Some may develop an enlarged liver (hepatomegaly) and/or spleen (splenomegaly).Without adequate therapy, there is risk of disease progression in the form of liver fibrosis. With time, one may develop liver scaring (cirrhosis) that can increase risk of liver failure, development of fluid in the abdomen (ascites), gastrointestinal bleeding from abnormal blood flow in the esophagus and stomach, confusion associated with a poorly functioning liver, and even liver cancer. | 124 | Autoimmune Hepatitis |
nord_124_2 | Causes of Autoimmune Hepatitis | At this time, the exact cause of autoimmune hepatitis is unknown. It is believed to be due to a combination of environmental, genetic, and immunologic factors. A few environmental triggers, such as prescribed medications and infections, have been associated with the development of AIH. Some of the medications thought to play a role in those with drug-induced AIH include nitrofurantoin, minocycline, and hydralazine. Infections such as viral hepatitis (hepatitis A, B, C, and D), herpes simplex virus, and cytomegalovirus have also been linked to disease onset.AIH is considered an “autoimmune” disease which means something (whether environmental, genetic, and/or immunologic factors) somehow triggers the immune system to think the cells in your liver are dangerous. This causes the cells in your body that usually attack foreign invaders (like viruses and bacteria) to start attacking the liver. This leads to inflammation and liver damage. | Causes of Autoimmune Hepatitis. At this time, the exact cause of autoimmune hepatitis is unknown. It is believed to be due to a combination of environmental, genetic, and immunologic factors. A few environmental triggers, such as prescribed medications and infections, have been associated with the development of AIH. Some of the medications thought to play a role in those with drug-induced AIH include nitrofurantoin, minocycline, and hydralazine. Infections such as viral hepatitis (hepatitis A, B, C, and D), herpes simplex virus, and cytomegalovirus have also been linked to disease onset.AIH is considered an “autoimmune” disease which means something (whether environmental, genetic, and/or immunologic factors) somehow triggers the immune system to think the cells in your liver are dangerous. This causes the cells in your body that usually attack foreign invaders (like viruses and bacteria) to start attacking the liver. This leads to inflammation and liver damage. | 124 | Autoimmune Hepatitis |
nord_124_3 | Affects of Autoimmune Hepatitis | Autoimmune hepatitis is a rare disorder that affects females 4 times as often as males. Type 1 is more common and is usually diagnosed in adults. Type 2 is more common in children and often involves a more severe disease process. There are also variant types of AIH; these include individuals with AIH and one of the other autoimmune liver diseases (primary sclerosing cholangitis or primary biliary cholangitis).Those with other autoimmune conditions have a 25-50% chance of developing another one and thus a higher risk for developing AIH. The new cases per year (incidence) are estimated at 1-2 per 100,000 and total cases (prevalence) are approximately 24 per 100,000. Studies suggest that the incidence of AIH is increasing and the reason is unknown. | Affects of Autoimmune Hepatitis. Autoimmune hepatitis is a rare disorder that affects females 4 times as often as males. Type 1 is more common and is usually diagnosed in adults. Type 2 is more common in children and often involves a more severe disease process. There are also variant types of AIH; these include individuals with AIH and one of the other autoimmune liver diseases (primary sclerosing cholangitis or primary biliary cholangitis).Those with other autoimmune conditions have a 25-50% chance of developing another one and thus a higher risk for developing AIH. The new cases per year (incidence) are estimated at 1-2 per 100,000 and total cases (prevalence) are approximately 24 per 100,000. Studies suggest that the incidence of AIH is increasing and the reason is unknown. | 124 | Autoimmune Hepatitis |
nord_124_4 | Related disorders of Autoimmune Hepatitis | Other disorders can have similar symptoms to autoimmune hepatitis and need to be considered when making a diagnosis. Alpha-1 antitrypsin deficiency: A genetic disorder where there is liver and lung damage because the body does not make enough alpha-1 antitrypsin protease protein or it makes a defective one. This protein helps to decrease activity of other proteins in the body and without enough or the correct form it is unable to do this, leading to damage. (For more information on this disorder, choose “Alpha-1 antitrypsin deficiency” as your search term in the Rare Disease Database.)Alcoholic hepatitis: Inflammation of the liver, with deposition of fat, and scarring of the liver with alcohol intake. Mild forms can be reversed with alcohol abstinence. Symptoms include loss of appetite, nausea, vomiting, abdominal pain, fever and yellowing of the eye white and skin (jaundice).Hemochromatosis: Disorder of iron sensing and transport in the body which leads to a build-up of iron in the liver causing liver damage. Symptoms may include bronzing of the skin, diabetes, fatigue, and muscle pain. (For more information on this disorder, choose “Hemochromatosis” as your search term in the Rare Disease Database.)Nonalcoholic fatty liver disease (NASH): Deposition of fat into the liver in the absence of alcohol intake and other liver diseases. This leads to inflammation of the liver and scaring of the liver. People who are overweight have a higher chance of developing NASH. This disease may have no symptoms and may have an elevation of liver enzymes and even autoimmune antibodies on routine blood work. Primary biliary cholangitis (PBC): An autoimmune disease of the liver where some of the small to medium sized bile ducts in the liver are destroyed by the patient’s immune system. Bile is made in the liver to help with fat digestion. In this disease the bile and other toxins build up in the liver and cause damage. This disease is more common in women and in those with other autoimmune diseases including AIH. Symptoms include loss of appetite, nausea, vomiting, abdominal pain, fever and yellowing of the eye white and skin (jaundice). (For more information on this disorder, choose “Primary biliary cholangitis” as your search term in the Rare Disease Database.)Primary sclerosing cholangitis (PSC): An autoimmune disease in the liver that results in repeated inflammation of the intra- and/or extrahepatic bile ducts resulting in scaring. This disease is more common in males and those with inflammatory bowel disease such as ulcerative colitis. Symptoms include loss of appetite, nausea, vomiting, abdominal pain, fever and yellowing of the eye white and skin (jaundice). (For more information on this disorder, choose “Primary sclerosing cholangitis” as your search term in the Rare Disease Database.)Viral hepatitis: There are five main kinds of viral hepatitis (A, B, C, D, E). Hepatitis A is usually transmitted via contaminated food, water, shellfish, and daycares. Hepatitis B can be transmitted by blood, sexual contact, and between mother and baby around the time of delivery. Hepatitis C is more commonly transmitted through blood (transfusion, shared needles), but can also be transmitted through sexual contact. Hepatitis D is more common in Africa and Eastern Europe and is transmitted through blood and sexual contact. Hepatitis B must be present for hepatitis D. Hepatitis E is common in travelers to Pakistan, India, SE Asia, Africa, and Mexico and usually transmitted through contaminated food and water. If it occurs during pregnancy there is a high death rate of both mother and child. Symptoms for all viral hepatitis are similar and include decreased appetite, fatigue, fever, nausea, vomiting, abdominal pain on the upper right, and yellowing of the skin or white of eyes (jaundice).Wilson’s disease: A rare genetic disorder in copper transport which causes a buildup of copper in the body mostly in the liver, eyes, and brain. Symptoms can include movement disorders, green/brown rings in the eyes (Kayser-Fleischer rings), anemia, and kidney problems. (For more information on this disorder, choose “Wilson’s disease” as your search term in the Rare Disease Database.) | Related disorders of Autoimmune Hepatitis. Other disorders can have similar symptoms to autoimmune hepatitis and need to be considered when making a diagnosis. Alpha-1 antitrypsin deficiency: A genetic disorder where there is liver and lung damage because the body does not make enough alpha-1 antitrypsin protease protein or it makes a defective one. This protein helps to decrease activity of other proteins in the body and without enough or the correct form it is unable to do this, leading to damage. (For more information on this disorder, choose “Alpha-1 antitrypsin deficiency” as your search term in the Rare Disease Database.)Alcoholic hepatitis: Inflammation of the liver, with deposition of fat, and scarring of the liver with alcohol intake. Mild forms can be reversed with alcohol abstinence. Symptoms include loss of appetite, nausea, vomiting, abdominal pain, fever and yellowing of the eye white and skin (jaundice).Hemochromatosis: Disorder of iron sensing and transport in the body which leads to a build-up of iron in the liver causing liver damage. Symptoms may include bronzing of the skin, diabetes, fatigue, and muscle pain. (For more information on this disorder, choose “Hemochromatosis” as your search term in the Rare Disease Database.)Nonalcoholic fatty liver disease (NASH): Deposition of fat into the liver in the absence of alcohol intake and other liver diseases. This leads to inflammation of the liver and scaring of the liver. People who are overweight have a higher chance of developing NASH. This disease may have no symptoms and may have an elevation of liver enzymes and even autoimmune antibodies on routine blood work. Primary biliary cholangitis (PBC): An autoimmune disease of the liver where some of the small to medium sized bile ducts in the liver are destroyed by the patient’s immune system. Bile is made in the liver to help with fat digestion. In this disease the bile and other toxins build up in the liver and cause damage. This disease is more common in women and in those with other autoimmune diseases including AIH. Symptoms include loss of appetite, nausea, vomiting, abdominal pain, fever and yellowing of the eye white and skin (jaundice). (For more information on this disorder, choose “Primary biliary cholangitis” as your search term in the Rare Disease Database.)Primary sclerosing cholangitis (PSC): An autoimmune disease in the liver that results in repeated inflammation of the intra- and/or extrahepatic bile ducts resulting in scaring. This disease is more common in males and those with inflammatory bowel disease such as ulcerative colitis. Symptoms include loss of appetite, nausea, vomiting, abdominal pain, fever and yellowing of the eye white and skin (jaundice). (For more information on this disorder, choose “Primary sclerosing cholangitis” as your search term in the Rare Disease Database.)Viral hepatitis: There are five main kinds of viral hepatitis (A, B, C, D, E). Hepatitis A is usually transmitted via contaminated food, water, shellfish, and daycares. Hepatitis B can be transmitted by blood, sexual contact, and between mother and baby around the time of delivery. Hepatitis C is more commonly transmitted through blood (transfusion, shared needles), but can also be transmitted through sexual contact. Hepatitis D is more common in Africa and Eastern Europe and is transmitted through blood and sexual contact. Hepatitis B must be present for hepatitis D. Hepatitis E is common in travelers to Pakistan, India, SE Asia, Africa, and Mexico and usually transmitted through contaminated food and water. If it occurs during pregnancy there is a high death rate of both mother and child. Symptoms for all viral hepatitis are similar and include decreased appetite, fatigue, fever, nausea, vomiting, abdominal pain on the upper right, and yellowing of the skin or white of eyes (jaundice).Wilson’s disease: A rare genetic disorder in copper transport which causes a buildup of copper in the body mostly in the liver, eyes, and brain. Symptoms can include movement disorders, green/brown rings in the eyes (Kayser-Fleischer rings), anemia, and kidney problems. (For more information on this disorder, choose “Wilson’s disease” as your search term in the Rare Disease Database.) | 124 | Autoimmune Hepatitis |
nord_124_5 | Diagnosis of Autoimmune Hepatitis | Diagnosis of AIH can be complex, and is frequently completed after going through several steps. This includes meeting with your doctor to discuss your past medical problems, your current symptoms, a complete physical exam, blood work, and a liver biopsy. Clinical Testing and Work-UpInitial bloodwork will include checking for signs of liver inflammation, liver function, autoimmune markers, and other blood tests to rule out other causes of liver disease. The inflammation tests will include checking the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltranspeptidase (GGT). Liver function is accessed by checking prothrombin time (PT) and international normalized ratio (INR). These tests can show if you are likely to bleed too much which can happen if the liver is damaged and is not working very well. Albumin is also checked. This is a protein that the liver makes and if it is low it can indicate you may have cirrhosis. Total bilirubin also is completed along with other liver tests. Increased bilirubin may indicate severe inflammation associated with the disease, but may also indicate decreased liver function.Autoimmune markers that will be checked to include the antinuclear antibody (ANA), smooth muscle antibody (ASMA), liver kidney microsomal antibody (LKM), and immunoglobulin G (IgG). Many autoimmune diseases will cause an elevated ANA and IgG so if those are elevated it does not mean you have AIH, just that you may be more likely to have an autoimmune condition. ASMA and LKM are more specific to AIH when they are elevated alongside elevated liver tests. Other bloodwork to help make sure that you do not have any other liver disease that could be presenting with similar symptoms to AIH include checking for viral hepatitis (hepatitis, A, B, C, D, E), Wilsons disease (ceruloplasmin levels), hemochromatosis (complete blood count panel (CBC) and anemia panel), alpha1-antitrypsin deficiency (measure alpha 1-antitryspin levels), and alcohol levels in the blood.A liver biopsy is done to help confirm autoimmune hepatitis and also to stage the amount of fibrosis present. This procedure involves you lying on a table and having part of the right abdomen numbed. The doctor then passes a needle into to the liver. The liver tissue is sent to a pathologist who looks at the sample under a microscope and does special staining to further examine it. A liver biopsy may not completely exclude or confirm AIH. This procedure is typically done as a same day procedure and usually you get to go home 4-5 hours after the test.A fibroscan is sometimes done between liver biopsies to help quantify the amount of liver fibrosis and fat in the liver or to get an initial idea of how healthy the liver is, but the liver biopsy is the best current test. | Diagnosis of Autoimmune Hepatitis. Diagnosis of AIH can be complex, and is frequently completed after going through several steps. This includes meeting with your doctor to discuss your past medical problems, your current symptoms, a complete physical exam, blood work, and a liver biopsy. Clinical Testing and Work-UpInitial bloodwork will include checking for signs of liver inflammation, liver function, autoimmune markers, and other blood tests to rule out other causes of liver disease. The inflammation tests will include checking the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltranspeptidase (GGT). Liver function is accessed by checking prothrombin time (PT) and international normalized ratio (INR). These tests can show if you are likely to bleed too much which can happen if the liver is damaged and is not working very well. Albumin is also checked. This is a protein that the liver makes and if it is low it can indicate you may have cirrhosis. Total bilirubin also is completed along with other liver tests. Increased bilirubin may indicate severe inflammation associated with the disease, but may also indicate decreased liver function.Autoimmune markers that will be checked to include the antinuclear antibody (ANA), smooth muscle antibody (ASMA), liver kidney microsomal antibody (LKM), and immunoglobulin G (IgG). Many autoimmune diseases will cause an elevated ANA and IgG so if those are elevated it does not mean you have AIH, just that you may be more likely to have an autoimmune condition. ASMA and LKM are more specific to AIH when they are elevated alongside elevated liver tests. Other bloodwork to help make sure that you do not have any other liver disease that could be presenting with similar symptoms to AIH include checking for viral hepatitis (hepatitis, A, B, C, D, E), Wilsons disease (ceruloplasmin levels), hemochromatosis (complete blood count panel (CBC) and anemia panel), alpha1-antitrypsin deficiency (measure alpha 1-antitryspin levels), and alcohol levels in the blood.A liver biopsy is done to help confirm autoimmune hepatitis and also to stage the amount of fibrosis present. This procedure involves you lying on a table and having part of the right abdomen numbed. The doctor then passes a needle into to the liver. The liver tissue is sent to a pathologist who looks at the sample under a microscope and does special staining to further examine it. A liver biopsy may not completely exclude or confirm AIH. This procedure is typically done as a same day procedure and usually you get to go home 4-5 hours after the test.A fibroscan is sometimes done between liver biopsies to help quantify the amount of liver fibrosis and fat in the liver or to get an initial idea of how healthy the liver is, but the liver biopsy is the best current test. | 124 | Autoimmune Hepatitis |
nord_124_6 | Therapies of Autoimmune Hepatitis | Treatment
Those with AIH are usually started on corticosteroids and then placed on other immunosuppressive agents. Most physicians target a goal either to completely stop the steroids or taper them down to the lowest dose possible as the disease gets into remission. Most people will stay on an immunosuppressant for life because without one the disease relapse rate is >80%. If you have a relapse or flare (liver tests increase while on therapy) then steroids are either restarted or the dose is increased if you are already taking them. Everyone does not necessarily tolerate or respond to the same treatment, so your doctor will have to determine what works best for you. With these medications, your risk of infection is higher because the immune system is being suppressed. The current medication options will be reviewed below.Corticosteroids such as prednisone, prednisolone, or budesonide are usually used to help suppress the immune system (so the liver is not attacked) and calm down the inflammation in the liver. Prednisone is a common first treatment. It has been used for many years and tends to work for many. Unfortunately, there are several side effects of these medications including bone loss (osteoporosis), high blood sugar, increased appetite, insomnia, mood changes, muscle pain, depression, and anxiety. Budesonide tends to have fewer of the side effects, but has been less studied. Azathioprine (Imuran) is commonly started during the tapering of prednisone. This medication tends to have less severe side effects compared to the prednisone so it is usually the drug of choice for long-term use. Nausea and vomiting occur in 10-15% of people taking azathioprine; therefore, an alternative treatment is used if it is too severe. There is an increased risk of lymphoma with this medication. Some people are unable to metabolize this medication which can be determined with some additional blood tests. While on this medication, white blood cell counts need to be monitored.Mycophenolate mofetil (Cellcept) is another option if one cannot tolerate azathioprine. It can also cause a significant amount of GI symptoms including abdominal pain, nausea, vomiting, diarrhea, constipation, and anorexia. Some may also have their kidney function affected by this medication so that must be monitored by bloodwork. Females of childbearing age must take a pregnancy test prior to starting this medication and use two forms of birth control while on the medication because it is associated with birth defects. Breastfeeding must be avoided until 6 months after this medication has been stopped because it is unknown if it is excreted in the breast milk. Cyclosporine, sirolimus (Rapamune), and tacrolimus (Prograf) are other alternative treatments to azathioprine and mycophenolate mofetil. These medications can also lead to nausea, diarrhea, constipation, abdominal pain, high blood pressure, elevated cholesterol, joint pain, diabetes, and gingivitis.It is important for patients to adopt a healthy diet and exercise routine to obtain an ideal body weight. The best diet to follow is one with a minimal amount of processed food and high in lean protein, vegetables, and fruits. Those that are overweight can have an increased risk of fatty liver disease and worse outcomes. | Therapies of Autoimmune Hepatitis. Treatment
Those with AIH are usually started on corticosteroids and then placed on other immunosuppressive agents. Most physicians target a goal either to completely stop the steroids or taper them down to the lowest dose possible as the disease gets into remission. Most people will stay on an immunosuppressant for life because without one the disease relapse rate is >80%. If you have a relapse or flare (liver tests increase while on therapy) then steroids are either restarted or the dose is increased if you are already taking them. Everyone does not necessarily tolerate or respond to the same treatment, so your doctor will have to determine what works best for you. With these medications, your risk of infection is higher because the immune system is being suppressed. The current medication options will be reviewed below.Corticosteroids such as prednisone, prednisolone, or budesonide are usually used to help suppress the immune system (so the liver is not attacked) and calm down the inflammation in the liver. Prednisone is a common first treatment. It has been used for many years and tends to work for many. Unfortunately, there are several side effects of these medications including bone loss (osteoporosis), high blood sugar, increased appetite, insomnia, mood changes, muscle pain, depression, and anxiety. Budesonide tends to have fewer of the side effects, but has been less studied. Azathioprine (Imuran) is commonly started during the tapering of prednisone. This medication tends to have less severe side effects compared to the prednisone so it is usually the drug of choice for long-term use. Nausea and vomiting occur in 10-15% of people taking azathioprine; therefore, an alternative treatment is used if it is too severe. There is an increased risk of lymphoma with this medication. Some people are unable to metabolize this medication which can be determined with some additional blood tests. While on this medication, white blood cell counts need to be monitored.Mycophenolate mofetil (Cellcept) is another option if one cannot tolerate azathioprine. It can also cause a significant amount of GI symptoms including abdominal pain, nausea, vomiting, diarrhea, constipation, and anorexia. Some may also have their kidney function affected by this medication so that must be monitored by bloodwork. Females of childbearing age must take a pregnancy test prior to starting this medication and use two forms of birth control while on the medication because it is associated with birth defects. Breastfeeding must be avoided until 6 months after this medication has been stopped because it is unknown if it is excreted in the breast milk. Cyclosporine, sirolimus (Rapamune), and tacrolimus (Prograf) are other alternative treatments to azathioprine and mycophenolate mofetil. These medications can also lead to nausea, diarrhea, constipation, abdominal pain, high blood pressure, elevated cholesterol, joint pain, diabetes, and gingivitis.It is important for patients to adopt a healthy diet and exercise routine to obtain an ideal body weight. The best diet to follow is one with a minimal amount of processed food and high in lean protein, vegetables, and fruits. Those that are overweight can have an increased risk of fatty liver disease and worse outcomes. | 124 | Autoimmune Hepatitis |
nord_125_0 | Overview of Autoimmune Polyendocrine Syndrome Type II | Autoimmune polyendocrine syndrome type II, also known as Schmidt syndrome, is a rare autoimmune disorder in which there is a steep drop in production of several essential hormones by the glands that secrete these hormones. When first described, this disorder was thought to involve only adrenal insufficiency (Addison's disease) and thyroid insufficiency (Hashimoto's thyroiditis). However, over time, as more patients were studied, the scope of the disorder was expanded to include disorders of other underperforming endocrine glands. These include the gonads, which secrete sex hormones; the pancreas which secretes insulin and is intimately tied up with diabetes mellitus; and sometimes the parathyroid glands. Failure of the endocrine glands to function is usually accompanied by signs of malnutrition because the ability of the intestinal tract to absorb nutrients is reduced dramatically. Since the combination of affected glands differs from patient to patient, the signs of this disorder are diverse.Most cases of this disorder are sporadic although some clinical researchers believe that there is a familial or hereditary trait associated with AIPS-II. If so, it may involve a complex interaction among many genes. | Overview of Autoimmune Polyendocrine Syndrome Type II. Autoimmune polyendocrine syndrome type II, also known as Schmidt syndrome, is a rare autoimmune disorder in which there is a steep drop in production of several essential hormones by the glands that secrete these hormones. When first described, this disorder was thought to involve only adrenal insufficiency (Addison's disease) and thyroid insufficiency (Hashimoto's thyroiditis). However, over time, as more patients were studied, the scope of the disorder was expanded to include disorders of other underperforming endocrine glands. These include the gonads, which secrete sex hormones; the pancreas which secretes insulin and is intimately tied up with diabetes mellitus; and sometimes the parathyroid glands. Failure of the endocrine glands to function is usually accompanied by signs of malnutrition because the ability of the intestinal tract to absorb nutrients is reduced dramatically. Since the combination of affected glands differs from patient to patient, the signs of this disorder are diverse.Most cases of this disorder are sporadic although some clinical researchers believe that there is a familial or hereditary trait associated with AIPS-II. If so, it may involve a complex interaction among many genes. | 125 | Autoimmune Polyendocrine Syndrome Type II |
nord_125_1 | Symptoms of Autoimmune Polyendocrine Syndrome Type II | Many conditions and symptoms are associated with this disorder. The symptoms may vary greatly among affected individuals. Addison's disease is a rare disorder characterized by chronic and insufficient functioning of the outer layer of the adrenal gland (adrenal cortex). Patients with Addison's disease have a deficiency in the production of glucocorticoid hormones which are manufactured by the adrenal gland. These hormones (especially cortisol and aldosterone) are involved in carbohydrates, fat and protein metabolism, carbohydrate and blood sugar storage, and they fight inflammation and suppress the immune response. The deficiency in glucocorticoid causes an increased release of sodium and decreased release of potassium in the urine, sweat, saliva, stomach and intestines. These changes can cause low blood pressure and increased water excretion that can lead to severe dehydration. (For more information on this disorder choose “Addison's Disease” as your search term in the Rare Disease Database).Hypothyroidism (underactive thyroid) is a disorder that can be genetic or acquired and may occur alone or as a symptom of another illness. Major symptoms may include the development of an enlarged thyroid gland in the neck, a dull facial expression, puffiness and swelling around the eyes, drooping eyelids, thinning hair which is coarse and dry, and poor memory. Hypothyroidism can be caused by disorders of the hypothalamus or pituitary centers in the brain, disorders that affect control of the thyroid hormone, blockage in the metabolic process of transporting thyroid or iodine in the thyroid gland itself, or the result of a hereditary disorder called Hashimoto's thyroiditis. Hashimoto's thyroiditis is an autoimmune disorder in which the body's natural defenses against invading organisms (i.e., antibodies, lymphocytes etc.) suddenly begin to attack healthy tissue. (For more information on these disorders choose “Hypothyroidism” and “Hashimoto” as your search terms in the Rare Disease Database).Some (but not all) of the following additional findings may be present in patients with autoimmune polyendocrine type II :Diabetes mellitus: This type of diabetes generally starts during childhood or adolescence. The starches and sugars (carbohydrates) in the foods we eat are normally processed by digestive juices into glucose. The glucose circulates in the blood as a major energy source for body functions. A hormone produced by the pancreas (insulin) regulates the body's use of glucose. In diabetes mellitus, the pancreas does not manufacture the correct amount of insulin needed to metabolize sugar. As a result, the patient needs daily injections of insulin to regulate blood sugar levels. Symptoms of this disorder may be frequent urination, extreme thirst, constant hunger, weight loss, itching of the skin, changes in vision, slow healing of cuts and bruises, and in children there is a failure to grow and develop normally. (For more information on this disorder choose “Insulin-Dependent Diabetes” as your search term in the Rare Disease Database).Hypoparathyroidism: This disorder causes lower than normal levels of calcium in the blood due to insufficient levels of parathyroid hormones. This condition can be inherited, associated with other disorders, or the result of a neck injury. Symptoms of hypoparathyroidism may be weakness, muscle cramps, abnormal sensations of the hands such as burning and numbness, excessive nervousness, loss of memory, headaches, cramping of wrists and feet, and spasms in facial muscles. (For more information on this disorder choose “Hypoparathyroidism” as your search term in the Rare Disease Database).Gonadal failure: This refers to the failure of the organ that produces sex cells (gonads-or testes in the male, and ovaries in the female) to function properly causing an absence of secondary sex characteristics.Pernicious anemia: This is a blood disorder resulting from an impaired absorption of vitamin B-12. This vitamin is used in the production of red blood cells. Healthy individuals absorb sufficient amounts of vitamin B-12 in their normal diet with the help of a substance secreted by the stomach called intrinsic factor. Patients with pernicious anemia generally lack intrinsic factor and can not absorb sufficient amounts of vitamin B-12. Symptoms of vitamin B-12 deficiency usually appear years after absorption of the vitamin ceases because B-12 is stored in large quantities in the liver. Symptoms of this disorder may be shortness of breath, fatigue, weakness, rapid heartbeat, angina, anorexia, abdominal pain, indigestion, and possibly intermittent constipation and diarrhea. (For more information on this disorder choose “Pernicious Anemia” as your search term in the Rare Disease Database).Vitiligo: This is a skin condition in which there is an absence of pigment producing cells (melanocytes) causing decreased pigmentation of the skin. These “white spots” on the skin appear most often on the face, neck, hands, abdomen, and thighs although they may appear on all parts of the skin. Vitiligo is sometimes familial, but the exact mode of heredity is not yet understood. (For more information on this disorder choose “Vitiligo” as your search term in the Rare Disease Database).Celiac sprue: This chronic hereditary intestinal malabsorption disorder is caused by intolerance to gluten. The most common symptoms of this disorder are weight loss, chronic diarrhea, abdominal cramping and bloating, intestinal gas and abdominal distention and muscle wasting. Celiac sprue is a hereditary congenital disorder. Gluten is a protein that is present in wheat, oats, barley, rye and probably millet. Patients with celiac sprue cannot properly absorb a part of gluten called gliadin. This causes intestinal abnormalities as well as physiological deficiencies. Although the disorder begins in infancy, it is sometimes not diagnosed until the patient reaches adulthood. (For more information on this disorder choose “Celiac Sprue” as your search term in the Rare Disease Database).Myasthenia gravis: Sometimes this disorder can be associated with autoimmune polyendocrine syndrome type II. Myasthenia gravis is a chronic neuromuscular disease characterized by weakness and abnormally rapid fatigue of the voluntary muscles, with improvement following rest. Any group of muscles may be affected, but those around the eyes and the muscles used for swallowing are the most commonly involved. (For more information on this disorder choose “Myasthenia Gravis” as your search term in the Rare Disease Database).Grave's disease: This is a disorder that affects the thyroid gland. It is thought to occur as a result of an imbalance in the immune system. This disorder causes increased thyroid secretion (hyperthyroidism), enlargement of the thyroid gland and protrusion of the eyeballs. The exact cause of this disorder is not known. It is thought to be inherited as an autosomal recessive trait. (For more information on this disorder choose “Graves Disease as your search term in the Rare Disease Database). | Symptoms of Autoimmune Polyendocrine Syndrome Type II. Many conditions and symptoms are associated with this disorder. The symptoms may vary greatly among affected individuals. Addison's disease is a rare disorder characterized by chronic and insufficient functioning of the outer layer of the adrenal gland (adrenal cortex). Patients with Addison's disease have a deficiency in the production of glucocorticoid hormones which are manufactured by the adrenal gland. These hormones (especially cortisol and aldosterone) are involved in carbohydrates, fat and protein metabolism, carbohydrate and blood sugar storage, and they fight inflammation and suppress the immune response. The deficiency in glucocorticoid causes an increased release of sodium and decreased release of potassium in the urine, sweat, saliva, stomach and intestines. These changes can cause low blood pressure and increased water excretion that can lead to severe dehydration. (For more information on this disorder choose “Addison's Disease” as your search term in the Rare Disease Database).Hypothyroidism (underactive thyroid) is a disorder that can be genetic or acquired and may occur alone or as a symptom of another illness. Major symptoms may include the development of an enlarged thyroid gland in the neck, a dull facial expression, puffiness and swelling around the eyes, drooping eyelids, thinning hair which is coarse and dry, and poor memory. Hypothyroidism can be caused by disorders of the hypothalamus or pituitary centers in the brain, disorders that affect control of the thyroid hormone, blockage in the metabolic process of transporting thyroid or iodine in the thyroid gland itself, or the result of a hereditary disorder called Hashimoto's thyroiditis. Hashimoto's thyroiditis is an autoimmune disorder in which the body's natural defenses against invading organisms (i.e., antibodies, lymphocytes etc.) suddenly begin to attack healthy tissue. (For more information on these disorders choose “Hypothyroidism” and “Hashimoto” as your search terms in the Rare Disease Database).Some (but not all) of the following additional findings may be present in patients with autoimmune polyendocrine type II :Diabetes mellitus: This type of diabetes generally starts during childhood or adolescence. The starches and sugars (carbohydrates) in the foods we eat are normally processed by digestive juices into glucose. The glucose circulates in the blood as a major energy source for body functions. A hormone produced by the pancreas (insulin) regulates the body's use of glucose. In diabetes mellitus, the pancreas does not manufacture the correct amount of insulin needed to metabolize sugar. As a result, the patient needs daily injections of insulin to regulate blood sugar levels. Symptoms of this disorder may be frequent urination, extreme thirst, constant hunger, weight loss, itching of the skin, changes in vision, slow healing of cuts and bruises, and in children there is a failure to grow and develop normally. (For more information on this disorder choose “Insulin-Dependent Diabetes” as your search term in the Rare Disease Database).Hypoparathyroidism: This disorder causes lower than normal levels of calcium in the blood due to insufficient levels of parathyroid hormones. This condition can be inherited, associated with other disorders, or the result of a neck injury. Symptoms of hypoparathyroidism may be weakness, muscle cramps, abnormal sensations of the hands such as burning and numbness, excessive nervousness, loss of memory, headaches, cramping of wrists and feet, and spasms in facial muscles. (For more information on this disorder choose “Hypoparathyroidism” as your search term in the Rare Disease Database).Gonadal failure: This refers to the failure of the organ that produces sex cells (gonads-or testes in the male, and ovaries in the female) to function properly causing an absence of secondary sex characteristics.Pernicious anemia: This is a blood disorder resulting from an impaired absorption of vitamin B-12. This vitamin is used in the production of red blood cells. Healthy individuals absorb sufficient amounts of vitamin B-12 in their normal diet with the help of a substance secreted by the stomach called intrinsic factor. Patients with pernicious anemia generally lack intrinsic factor and can not absorb sufficient amounts of vitamin B-12. Symptoms of vitamin B-12 deficiency usually appear years after absorption of the vitamin ceases because B-12 is stored in large quantities in the liver. Symptoms of this disorder may be shortness of breath, fatigue, weakness, rapid heartbeat, angina, anorexia, abdominal pain, indigestion, and possibly intermittent constipation and diarrhea. (For more information on this disorder choose “Pernicious Anemia” as your search term in the Rare Disease Database).Vitiligo: This is a skin condition in which there is an absence of pigment producing cells (melanocytes) causing decreased pigmentation of the skin. These “white spots” on the skin appear most often on the face, neck, hands, abdomen, and thighs although they may appear on all parts of the skin. Vitiligo is sometimes familial, but the exact mode of heredity is not yet understood. (For more information on this disorder choose “Vitiligo” as your search term in the Rare Disease Database).Celiac sprue: This chronic hereditary intestinal malabsorption disorder is caused by intolerance to gluten. The most common symptoms of this disorder are weight loss, chronic diarrhea, abdominal cramping and bloating, intestinal gas and abdominal distention and muscle wasting. Celiac sprue is a hereditary congenital disorder. Gluten is a protein that is present in wheat, oats, barley, rye and probably millet. Patients with celiac sprue cannot properly absorb a part of gluten called gliadin. This causes intestinal abnormalities as well as physiological deficiencies. Although the disorder begins in infancy, it is sometimes not diagnosed until the patient reaches adulthood. (For more information on this disorder choose “Celiac Sprue” as your search term in the Rare Disease Database).Myasthenia gravis: Sometimes this disorder can be associated with autoimmune polyendocrine syndrome type II. Myasthenia gravis is a chronic neuromuscular disease characterized by weakness and abnormally rapid fatigue of the voluntary muscles, with improvement following rest. Any group of muscles may be affected, but those around the eyes and the muscles used for swallowing are the most commonly involved. (For more information on this disorder choose “Myasthenia Gravis” as your search term in the Rare Disease Database).Grave's disease: This is a disorder that affects the thyroid gland. It is thought to occur as a result of an imbalance in the immune system. This disorder causes increased thyroid secretion (hyperthyroidism), enlargement of the thyroid gland and protrusion of the eyeballs. The exact cause of this disorder is not known. It is thought to be inherited as an autosomal recessive trait. (For more information on this disorder choose “Graves Disease as your search term in the Rare Disease Database). | 125 | Autoimmune Polyendocrine Syndrome Type II |
nord_125_2 | Causes of Autoimmune Polyendocrine Syndrome Type II | The exact cause of AIPS-II is not known, but it is thought to result from one or more abnormal immune responses. Autoimmune reactions occur when, for reasons not quite clear, the body mistakenly reacts to a normal antibody as if it were a foreign one. | Causes of Autoimmune Polyendocrine Syndrome Type II. The exact cause of AIPS-II is not known, but it is thought to result from one or more abnormal immune responses. Autoimmune reactions occur when, for reasons not quite clear, the body mistakenly reacts to a normal antibody as if it were a foreign one. | 125 | Autoimmune Polyendocrine Syndrome Type II |
nord_125_3 | Affects of Autoimmune Polyendocrine Syndrome Type II | Report suggest that the prevalence of AIPS-II is about 14 to 20 cases per million of population and that it affects females 3 to 4 times as often as it does males. AIPS-II usually strikes in the third or fourth decade of life. | Affects of Autoimmune Polyendocrine Syndrome Type II. Report suggest that the prevalence of AIPS-II is about 14 to 20 cases per million of population and that it affects females 3 to 4 times as often as it does males. AIPS-II usually strikes in the third or fourth decade of life. | 125 | Autoimmune Polyendocrine Syndrome Type II |
nord_125_4 | Related disorders of Autoimmune Polyendocrine Syndrome Type II | Symptoms of the following disorders can be similar to those of Schmidt Syndrome. Comparisons may be useful for a differential diagnosis:APECED Syndrome (Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal) is a very rare genetic syndrome involving the autoimmune system. APECED Syndrome is a Type I polyglandular Autoimmune syndrome. This disorder is characterized by a combination of at least two of the following diseases: Hypoparathyroidism, Adrenocortical Failure or Candidiasis. Beginning in childhood, yeast infections of either the mouth or nails is usually one of the first apparent symptoms of this syndrome. There may be an inability to adequately absorb nutrients with resulting diarrhea. Anemia, autoimmune thyroid disease, and loss or delay of sexual development may also occur. (For more information on this disorder choose “APECED Syndrome as your search term in the Rare Disease Database.) | Related disorders of Autoimmune Polyendocrine Syndrome Type II. Symptoms of the following disorders can be similar to those of Schmidt Syndrome. Comparisons may be useful for a differential diagnosis:APECED Syndrome (Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal) is a very rare genetic syndrome involving the autoimmune system. APECED Syndrome is a Type I polyglandular Autoimmune syndrome. This disorder is characterized by a combination of at least two of the following diseases: Hypoparathyroidism, Adrenocortical Failure or Candidiasis. Beginning in childhood, yeast infections of either the mouth or nails is usually one of the first apparent symptoms of this syndrome. There may be an inability to adequately absorb nutrients with resulting diarrhea. Anemia, autoimmune thyroid disease, and loss or delay of sexual development may also occur. (For more information on this disorder choose “APECED Syndrome as your search term in the Rare Disease Database.) | 125 | Autoimmune Polyendocrine Syndrome Type II |
nord_125_5 | Diagnosis of Autoimmune Polyendocrine Syndrome Type II | Diagnosis of Autoimmune Polyendocrine Syndrome Type II. | 125 | Autoimmune Polyendocrine Syndrome Type II |
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nord_125_6 | Therapies of Autoimmune Polyendocrine Syndrome Type II | Each disorder in a case of autoimmune polyendocrine type II is treated separately. For many of the specific disorders, treatment is focused on hormone replacement therapy. | Therapies of Autoimmune Polyendocrine Syndrome Type II. Each disorder in a case of autoimmune polyendocrine type II is treated separately. For many of the specific disorders, treatment is focused on hormone replacement therapy. | 125 | Autoimmune Polyendocrine Syndrome Type II |
nord_126_0 | Overview of Autoimmune Polyglandular Syndrome Type 1 | Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder of immune-cell dysfunction with multiple autoimmunities. It presents as a group of symptoms including potentially life-threatening endocrine gland and gastrointestinal dysfunctions. Autoimmune disorders occur when antibodies and immune cells are launched by the body against one or several antigens of its own tissues. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. HLA-DR/DQ genes also play a role in predisposing to which of the component autoimmune disease the patient actually develops.APS-1 needs to be distinguished from the unrelated but more common APS-2 which is characterized by type-1 diabetes and autoimmune thyroid diseases. | Overview of Autoimmune Polyglandular Syndrome Type 1. Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder of immune-cell dysfunction with multiple autoimmunities. It presents as a group of symptoms including potentially life-threatening endocrine gland and gastrointestinal dysfunctions. Autoimmune disorders occur when antibodies and immune cells are launched by the body against one or several antigens of its own tissues. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. HLA-DR/DQ genes also play a role in predisposing to which of the component autoimmune disease the patient actually develops.APS-1 needs to be distinguished from the unrelated but more common APS-2 which is characterized by type-1 diabetes and autoimmune thyroid diseases. | 126 | Autoimmune Polyglandular Syndrome Type 1 |
nord_126_1 | Symptoms of Autoimmune Polyglandular Syndrome Type 1 | While the symptoms of APS-1 are variable in each patient, they often will have components of at least two of the three major conditions that result from this syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency.Chronic mucocutaneous candidiasis (CMC), a condition of recurrent candidiasis infections that may involve the skin, nails, oral, anal and genital mucosa, is a hallmark of APS-1. It is often the first manifestation of APS-1, typically appearing and recurring frequently within the first two years of life. The CMC of APS-1 generally presents in babies as thrush (oral candidiasis), diaper rash, and/or nail involvement. (For further information on CMC, please see ‘Related Disorders’ section of this report.)The term ectodermal dystrophy refers to the particular abnormalities of the nails, dental enamel (enamel hypoplasia of permanent teeth), hair (alopecia), corneas (keratopathy) and skin (vitiligo–areas of depigmention of the skin) that may be seen in patients with APS-1. These findings are not all necessarily present in every patient with APS-1. However, alopecia and vitiligo are caused by specific autoimmunities, while nail deformities result from chronic candidiasis. The cause of dental enamel hypoplasia in APS-1 has not yet been determined.Metaphyseal dysplasia, a bone disorder in which the ends (metaphyses) of the bones are abnormally broad, has also recently been described in the legs in people with APS-1.Patients with APS-1 have a defect of the immune system involving a particular subset of T-cells called Treg (T-regulatory) cells. It is suggested that this Treg-cell defect leads to the wide spread loss of immune tolerance, causing the autoimmunities in the disease. However, a specific defect in immunity to candidiasis indicates the presence of an immune effector defect also. Possibly, the invariable presence of auto-antibodies to the interferon family of immunological molecules called cytokines may prove to be the underlying reason.The first endocrine gland dysfunction to occur in APS-1 is usually hypoparathyroidism (under functioning of the parathyroid glands). More than 75% of patients develop hypoparathyroidism, usually before age 10-years. Dysfunction of the parathyroid glands leads to below-normal level of serum calcium together with elevated phosphorus levels. In turn, this can lead to a host of clinical findings, including muscle cramping and spasms, rigidity (tetany) and even seizures. (For further information on hypoparathyroidism, see Related Disorders Section of this report.)Adrenocortical insufficiency (Addison’s disease) is typically the second endocrine disorder to appear in APS-1. Adrenocortical insufficiency is characterized by chronic and insufficient functioning of the cortex (outer layer) of the adrenal gland. This malfunction results in a deficiency of the glucocorticoid and salt retaining hormones cortisol and aldosterone respectively. Deficiencies of these hormones may lead to weakness, muscle cramps, faintness, diarrhea, nausea and vomiting, low blood pressure, dehydration, and salt craving. These side-effects can become pronounced and life-threatening if not correctly identified and treated. However, steroid replacement therapy can precipitate or worsen hypocalcemia when hypoparathyroidism has not been already identified. (For further information on adrenocortical insufficiency, see Related Disorders Section of this report.)Patients with APS-1 can also develop many other autoimmune disorders, including autoimmune liver disease (chronic active hepatitis), ovarian failure (hypogonadism), early onset pernicious anemia from atrophic gastritis, and a variety of gastrointestinal problems resulting in chronic malabsorption and diarrhea. Insulin-dependent diabetes may also occur, albeit more often in Scandinavian patients than is seen in the US. | Symptoms of Autoimmune Polyglandular Syndrome Type 1. While the symptoms of APS-1 are variable in each patient, they often will have components of at least two of the three major conditions that result from this syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency.Chronic mucocutaneous candidiasis (CMC), a condition of recurrent candidiasis infections that may involve the skin, nails, oral, anal and genital mucosa, is a hallmark of APS-1. It is often the first manifestation of APS-1, typically appearing and recurring frequently within the first two years of life. The CMC of APS-1 generally presents in babies as thrush (oral candidiasis), diaper rash, and/or nail involvement. (For further information on CMC, please see ‘Related Disorders’ section of this report.)The term ectodermal dystrophy refers to the particular abnormalities of the nails, dental enamel (enamel hypoplasia of permanent teeth), hair (alopecia), corneas (keratopathy) and skin (vitiligo–areas of depigmention of the skin) that may be seen in patients with APS-1. These findings are not all necessarily present in every patient with APS-1. However, alopecia and vitiligo are caused by specific autoimmunities, while nail deformities result from chronic candidiasis. The cause of dental enamel hypoplasia in APS-1 has not yet been determined.Metaphyseal dysplasia, a bone disorder in which the ends (metaphyses) of the bones are abnormally broad, has also recently been described in the legs in people with APS-1.Patients with APS-1 have a defect of the immune system involving a particular subset of T-cells called Treg (T-regulatory) cells. It is suggested that this Treg-cell defect leads to the wide spread loss of immune tolerance, causing the autoimmunities in the disease. However, a specific defect in immunity to candidiasis indicates the presence of an immune effector defect also. Possibly, the invariable presence of auto-antibodies to the interferon family of immunological molecules called cytokines may prove to be the underlying reason.The first endocrine gland dysfunction to occur in APS-1 is usually hypoparathyroidism (under functioning of the parathyroid glands). More than 75% of patients develop hypoparathyroidism, usually before age 10-years. Dysfunction of the parathyroid glands leads to below-normal level of serum calcium together with elevated phosphorus levels. In turn, this can lead to a host of clinical findings, including muscle cramping and spasms, rigidity (tetany) and even seizures. (For further information on hypoparathyroidism, see Related Disorders Section of this report.)Adrenocortical insufficiency (Addison’s disease) is typically the second endocrine disorder to appear in APS-1. Adrenocortical insufficiency is characterized by chronic and insufficient functioning of the cortex (outer layer) of the adrenal gland. This malfunction results in a deficiency of the glucocorticoid and salt retaining hormones cortisol and aldosterone respectively. Deficiencies of these hormones may lead to weakness, muscle cramps, faintness, diarrhea, nausea and vomiting, low blood pressure, dehydration, and salt craving. These side-effects can become pronounced and life-threatening if not correctly identified and treated. However, steroid replacement therapy can precipitate or worsen hypocalcemia when hypoparathyroidism has not been already identified. (For further information on adrenocortical insufficiency, see Related Disorders Section of this report.)Patients with APS-1 can also develop many other autoimmune disorders, including autoimmune liver disease (chronic active hepatitis), ovarian failure (hypogonadism), early onset pernicious anemia from atrophic gastritis, and a variety of gastrointestinal problems resulting in chronic malabsorption and diarrhea. Insulin-dependent diabetes may also occur, albeit more often in Scandinavian patients than is seen in the US. | 126 | Autoimmune Polyglandular Syndrome Type 1 |
nord_126_2 | Causes of Autoimmune Polyglandular Syndrome Type 1 | APS-1 is caused by mutations in the AIRE gene. To date, more than 60 mutations in the AIRE gene have been identified in people with APS-1.The AIRE gene is responsible for the production of a protein called ‘autoimmune regulator’ which is highly expressed in the thymus gland, and generates thymus derived or T lymphocytes. If there is a deficiency of this protein, then those T-cells which have receptors capable of interacting with self-antigens can escape into the circulation (instead of being destroyed in the thymus and not released) and result in autoimmunities. For reasons that are still unclear, defects of the autoimmune regulator protein seem to mostly affect endocrine (hormone-producing) glands.APS-1 is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Autoimmune Polyglandular Syndrome Type 1. APS-1 is caused by mutations in the AIRE gene. To date, more than 60 mutations in the AIRE gene have been identified in people with APS-1.The AIRE gene is responsible for the production of a protein called ‘autoimmune regulator’ which is highly expressed in the thymus gland, and generates thymus derived or T lymphocytes. If there is a deficiency of this protein, then those T-cells which have receptors capable of interacting with self-antigens can escape into the circulation (instead of being destroyed in the thymus and not released) and result in autoimmunities. For reasons that are still unclear, defects of the autoimmune regulator protein seem to mostly affect endocrine (hormone-producing) glands.APS-1 is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 126 | Autoimmune Polyglandular Syndrome Type 1 |
nord_126_3 | Affects of Autoimmune Polyglandular Syndrome Type 1 | APS-I is a very rare disorder that tends to cluster in certain homogenous populations, including certain groups of Finns, Iranian Jews, and Sardinians. However, it can be found in numerous populations and among multiple ethnic groups. In the US, APS-1 probably affects as few as 1 in every 2-3 million newborns. | Affects of Autoimmune Polyglandular Syndrome Type 1. APS-I is a very rare disorder that tends to cluster in certain homogenous populations, including certain groups of Finns, Iranian Jews, and Sardinians. However, it can be found in numerous populations and among multiple ethnic groups. In the US, APS-1 probably affects as few as 1 in every 2-3 million newborns. | 126 | Autoimmune Polyglandular Syndrome Type 1 |
nord_126_4 | Related disorders of Autoimmune Polyglandular Syndrome Type 1 | The following disorders, which are components of APS-1, can also occur on their own, separate from the diagnosis of APS-1:Chronic mucocutaneous candidiasis (CMC) refers to a condition of persistent or recurrent yeast infections of the skin, nails, and/or mucous membranes. The most prevalent of these organisms is Candida albicans. When significant CMC occurs, it is often a sign of an underlying T cell disorder, including APS-1. Fortunately the conazole class of drugs has made this disease more easily managed than in former years. Candida is yeast that is part of the normal flora of the gastrointestinal tract, skin, and mucous membranes. Healthy, intact skin and an intact immune system usually provide effective barriers to prevent candida invading these tissues.People with CMC present with recurrent or persistent candidiasis infections of the oral cavity (thrush) and other mucous membranes, but often have more extensive involvement. The nails may be markedly thickened and discolored with significant swelling of the surrounding tissue. The scalp may be involved, leading to alopecia in areas of scarring. However, alopecia is more commonly an autoimmune disorder which can result in alopecia universalis where all bodily hair is lost. There may be clinically significant esophageal candidiasis also in APS-1. Oropharygeal cancers and cancers of the stomach and tongue occur at increased frequencies in APS-1. CMC is definitively diagnosed by the presence of Candida on fungal skin scrapings.Hypoparathyroidism is a condition characterized by insufficient production of parathyroid hormones by the parathyroid glands, the small, oval glands located behind the thyroid gland in the neck. Parathyroid hormones (along with vitamin D) play a role in regulating levels of calcium in the blood. Due to a deficiency of parathyroid hormones, affected individuals exhibit abnormally low levels of calcium in the blood (hypocalcaemia) often accompanied by elevated phosphorus.Symptoms and findings associated with hypoparathyroidism may include weakness, muscle cramps, excessive nervousness, headaches, and/or increased excitability (hyper excitability) of nerves. This can lead to uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms, and/or face (tetany).Hypoparathyroidism in APS-1 has an autoimmune cause, but it can occur as a separate disorder associated with maldevelopment of the thymus, aortic arch and parathyroid glands (DiGeorge syndrome) or may also arise as a separate inherited disorder. While an antibody to antigens present on the surface of parathyroid cells (the calcium sensing receptor) had previously been reported in APS-1, more recently, researchers from University Hospital in Uppsala, Sweden have isolated another auto-antigen involved. Chronic adrenocortical insufficiency (Addison’s disease) is a rare disorder characterized by chronic, usually progressive, inadequate production of the steroid hormones cortisol and aldosterone by the outer layer of cells of the adrenal glands (adrenal cortex). Classical Addison’s disease is a consequence of the loss of both of these hormones.Cortisol affects carbohydrate metabolism, connective tissue development, arterial tone and the amount of water in the body. The level of cortisol rises in response to physical and emotional stresses. Aldosterone affects the sodium (retention) and potassium (excretion) equilibria in the body. When these hormone levels are subnormal, blood pressure and blood volume drop due to increased excretion of salt and thereby water. Dehydration can occur. Major symptoms of Addison’s disease include fatigue, weakness, gastrointestinal discomfort, salt craving and changes in skin color (hyperpigmentation). Electrolyte disturbances include elevations in serum potassium and low serum sodium levels. Adrenal autoimmunity is associated with auto antibodies against an adrenocortical enzyme named 21-hydroxylase.An acute, life-threatening state of extreme insufficiency of adrenocortical hormones (Addisonian crisis) may occur in the form of a sudden loss of strength, dehydration, and faintness from hypotension. Females with APS-1 usually develop significant ovarian failures associated with autoantibodies against the side chain cleavage and 17 alpha hydroxylase enzymes of the ovaries. Hypogonadism is common and infertility is usually present. Additional concerns with APS-1:Autoimmunities can also involve the anterior pituitary gland (hypophysitis), the gastric mucosa (antibodies seen include parietal cell antibodies (antibodies against the hydrogen-potassium ATPase enzyme), and intrinsic factor binding proteins), celiac disease (antibodies against tissue transglutaminase enzyme of the intestinal mucosa), inflammatory bowel disease with an autoimmunity directed at the serotonin rich cells of the small intestine (antibodies against the tryptophan hydroxylase enzyme), and interferons as mentioned above. Many patients are born with hypoplastic spleens, leaving them subject to septicemia especially by strep pneumonia bacteria. It is advised that APS-1 patients be vaccinated against pneumococcus. The predisposition to GI cancers, especially involving the tongue and/or stomach, was also mentioned above. | Related disorders of Autoimmune Polyglandular Syndrome Type 1. The following disorders, which are components of APS-1, can also occur on their own, separate from the diagnosis of APS-1:Chronic mucocutaneous candidiasis (CMC) refers to a condition of persistent or recurrent yeast infections of the skin, nails, and/or mucous membranes. The most prevalent of these organisms is Candida albicans. When significant CMC occurs, it is often a sign of an underlying T cell disorder, including APS-1. Fortunately the conazole class of drugs has made this disease more easily managed than in former years. Candida is yeast that is part of the normal flora of the gastrointestinal tract, skin, and mucous membranes. Healthy, intact skin and an intact immune system usually provide effective barriers to prevent candida invading these tissues.People with CMC present with recurrent or persistent candidiasis infections of the oral cavity (thrush) and other mucous membranes, but often have more extensive involvement. The nails may be markedly thickened and discolored with significant swelling of the surrounding tissue. The scalp may be involved, leading to alopecia in areas of scarring. However, alopecia is more commonly an autoimmune disorder which can result in alopecia universalis where all bodily hair is lost. There may be clinically significant esophageal candidiasis also in APS-1. Oropharygeal cancers and cancers of the stomach and tongue occur at increased frequencies in APS-1. CMC is definitively diagnosed by the presence of Candida on fungal skin scrapings.Hypoparathyroidism is a condition characterized by insufficient production of parathyroid hormones by the parathyroid glands, the small, oval glands located behind the thyroid gland in the neck. Parathyroid hormones (along with vitamin D) play a role in regulating levels of calcium in the blood. Due to a deficiency of parathyroid hormones, affected individuals exhibit abnormally low levels of calcium in the blood (hypocalcaemia) often accompanied by elevated phosphorus.Symptoms and findings associated with hypoparathyroidism may include weakness, muscle cramps, excessive nervousness, headaches, and/or increased excitability (hyper excitability) of nerves. This can lead to uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms, and/or face (tetany).Hypoparathyroidism in APS-1 has an autoimmune cause, but it can occur as a separate disorder associated with maldevelopment of the thymus, aortic arch and parathyroid glands (DiGeorge syndrome) or may also arise as a separate inherited disorder. While an antibody to antigens present on the surface of parathyroid cells (the calcium sensing receptor) had previously been reported in APS-1, more recently, researchers from University Hospital in Uppsala, Sweden have isolated another auto-antigen involved. Chronic adrenocortical insufficiency (Addison’s disease) is a rare disorder characterized by chronic, usually progressive, inadequate production of the steroid hormones cortisol and aldosterone by the outer layer of cells of the adrenal glands (adrenal cortex). Classical Addison’s disease is a consequence of the loss of both of these hormones.Cortisol affects carbohydrate metabolism, connective tissue development, arterial tone and the amount of water in the body. The level of cortisol rises in response to physical and emotional stresses. Aldosterone affects the sodium (retention) and potassium (excretion) equilibria in the body. When these hormone levels are subnormal, blood pressure and blood volume drop due to increased excretion of salt and thereby water. Dehydration can occur. Major symptoms of Addison’s disease include fatigue, weakness, gastrointestinal discomfort, salt craving and changes in skin color (hyperpigmentation). Electrolyte disturbances include elevations in serum potassium and low serum sodium levels. Adrenal autoimmunity is associated with auto antibodies against an adrenocortical enzyme named 21-hydroxylase.An acute, life-threatening state of extreme insufficiency of adrenocortical hormones (Addisonian crisis) may occur in the form of a sudden loss of strength, dehydration, and faintness from hypotension. Females with APS-1 usually develop significant ovarian failures associated with autoantibodies against the side chain cleavage and 17 alpha hydroxylase enzymes of the ovaries. Hypogonadism is common and infertility is usually present. Additional concerns with APS-1:Autoimmunities can also involve the anterior pituitary gland (hypophysitis), the gastric mucosa (antibodies seen include parietal cell antibodies (antibodies against the hydrogen-potassium ATPase enzyme), and intrinsic factor binding proteins), celiac disease (antibodies against tissue transglutaminase enzyme of the intestinal mucosa), inflammatory bowel disease with an autoimmunity directed at the serotonin rich cells of the small intestine (antibodies against the tryptophan hydroxylase enzyme), and interferons as mentioned above. Many patients are born with hypoplastic spleens, leaving them subject to septicemia especially by strep pneumonia bacteria. It is advised that APS-1 patients be vaccinated against pneumococcus. The predisposition to GI cancers, especially involving the tongue and/or stomach, was also mentioned above. | 126 | Autoimmune Polyglandular Syndrome Type 1 |
nord_126_5 | Diagnosis of Autoimmune Polyglandular Syndrome Type 1 | APS-1 is diagnosed definitively through DNA analysis (via blood test) of mutations in the AIRE gene. The diagnosis should be strongly considered in people under 30 years of age who present with at least two of the three typical disease components (CMC, hypoparathyroidism, and/or Addison’s disease). Recently, typical AIRE mutations have been identified in patients who have only one of these three cardinal features, but have other less common APS-1 associated autoimmunities. Since virtually all APS-1 patients have interferon autoantibodies, such antibodies when more freely available will serve as a less expensive diagnostic test.A clinical history and physical exam that suggests more than one endocrine disorder, with or without CMC, should prompt the physician to obtain serum endocrine autoantibody blood tests. | Diagnosis of Autoimmune Polyglandular Syndrome Type 1. APS-1 is diagnosed definitively through DNA analysis (via blood test) of mutations in the AIRE gene. The diagnosis should be strongly considered in people under 30 years of age who present with at least two of the three typical disease components (CMC, hypoparathyroidism, and/or Addison’s disease). Recently, typical AIRE mutations have been identified in patients who have only one of these three cardinal features, but have other less common APS-1 associated autoimmunities. Since virtually all APS-1 patients have interferon autoantibodies, such antibodies when more freely available will serve as a less expensive diagnostic test.A clinical history and physical exam that suggests more than one endocrine disorder, with or without CMC, should prompt the physician to obtain serum endocrine autoantibody blood tests. | 126 | Autoimmune Polyglandular Syndrome Type 1 |
nord_126_6 | Therapies of Autoimmune Polyglandular Syndrome Type 1 | TreatmentTreatment of APS-1 is currently directed toward the specific diseases that are apparent in each patient. In general, replacement therapy of the endocrine hormones that may be lacking, and patient education about the signs and symptoms of these deficiencies, are integral to treatment success. The educational aspect is of extreme importance, as this allows the patient to self-monitor, hopefully avoiding a life-threatening situation.Addison’s disease is treated with drugs such as hydrocortisone and fludrocortisone to replace the cortisol and aldosterone that are deficient in such patients.Hypoparathyroidism is treated with oral calcium supplements and activated forms (1, 25 dihydroxy) of vitamin D such as Calctriol or Rocaltrol. Recently, parathyroid hormone has become available as a treatment. For chronic mucocutaneous candidiasis, oral fluconazole (Diflucan) is prescribed. | Therapies of Autoimmune Polyglandular Syndrome Type 1. TreatmentTreatment of APS-1 is currently directed toward the specific diseases that are apparent in each patient. In general, replacement therapy of the endocrine hormones that may be lacking, and patient education about the signs and symptoms of these deficiencies, are integral to treatment success. The educational aspect is of extreme importance, as this allows the patient to self-monitor, hopefully avoiding a life-threatening situation.Addison’s disease is treated with drugs such as hydrocortisone and fludrocortisone to replace the cortisol and aldosterone that are deficient in such patients.Hypoparathyroidism is treated with oral calcium supplements and activated forms (1, 25 dihydroxy) of vitamin D such as Calctriol or Rocaltrol. Recently, parathyroid hormone has become available as a treatment. For chronic mucocutaneous candidiasis, oral fluconazole (Diflucan) is prescribed. | 126 | Autoimmune Polyglandular Syndrome Type 1 |
nord_127_0 | Overview of Autoinflammation with Infantile Enterocolitis | Autoinflammation with infantile enterocolitis (AIFEC) is a newly identified and extremely rare inflammatory disorder that manifests early in infancy and affects patients throughout adulthood. AIFEC is caused by a change (mutation) in the NLRC4 gene, resulting in increased inflammation and damage to healthy tissues (autoinflammation). Patients with NLRC4 mutations present with enterocolitis (inflammation of the digestive tract causing diarrhea) in infancy and flares of severe and sometimes life-threatening autoinflammation throughout life. Macrophage activation syndrome (MAS), the type of autoinflammation seen in AIFEC, causes fevers, enlarged spleen, blood disturbances, and can progress to organ damage and death if not treated. | Overview of Autoinflammation with Infantile Enterocolitis. Autoinflammation with infantile enterocolitis (AIFEC) is a newly identified and extremely rare inflammatory disorder that manifests early in infancy and affects patients throughout adulthood. AIFEC is caused by a change (mutation) in the NLRC4 gene, resulting in increased inflammation and damage to healthy tissues (autoinflammation). Patients with NLRC4 mutations present with enterocolitis (inflammation of the digestive tract causing diarrhea) in infancy and flares of severe and sometimes life-threatening autoinflammation throughout life. Macrophage activation syndrome (MAS), the type of autoinflammation seen in AIFEC, causes fevers, enlarged spleen, blood disturbances, and can progress to organ damage and death if not treated. | 127 | Autoinflammation with Infantile Enterocolitis |
nord_127_1 | Symptoms of Autoinflammation with Infantile Enterocolitis | AIFEC is characterized by a variety of symptoms related to the activation of inflammatory processes. The overactivation of the patient’s immune system is destructive to the patient’s healthy tissues and may be life-threatening. Symptoms often occur in flares alternating with largely symptom-free periods. The exact cause of the flares is not completely understood, but may be linked to emotional stress, physical stress, and/or stresses on the immune system such as viral or bacterial infections.Though fever and flu-like symptoms are the most common symptoms in AIFEC patients, many patients also develop enterocolitis, or inflammation of the digestive tract. This enterocolitis can range in severity from mild to life-threatening in AIFEC patients. It usually causes a severe watery diarrhea, and may also cause vomiting. This diarrhea usually occurs only in infancy and resolves after the child is about 1-year-old. Patients with severe diarrhea may need extra nutrition in the hospital in the form of fluid provided into a vein (total parenteral nutrition, TPN). The other inflammatory symptoms usually persist into adulthood.The type of autoinflammation seen in AIFEC is sometimes called macrophage activation syndrome (but MAS is not only found in AIFEC) because one kind of immune cells, macrophages, appear to be particularly overactivated. MAS can cause fever, fast heart rate, decreased numbers of cells in the blood, clotting problems, increased fats in the blood, changes in iron handling, large spleen, and other blood abnormalities that indicate inflammation. Less commonly, organ-specific symptoms can include spotted, bumpy, and/or itchy rashes, loss of consciousness, seizures, breathing problems, and liver dysfunction. Without treatment, symptoms may progress to severe blood clotting problems (DIC), organ failure, and death. Muscle pain, joint pain, anemia (decreased ability for the blood to carry oxygen), and short height have also been observed in adults with AIFEC. | Symptoms of Autoinflammation with Infantile Enterocolitis. AIFEC is characterized by a variety of symptoms related to the activation of inflammatory processes. The overactivation of the patient’s immune system is destructive to the patient’s healthy tissues and may be life-threatening. Symptoms often occur in flares alternating with largely symptom-free periods. The exact cause of the flares is not completely understood, but may be linked to emotional stress, physical stress, and/or stresses on the immune system such as viral or bacterial infections.Though fever and flu-like symptoms are the most common symptoms in AIFEC patients, many patients also develop enterocolitis, or inflammation of the digestive tract. This enterocolitis can range in severity from mild to life-threatening in AIFEC patients. It usually causes a severe watery diarrhea, and may also cause vomiting. This diarrhea usually occurs only in infancy and resolves after the child is about 1-year-old. Patients with severe diarrhea may need extra nutrition in the hospital in the form of fluid provided into a vein (total parenteral nutrition, TPN). The other inflammatory symptoms usually persist into adulthood.The type of autoinflammation seen in AIFEC is sometimes called macrophage activation syndrome (but MAS is not only found in AIFEC) because one kind of immune cells, macrophages, appear to be particularly overactivated. MAS can cause fever, fast heart rate, decreased numbers of cells in the blood, clotting problems, increased fats in the blood, changes in iron handling, large spleen, and other blood abnormalities that indicate inflammation. Less commonly, organ-specific symptoms can include spotted, bumpy, and/or itchy rashes, loss of consciousness, seizures, breathing problems, and liver dysfunction. Without treatment, symptoms may progress to severe blood clotting problems (DIC), organ failure, and death. Muscle pain, joint pain, anemia (decreased ability for the blood to carry oxygen), and short height have also been observed in adults with AIFEC. | 127 | Autoinflammation with Infantile Enterocolitis |
nord_127_2 | Causes of Autoinflammation with Infantile Enterocolitis | AIFEC is caused by a mutation in the NLCR4 gene resulting in activation of the NLRC4 protein, an important component of the immune system in healthy individuals. Proteins found on the surface of certain bacteria such as Salmonella and Pseudomonas are normally recognized by a receptor (NAIP) found on the patient’s immune system and intestinal cells – this is a way for the human body to recognize foreign bacteria so that it can begin to fight them off. When the NAIP receptor senses bacteria, it then activates NLRC4. Once activated, NLRC4 quickly works with other proteins to form a complex called the NLRC4 inflammasome. This inflammasome complex works inside cells of the immune system (including macrophages) to generate inflammatory cytokines, like IL-1 and IL-18, and to trigger cells infected with the bacteria to die. The activated immune system can also cause intestinal cells infected with the bacteria to be shed into the gut lumen. This causes diarrhea, but also prevents the bacteria from crossing over from the gut into the rest of the body where they could cause more damage.When mutations cause the NLRC4 protein to always be active, it results in widespread activation of the immune system even when bacteria are not present. This uncontrolled activation causes damage to the patient’s healthy cells resulting in the symptoms of AIFEC. When NLRC4 is always active in intestinal cells, it causes constant shedding of the lining of the GI tract causing enterocolitis (diarrhea). It is not yet understood why diarrhea is present only in infancy, but it may relate to the fact that an infant’s gut bacteria (microbiota) is still developing.AIFEC follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. AIFEC has been observed in some patients due to somatic mutations, meaning the mutation isn’t even present in all of the patient’s cells. | Causes of Autoinflammation with Infantile Enterocolitis. AIFEC is caused by a mutation in the NLCR4 gene resulting in activation of the NLRC4 protein, an important component of the immune system in healthy individuals. Proteins found on the surface of certain bacteria such as Salmonella and Pseudomonas are normally recognized by a receptor (NAIP) found on the patient’s immune system and intestinal cells – this is a way for the human body to recognize foreign bacteria so that it can begin to fight them off. When the NAIP receptor senses bacteria, it then activates NLRC4. Once activated, NLRC4 quickly works with other proteins to form a complex called the NLRC4 inflammasome. This inflammasome complex works inside cells of the immune system (including macrophages) to generate inflammatory cytokines, like IL-1 and IL-18, and to trigger cells infected with the bacteria to die. The activated immune system can also cause intestinal cells infected with the bacteria to be shed into the gut lumen. This causes diarrhea, but also prevents the bacteria from crossing over from the gut into the rest of the body where they could cause more damage.When mutations cause the NLRC4 protein to always be active, it results in widespread activation of the immune system even when bacteria are not present. This uncontrolled activation causes damage to the patient’s healthy cells resulting in the symptoms of AIFEC. When NLRC4 is always active in intestinal cells, it causes constant shedding of the lining of the GI tract causing enterocolitis (diarrhea). It is not yet understood why diarrhea is present only in infancy, but it may relate to the fact that an infant’s gut bacteria (microbiota) is still developing.AIFEC follows an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. AIFEC has been observed in some patients due to somatic mutations, meaning the mutation isn’t even present in all of the patient’s cells. | 127 | Autoinflammation with Infantile Enterocolitis |
nord_127_3 | Affects of Autoinflammation with Infantile Enterocolitis | Very few patients have been identified with the activating NLRC4 mutations that cause AIFEC. Seven patients have been identified since the first patients were diagnosed in 2014. Due to the low number of patients, it is so far unclear what puts patients at increased risk of acquiring the disease-causing mutation other than having a parent with the disease. | Affects of Autoinflammation with Infantile Enterocolitis. Very few patients have been identified with the activating NLRC4 mutations that cause AIFEC. Seven patients have been identified since the first patients were diagnosed in 2014. Due to the low number of patients, it is so far unclear what puts patients at increased risk of acquiring the disease-causing mutation other than having a parent with the disease. | 127 | Autoinflammation with Infantile Enterocolitis |
nord_127_4 | Related disorders of Autoinflammation with Infantile Enterocolitis | NLRC4 gene mutations (different ones than those implicated in AIFEC) are also associated with familial cold autoinflammatory syndrome (FCAS4). Symptoms of FCAS4, which occur after exposure to cold temperatures, included fevers, joint and muscle pain, skin rashes, conjunctivitis (pink eye), and limb swelling. (For more information on this condition, search for “FCAS” in the Rare Disease Database.) | Related disorders of Autoinflammation with Infantile Enterocolitis. NLRC4 gene mutations (different ones than those implicated in AIFEC) are also associated with familial cold autoinflammatory syndrome (FCAS4). Symptoms of FCAS4, which occur after exposure to cold temperatures, included fevers, joint and muscle pain, skin rashes, conjunctivitis (pink eye), and limb swelling. (For more information on this condition, search for “FCAS” in the Rare Disease Database.) | 127 | Autoinflammation with Infantile Enterocolitis |
nord_127_5 | Diagnosis of Autoinflammation with Infantile Enterocolitis | The physician will first perform a clinical evaluation based on the patient’s symptoms. Blood tests will likely show a variety of blood abnormalities including: markers of inflammation (high CRP, high ferritin, high IL2R), signs of overactive NLRC4 (high IL18), as well as pancytopenia (decreased cells in the blood). Exam of the patient’s gastrointestinal tract (endoscopy or colonoscopy), including intestinal biopsies, may show intestinal lesions/injuries and inflammation in infants. A bone marrow biopsy may show signs that overactive immune cells are targeting healthy cells. If skin lesions are present, the physician may biopsy them to see if inflammatory cells are present. Eventually genetic tests will show an activating mutation of the NLCR4 gene. | Diagnosis of Autoinflammation with Infantile Enterocolitis. The physician will first perform a clinical evaluation based on the patient’s symptoms. Blood tests will likely show a variety of blood abnormalities including: markers of inflammation (high CRP, high ferritin, high IL2R), signs of overactive NLRC4 (high IL18), as well as pancytopenia (decreased cells in the blood). Exam of the patient’s gastrointestinal tract (endoscopy or colonoscopy), including intestinal biopsies, may show intestinal lesions/injuries and inflammation in infants. A bone marrow biopsy may show signs that overactive immune cells are targeting healthy cells. If skin lesions are present, the physician may biopsy them to see if inflammatory cells are present. Eventually genetic tests will show an activating mutation of the NLCR4 gene. | 127 | Autoinflammation with Infantile Enterocolitis |
nord_127_6 | Therapies of Autoinflammation with Infantile Enterocolitis | Treatment
AIFEC is so recently identified and so few patients have been diagnosed that no medications are currently considered standard. Treatment is often by trial and error because one patient may respond differently to a drug than another patient. Some of the drugs that have been used with varying success are general anti-inflammatory drugs like corticosteroids, cyclosporine, and IVIg. Some more specific therapies targeted to the patient’s overactive immune system include IL1 inhibitor (anakinra), TNF inhibitor (infliximab), and integrin-inhibitors (vedolizumab). | Therapies of Autoinflammation with Infantile Enterocolitis. Treatment
AIFEC is so recently identified and so few patients have been diagnosed that no medications are currently considered standard. Treatment is often by trial and error because one patient may respond differently to a drug than another patient. Some of the drugs that have been used with varying success are general anti-inflammatory drugs like corticosteroids, cyclosporine, and IVIg. Some more specific therapies targeted to the patient’s overactive immune system include IL1 inhibitor (anakinra), TNF inhibitor (infliximab), and integrin-inhibitors (vedolizumab). | 127 | Autoinflammation with Infantile Enterocolitis |
nord_128_0 | Overview of Autosomal Dominant Hereditary Ataxia | SummaryThe hereditary ataxias are a group of neurological disorders (ataxias) of varying degrees of rarity that are inherited, in contrast to a related group of neurological disorders that are acquired through accidents, injuries, or other external agents. The hereditary ataxias are characterized by degenerative changes in the brain and spinal cord that lead to an awkward, uncoordinated walk (gait) accompanied often by poor eye-hand coordination and abnormal speech (dysarthria). Hereditary ataxia in one or another of its forms may present at almost any time between infancy and adulthood.The classification of hereditary ataxias is complex with several schools of thought vying for recognition. This report follows the classification presented by Dr. Thomas D. Bird and the University of Washington's GeneReviews.This classification is based on the pattern of inheritance or mode of genetic transmission of the disorder: i.e., autosomal dominant, autosomal recessive and X-linked. The autosomal dominant ataxias, also called the spinocerebellar ataxias, are usually identified as SCA1 through SCA37. Also included are several “episodic ataxias”, as well as a very rare disorder known as DRPLA (dentato-rubro-pallido-luysian atrophy). This report deals with the autosomal dominant hereditary ataxias. There are fewer autosomal recessive hereditary ataxias than autosomal dominant hereditary ataxias, and X-linked forms of ataxia are very rare.IntroductionAt one time, all autosomal dominant ataxias were called Marie's ataxia and all autosomal recessive ataxias were called Friedreich's ataxia. This is no longer appropriate because there is now much more accurate information about these diseases. | Overview of Autosomal Dominant Hereditary Ataxia. SummaryThe hereditary ataxias are a group of neurological disorders (ataxias) of varying degrees of rarity that are inherited, in contrast to a related group of neurological disorders that are acquired through accidents, injuries, or other external agents. The hereditary ataxias are characterized by degenerative changes in the brain and spinal cord that lead to an awkward, uncoordinated walk (gait) accompanied often by poor eye-hand coordination and abnormal speech (dysarthria). Hereditary ataxia in one or another of its forms may present at almost any time between infancy and adulthood.The classification of hereditary ataxias is complex with several schools of thought vying for recognition. This report follows the classification presented by Dr. Thomas D. Bird and the University of Washington's GeneReviews.This classification is based on the pattern of inheritance or mode of genetic transmission of the disorder: i.e., autosomal dominant, autosomal recessive and X-linked. The autosomal dominant ataxias, also called the spinocerebellar ataxias, are usually identified as SCA1 through SCA37. Also included are several “episodic ataxias”, as well as a very rare disorder known as DRPLA (dentato-rubro-pallido-luysian atrophy). This report deals with the autosomal dominant hereditary ataxias. There are fewer autosomal recessive hereditary ataxias than autosomal dominant hereditary ataxias, and X-linked forms of ataxia are very rare.IntroductionAt one time, all autosomal dominant ataxias were called Marie's ataxia and all autosomal recessive ataxias were called Friedreich's ataxia. This is no longer appropriate because there is now much more accurate information about these diseases. | 128 | Autosomal Dominant Hereditary Ataxia |
nord_128_1 | Symptoms of Autosomal Dominant Hereditary Ataxia | Ataxia is most often associated with degeneration of the region of the brain known as the cerebellum where movement, posture, and balance are coordinated. Thus, many of the symptoms and signs are those expected from cerebellar dysfunction. Ataxia may also be associated with damage (lesions) to the spinal cord. Symptoms and signs often include a characteristic wide-based and unsteady way of walking (gait) that may be accompanied by awkward eye-hand coordination and slow, weak, or imprecise speech.Other symptoms and signs may include involuntary eye movement (nystagmus) or double vision (diplopia), sensory loss, and cognitive impairment.
Some types of ataxia may be complicated by vision disorders including optic atrophy, retinitis pigmentosa, and eye movement paralysis (ophthalmoplegia).Other types of hereditary ataxia may be associated with heart disease, breathing problems, bone abnormalities and diabetes.Some clinical features that may be associated with specific forms of autosomal dominant hereditary ataxia are listed below. In this list, SCA refers to spinocerebellar ataxia; DRPLA refers to dentato-rubro-pallido-luysian atrophy; EA refers to episodic ataxia; and SAX refers to spastic ataxia.SCA1: Tremors of the hands (Parkinson-like), numbness in fingers and toes (peripheral neuropathy)SCA2: Involuntary, irregular eye movements that occur when changing focus from one point to another (saccade), numbness of fingers and toes (peripheral neuropathy), loss of deep tendon reflexes such as at the kneecap, sometimes dementiaSCA3 (Machado Joseph Disease): Hand tremors, some rigidity, slowness of movement (extrapyramidal signs), involuntary eye movement (nystagmus), drawn back eyelids (lid retraction), numbness (sensory loss), eye jerking (saccade), muscle weakness and wasting (amyotrophy) with muscle twitches, most common dominant genetic ataxiaSCA4: Progressive painless clumsiness, muscle weakness and atrophySCA5: Early onset and slow progressionSCA6: Very slow course, usually adult onsetSCA7: Damage to the retina (retinopathy) with vision lossSCA8: Decreased sense of vibrationsSCA10: Occasional seizuresSCA11: Mild signs, able to walk aboutSCA12: Early tremor, late dementiaSCA13: Mild intellectual disability, short statureSCA14: Slow progression of diseaseSCA15: Very slow worsening of the walk or gaitSCA16: Head tremorSCA17: Mental function declinesSCA18: Ataxia with early sensory/motor neuropathy, nystagmus, dysarthria, decreased tendon reflexesSCA19/22: Mild ataxia, spasms (myoclonus), mental deterioration and tremor, slow worsening of the walk or gaitSCA20: Early dysarthria, spasmodic dysphonia, hyperreflexia, bradykinesiaSCA21: Mild mental deteriorationSCA23: Dysarthria, abnormal eye movements, reduced vibration and position senseSCA25: Associated sensory neuropathySCA26: Dysarthria, irregular visual pursuitsSCA27: Early onset tremor, cognitive deficitsSCA28: Nystagmus, ptosisSCA29: childhood learning deficitsSCA30: Hyper reflexia, adult onsetSCA31: Normal sensation, adult onsetSCA32: Males infertileSCA34: Skin lesionsSCA35: Hyperreflexia, babinski responsesSCA36: Tongue atrophy, adult onsetSCA37: Abnormal vertical eye movementsSCA38: Adult onset, axonal neuropathySCA40: Adult onset, brisk reflexes, spasticitySCA42: Mild pyramidal signs, saccadic pursuitADCADN: Deafness, sensory loss, narcolepsyHypomyelinating leukoencephalopathy: Hypomyelination, basal ganglia atrophy, rigidity, dystonia, choreaGRID2-related spinocerebellar ataxia: Cognitive delay, abnormal eye movements, hearing lossPure cerebellar ataxia: Other family members may have frontotemporal dementia or motor neuron diseaseCerebellar atrophy with epileptic encephalopathy: Infantile seizures, intellectual deficits, microcephalyRapid-onset ataxia: Cerebellar atrophyDRPLA: Rapid, sudden involuntary movements (chorea), seizures, dementia, shocklike spasms (myoclonus), more common in JapanEA1: Involuntary, rippling, muscular motion (myokymia), startle- or exercise-induced,EA2: Involuntary rapid eye movements (nystagmus), dizziness (vertigo)EA3: Vertigo, spasticity, involuntary eye movements (vestibulo-ocular reflex), ringing in the ears (tinnitus), double vision (diplopia)EA4: Vertigo, rippling of muscles (myokymia), ringing in ears (tinnitus), double vision, and blurred visionEA5: Childhood to adolescent onsetEA6: Seizures, migraine, childhood onsetEA7: Vertigo, weakness, ? seizures, childhood to adolescent onsetCAPOS: Cerebellar ataxia, areflexia, Pes cavus, optic atrophy, sensorineural hearing loss, also alternating hemiplegiaEpisodic ataxia with neonatal epilepsy: neonatal epilepsy, later-onset episodic ataxia, autism, hypotonia, dystoniaSAX1: Progressive leg spasticity, gait ataxia | Symptoms of Autosomal Dominant Hereditary Ataxia. Ataxia is most often associated with degeneration of the region of the brain known as the cerebellum where movement, posture, and balance are coordinated. Thus, many of the symptoms and signs are those expected from cerebellar dysfunction. Ataxia may also be associated with damage (lesions) to the spinal cord. Symptoms and signs often include a characteristic wide-based and unsteady way of walking (gait) that may be accompanied by awkward eye-hand coordination and slow, weak, or imprecise speech.Other symptoms and signs may include involuntary eye movement (nystagmus) or double vision (diplopia), sensory loss, and cognitive impairment.
Some types of ataxia may be complicated by vision disorders including optic atrophy, retinitis pigmentosa, and eye movement paralysis (ophthalmoplegia).Other types of hereditary ataxia may be associated with heart disease, breathing problems, bone abnormalities and diabetes.Some clinical features that may be associated with specific forms of autosomal dominant hereditary ataxia are listed below. In this list, SCA refers to spinocerebellar ataxia; DRPLA refers to dentato-rubro-pallido-luysian atrophy; EA refers to episodic ataxia; and SAX refers to spastic ataxia.SCA1: Tremors of the hands (Parkinson-like), numbness in fingers and toes (peripheral neuropathy)SCA2: Involuntary, irregular eye movements that occur when changing focus from one point to another (saccade), numbness of fingers and toes (peripheral neuropathy), loss of deep tendon reflexes such as at the kneecap, sometimes dementiaSCA3 (Machado Joseph Disease): Hand tremors, some rigidity, slowness of movement (extrapyramidal signs), involuntary eye movement (nystagmus), drawn back eyelids (lid retraction), numbness (sensory loss), eye jerking (saccade), muscle weakness and wasting (amyotrophy) with muscle twitches, most common dominant genetic ataxiaSCA4: Progressive painless clumsiness, muscle weakness and atrophySCA5: Early onset and slow progressionSCA6: Very slow course, usually adult onsetSCA7: Damage to the retina (retinopathy) with vision lossSCA8: Decreased sense of vibrationsSCA10: Occasional seizuresSCA11: Mild signs, able to walk aboutSCA12: Early tremor, late dementiaSCA13: Mild intellectual disability, short statureSCA14: Slow progression of diseaseSCA15: Very slow worsening of the walk or gaitSCA16: Head tremorSCA17: Mental function declinesSCA18: Ataxia with early sensory/motor neuropathy, nystagmus, dysarthria, decreased tendon reflexesSCA19/22: Mild ataxia, spasms (myoclonus), mental deterioration and tremor, slow worsening of the walk or gaitSCA20: Early dysarthria, spasmodic dysphonia, hyperreflexia, bradykinesiaSCA21: Mild mental deteriorationSCA23: Dysarthria, abnormal eye movements, reduced vibration and position senseSCA25: Associated sensory neuropathySCA26: Dysarthria, irregular visual pursuitsSCA27: Early onset tremor, cognitive deficitsSCA28: Nystagmus, ptosisSCA29: childhood learning deficitsSCA30: Hyper reflexia, adult onsetSCA31: Normal sensation, adult onsetSCA32: Males infertileSCA34: Skin lesionsSCA35: Hyperreflexia, babinski responsesSCA36: Tongue atrophy, adult onsetSCA37: Abnormal vertical eye movementsSCA38: Adult onset, axonal neuropathySCA40: Adult onset, brisk reflexes, spasticitySCA42: Mild pyramidal signs, saccadic pursuitADCADN: Deafness, sensory loss, narcolepsyHypomyelinating leukoencephalopathy: Hypomyelination, basal ganglia atrophy, rigidity, dystonia, choreaGRID2-related spinocerebellar ataxia: Cognitive delay, abnormal eye movements, hearing lossPure cerebellar ataxia: Other family members may have frontotemporal dementia or motor neuron diseaseCerebellar atrophy with epileptic encephalopathy: Infantile seizures, intellectual deficits, microcephalyRapid-onset ataxia: Cerebellar atrophyDRPLA: Rapid, sudden involuntary movements (chorea), seizures, dementia, shocklike spasms (myoclonus), more common in JapanEA1: Involuntary, rippling, muscular motion (myokymia), startle- or exercise-induced,EA2: Involuntary rapid eye movements (nystagmus), dizziness (vertigo)EA3: Vertigo, spasticity, involuntary eye movements (vestibulo-ocular reflex), ringing in the ears (tinnitus), double vision (diplopia)EA4: Vertigo, rippling of muscles (myokymia), ringing in ears (tinnitus), double vision, and blurred visionEA5: Childhood to adolescent onsetEA6: Seizures, migraine, childhood onsetEA7: Vertigo, weakness, ? seizures, childhood to adolescent onsetCAPOS: Cerebellar ataxia, areflexia, Pes cavus, optic atrophy, sensorineural hearing loss, also alternating hemiplegiaEpisodic ataxia with neonatal epilepsy: neonatal epilepsy, later-onset episodic ataxia, autism, hypotonia, dystoniaSAX1: Progressive leg spasticity, gait ataxia | 128 | Autosomal Dominant Hereditary Ataxia |
nord_128_2 | Causes of Autosomal Dominant Hereditary Ataxia | As noted above, some forms of the hereditary ataxias are transmitted in a dominant mode, others are transmitted through a recessive mode, and still others are transmitted in an X-linked fashion. This report deals with the disorders transmitted in an autosomal dominant fashion.For many of the ataxias, the chromosomal site of the faulty gene is known or the actual gene involved has been identified. These are listed below for autosomal dominant hereditary ataxias. Little p indicated the short arm of the chromosome, little q represents the long arm of the chromosome. SCA1: 6p23; ATXN1
SCA2: 12q24; ATXN2
SCA3: 14q24.3-q31; ATXN3
SCA4: 16q22.1
SCA5: 11p11-q11; SPTBN2
SCA6: 19p13; CACNA1A
SCA7: 3p21.1-p12; ATXN7
SCA8: 13q21; ATXN8 / ATXN80S
SCA10: 22q13; ATXN10
SCA11: 15q14-q21.3; TTBK2
SCA12: 5q31-q33; PPP2R2B
SCA13: 19q13.3-q13.4; KCNC3
SCA14: 19q13.4-qter; PRKCG
SCA15: ITPR1
SCA16: 8q22.1-q24.1; SCA16
SCA17: 6q27; TBP
SCA18: IFRD1
SCA19/22: KCND3
SCA20: 11q12.2-11q12.3
SCA21: 7p21-p15; TMEM240
SCA22: 1p21-q23; KND3
SCA23: PDYN
SCA25: 2p15-21; SCA25
SCA26: 19p13.3; EEF2
SCA27: FGF14
SCA28: AFG3L2
SCA29: 3p26; ITPR1
SCA30: 4q34.3-q35.1
SCA31: BEAN1
SCA32: 7q32
SCA34: 6p12.3-q16.2; ELOVL4
SCA35: TGM6
SCA36: NOP56
SCA37:1p32
SCA38: ELOVL5
SCA40: CCDC88C
SCA42: CACNA1G
DRPLA: 12p13.31; ATN1
ADCADN: DNMT1
Hypomyelinating leukoencephalopathy: TUBB4A
GRID2-related spinocerebellar ataxia: GRID2
Pure Cerebellar Ataxia: C9orf72
Cerebellar atrophy with epileptic encephalopathy: FGF12
Rapid-onset ataxia: ATP1A3
EA1: 12p13; KCNA1
EA2: 19p13; CACNA1A
2q22-q23; CACNB4
EA3: 1q42
EA5: CACNB4
EA6: SLC1A3
EA7: 1q13
Episodic ataxia with neonatal epilepsy: SCN2A
CAPOS: ATP1A3
SAX1: 12p13; VAMP1Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p11-q11” refers to a region between band 11 on the short arm of chromosome 11 and band 11 on the long arm of chromosome 11. 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.
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 regardless of the gender of the resulting child.Autosomal dominant hereditary ataxias have been further classified as trinucleotide repeat disorders. A trinucleotide repeat is a segment of DNA that is repeated. An abnormally large number of repeated segments of DNA can interfere with normal protein function. Trinucleotide repeats are unstable and can change in length when a gene containing them is passed to the next generation. An increased number of repeats often leads to an earlier age of onset and more severe disease.Some forms of ataxia are not hereditary and can occur as a result of severe infections or side effects of drugs or alcohol. In many cases, ataxia is a symptom of another neurological disorder rather than a distinct and separate illness. | Causes of Autosomal Dominant Hereditary Ataxia. As noted above, some forms of the hereditary ataxias are transmitted in a dominant mode, others are transmitted through a recessive mode, and still others are transmitted in an X-linked fashion. This report deals with the disorders transmitted in an autosomal dominant fashion.For many of the ataxias, the chromosomal site of the faulty gene is known or the actual gene involved has been identified. These are listed below for autosomal dominant hereditary ataxias. Little p indicated the short arm of the chromosome, little q represents the long arm of the chromosome. SCA1: 6p23; ATXN1
SCA2: 12q24; ATXN2
SCA3: 14q24.3-q31; ATXN3
SCA4: 16q22.1
SCA5: 11p11-q11; SPTBN2
SCA6: 19p13; CACNA1A
SCA7: 3p21.1-p12; ATXN7
SCA8: 13q21; ATXN8 / ATXN80S
SCA10: 22q13; ATXN10
SCA11: 15q14-q21.3; TTBK2
SCA12: 5q31-q33; PPP2R2B
SCA13: 19q13.3-q13.4; KCNC3
SCA14: 19q13.4-qter; PRKCG
SCA15: ITPR1
SCA16: 8q22.1-q24.1; SCA16
SCA17: 6q27; TBP
SCA18: IFRD1
SCA19/22: KCND3
SCA20: 11q12.2-11q12.3
SCA21: 7p21-p15; TMEM240
SCA22: 1p21-q23; KND3
SCA23: PDYN
SCA25: 2p15-21; SCA25
SCA26: 19p13.3; EEF2
SCA27: FGF14
SCA28: AFG3L2
SCA29: 3p26; ITPR1
SCA30: 4q34.3-q35.1
SCA31: BEAN1
SCA32: 7q32
SCA34: 6p12.3-q16.2; ELOVL4
SCA35: TGM6
SCA36: NOP56
SCA37:1p32
SCA38: ELOVL5
SCA40: CCDC88C
SCA42: CACNA1G
DRPLA: 12p13.31; ATN1
ADCADN: DNMT1
Hypomyelinating leukoencephalopathy: TUBB4A
GRID2-related spinocerebellar ataxia: GRID2
Pure Cerebellar Ataxia: C9orf72
Cerebellar atrophy with epileptic encephalopathy: FGF12
Rapid-onset ataxia: ATP1A3
EA1: 12p13; KCNA1
EA2: 19p13; CACNA1A
2q22-q23; CACNB4
EA3: 1q42
EA5: CACNB4
EA6: SLC1A3
EA7: 1q13
Episodic ataxia with neonatal epilepsy: SCN2A
CAPOS: ATP1A3
SAX1: 12p13; VAMP1Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p11-q11” refers to a region between band 11 on the short arm of chromosome 11 and band 11 on the long arm of chromosome 11. 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.
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 regardless of the gender of the resulting child.Autosomal dominant hereditary ataxias have been further classified as trinucleotide repeat disorders. A trinucleotide repeat is a segment of DNA that is repeated. An abnormally large number of repeated segments of DNA can interfere with normal protein function. Trinucleotide repeats are unstable and can change in length when a gene containing them is passed to the next generation. An increased number of repeats often leads to an earlier age of onset and more severe disease.Some forms of ataxia are not hereditary and can occur as a result of severe infections or side effects of drugs or alcohol. In many cases, ataxia is a symptom of another neurological disorder rather than a distinct and separate illness. | 128 | Autosomal Dominant Hereditary Ataxia |
nord_128_3 | Affects of Autosomal Dominant Hereditary Ataxia | Hereditary ataxias affect males and females in equal numbers. It is estimated that 150,000 people in the United States are affected by, or at risk for, hereditary ataxia. There is variation among the specific forms of hereditary ataxia as to when they typically first appear. Some ataxias are more common in certain ethnic groups. For example, SCA3 is more common in the Portuguese population, SCA10 is more common in the Mexican population, and DRPLA is more common in Japan. | Affects of Autosomal Dominant Hereditary Ataxia. Hereditary ataxias affect males and females in equal numbers. It is estimated that 150,000 people in the United States are affected by, or at risk for, hereditary ataxia. There is variation among the specific forms of hereditary ataxia as to when they typically first appear. Some ataxias are more common in certain ethnic groups. For example, SCA3 is more common in the Portuguese population, SCA10 is more common in the Mexican population, and DRPLA is more common in Japan. | 128 | Autosomal Dominant Hereditary Ataxia |
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