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Causes of Mixed Cryoglobulinemia
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Mixed cryoglobulinemia is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunogic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of mixed cryoglobulinemia have not been conclusively identified.Mixed cryoglobulinemia has been associated with various infectious agents and immune disorders. In the majority of cases, chronic infection with the hepatitis C virus is believed to play a role the development of the disorder. Mixed cryoglobulinemia affects approximately 30%-50% of individuals with chronic hepatitis C infection. However, only 10%-30% of those individuals actually develop symptoms of mixed cryoglobulinemia (although their blood contains abnormal cryoglobulins). Why some individuals with hepatitis C virus infection develop symptomatic mixed cryoglobulinemia and others do not, is not fully understood.Additionally, mixed cryoglobulinemia has been associated with other disorders including systemic lupus erythematosus, Sjogren’s syndrome, human immunodeficiency virus (HIV), rheumatoid arthritis, and, in extremely rare cases, lymphoma. In less than 5% of cases, mixed cryoglobulinemia has been associated with infection with the hepatitis B virus. In rare cases, no underlying disorder can be identified in affected individuals. These individuals are referred to as having essential mixed cryoglobulinemia. The number of individuals diagnosed with essential mixed cryoglobulinemia has dramatically decreased since the association with the hepatitis C virus was established.The symptoms of mixed cryoglobulinemia are caused by deposition of abnormal immune complexes (cryoglobulins) in the blood vessels and surrounding tissues of the body. These large immune complexes stick to the walls of the blood vessels restricting blood flow to various organs. In addition, they may cause an immune system response, in which white blood cells are sent to the affected blood vessels, causing inflammation and damage to the blood vessels and surrounding tissue.
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Causes of Mixed Cryoglobulinemia. Mixed cryoglobulinemia is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunogic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of mixed cryoglobulinemia have not been conclusively identified.Mixed cryoglobulinemia has been associated with various infectious agents and immune disorders. In the majority of cases, chronic infection with the hepatitis C virus is believed to play a role the development of the disorder. Mixed cryoglobulinemia affects approximately 30%-50% of individuals with chronic hepatitis C infection. However, only 10%-30% of those individuals actually develop symptoms of mixed cryoglobulinemia (although their blood contains abnormal cryoglobulins). Why some individuals with hepatitis C virus infection develop symptomatic mixed cryoglobulinemia and others do not, is not fully understood.Additionally, mixed cryoglobulinemia has been associated with other disorders including systemic lupus erythematosus, Sjogren’s syndrome, human immunodeficiency virus (HIV), rheumatoid arthritis, and, in extremely rare cases, lymphoma. In less than 5% of cases, mixed cryoglobulinemia has been associated with infection with the hepatitis B virus. In rare cases, no underlying disorder can be identified in affected individuals. These individuals are referred to as having essential mixed cryoglobulinemia. The number of individuals diagnosed with essential mixed cryoglobulinemia has dramatically decreased since the association with the hepatitis C virus was established.The symptoms of mixed cryoglobulinemia are caused by deposition of abnormal immune complexes (cryoglobulins) in the blood vessels and surrounding tissues of the body. These large immune complexes stick to the walls of the blood vessels restricting blood flow to various organs. In addition, they may cause an immune system response, in which white blood cells are sent to the affected blood vessels, causing inflammation and damage to the blood vessels and surrounding tissue.
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Mixed Cryoglobulinemia
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Affects of Mixed Cryoglobulinemia
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Mixed cryoglobulinemia is believed to be a rare disorder, but the exact incidence and prevalence in the general population is unknown. Less than 1% of HCV-infected patients in Northern Europe and North America develop cryoglobulinemia while 2-5% of HCV-infected patients in South Europe develop the disorder. Mixed cryoglobulinemia most often presents in individuals between the ages of 40-60. Females are affected three times as often as males. Approximately 90% of cases of mixed cryoglobulinemia are associated with infection with the hepatitis C virus.
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Affects of Mixed Cryoglobulinemia. Mixed cryoglobulinemia is believed to be a rare disorder, but the exact incidence and prevalence in the general population is unknown. Less than 1% of HCV-infected patients in Northern Europe and North America develop cryoglobulinemia while 2-5% of HCV-infected patients in South Europe develop the disorder. Mixed cryoglobulinemia most often presents in individuals between the ages of 40-60. Females are affected three times as often as males. Approximately 90% of cases of mixed cryoglobulinemia are associated with infection with the hepatitis C virus.
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Mixed Cryoglobulinemia
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Related disorders of Mixed Cryoglobulinemia
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Symptoms of the following disorders can be similar to those of mixed cryoglobulinemia. Comparisons may be useful for a differential diagnosis.There are numerous disorders that overlap, occur in conjunction with or have signs and symptoms that are similar to cryoglobulinemia. These disorders include Sjogren’s syndrome, rheumatoid arthritis, B-cell lymphomas, autoimmune hepatitis, systemic lupus erythematosus, Waldenstrom’s macroglobulinemia, multiple myeloma, hemolytic uremic syndrome, antiophospholipid syndrome, and polyarteritis nodosa. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Mixed Cryoglobulinemia. Symptoms of the following disorders can be similar to those of mixed cryoglobulinemia. Comparisons may be useful for a differential diagnosis.There are numerous disorders that overlap, occur in conjunction with or have signs and symptoms that are similar to cryoglobulinemia. These disorders include Sjogren’s syndrome, rheumatoid arthritis, B-cell lymphomas, autoimmune hepatitis, systemic lupus erythematosus, Waldenstrom’s macroglobulinemia, multiple myeloma, hemolytic uremic syndrome, antiophospholipid syndrome, and polyarteritis nodosa. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Mixed Cryoglobulinemia
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Diagnosis of Mixed Cryoglobulinemia
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A diagnosis of mixed cryoglobulinemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a blood test to detect the presence of cryoglobulins.Clinical Testing and WorkupThe key test for mixed cryoglobulinemia is a blood test. When a blood sample is taken, its temperature is 37 Celsius. It is essential that the sample remains at this temperature until it is placed in a room-temperature centrifuge. Usually, the sample will be stored in a water bath or a container that preserves the sample at body temperature. The sample may be required to be stored for 5-7 days. Eventually, the sample will be spun down in the centrifuge to separate out the cells. If cryoglobulinemia is present, this will cause a white precipitate to form that redissolves upon rewarming.Additional routine viral and antibody tests may be performed such as a test to detect rheumatoid factor, which is positive in 80%-90% of cases.In some cases, tests to measure the levels of certain proteins known as complement may be performed. Individuals with cryoglobulinemia often have low levels of complement (hypocomplementemia), especially low C4 levels. Blood tests can reveal characteristic low levels of complement, which can aid in a diagnosis of cryoglobulinemia.Additional tests may be performed to detect underlying disorders potentially associated with cryoglobulinemia such as liver function tests that can reveal hepatitis C virus infection.
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Diagnosis of Mixed Cryoglobulinemia. A diagnosis of mixed cryoglobulinemia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a blood test to detect the presence of cryoglobulins.Clinical Testing and WorkupThe key test for mixed cryoglobulinemia is a blood test. When a blood sample is taken, its temperature is 37 Celsius. It is essential that the sample remains at this temperature until it is placed in a room-temperature centrifuge. Usually, the sample will be stored in a water bath or a container that preserves the sample at body temperature. The sample may be required to be stored for 5-7 days. Eventually, the sample will be spun down in the centrifuge to separate out the cells. If cryoglobulinemia is present, this will cause a white precipitate to form that redissolves upon rewarming.Additional routine viral and antibody tests may be performed such as a test to detect rheumatoid factor, which is positive in 80%-90% of cases.In some cases, tests to measure the levels of certain proteins known as complement may be performed. Individuals with cryoglobulinemia often have low levels of complement (hypocomplementemia), especially low C4 levels. Blood tests can reveal characteristic low levels of complement, which can aid in a diagnosis of cryoglobulinemia.Additional tests may be performed to detect underlying disorders potentially associated with cryoglobulinemia such as liver function tests that can reveal hepatitis C virus infection.
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Mixed Cryoglobulinemia
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Therapies of Mixed Cryoglobulinemia
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TreatmentThe treatment of mixed cryoglobulinemia may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, kidney specialists (nephrologists), liver specialists (hepatologists), specialists in diagnosing and treating blood disorders (hematologists), and other healthcare professionals may need to systematically and comprehensively plan an affect individual’s treatment.Initial treatment is directed against the underlying condition associated with the disorder, which in most cases will be infection with the hepatitis C virus. Affected individuals are treated with pegylated interferon usually in conjunction with ribavirin to eradicate the hepatitis C virus. This treatment often leads to significant clinical improvement.Additional therapies are tailored to the individual patient based upon numerous factors including the severity and progression of the disease, specific organ involvement, any associated disorders, overall health, patient preference, and additional factors. These therapies may be used alone or in conjunction with one another.Immunosuppressive drugs such as corticosteroids, cyclophosphamide, or azathioprine may be used in individuals with organ involvement including vasculitis, kidney disease, neurological symptoms, or disabling skin abnormalities. These drugs require careful monitoring because they can cause virus replication. Immunosuppressive drugs may be the initial therapy in individuals without a known underlying cause to their cryoglobulinemia (essential mixed cryoglobulinemia).A newer immunosuppressive drug known as rituximab has been increasingly used for the major complications associated with mixed cryoglobulinemia (see Investigational Therapies below).Additional treatment is symptomatic and can include non-steroidal anti-inflammatories drugs (NSAIDs) for the treatment of fatigue and arthralgia. Some individuals may be treated with a low antigen complement (LAC) diet. This diet is designed to promote the clearance of circulating immune complexes (cryoglobulins) from the blood. The LAC diet is best for individuals with mild mixed cryoglobulinemia and often used in conjunction with low doses of corticosteroids.
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Therapies of Mixed Cryoglobulinemia. TreatmentThe treatment of mixed cryoglobulinemia may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, neurologists, kidney specialists (nephrologists), liver specialists (hepatologists), specialists in diagnosing and treating blood disorders (hematologists), and other healthcare professionals may need to systematically and comprehensively plan an affect individual’s treatment.Initial treatment is directed against the underlying condition associated with the disorder, which in most cases will be infection with the hepatitis C virus. Affected individuals are treated with pegylated interferon usually in conjunction with ribavirin to eradicate the hepatitis C virus. This treatment often leads to significant clinical improvement.Additional therapies are tailored to the individual patient based upon numerous factors including the severity and progression of the disease, specific organ involvement, any associated disorders, overall health, patient preference, and additional factors. These therapies may be used alone or in conjunction with one another.Immunosuppressive drugs such as corticosteroids, cyclophosphamide, or azathioprine may be used in individuals with organ involvement including vasculitis, kidney disease, neurological symptoms, or disabling skin abnormalities. These drugs require careful monitoring because they can cause virus replication. Immunosuppressive drugs may be the initial therapy in individuals without a known underlying cause to their cryoglobulinemia (essential mixed cryoglobulinemia).A newer immunosuppressive drug known as rituximab has been increasingly used for the major complications associated with mixed cryoglobulinemia (see Investigational Therapies below).Additional treatment is symptomatic and can include non-steroidal anti-inflammatories drugs (NSAIDs) for the treatment of fatigue and arthralgia. Some individuals may be treated with a low antigen complement (LAC) diet. This diet is designed to promote the clearance of circulating immune complexes (cryoglobulins) from the blood. The LAC diet is best for individuals with mild mixed cryoglobulinemia and often used in conjunction with low doses of corticosteroids.
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Mixed Cryoglobulinemia
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Overview of MN1 C-Terminal Truncation Syndrome
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SummaryMN1 C-terminal truncation (MCTT) syndrome is a rare autosomal dominant genetic disorder caused by a genetic change at one end (the C-terminal) of the MN1 gene. The genetic disorder is characterized by intellectual disability with delayed or absent speech, delayed gross motor development, distinctive structural changes in the brain (rhombencephalosynapsis), unique facial features, and hearing loss. This new syndrome was first reported in 2020. There is ongoing research to better understand the spectrum of symptoms, the long-term prognosis, and gather knowledge to provide the most appropriate genetic counseling.
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Overview of MN1 C-Terminal Truncation Syndrome. SummaryMN1 C-terminal truncation (MCTT) syndrome is a rare autosomal dominant genetic disorder caused by a genetic change at one end (the C-terminal) of the MN1 gene. The genetic disorder is characterized by intellectual disability with delayed or absent speech, delayed gross motor development, distinctive structural changes in the brain (rhombencephalosynapsis), unique facial features, and hearing loss. This new syndrome was first reported in 2020. There is ongoing research to better understand the spectrum of symptoms, the long-term prognosis, and gather knowledge to provide the most appropriate genetic counseling.
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MN1 C-Terminal Truncation Syndrome
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Symptoms of MN1 C-Terminal Truncation Syndrome
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The symptoms and physical findings associated with MCTT syndrome may vary from one person to another (variable expression). Affected individuals or parents of affected children should talk to their physicians and consult with a medical genetics team about their specific case and associated symptoms. To date, a total of 25 patients have been reported in the medical literature, but other patients are known anecdotally. The majority individuals with MCTT syndrome have mild to moderate intellectual disability and severe expressive language delay or absent speech. Most have gross motor delay but are able to walk independently at a later age. Some individuals have mild to moderate hearing impairment of conductive and/or sensorineural nature. Low muscle strength, also known as floppy baby (hypotonia) and feeding difficulty due to poor ability to suck are also frequently seen during infancy. The height and weight (growth parameters) of affected children are typically normal. Individuals with MCTT syndrome may have distinctive imaging findings of the brain. Magnetic resonance imaging (MRI) shows abnormal development of the cerebral cortex (perisylvian polymicrogyria and/or cortical dysplasia), fusion of the structures in cerebellum (rhombencephalosynapsis), and the presence of embryonic vessel construction (persistent trigeminal artery) that may be important when considering surgical approaches. Characteristic features of the head and facial (craniofacial) region include tall forehead, flattened midface, prominent eyes, widely set eyes (hypertelorism), downslanting eyes, low-set ears with abnormal shape, and a short, upturned nose especially in infancy. Skull shape abnormality is also frequently observed. Some will have premature fusion of skull bones (craniosynostosis) which may require surgical intervention. Neurosurgical care should be customized. Abnormality of the curvature of the spine (scoliosis/lordosis/kyphosis), congenital structural heart defects, seizures, and behavioral problems have been observed in some individuals with MCTT syndrome. Due to the limited case reports of MCTT syndrome, it is unknown if the life span of individuals with MCTT syndrome is affected. The oldest individual known to the authors is a healthy male in his late 30’s who lives a full life under the care of his family, demonstrating survival into adulthood is probable. It is likely that MCTT syndrome is both underrecognized and underreported in adults.
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Symptoms of MN1 C-Terminal Truncation Syndrome. The symptoms and physical findings associated with MCTT syndrome may vary from one person to another (variable expression). Affected individuals or parents of affected children should talk to their physicians and consult with a medical genetics team about their specific case and associated symptoms. To date, a total of 25 patients have been reported in the medical literature, but other patients are known anecdotally. The majority individuals with MCTT syndrome have mild to moderate intellectual disability and severe expressive language delay or absent speech. Most have gross motor delay but are able to walk independently at a later age. Some individuals have mild to moderate hearing impairment of conductive and/or sensorineural nature. Low muscle strength, also known as floppy baby (hypotonia) and feeding difficulty due to poor ability to suck are also frequently seen during infancy. The height and weight (growth parameters) of affected children are typically normal. Individuals with MCTT syndrome may have distinctive imaging findings of the brain. Magnetic resonance imaging (MRI) shows abnormal development of the cerebral cortex (perisylvian polymicrogyria and/or cortical dysplasia), fusion of the structures in cerebellum (rhombencephalosynapsis), and the presence of embryonic vessel construction (persistent trigeminal artery) that may be important when considering surgical approaches. Characteristic features of the head and facial (craniofacial) region include tall forehead, flattened midface, prominent eyes, widely set eyes (hypertelorism), downslanting eyes, low-set ears with abnormal shape, and a short, upturned nose especially in infancy. Skull shape abnormality is also frequently observed. Some will have premature fusion of skull bones (craniosynostosis) which may require surgical intervention. Neurosurgical care should be customized. Abnormality of the curvature of the spine (scoliosis/lordosis/kyphosis), congenital structural heart defects, seizures, and behavioral problems have been observed in some individuals with MCTT syndrome. Due to the limited case reports of MCTT syndrome, it is unknown if the life span of individuals with MCTT syndrome is affected. The oldest individual known to the authors is a healthy male in his late 30’s who lives a full life under the care of his family, demonstrating survival into adulthood is probable. It is likely that MCTT syndrome is both underrecognized and underreported in adults.
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Causes of MN1 C-Terminal Truncation Syndrome
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MCTT syndrome is caused by a disease-causing mutation at the “C-terminal” of the MN1 gene which terminates the protein product prematurely. When such a disease-causing (pathogenic) change occurs, the protein product may absent, insufficient or faulty. Different organ systems could be affected depending on the function and place of action of the affected protein. In MCTT syndrome, the genetic change creates an abnormal protein that is shorter than usual, and this affects its usual dynamic and interaction within the body, in particular the development of the brain. Therefore, the symptoms of the syndrome are largely related to neurodevelopmental issues. Several disease-causing genetic changes have been reported in the medical literature. These alterations usually occur in de novo fashion, meaning that the change is new and not inherited from either parent. The likelihood of these parents having another child with the same syndrome is low. MCTT syndrome follows an autosomal dominant inheritance pattern, so one disease-causing genetic change is sufficient to cause the disease. An individual with a disease causing change in the MN1 gene has a 50% chance in each pregnancy of passing the change to his/her offspring. The risk is the same for male and female children. In very rare cases, a parent with a MN1 pathogenic gene variant in some body and reproductive cells (somatic and germline mosaicism) may be mildly or minimally affected. Only one such case has been ever reported, where the father carried a mosaic mutation, had two affected siblings and presented with mild features of dysplastic ears and a high and narrow palate. In such circumstances, individuals are recommended to seek the advice of a clinical geneticist for genetic evaluation and counseling, and to discuss reproductive options and any concerns regarding potential risks to future children.
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Causes of MN1 C-Terminal Truncation Syndrome. MCTT syndrome is caused by a disease-causing mutation at the “C-terminal” of the MN1 gene which terminates the protein product prematurely. When such a disease-causing (pathogenic) change occurs, the protein product may absent, insufficient or faulty. Different organ systems could be affected depending on the function and place of action of the affected protein. In MCTT syndrome, the genetic change creates an abnormal protein that is shorter than usual, and this affects its usual dynamic and interaction within the body, in particular the development of the brain. Therefore, the symptoms of the syndrome are largely related to neurodevelopmental issues. Several disease-causing genetic changes have been reported in the medical literature. These alterations usually occur in de novo fashion, meaning that the change is new and not inherited from either parent. The likelihood of these parents having another child with the same syndrome is low. MCTT syndrome follows an autosomal dominant inheritance pattern, so one disease-causing genetic change is sufficient to cause the disease. An individual with a disease causing change in the MN1 gene has a 50% chance in each pregnancy of passing the change to his/her offspring. The risk is the same for male and female children. In very rare cases, a parent with a MN1 pathogenic gene variant in some body and reproductive cells (somatic and germline mosaicism) may be mildly or minimally affected. Only one such case has been ever reported, where the father carried a mosaic mutation, had two affected siblings and presented with mild features of dysplastic ears and a high and narrow palate. In such circumstances, individuals are recommended to seek the advice of a clinical geneticist for genetic evaluation and counseling, and to discuss reproductive options and any concerns regarding potential risks to future children.
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MN1 C-Terminal Truncation Syndrome
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Affects of MN1 C-Terminal Truncation Syndrome
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MCTT syndrome was first identified by two groups of researchers in 2020, reporting 22 and 3 individuals, respectively. With the increasing availability of genetic testing and recognition of the syndrome, more patients have been identified. However, many individuals may still be undiagnosed. Patients have been identified from various parts of the world and among different ethnic backgrounds. Males and females are affected equally.
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Affects of MN1 C-Terminal Truncation Syndrome. MCTT syndrome was first identified by two groups of researchers in 2020, reporting 22 and 3 individuals, respectively. With the increasing availability of genetic testing and recognition of the syndrome, more patients have been identified. However, many individuals may still be undiagnosed. Patients have been identified from various parts of the world and among different ethnic backgrounds. Males and females are affected equally.
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MN1 C-Terminal Truncation Syndrome
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Related disorders of MN1 C-Terminal Truncation Syndrome
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Gomez-Lopez-Hernandez syndrome (GLHS) is a rare syndrome which shares some similar symptoms with MCTT syndrome. Individuals with GLHS have skull shape abnormalities, craniosynostosis and rhombencephalosynapsis. Unlike MCTT syndrome, they have additional symptoms of the scalp (alopecia) and nerve (trigeminal anesthesia). The genetic cause of GLHS is unknown, and people who have had this diagnosis for many years should have a new genetic evaluation. It is possible that a person with this diagnosis may have an MN1 gene mutation.
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Related disorders of MN1 C-Terminal Truncation Syndrome. Gomez-Lopez-Hernandez syndrome (GLHS) is a rare syndrome which shares some similar symptoms with MCTT syndrome. Individuals with GLHS have skull shape abnormalities, craniosynostosis and rhombencephalosynapsis. Unlike MCTT syndrome, they have additional symptoms of the scalp (alopecia) and nerve (trigeminal anesthesia). The genetic cause of GLHS is unknown, and people who have had this diagnosis for many years should have a new genetic evaluation. It is possible that a person with this diagnosis may have an MN1 gene mutation.
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MN1 C-Terminal Truncation Syndrome
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Diagnosis of MN1 C-Terminal Truncation Syndrome
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MCTT syndrome is usually diagnosed in early childhood or at a later age by the identification of characteristic symptoms, a detailed patient and family history and a thorough clinical evaluation and investigation. The diagnosis of MCTT syndrome is confirmed by identifying a disease-causing genetic change at the C-terminal of the MN1 gene. This could be achieved by performing targeted genetic testing (MN1 sequencing) or comprehensive genomic testing (exome sequencing/ genome sequencing).
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Diagnosis of MN1 C-Terminal Truncation Syndrome. MCTT syndrome is usually diagnosed in early childhood or at a later age by the identification of characteristic symptoms, a detailed patient and family history and a thorough clinical evaluation and investigation. The diagnosis of MCTT syndrome is confirmed by identifying a disease-causing genetic change at the C-terminal of the MN1 gene. This could be achieved by performing targeted genetic testing (MN1 sequencing) or comprehensive genomic testing (exome sequencing/ genome sequencing).
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MN1 C-Terminal Truncation Syndrome
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Therapies of MN1 C-Terminal Truncation Syndrome
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Currently, there is no evidenced-based protocol or guidelines for treating MCTT syndrome. However, providers can offer treatment for people with MCTT based on the specific symptoms that are apparent in each individual. For developmental delay, early developmental intervention and educational training may be beneficial. Physiotherapy, occupational therapy and speech therapy are useful for most individuals. The training focus could emphasize alternative non-verbal communication methods (for example, sign language). Individuals with craniosynostosis should have a formal neurosurgical evaluation and may require surgery. Surgery is performed to improve the appearance of the child’s head. Rarely is it performed to relieve increased intracranial pressure. Surgery may not be necessary for some individuals. Hearing aids may be beneficial for individuals with hearing impairment. Individuals with seizure(s) may benefit from antiepileptic drugs as per neurologist’s assessment. Genetic counseling is recommended for affected individuals and their families.
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Therapies of MN1 C-Terminal Truncation Syndrome. Currently, there is no evidenced-based protocol or guidelines for treating MCTT syndrome. However, providers can offer treatment for people with MCTT based on the specific symptoms that are apparent in each individual. For developmental delay, early developmental intervention and educational training may be beneficial. Physiotherapy, occupational therapy and speech therapy are useful for most individuals. The training focus could emphasize alternative non-verbal communication methods (for example, sign language). Individuals with craniosynostosis should have a formal neurosurgical evaluation and may require surgery. Surgery is performed to improve the appearance of the child’s head. Rarely is it performed to relieve increased intracranial pressure. Surgery may not be necessary for some individuals. Hearing aids may be beneficial for individuals with hearing impairment. Individuals with seizure(s) may benefit from antiepileptic drugs as per neurologist’s assessment. Genetic counseling is recommended for affected individuals and their families.
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MN1 C-Terminal Truncation Syndrome
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Overview of Moebius Syndrome
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SummaryMoebius syndrome is a rare neurological disorder characterized by weakness or paralysis (palsy) of multiple cranial nerves, most often the 6th (abducens) and 7th (facial) nerves. Other cranial nerves are sometimes affected. The disorder is present at birth (congenital). If the 7th nerve is involved, the individual with Moebius syndrome is unable to smile, frown, pucker the lips, raise the eyebrows, or close the eyelids. If the 6th nerve is affected, the eye cannot turn outward past the midline. Other abnormalities include underdevelopment of the pectoral muscles and defects of the limbs. Moebius syndrome is not progressive. The exact cause is unknown. It appears to occur randomly (sporadically) in most cases; however, some cases occur in families suggesting that there may be a genetic component.IntroductionCongenital facial and abducens palsy was first described by Von Graefe (1880) and Moebius (1888), a German neurologist after whom the syndrome was later named.
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Overview of Moebius Syndrome. SummaryMoebius syndrome is a rare neurological disorder characterized by weakness or paralysis (palsy) of multiple cranial nerves, most often the 6th (abducens) and 7th (facial) nerves. Other cranial nerves are sometimes affected. The disorder is present at birth (congenital). If the 7th nerve is involved, the individual with Moebius syndrome is unable to smile, frown, pucker the lips, raise the eyebrows, or close the eyelids. If the 6th nerve is affected, the eye cannot turn outward past the midline. Other abnormalities include underdevelopment of the pectoral muscles and defects of the limbs. Moebius syndrome is not progressive. The exact cause is unknown. It appears to occur randomly (sporadically) in most cases; however, some cases occur in families suggesting that there may be a genetic component.IntroductionCongenital facial and abducens palsy was first described by Von Graefe (1880) and Moebius (1888), a German neurologist after whom the syndrome was later named.
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Moebius Syndrome
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Symptoms of Moebius Syndrome
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The abnormalities and severity of Moebius syndrome vary greatly from one person-to-another. The classically accepted diagnostic criteria include: 1) facial paralysis or weakness affecting at least one but usually both sides of the face (7th cranial nerve), 2) paralysis of sideways (lateral) movement of the eyes (6th cranial nerve); and 3) preservation of vertical movements of the eyes. Less often, other cranial nerves, including the 5th, 8th, 9th, 10th, 11th, and 12th may be affected.Infants with Moebius syndrome may drool excessively and exhibit crossed eyes (strabismus). Because the eyes do not move from side-to-side (laterally), the child is forced to turn the head to follow objects. Infants who lack facial expression often are described as having a “mask-like” face that is especially obvious when laughing or crying. Affected infants may also have difficulties feeding, including problems swallowing and poor sucking. Corneal ulceration may occur because the eyelids remain open during sleep.There are a wide variety of additional abnormalities. Some children with Moebius syndrome have a short, malformed tongue and/or an abnormally small jaw (micrognathia). Cleft palate may also be present. These abnormalities contribute to feeding and breathing difficulties. Children with cleft palate are prone to ear infections (otitis media). There may be external ear anomalies including underdevelopment of the outer portion of the ear (microtia) or total absence of the outer portion of the ear (anotia). If the 8th cranial nerve is affected, there is likely hearing loss. Dental abnormalities are not uncommon. There is an increased risk for childhood cavities. Some affected children have difficulties with speech and delays in speech development. Skeletal malformations of the limbs occur in over half of children with Moebius sydrome. Lower limb malformations include clubbed feet and underdevelopment of the lower legs; upper extremities may have webbing of the fingers (syndactyly), underdevelopment or absence of the fingers, and/or underdevelopment of the hand. In a few children there may be abnormal side-to-side curvature of the spine (scoliosis), and in approximately 15% of patients underdevelopment of the chest (pectoral) muscles and the breast on one side of the body also occur (see Poland-Moebius syndrome in the Related Disorder section below).Some affected children exhibit delay in attaining certain milestones such as crawling or walking, most likely due to upper body weakness; however, most children eventually catch-up. Moebius syndrome rarely is associated with minor intellectual disability. Some children have been classified as being on the “autistic spectrum”. The exact relationship between Moebius syndrome and autism is unknown. Some studies have suggested that autism spectrum disorders occur with greater frequency in children with Moebius syndrome; other studies have not confirmed this and suggest that any such relationship is overstated. Moebius syndrome is often associated with a variety of social and psychological consequences. The lack of facial expressions and the inability to smile can cause observers to misinterpret what an affected individual is thinking or feeling or intends. Although clinical anxiety and depression are not more common in children and adolescents with Moebius syndrome, affected individuals may avoid social situations due to apprehension and frustration.
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Symptoms of Moebius Syndrome. The abnormalities and severity of Moebius syndrome vary greatly from one person-to-another. The classically accepted diagnostic criteria include: 1) facial paralysis or weakness affecting at least one but usually both sides of the face (7th cranial nerve), 2) paralysis of sideways (lateral) movement of the eyes (6th cranial nerve); and 3) preservation of vertical movements of the eyes. Less often, other cranial nerves, including the 5th, 8th, 9th, 10th, 11th, and 12th may be affected.Infants with Moebius syndrome may drool excessively and exhibit crossed eyes (strabismus). Because the eyes do not move from side-to-side (laterally), the child is forced to turn the head to follow objects. Infants who lack facial expression often are described as having a “mask-like” face that is especially obvious when laughing or crying. Affected infants may also have difficulties feeding, including problems swallowing and poor sucking. Corneal ulceration may occur because the eyelids remain open during sleep.There are a wide variety of additional abnormalities. Some children with Moebius syndrome have a short, malformed tongue and/or an abnormally small jaw (micrognathia). Cleft palate may also be present. These abnormalities contribute to feeding and breathing difficulties. Children with cleft palate are prone to ear infections (otitis media). There may be external ear anomalies including underdevelopment of the outer portion of the ear (microtia) or total absence of the outer portion of the ear (anotia). If the 8th cranial nerve is affected, there is likely hearing loss. Dental abnormalities are not uncommon. There is an increased risk for childhood cavities. Some affected children have difficulties with speech and delays in speech development. Skeletal malformations of the limbs occur in over half of children with Moebius sydrome. Lower limb malformations include clubbed feet and underdevelopment of the lower legs; upper extremities may have webbing of the fingers (syndactyly), underdevelopment or absence of the fingers, and/or underdevelopment of the hand. In a few children there may be abnormal side-to-side curvature of the spine (scoliosis), and in approximately 15% of patients underdevelopment of the chest (pectoral) muscles and the breast on one side of the body also occur (see Poland-Moebius syndrome in the Related Disorder section below).Some affected children exhibit delay in attaining certain milestones such as crawling or walking, most likely due to upper body weakness; however, most children eventually catch-up. Moebius syndrome rarely is associated with minor intellectual disability. Some children have been classified as being on the “autistic spectrum”. The exact relationship between Moebius syndrome and autism is unknown. Some studies have suggested that autism spectrum disorders occur with greater frequency in children with Moebius syndrome; other studies have not confirmed this and suggest that any such relationship is overstated. Moebius syndrome is often associated with a variety of social and psychological consequences. The lack of facial expressions and the inability to smile can cause observers to misinterpret what an affected individual is thinking or feeling or intends. Although clinical anxiety and depression are not more common in children and adolescents with Moebius syndrome, affected individuals may avoid social situations due to apprehension and frustration.
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Moebius Syndrome
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Causes of Moebius Syndrome
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Most cases of Moebius syndrome occur randomly for unknown reasons (sporadically) in the absence of a family history of the disorder. The syndrome is listed as Online Mendelian Inheritance in Man (OMIM) Number 15700, with a gene map locus of 13q12.2-q13. Sporadic mutations in PLXND1 and REV3L genes have also been identified in a number of patients and confirmed to cause a constellation of findings consistent with Moebius syndrome when introduced in animal models. In rare cases, familial patterns have been reported. Most likely, Moebius syndrome is multifactorial, which means that both genetic and environmental factors play some causative role. It is possible that in different cases there are different underlying causes (heterogeneity).
In familial cases, there is evidence that Moebius syndrome is inherited as an autosomal dominant trait. 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.The spectrum of findings in Moebius syndrome suggests a developmental defect of the hindbrain. Several different theories have been proposed to explain the cause of Moebius syndrome. One hypothesis is the disorder is the result of diminished or interrupted blood flow (ischemia) to the developing fetus during pregnancy (in utero). Recent research suggests that the lack of blood affects certain areas of the lower brainstem that contain the cranial nerve nuclei. This lack of blood flow could result from an environmental, mechanical or genetic cause. Nevertheless, cause of the syndrome remains inconclusive and more basic and clinical research is necessary.
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Causes of Moebius Syndrome. Most cases of Moebius syndrome occur randomly for unknown reasons (sporadically) in the absence of a family history of the disorder. The syndrome is listed as Online Mendelian Inheritance in Man (OMIM) Number 15700, with a gene map locus of 13q12.2-q13. Sporadic mutations in PLXND1 and REV3L genes have also been identified in a number of patients and confirmed to cause a constellation of findings consistent with Moebius syndrome when introduced in animal models. In rare cases, familial patterns have been reported. Most likely, Moebius syndrome is multifactorial, which means that both genetic and environmental factors play some causative role. It is possible that in different cases there are different underlying causes (heterogeneity).
In familial cases, there is evidence that Moebius syndrome is inherited as an autosomal dominant trait. 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.The spectrum of findings in Moebius syndrome suggests a developmental defect of the hindbrain. Several different theories have been proposed to explain the cause of Moebius syndrome. One hypothesis is the disorder is the result of diminished or interrupted blood flow (ischemia) to the developing fetus during pregnancy (in utero). Recent research suggests that the lack of blood affects certain areas of the lower brainstem that contain the cranial nerve nuclei. This lack of blood flow could result from an environmental, mechanical or genetic cause. Nevertheless, cause of the syndrome remains inconclusive and more basic and clinical research is necessary.
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Moebius Syndrome
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Affects of Moebius Syndrome
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Moebius syndrome affects males and females in equal numbers. The disorder is present at birth (congenital). The exact incidence and prevalence rates of Moebius syndrome are unknown. One estimate places the incidence at 1 case per 50,000 live births in the United States.
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Affects of Moebius Syndrome. Moebius syndrome affects males and females in equal numbers. The disorder is present at birth (congenital). The exact incidence and prevalence rates of Moebius syndrome are unknown. One estimate places the incidence at 1 case per 50,000 live births in the United States.
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Related disorders of Moebius Syndrome
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Symptoms and signs of the following disorders can be similar to those of Moebius syndrome. Comparisons may be useful for a differential diagnosis.Several investigators have reported cases in which the features of Moebius syndrome occur in association with Poland syndrome. This is sometimes referred to as “Poland-Moebius syndrome”. Poland syndrome is characterized by webbing of the fingers, absence or underdevelopment of the fingers or hands, and underdevelopment of the chest muscles and breast. Poland syndrome usually occurs on only one side of the body (ipsilateral). There is debate within the medical literature as to whether Moebius syndrome, Poland syndrome and Poland-Moebius syndrome represent three distinct disorders or three different expressions of one disorder. (For more information on this disorder, choose “Poland” as your search term in the Rare Disease Database.)Hereditary congenital facial palsy (HCFP) is characterized by isolated paralysis of the facial nerve, and subsets of HCFP have other associated findings, including hearing loss and strabismus. HCFP is differentiated from Moebius syndrome by the presence of full horizontal gaze. HOXB1 mutations on chromosome 17q21 have been identified in patients with HCFP. Human HOXA1 syndromes are rare disorders with complex neurological and systemic manifestations. The range and types of clinical findings in affected patients vary widely. Affected individuals present with Duane phenomenon (“horizontal gaze palsy”), characterized by restriction in lateral eye movement. Hearing loss, developmental delays, and a spectrum of internal carotid artery and conotruncal cardiac malformations also have been documented. Facial asymmetries and minor external ear malformations are also sometimes present. Affected individuals can also show signs of cognitive and behavioral impairments and some individuals have been classified as on the autism spectrum disorder (ASD). The abnormal gene has been identified and its location on chromosome 7 has been determined. Human HOXA1 syndromes are inherited as autosomal recessive genetic conditions. (For more information on this disorder, choose “HOXA1” as your search term in the Rare Disease Database.)There are other causes of congenital facial paralysis, in particular, hemifacial microsomia and possibly birth trauma. There are also acquired types of facial palsy. Melkersson-Rosenthal syndrome is characterized by sudden onset in childhood/adolescence, of bilateral or unilateral facial weakness, chronic swelling of the face (especially the lips) and a furrowed tongue. Other possible causes are: infections such as Ramsay-Hunt syndrome; systemic and neurological disorders including cerebral palsy, congenital muscular dystrophy, spinal muscular atrophy, Guillain-Barre syndrome, multiple sclerosis and autoimmune disorders; brain trauma; and brainstem tumors or damage. (For more information on this disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Moebius Syndrome. Symptoms and signs of the following disorders can be similar to those of Moebius syndrome. Comparisons may be useful for a differential diagnosis.Several investigators have reported cases in which the features of Moebius syndrome occur in association with Poland syndrome. This is sometimes referred to as “Poland-Moebius syndrome”. Poland syndrome is characterized by webbing of the fingers, absence or underdevelopment of the fingers or hands, and underdevelopment of the chest muscles and breast. Poland syndrome usually occurs on only one side of the body (ipsilateral). There is debate within the medical literature as to whether Moebius syndrome, Poland syndrome and Poland-Moebius syndrome represent three distinct disorders or three different expressions of one disorder. (For more information on this disorder, choose “Poland” as your search term in the Rare Disease Database.)Hereditary congenital facial palsy (HCFP) is characterized by isolated paralysis of the facial nerve, and subsets of HCFP have other associated findings, including hearing loss and strabismus. HCFP is differentiated from Moebius syndrome by the presence of full horizontal gaze. HOXB1 mutations on chromosome 17q21 have been identified in patients with HCFP. Human HOXA1 syndromes are rare disorders with complex neurological and systemic manifestations. The range and types of clinical findings in affected patients vary widely. Affected individuals present with Duane phenomenon (“horizontal gaze palsy”), characterized by restriction in lateral eye movement. Hearing loss, developmental delays, and a spectrum of internal carotid artery and conotruncal cardiac malformations also have been documented. Facial asymmetries and minor external ear malformations are also sometimes present. Affected individuals can also show signs of cognitive and behavioral impairments and some individuals have been classified as on the autism spectrum disorder (ASD). The abnormal gene has been identified and its location on chromosome 7 has been determined. Human HOXA1 syndromes are inherited as autosomal recessive genetic conditions. (For more information on this disorder, choose “HOXA1” as your search term in the Rare Disease Database.)There are other causes of congenital facial paralysis, in particular, hemifacial microsomia and possibly birth trauma. There are also acquired types of facial palsy. Melkersson-Rosenthal syndrome is characterized by sudden onset in childhood/adolescence, of bilateral or unilateral facial weakness, chronic swelling of the face (especially the lips) and a furrowed tongue. Other possible causes are: infections such as Ramsay-Hunt syndrome; systemic and neurological disorders including cerebral palsy, congenital muscular dystrophy, spinal muscular atrophy, Guillain-Barre syndrome, multiple sclerosis and autoimmune disorders; brain trauma; and brainstem tumors or damage. (For more information on this disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Moebius Syndrome
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Diagnosis of Moebius Syndrome
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A diagnosis of Moebius syndrome is based upon the characteristic signs/symptoms, a detailed patient history, and a thorough clinical evaluation. There are no diagnostic tests that confirm a diagnosis of Moebius syndrome. Some specialized tests may be performed to rule out other causes of facial palsy.
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Diagnosis of Moebius Syndrome. A diagnosis of Moebius syndrome is based upon the characteristic signs/symptoms, a detailed patient history, and a thorough clinical evaluation. There are no diagnostic tests that confirm a diagnosis of Moebius syndrome. Some specialized tests may be performed to rule out other causes of facial palsy.
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Therapies of Moebius Syndrome
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TreatmentThe treatment of Moebius syndrome is directed toward the specific abnormalities in each individual. Usually these children are managed by a multidisciplinary team, often in a craniofacial center. Involved specialists include: pediatricians; neurologists; plastic surgeons; ear, nose, and throat specialists (otolaryngologists); orthopedists; dental specialists; speech pathologists; specialists who assess and treat hearing problems (audiologists), specialists who treat eye abnormalities (ophthalmologists) and other healthcare professionals.Corrective procedures for facial paralysis involve transfer of muscle and/or graft nerves from another area of the face or the body. An old procedure, known as temporalis tendon transfer, involves taking the temporalis muscle, one of the muscles normally used for chewing (mastication), and transferring it to the corners of the mouth. This same type of operation can be also used to improve closure of the eyelids. If the paralysis is on only one side (unilateral), a “cross-facial nerve graft” is an option. The procedure involves taking a sensory nerve from the calf, attaching it to a branch of the functioning facial nerve on the normal side of the face and then waiting until the regenerating nerve fibers cross over the face to reach the paralyzed side where it is joined to a motor nerve of a thin muscle transferred to the face by microvascular anastomosis.The most recent procedure, called “the smile operation”, involves microvascular transfer of a muscle from the thigh (gracillis) to the face and connecting the nerves that normally supply the masseter muscle (one of the muscles used for chewing). This operation has shown remarkable results in terms of speech, facial mobility and self-esteem. Frequent lubrication for dry eyes is often necessary.Physical therapy may be needed for individuals with various orthopedic abnormalities. Occupational therapy may also be beneficial, especially in patients with abnormalities of the hands, fingers and toes. Speech therapy may be necessary for some affected children. Strabismus is usually surgically correctable, although some physicians recommend delaying these procedures as the condition sometimes improves with age. Operations may also be necessary for the various skeletal malformations affecting the limbs and jaws. Specialized procedures to correct abnormalities and/or underdevelopment of the chest wall and breast are available.Splints, braces and prostheses may be necessary for individuals with congenital limb abnormalities. Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Moebius Syndrome. TreatmentThe treatment of Moebius syndrome is directed toward the specific abnormalities in each individual. Usually these children are managed by a multidisciplinary team, often in a craniofacial center. Involved specialists include: pediatricians; neurologists; plastic surgeons; ear, nose, and throat specialists (otolaryngologists); orthopedists; dental specialists; speech pathologists; specialists who assess and treat hearing problems (audiologists), specialists who treat eye abnormalities (ophthalmologists) and other healthcare professionals.Corrective procedures for facial paralysis involve transfer of muscle and/or graft nerves from another area of the face or the body. An old procedure, known as temporalis tendon transfer, involves taking the temporalis muscle, one of the muscles normally used for chewing (mastication), and transferring it to the corners of the mouth. This same type of operation can be also used to improve closure of the eyelids. If the paralysis is on only one side (unilateral), a “cross-facial nerve graft” is an option. The procedure involves taking a sensory nerve from the calf, attaching it to a branch of the functioning facial nerve on the normal side of the face and then waiting until the regenerating nerve fibers cross over the face to reach the paralyzed side where it is joined to a motor nerve of a thin muscle transferred to the face by microvascular anastomosis.The most recent procedure, called “the smile operation”, involves microvascular transfer of a muscle from the thigh (gracillis) to the face and connecting the nerves that normally supply the masseter muscle (one of the muscles used for chewing). This operation has shown remarkable results in terms of speech, facial mobility and self-esteem. Frequent lubrication for dry eyes is often necessary.Physical therapy may be needed for individuals with various orthopedic abnormalities. Occupational therapy may also be beneficial, especially in patients with abnormalities of the hands, fingers and toes. Speech therapy may be necessary for some affected children. Strabismus is usually surgically correctable, although some physicians recommend delaying these procedures as the condition sometimes improves with age. Operations may also be necessary for the various skeletal malformations affecting the limbs and jaws. Specialized procedures to correct abnormalities and/or underdevelopment of the chest wall and breast are available.Splints, braces and prostheses may be necessary for individuals with congenital limb abnormalities. Genetic counseling may be of benefit for affected individuals and their families.
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Moebius Syndrome
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Overview of MOG Antibody Disease
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SummaryMOG antibody disease (MOGAD) is a neurological, immune-mediated disorder in which there is inflammation in the optic nerve, spinal cord and/or brain. Myelin oligodendrocyte glycoprotein (MOG) is a protein that is located on the surface of myelin sheaths in the central nervous system. While the function of this glycoprotein is not exactly known, MOG is a target of the immune system in this disease. The diagnosis is confirmed when MOG antibodies in the blood are found in patients who have repeated inflammatory attacks of the central nervous system. The specific symptoms and severity of MOGAD can vary from one individual to another, but include issues with vision, symptoms associated with damage to the spinal cord, as well as seizures. Treatments are given at onset, and are typically intravenous steroids, plasma exchange (PLEX) or intravenous immunoglobulin (IVIG). Those with MOG antibody disease should consider ongoing treatment with medications that suppress the immune system.IntroductionThose with MOG antibody disease may previously have been diagnosed with neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON) or multiple sclerosis (MS) because of the pattern of inflammation it causes including brain, spinal cord and optic nerve damage. Patients with persistently positive antibodies to MOG are at risk for recurrent events. Those with MOG antibody disease do not test positive for the NMO antibody called aquaporin 4 (AQP-4). AQP-4 is a water channel protein and those with NMOSD produce autoantibodies against AQP-4. MOG antibody disease and AQP-4 positive NMOSD are thought to have distinct immunological mechanisms. Furthermore, those with MOG antibody disease seem to be less likely to have other autoimmune disorders (such as rheumatoid arthritis, Hashimoto’s thyroiditis, etc.) than those with AQP-4 positive NMOSD.
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Overview of MOG Antibody Disease. SummaryMOG antibody disease (MOGAD) is a neurological, immune-mediated disorder in which there is inflammation in the optic nerve, spinal cord and/or brain. Myelin oligodendrocyte glycoprotein (MOG) is a protein that is located on the surface of myelin sheaths in the central nervous system. While the function of this glycoprotein is not exactly known, MOG is a target of the immune system in this disease. The diagnosis is confirmed when MOG antibodies in the blood are found in patients who have repeated inflammatory attacks of the central nervous system. The specific symptoms and severity of MOGAD can vary from one individual to another, but include issues with vision, symptoms associated with damage to the spinal cord, as well as seizures. Treatments are given at onset, and are typically intravenous steroids, plasma exchange (PLEX) or intravenous immunoglobulin (IVIG). Those with MOG antibody disease should consider ongoing treatment with medications that suppress the immune system.IntroductionThose with MOG antibody disease may previously have been diagnosed with neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON) or multiple sclerosis (MS) because of the pattern of inflammation it causes including brain, spinal cord and optic nerve damage. Patients with persistently positive antibodies to MOG are at risk for recurrent events. Those with MOG antibody disease do not test positive for the NMO antibody called aquaporin 4 (AQP-4). AQP-4 is a water channel protein and those with NMOSD produce autoantibodies against AQP-4. MOG antibody disease and AQP-4 positive NMOSD are thought to have distinct immunological mechanisms. Furthermore, those with MOG antibody disease seem to be less likely to have other autoimmune disorders (such as rheumatoid arthritis, Hashimoto’s thyroiditis, etc.) than those with AQP-4 positive NMOSD.
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Symptoms of MOG Antibody Disease
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MOG antibody disease preferentially causes inflammation in the optic nerve, but can also cause inflammation in the spinal cord, brain, and brainstem. Symptoms can include: Those with MOG antibody disease are more likely to have both optic nerves affected at the same time, and if the symptoms are in only one eye, the other optic nerve may show subclinical atrophy. Children can be found to have the MOG antibody in the setting of ADEM; however, a positive MOG antibody test in the setting of ADEM does not necessarily imply a course of MOGAD. In many children, the MOG antibody disappears within 1 year, and relapses do not occur. In some, the MOG antibody persists, and relapses may occur. When a relapse occurs, the diagnosis of MOGAD is confirmed. MOG antibody disease can also occur in relation to another condition called anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. NMDA receptor encephalitis is an autoimmune encephalitis that can cause psychosis, issues with memory and language, and seizures.
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Symptoms of MOG Antibody Disease. MOG antibody disease preferentially causes inflammation in the optic nerve, but can also cause inflammation in the spinal cord, brain, and brainstem. Symptoms can include: Those with MOG antibody disease are more likely to have both optic nerves affected at the same time, and if the symptoms are in only one eye, the other optic nerve may show subclinical atrophy. Children can be found to have the MOG antibody in the setting of ADEM; however, a positive MOG antibody test in the setting of ADEM does not necessarily imply a course of MOGAD. In many children, the MOG antibody disappears within 1 year, and relapses do not occur. In some, the MOG antibody persists, and relapses may occur. When a relapse occurs, the diagnosis of MOGAD is confirmed. MOG antibody disease can also occur in relation to another condition called anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. NMDA receptor encephalitis is an autoimmune encephalitis that can cause psychosis, issues with memory and language, and seizures.
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MOG Antibody Disease
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Causes of MOG Antibody Disease
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The exact cause of MOGAD is not known. In those with MOGAD, the immune system attacks the MOG protein found on nerves.
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Causes of MOG Antibody Disease. The exact cause of MOGAD is not known. In those with MOGAD, the immune system attacks the MOG protein found on nerves.
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Affects of MOG Antibody Disease
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Among patients with AQP-4 seronegative NMOSD, the frequency of a positive MOG antibody test ranges between 7.4% and 39%. Studies have indicated that between 40% and 58% of children diagnosed with ADEM are positive for the anti-MOG antibody. While there is significant overlap between MOGAD, NMOSD, and ADEM, it appears that MOGAD is a unique immunological condition. Some studies have shown that those with MOG antibody disease are on average younger and are likely to be male compared to those with AQP-4 positive NMOSD, but other studies have shown no age differences and varying gender distributions. One study revealed a higher proportion of those of Caucasian ethnicity among MOG patients, while others have not shown this difference.
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Affects of MOG Antibody Disease. Among patients with AQP-4 seronegative NMOSD, the frequency of a positive MOG antibody test ranges between 7.4% and 39%. Studies have indicated that between 40% and 58% of children diagnosed with ADEM are positive for the anti-MOG antibody. While there is significant overlap between MOGAD, NMOSD, and ADEM, it appears that MOGAD is a unique immunological condition. Some studies have shown that those with MOG antibody disease are on average younger and are likely to be male compared to those with AQP-4 positive NMOSD, but other studies have shown no age differences and varying gender distributions. One study revealed a higher proportion of those of Caucasian ethnicity among MOG patients, while others have not shown this difference.
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MOG Antibody Disease
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Related disorders of MOG Antibody Disease
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Symptoms of the following disorders can be similar to those of MOGAD. Comparisons may be useful for a differential diagnosis. MOGAD can be misdiagnosed as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM) and acute disseminated encephalomyelitis (ADEM) because of the pattern of inflammation it causes including brain, spinal cord and optic nerve damage.
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Related disorders of MOG Antibody Disease. Symptoms of the following disorders can be similar to those of MOGAD. Comparisons may be useful for a differential diagnosis. MOGAD can be misdiagnosed as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), transverse myelitis (TM) and acute disseminated encephalomyelitis (ADEM) because of the pattern of inflammation it causes including brain, spinal cord and optic nerve damage.
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Diagnosis of MOG Antibody Disease
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There are blood tests that can test for MOG antibodies. Only cell-based assays are considered reliable for the diagnosis of MOGAD because of the improved specificity over older ELISA tests. CSF analysis from a lumbar puncture may show increased white blood cell counts in some patients during a relapse, and oligoclonal bands are not usually found. Unlike anti-AQP4 antibodies, anti-MOG antibodies may decrease over time, and may not be detectable early in the disease process or during remission, and this is especially the case for MOG antibody disease associated ADEM. Those with persistent detection of anti-MOG may be more likely to have a relapsing rather than monophasic disease course. There appears to be no overlap between individuals with anti-MOG positivity and AQP-4 positivity, although there have been some isolated cases reported using the older ELISA assay. MRI findings are similar to those with MS and NMOSD, but there may be some differences. MOG antibody disease optic neuritis seems to predominantly affect the retrobulbar region, while AQP-4-associated optic neuritis is found intracranially. Furthermore, MOGAD lesions in the brain can look like lesions seen in those with ADEM.
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Diagnosis of MOG Antibody Disease. There are blood tests that can test for MOG antibodies. Only cell-based assays are considered reliable for the diagnosis of MOGAD because of the improved specificity over older ELISA tests. CSF analysis from a lumbar puncture may show increased white blood cell counts in some patients during a relapse, and oligoclonal bands are not usually found. Unlike anti-AQP4 antibodies, anti-MOG antibodies may decrease over time, and may not be detectable early in the disease process or during remission, and this is especially the case for MOG antibody disease associated ADEM. Those with persistent detection of anti-MOG may be more likely to have a relapsing rather than monophasic disease course. There appears to be no overlap between individuals with anti-MOG positivity and AQP-4 positivity, although there have been some isolated cases reported using the older ELISA assay. MRI findings are similar to those with MS and NMOSD, but there may be some differences. MOG antibody disease optic neuritis seems to predominantly affect the retrobulbar region, while AQP-4-associated optic neuritis is found intracranially. Furthermore, MOGAD lesions in the brain can look like lesions seen in those with ADEM.
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Therapies of MOG Antibody Disease
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Acute TreatmentsTreatment guidelines for MOG antibody disease have not been established. The following are possible treatments in the management of an acute event. Intravenous SteroidsAlthough there are no clinical trials that support a unique approach to treat patients with MOG antibody disease, it is well recognized as a standard of care to give high-dose intravenous methylprednisolone for suspected acute myelitis or optic neuritis, generally for 3 to 5 days, unless there are compelling reasons not to. The decision to offer continued steroids or add a new treatment is often based on the clinical course and MRI appearance at the end of 5 days of steroids. Those with MOG antibody disease seem to respond well to steroids. An oral steroid taper may be helpful to prevent steroid-withdrawal relapses. Plasma Exchange (PLEX)PLEX is believed to work in autoimmune CNS diseases through the removal of specific or nonspecific soluble factors likely to mediate, be responsible for, or contribute to inflammatory-mediated organ damage. PLEX is often recommended for moderate to aggressive forms of TM and ON, as is very often the case with MOG antibody disease, if there is not much improvement after being treated with intravenous steroids. If presenting symptoms are severe, PLEX may be initiated concurrently with steroids. There have been no prospective clinical trials that prove PLEX’s effectiveness in MOG antibody disease, but retrospective studies of TM treated with IV steroids followed by PLEX have shown a beneficial outcome. PLEX also has been shown to be effective in other autoimmune or inflammatory central nervous system disorders. Early treatment is beneficial – PLEX is typically started within days of administering steroids, very often before the course of steroids has finished. Particular benefit has been shown if started within the acute or sub-acute stage of the myelitis or if there is continued active inflammation on MRI. Intravenous Immunoglobulin (IVIG)Another option for treating anti-MOG associated acute inflammation is intravenous immunoglobulin (IVIG). Immunoglobulin comes from pooled blood that is donated from thousands of healthy people. As the name suggests, IVIG is given intravenously. IVIG is generally well-tolerated. Potential adverse reactions are uncommon, but usually occur during or immediately after an infusion and include headache, nausea, muscle pain, fever, chills, chest discomfort, skin and anaphylactic reactions. Reactions after an infusion can be more serious and include migraine headaches, aseptic meningitis, renal impairment and blood clots. Like corticosteroids and PLEX, there are no data confirming the value of IVIG in the setting of acute events. While most studies support the use of corticosteroids and/or PLEX in acute demyelinating syndromes, IVIG can be considered in certain circumstances. Other Acute TreatmentsIn cases of no response to either steroids or PLEX therapy and continued presence of active inflammation in the spinal cord, other forms of immune-based interventions may be required. The use of immunosuppressants or immunomodulatory agents may be considered in some patients. Initial presentation with aggressive forms of myelitis, or if particularly refractory to treatment with steroids and/or PLEX, aggressive immunosuppression is considered. Individuals should be monitored carefully as potential complications may arise from immunosuppression. As with all medications, risks versus benefits of aggressive immunosuppression need to be considered and discussed with the clinical care team. Long-Term TreatmentsInitially, the presence of anti-MOG was thought to be associated with fewer relapses and better outcomes than those with AQP-4 positive NMOSD, but studies with longer follow-up times indicate higher relapse rates than previously reported. A cohort study from 2016 found that 80% of those in the cohort had a multiphasic disease and an annualized relapse rate (AAR) of 0.9. They found that one third of patients with optic neuritis and around half of patients with spinal cord inflammation made a full recovery. In contrast, two other studies showed that the retinal neuro-axonal damage found after an acute attack of optic neuritis was as severe among anti-MOG positive individuals as individuals with AQP-4 positive NMOSD. Those with MOG antibody disease should consider ongoing treatment with medications that suppress the immune system. There are no FDA-approved medications for maintenance in MOG antibody disease, so anything prescribed is done off-label. The primary therapies used in the U.S. are mycophenolate mofetil (CellCept), rituximab (Rituxan), azathioprine (Imuran) and repeated IVIG infusions or subcutaneous immunoglobulin. Some studies from the United Kingdom have supported the use of IVIG to prevent relapses. Some patients presenting with optic neuritis or transverse myelitis who also test positive for the MOG antibody may start treatment after the initial event if the attack was severe and the individual does not want to risk a relapse. All of these medications carry a risk of infections, particularly upper respiratory infections and urinary tract infections (UTIs). Good hygiene and hand washing are important if on immunosuppressants, as is having a good urologist if at risk for UTIs. There is also the risk with any of these medications of the development of a rare brain infection called progressive multifocal leukoencephalopathy, or PML. PML is an infection caused by the reactivation of a virus, called the JC virus, which lives in the kidney. In someone who is immunosuppressed, this virus can escape the kidney, cross the blood-brain barrier, and enter the brain, causing profound inflammation. Although it can be treated, it is very devastating and sometimes fatal. It is important to know that exposure to these medications in MOG antibody disease has not led to a known case of PML. The known rate of incidence of PML if on Rituxan is estimated at 1 in 25,000 and the rate in CellCept is estimated at 1 in 6,000 based on data from use of these medications for immunosuppression for other purposes. The manufacturer of Imuran cautions about a risk of PML with Imuran as well, but the incidence of PML on Imuran is not documented. Clinical diligence and early intervention are important if PML is suspected. Chronic immunosuppression requires regular skin exams with a dermatologist since the immune system is the best defense against cancer cells developing, and any of these treatments can interfere with its normal functioning. Mycophenolate mofetil and azathioprine are both twice daily pills which broadly suppress the immune system. Both medications were originally FDA approved for organ transplant rejection prophylaxis, although azathioprine now is indicated in rheumatoid arthritis, and both have been widely used in several autoimmune disorders. These medications require frequent blood draws upfront, then generally twice yearly to monitor for liver toxicity and to ensure optimal immunosuppression (absolute lymphocyte count around 1 and total white blood cell count between 3 and 4). Azathioprine is the medication that has been around the longest. However, while the AAR seems to be low on azathioprine, one complication with this medication is that some are not able to stay in remission on azathioprine alone and have to also be on steroids (complications of steroids will be discussed below). Additionally, a long-term study of azathioprine found that the risk of lymphatic-proliferative cancers was reported to be 3%. A common side effect includes gastrointestinal upset, and this may manifest as bloating, constipation, nausea, diarrhea, and may vary throughout the course of one’s time on the medication. Azathioprine is contraindicated in pregnancy, so pregnancy planning is very important. It is FDA Category D (which means don’t take this drug during pregnancy unless it’s lifesaving) and is associated with an increased risk of miscarriages, 7% rate of congenital problems, and high rate of bone marrow suppression that recovers after birth. It is the least expensive of the medications. One study among those with MOG antibody disease found that the mean ARR for azathioprine was 0.99, with 41% of the attacks occurring during the first 6 months, and most of these early attacks were in those who were not also being treated with corticosteroids. Mycophenolate mofetil has a similar effect on the gastrointestinal system, though many report that the symptoms are milder with mycophenolate as compared with azathioprine. Additionally, some patients complain of headaches with mycophenolate, particularly in the beginning; these tend to wane with ongoing use. Lymphoma may be a risk of this medication; however, there have been no cases reported in MOG antibody disease patients while on this medication, so the risk is likely low. Mycophenolate is also contraindicated in pregnancy, so, again, planning is very important. It is also an FDA Category D (don’t take this drug during pregnancy unless it’s lifesaving) and carries a 45% chance of miscarriage. Of those that do not miscarry, 22% have congenital defects mostly in the face (mouth, ears). Rituximab is an intravascular infusion which works differently from the other two agents listed above. Rather than being a broad immunosuppressant, rituximab completely depletes one particular type of white blood cell called B-cells, which has downstream effects on the rest of the immune system. Though protocols are slightly different, in general, it is given two times twice a year (4 infusions total) and is given in an outpatient infusion center. This is because of a 30% risk of an infusion reaction without pre-medication with some cocktail of methylprednisolone, diphenhydramine and perhaps acetaminophen. The medication is quite well-tolerated. There are generally no side effects to the medication. There is no lymphoma risk with this medication. There is a monthly blood test to monitor the B-cell CD20 expression. Rituximab is safer in pregnancy than the other two previously described, (Category C; may be toxic in animals or no human data) — there are no official FDA reports of birth defects in cases of pregnancy with rituximab, but babies are born with no CD20 cells. It does not appear to increase risk of infection in babies as the cells re-populate within 6-18 months. In monkey studies performed by the manufacturer, there was no toxicity on the fetus, and monkey babies were born with no CD20 cells, again with no infection risks. In the largest case series published in February 2011, out of 153 women who became pregnant on rituximab, there were 4 post-natal infections and two congenital abnormalities (1 club foot, 1 heart defect), but these women were also on other immunosuppressant medications during the pregnancy, including azathioprine and mycophenolate. They concluded that rituximab does not increase the risk of congenital malformations above the natural rate of 1-2%. Planned pregnancy is still recommended. A study looking at rituximab among those with MOG antibody disease found that three out of nine patients experienced a decline in the ARR, and most relapses occurred either soon after an infusion or at the end-of-dose period. Low-dose prednisone is used as well, more often outside of the U.S. As noted above, some clinicians also use it in combination with azathioprine for those who continue to relapse on azathioprine alone. Its use is oftentimes not favored in the U.S. for maintenance therapy due to the potential complications associated with long-term steroid use, including diabetes, osteoporosis, weight gain, mood instability, hypertension, skin changes, etc. IVIG has also been used as a maintenance treatment in MOG antibody disease. One retrospective study looked at treatment, AARs, and disability among 59 patients with MOG antibody disease. This study included 7 patients who were using IVIG as a maintenance therapy. Out of these 7 patients, 3 had relapses while on treatment with IVIG, with 3 out of 7 (43%) having treatment failure. Half of the relapses occurred when weaning IVIG doses or increasing dosing intervals. Another prospective study looking at AARs and disability in 102 children with MOG antibody disease found that maintenance treatment with IVIG reduced the median AAR from 2.16 to 0.51. They also found that 4 (33.3%) out of the 12 patients treated with maintenance IVIG relapsed. Some physicians may also prescribe subcutaneous immunoglobulin. Studies have shown that conventional treatments for MS are not effective and may cause adverse reactions in AQP4-positive NMOSD. Since there is not enough information about their use in MOG antibody disease, and because they may not reduce relapse rates, or they may lead to adverse effects, treatments for MS are not recommended in MOG antibody disease. Long-Term CareAfter the acute phase, rehabilitative care to improve functional skills and prevent secondary complications of immobility involves both psychological and physical accommodations. There is very little written in the medical literature specifically dealing with rehabilitation after MOGAD. However, much has been written regarding recovery from spinal cord injury (SCI), in general, and this literature applies. The physical issues include visual issues, bladder dysfunction, bowel dysfunction, sexual dysfunction, maintenance of skin integrity, spasticity, pain, depression and fatigue. Rehabilitation and learning how to do activities of daily living (i.e., dressing) with mobility issues is an important part of treatment and recovery from MOGAD.
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Therapies of MOG Antibody Disease. Acute TreatmentsTreatment guidelines for MOG antibody disease have not been established. The following are possible treatments in the management of an acute event. Intravenous SteroidsAlthough there are no clinical trials that support a unique approach to treat patients with MOG antibody disease, it is well recognized as a standard of care to give high-dose intravenous methylprednisolone for suspected acute myelitis or optic neuritis, generally for 3 to 5 days, unless there are compelling reasons not to. The decision to offer continued steroids or add a new treatment is often based on the clinical course and MRI appearance at the end of 5 days of steroids. Those with MOG antibody disease seem to respond well to steroids. An oral steroid taper may be helpful to prevent steroid-withdrawal relapses. Plasma Exchange (PLEX)PLEX is believed to work in autoimmune CNS diseases through the removal of specific or nonspecific soluble factors likely to mediate, be responsible for, or contribute to inflammatory-mediated organ damage. PLEX is often recommended for moderate to aggressive forms of TM and ON, as is very often the case with MOG antibody disease, if there is not much improvement after being treated with intravenous steroids. If presenting symptoms are severe, PLEX may be initiated concurrently with steroids. There have been no prospective clinical trials that prove PLEX’s effectiveness in MOG antibody disease, but retrospective studies of TM treated with IV steroids followed by PLEX have shown a beneficial outcome. PLEX also has been shown to be effective in other autoimmune or inflammatory central nervous system disorders. Early treatment is beneficial – PLEX is typically started within days of administering steroids, very often before the course of steroids has finished. Particular benefit has been shown if started within the acute or sub-acute stage of the myelitis or if there is continued active inflammation on MRI. Intravenous Immunoglobulin (IVIG)Another option for treating anti-MOG associated acute inflammation is intravenous immunoglobulin (IVIG). Immunoglobulin comes from pooled blood that is donated from thousands of healthy people. As the name suggests, IVIG is given intravenously. IVIG is generally well-tolerated. Potential adverse reactions are uncommon, but usually occur during or immediately after an infusion and include headache, nausea, muscle pain, fever, chills, chest discomfort, skin and anaphylactic reactions. Reactions after an infusion can be more serious and include migraine headaches, aseptic meningitis, renal impairment and blood clots. Like corticosteroids and PLEX, there are no data confirming the value of IVIG in the setting of acute events. While most studies support the use of corticosteroids and/or PLEX in acute demyelinating syndromes, IVIG can be considered in certain circumstances. Other Acute TreatmentsIn cases of no response to either steroids or PLEX therapy and continued presence of active inflammation in the spinal cord, other forms of immune-based interventions may be required. The use of immunosuppressants or immunomodulatory agents may be considered in some patients. Initial presentation with aggressive forms of myelitis, or if particularly refractory to treatment with steroids and/or PLEX, aggressive immunosuppression is considered. Individuals should be monitored carefully as potential complications may arise from immunosuppression. As with all medications, risks versus benefits of aggressive immunosuppression need to be considered and discussed with the clinical care team. Long-Term TreatmentsInitially, the presence of anti-MOG was thought to be associated with fewer relapses and better outcomes than those with AQP-4 positive NMOSD, but studies with longer follow-up times indicate higher relapse rates than previously reported. A cohort study from 2016 found that 80% of those in the cohort had a multiphasic disease and an annualized relapse rate (AAR) of 0.9. They found that one third of patients with optic neuritis and around half of patients with spinal cord inflammation made a full recovery. In contrast, two other studies showed that the retinal neuro-axonal damage found after an acute attack of optic neuritis was as severe among anti-MOG positive individuals as individuals with AQP-4 positive NMOSD. Those with MOG antibody disease should consider ongoing treatment with medications that suppress the immune system. There are no FDA-approved medications for maintenance in MOG antibody disease, so anything prescribed is done off-label. The primary therapies used in the U.S. are mycophenolate mofetil (CellCept), rituximab (Rituxan), azathioprine (Imuran) and repeated IVIG infusions or subcutaneous immunoglobulin. Some studies from the United Kingdom have supported the use of IVIG to prevent relapses. Some patients presenting with optic neuritis or transverse myelitis who also test positive for the MOG antibody may start treatment after the initial event if the attack was severe and the individual does not want to risk a relapse. All of these medications carry a risk of infections, particularly upper respiratory infections and urinary tract infections (UTIs). Good hygiene and hand washing are important if on immunosuppressants, as is having a good urologist if at risk for UTIs. There is also the risk with any of these medications of the development of a rare brain infection called progressive multifocal leukoencephalopathy, or PML. PML is an infection caused by the reactivation of a virus, called the JC virus, which lives in the kidney. In someone who is immunosuppressed, this virus can escape the kidney, cross the blood-brain barrier, and enter the brain, causing profound inflammation. Although it can be treated, it is very devastating and sometimes fatal. It is important to know that exposure to these medications in MOG antibody disease has not led to a known case of PML. The known rate of incidence of PML if on Rituxan is estimated at 1 in 25,000 and the rate in CellCept is estimated at 1 in 6,000 based on data from use of these medications for immunosuppression for other purposes. The manufacturer of Imuran cautions about a risk of PML with Imuran as well, but the incidence of PML on Imuran is not documented. Clinical diligence and early intervention are important if PML is suspected. Chronic immunosuppression requires regular skin exams with a dermatologist since the immune system is the best defense against cancer cells developing, and any of these treatments can interfere with its normal functioning. Mycophenolate mofetil and azathioprine are both twice daily pills which broadly suppress the immune system. Both medications were originally FDA approved for organ transplant rejection prophylaxis, although azathioprine now is indicated in rheumatoid arthritis, and both have been widely used in several autoimmune disorders. These medications require frequent blood draws upfront, then generally twice yearly to monitor for liver toxicity and to ensure optimal immunosuppression (absolute lymphocyte count around 1 and total white blood cell count between 3 and 4). Azathioprine is the medication that has been around the longest. However, while the AAR seems to be low on azathioprine, one complication with this medication is that some are not able to stay in remission on azathioprine alone and have to also be on steroids (complications of steroids will be discussed below). Additionally, a long-term study of azathioprine found that the risk of lymphatic-proliferative cancers was reported to be 3%. A common side effect includes gastrointestinal upset, and this may manifest as bloating, constipation, nausea, diarrhea, and may vary throughout the course of one’s time on the medication. Azathioprine is contraindicated in pregnancy, so pregnancy planning is very important. It is FDA Category D (which means don’t take this drug during pregnancy unless it’s lifesaving) and is associated with an increased risk of miscarriages, 7% rate of congenital problems, and high rate of bone marrow suppression that recovers after birth. It is the least expensive of the medications. One study among those with MOG antibody disease found that the mean ARR for azathioprine was 0.99, with 41% of the attacks occurring during the first 6 months, and most of these early attacks were in those who were not also being treated with corticosteroids. Mycophenolate mofetil has a similar effect on the gastrointestinal system, though many report that the symptoms are milder with mycophenolate as compared with azathioprine. Additionally, some patients complain of headaches with mycophenolate, particularly in the beginning; these tend to wane with ongoing use. Lymphoma may be a risk of this medication; however, there have been no cases reported in MOG antibody disease patients while on this medication, so the risk is likely low. Mycophenolate is also contraindicated in pregnancy, so, again, planning is very important. It is also an FDA Category D (don’t take this drug during pregnancy unless it’s lifesaving) and carries a 45% chance of miscarriage. Of those that do not miscarry, 22% have congenital defects mostly in the face (mouth, ears). Rituximab is an intravascular infusion which works differently from the other two agents listed above. Rather than being a broad immunosuppressant, rituximab completely depletes one particular type of white blood cell called B-cells, which has downstream effects on the rest of the immune system. Though protocols are slightly different, in general, it is given two times twice a year (4 infusions total) and is given in an outpatient infusion center. This is because of a 30% risk of an infusion reaction without pre-medication with some cocktail of methylprednisolone, diphenhydramine and perhaps acetaminophen. The medication is quite well-tolerated. There are generally no side effects to the medication. There is no lymphoma risk with this medication. There is a monthly blood test to monitor the B-cell CD20 expression. Rituximab is safer in pregnancy than the other two previously described, (Category C; may be toxic in animals or no human data) — there are no official FDA reports of birth defects in cases of pregnancy with rituximab, but babies are born with no CD20 cells. It does not appear to increase risk of infection in babies as the cells re-populate within 6-18 months. In monkey studies performed by the manufacturer, there was no toxicity on the fetus, and monkey babies were born with no CD20 cells, again with no infection risks. In the largest case series published in February 2011, out of 153 women who became pregnant on rituximab, there were 4 post-natal infections and two congenital abnormalities (1 club foot, 1 heart defect), but these women were also on other immunosuppressant medications during the pregnancy, including azathioprine and mycophenolate. They concluded that rituximab does not increase the risk of congenital malformations above the natural rate of 1-2%. Planned pregnancy is still recommended. A study looking at rituximab among those with MOG antibody disease found that three out of nine patients experienced a decline in the ARR, and most relapses occurred either soon after an infusion or at the end-of-dose period. Low-dose prednisone is used as well, more often outside of the U.S. As noted above, some clinicians also use it in combination with azathioprine for those who continue to relapse on azathioprine alone. Its use is oftentimes not favored in the U.S. for maintenance therapy due to the potential complications associated with long-term steroid use, including diabetes, osteoporosis, weight gain, mood instability, hypertension, skin changes, etc. IVIG has also been used as a maintenance treatment in MOG antibody disease. One retrospective study looked at treatment, AARs, and disability among 59 patients with MOG antibody disease. This study included 7 patients who were using IVIG as a maintenance therapy. Out of these 7 patients, 3 had relapses while on treatment with IVIG, with 3 out of 7 (43%) having treatment failure. Half of the relapses occurred when weaning IVIG doses or increasing dosing intervals. Another prospective study looking at AARs and disability in 102 children with MOG antibody disease found that maintenance treatment with IVIG reduced the median AAR from 2.16 to 0.51. They also found that 4 (33.3%) out of the 12 patients treated with maintenance IVIG relapsed. Some physicians may also prescribe subcutaneous immunoglobulin. Studies have shown that conventional treatments for MS are not effective and may cause adverse reactions in AQP4-positive NMOSD. Since there is not enough information about their use in MOG antibody disease, and because they may not reduce relapse rates, or they may lead to adverse effects, treatments for MS are not recommended in MOG antibody disease. Long-Term CareAfter the acute phase, rehabilitative care to improve functional skills and prevent secondary complications of immobility involves both psychological and physical accommodations. There is very little written in the medical literature specifically dealing with rehabilitation after MOGAD. However, much has been written regarding recovery from spinal cord injury (SCI), in general, and this literature applies. The physical issues include visual issues, bladder dysfunction, bowel dysfunction, sexual dysfunction, maintenance of skin integrity, spasticity, pain, depression and fatigue. Rehabilitation and learning how to do activities of daily living (i.e., dressing) with mobility issues is an important part of treatment and recovery from MOGAD.
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Overview of Monilethrix
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Monilethrix is a rare inherited disorder characterized by sparse, dry, and/or brittle hair that often breaks before reaching more than a few inches in length. The hair may lack luster, and there may be patchy areas of hair loss (alopecia). Another common symptom may be the appearance of elevated spots (papules) surrounding the hair follicles that may be covered with gray or brown crusts or scales (perifollicular hyperkeratosis). When viewed under a microscope, the hair shaft resembles a string of evenly-spaced beads. In most cases, monilethrix is inherited as an autosomal dominant trait.
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Overview of Monilethrix. Monilethrix is a rare inherited disorder characterized by sparse, dry, and/or brittle hair that often breaks before reaching more than a few inches in length. The hair may lack luster, and there may be patchy areas of hair loss (alopecia). Another common symptom may be the appearance of elevated spots (papules) surrounding the hair follicles that may be covered with gray or brown crusts or scales (perifollicular hyperkeratosis). When viewed under a microscope, the hair shaft resembles a string of evenly-spaced beads. In most cases, monilethrix is inherited as an autosomal dominant trait.
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Monilethrix
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Symptoms of Monilethrix
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In most cases of monilethrix, the hair is normal at birth; it may then be slowly replaced by abnormal hair during the first few months to two years of life. In some rare cases, the hair may be abnormal at birth (congenital). The hair may be sparse, dry, lusterless, and/or brittle. In addition, the hair is unusually short and breaks off before growing longer than a few inches.Scalp hair is most frequently affected by monilethrix. The entire scalp or small areas of the scalp may be involved. In some cases, the eyelashes, eyebrows, pubic hair, and/or other body hair may also be affected. In addition, the patchy loss of hair (alopecia) is a common characteristic of this disorder. Progressive hair loss may lead to scattered bald patches or baldness. In most cases of monilethrix, a skin condition known as perifollicular hyperkeratosis may develop. The condition is characterized by firm dark lesions (papules) covered with gray-brown scales and crusts that appear on the skin, especially the scalp. The severity and progression of symptoms may vary greatly from case to case. In some cases, individuals with monilethrix may experience remission of the disorder for no apparent reason (spontaneously), most often during puberty or pregnancy. In other cases, the condition may remain the same throughout life or the symptoms may become progressively worse.
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Symptoms of Monilethrix. In most cases of monilethrix, the hair is normal at birth; it may then be slowly replaced by abnormal hair during the first few months to two years of life. In some rare cases, the hair may be abnormal at birth (congenital). The hair may be sparse, dry, lusterless, and/or brittle. In addition, the hair is unusually short and breaks off before growing longer than a few inches.Scalp hair is most frequently affected by monilethrix. The entire scalp or small areas of the scalp may be involved. In some cases, the eyelashes, eyebrows, pubic hair, and/or other body hair may also be affected. In addition, the patchy loss of hair (alopecia) is a common characteristic of this disorder. Progressive hair loss may lead to scattered bald patches or baldness. In most cases of monilethrix, a skin condition known as perifollicular hyperkeratosis may develop. The condition is characterized by firm dark lesions (papules) covered with gray-brown scales and crusts that appear on the skin, especially the scalp. The severity and progression of symptoms may vary greatly from case to case. In some cases, individuals with monilethrix may experience remission of the disorder for no apparent reason (spontaneously), most often during puberty or pregnancy. In other cases, the condition may remain the same throughout life or the symptoms may become progressively worse.
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Monilethrix
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nord_818_2
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Causes of Monilethrix
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In most cases, monilethrix is inherited as an autosomal genetic trait. Genetic diseases are determined by two genes, 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 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.Some cases of monilethrix result from defects (mutations) in the hair cortex keratin gene(s) (HB1; KRTHB1 and HB6; KRTHB6) located on the long arm (q) of chromosome 12 (12q13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 12p13” refers to band 13 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The physical findings associated with monilethrix may result from abnormalities of the hard keratin of hair and nails.
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Causes of Monilethrix. In most cases, monilethrix is inherited as an autosomal genetic trait. Genetic diseases are determined by two genes, 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 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.Some cases of monilethrix result from defects (mutations) in the hair cortex keratin gene(s) (HB1; KRTHB1 and HB6; KRTHB6) located on the long arm (q) of chromosome 12 (12q13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. 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 12p13” refers to band 13 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The physical findings associated with monilethrix may result from abnormalities of the hard keratin of hair and nails.
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Monilethrix
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Affects of Monilethrix
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Monilethrix affects males and females in equal numbers. The exact number of people affected by this disorder is not known. Monilethrix may be apparent at birth or by the age of two years. In some cases, the symptoms may improve at puberty or during pregnancy; in other cases, the symptoms may remain the same throughout life.
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Affects of Monilethrix. Monilethrix affects males and females in equal numbers. The exact number of people affected by this disorder is not known. Monilethrix may be apparent at birth or by the age of two years. In some cases, the symptoms may improve at puberty or during pregnancy; in other cases, the symptoms may remain the same throughout life.
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Monilethrix
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Related disorders of Monilethrix
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Symptoms of the following disorders can be similar to those of Monilethrix. Comparisons may be useful for a differential diagnosis:Alopecia Areata is a rare disorder characterized by the progressive loss of hair. It often begins suddenly with oval or round bald patches appearing on the scalp; however, other areas of hairy skin may also be involved. Gradually, the affected skin becomes white and smooth. The hair may regrow in these areas within weeks; at the same time, additional patches of hair loss may occur elsewhere. In some cases, hair regrowth may occur in one area of the scalp but not in others; in other cases, the loss of hair may be permanent and lead to baldness. In a few rare cases, all body hair may be lost. Cases with onset during childhood tend to be more severe than those with an adult onset. The exact cause of Alopecia Areata is not known. (For more information on this disorder, choose “Alopecia Areata” as your search term in the Rare Disease Database.)Pseudomonilethrix is an extremely rare disorder characterized by sparse, dry, and brittle hair that breaks easily. The loss of hair (alopecia) is a common finding in children with Pseudomonilethrix. There are structural differences between the hair of individuals with Monilethrix and those with Pseudomonilethrix; such differences can only be seen when the hair is viewed under a microscope. Pseudomonilethrix is thought to be inherited as an autosomal dominant genetic trait.Trichorrhexis Nodosa is a condition in which an affected individual's hair breaks and splits easily. This may result in scattered patches of hair loss (alopecia) on the scalp. When viewed under a microscope, the hair shafts appear to be covered with white bumps or swellings. These swellings are sites where the outer layers of the hair shafts have broken and split into strands. There are many other disorders that may be characterized by abnormal hair development. These disorders, which include Menkes Disease, Netherton Syndrome, and Tay Syndrome, are characterized by other symptoms and physical characteristics in addition to abnormal hair development. These additional abnormalities can be used to distinguish these disorders from Monilethrix. (For more information on these disorders, choose “Menkes,” “Netherton,” or “Tay” as your search terms in the Rare Disease Database.)
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Related disorders of Monilethrix. Symptoms of the following disorders can be similar to those of Monilethrix. Comparisons may be useful for a differential diagnosis:Alopecia Areata is a rare disorder characterized by the progressive loss of hair. It often begins suddenly with oval or round bald patches appearing on the scalp; however, other areas of hairy skin may also be involved. Gradually, the affected skin becomes white and smooth. The hair may regrow in these areas within weeks; at the same time, additional patches of hair loss may occur elsewhere. In some cases, hair regrowth may occur in one area of the scalp but not in others; in other cases, the loss of hair may be permanent and lead to baldness. In a few rare cases, all body hair may be lost. Cases with onset during childhood tend to be more severe than those with an adult onset. The exact cause of Alopecia Areata is not known. (For more information on this disorder, choose “Alopecia Areata” as your search term in the Rare Disease Database.)Pseudomonilethrix is an extremely rare disorder characterized by sparse, dry, and brittle hair that breaks easily. The loss of hair (alopecia) is a common finding in children with Pseudomonilethrix. There are structural differences between the hair of individuals with Monilethrix and those with Pseudomonilethrix; such differences can only be seen when the hair is viewed under a microscope. Pseudomonilethrix is thought to be inherited as an autosomal dominant genetic trait.Trichorrhexis Nodosa is a condition in which an affected individual's hair breaks and splits easily. This may result in scattered patches of hair loss (alopecia) on the scalp. When viewed under a microscope, the hair shafts appear to be covered with white bumps or swellings. These swellings are sites where the outer layers of the hair shafts have broken and split into strands. There are many other disorders that may be characterized by abnormal hair development. These disorders, which include Menkes Disease, Netherton Syndrome, and Tay Syndrome, are characterized by other symptoms and physical characteristics in addition to abnormal hair development. These additional abnormalities can be used to distinguish these disorders from Monilethrix. (For more information on these disorders, choose “Menkes,” “Netherton,” or “Tay” as your search terms in the Rare Disease Database.)
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Monilethrix
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Diagnosis of Monilethrix
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Diagnosis of Monilethrix.
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Monilethrix
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nord_818_6
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Therapies of Monilethrix
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The diagnosis of monilethrix may be confirmed by a thorough clinical evaluation and microscopic examination of the hair. When viewed under a microscope, the hair resembles a string of evenly-spaced beads.No specific treatment exists for monilethrix. Spontaneous resolution following puberty has occurred in some cases. In affected females, the condition improves during pregnancy. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Monilethrix. The diagnosis of monilethrix may be confirmed by a thorough clinical evaluation and microscopic examination of the hair. When viewed under a microscope, the hair resembles a string of evenly-spaced beads.No specific treatment exists for monilethrix. Spontaneous resolution following puberty has occurred in some cases. In affected females, the condition improves during pregnancy. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Monilethrix
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nord_819_0
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Overview of Mosaic Trisomy 22
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SummaryMosaic trisomy 22 is a rare chromosomal disorder in which chromosome 22 appears three times (trisomy) rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 22, whereas others have the normal chromosomal pair. Mosaic trisomy 22 appears more commonly in females. The range and severity of associated symptoms and findings may vary. The characteristic features of mosaic trisomy 22 typically include prenatal and postnatal growth failure or delay, asymmetrical development of the two sides of the body (hemidystrophy) and congenital heart defects. While some patients with mosaic trisomy 22 have abnormal cognitive development, normal development has been documented for some children.
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Overview of Mosaic Trisomy 22. SummaryMosaic trisomy 22 is a rare chromosomal disorder in which chromosome 22 appears three times (trisomy) rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 22, whereas others have the normal chromosomal pair. Mosaic trisomy 22 appears more commonly in females. The range and severity of associated symptoms and findings may vary. The characteristic features of mosaic trisomy 22 typically include prenatal and postnatal growth failure or delay, asymmetrical development of the two sides of the body (hemidystrophy) and congenital heart defects. While some patients with mosaic trisomy 22 have abnormal cognitive development, normal development has been documented for some children.
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Mosaic Trisomy 22
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nord_819_1
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Symptoms of Mosaic Trisomy 22
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The symptoms and physical findings associated with Mosaic trisomy 22 may depend on the percentage and distribution of cells containing the extra 22nd chromosome. However, the disorder is often characterized by (1) growth and developmental delays, (2) asymmetric body development, and (3) congenital heart diseases. Intrauterine growth restriction (IUGR) and postnatal growth failure were found in more than 70% patients with mosaic trisomy 22. While many affected children have developmental delay, up to 40% of all reported patients have normal developmental outcomes. It has been shown that there was no correlation between the percentage of trisomic cells and the severity of developmental delay.In many affected individuals, there is asymmetric development of two sides of the body, causing the body to appear dissimilar from one side to the other (hemidystrophy). For example, one leg may appear shorter than the other. In addition, in many individuals with hemidystrophy, there is associated hearing loss affecting one ear (unilateral hearing impairment).Patients with mosaic trisomy 22 often have congenital heart defects. Atrial septal defects and ventricular septal defects are the most common cardiac malformations for these patients. In the atrial septal defect, a “hole” in the wall separating the two top chambers (atrias) of the heart remains open after birth. This allows oxygen-rich blood to enter the oxygen-poor chamber (right atrium). On the other hand, the ventricular septal defect is a “hole” in the wall separating the two lower chambers (ventricles) of the heart. Abnormal physical features are frequently seen in patients with mosaic trisomy 22. Some common presentations include skin fold of the upper eyelid covering the inner corner of the eye (epicanthic folds), dents/dimples located near the front of the external ear (preauricular pits) and flat nasal bridge. Other features include underdeveloped middle phalanx of 5th finger (mesobrachydactyly or clinodactyly), abnormal palmar flexion creases and kidney (renal) malformations. A few patients may have linear pigmentary changes along Blaschko lines.A small subset of female patients may have abnormal development of the ovaries (ovarian dysgenesis, streak ovaries). The ovaries are essential glands for female reproductive cells (eggs) and certain female hormones. Therefore, ovarian dysgenesis may be associated with delayed or failed development of secondary sexual characteristics during puberty (e.g., breast development, the appearance of pubic hair, menstruation) and infertility.
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Symptoms of Mosaic Trisomy 22. The symptoms and physical findings associated with Mosaic trisomy 22 may depend on the percentage and distribution of cells containing the extra 22nd chromosome. However, the disorder is often characterized by (1) growth and developmental delays, (2) asymmetric body development, and (3) congenital heart diseases. Intrauterine growth restriction (IUGR) and postnatal growth failure were found in more than 70% patients with mosaic trisomy 22. While many affected children have developmental delay, up to 40% of all reported patients have normal developmental outcomes. It has been shown that there was no correlation between the percentage of trisomic cells and the severity of developmental delay.In many affected individuals, there is asymmetric development of two sides of the body, causing the body to appear dissimilar from one side to the other (hemidystrophy). For example, one leg may appear shorter than the other. In addition, in many individuals with hemidystrophy, there is associated hearing loss affecting one ear (unilateral hearing impairment).Patients with mosaic trisomy 22 often have congenital heart defects. Atrial septal defects and ventricular septal defects are the most common cardiac malformations for these patients. In the atrial septal defect, a “hole” in the wall separating the two top chambers (atrias) of the heart remains open after birth. This allows oxygen-rich blood to enter the oxygen-poor chamber (right atrium). On the other hand, the ventricular septal defect is a “hole” in the wall separating the two lower chambers (ventricles) of the heart. Abnormal physical features are frequently seen in patients with mosaic trisomy 22. Some common presentations include skin fold of the upper eyelid covering the inner corner of the eye (epicanthic folds), dents/dimples located near the front of the external ear (preauricular pits) and flat nasal bridge. Other features include underdeveloped middle phalanx of 5th finger (mesobrachydactyly or clinodactyly), abnormal palmar flexion creases and kidney (renal) malformations. A few patients may have linear pigmentary changes along Blaschko lines.A small subset of female patients may have abnormal development of the ovaries (ovarian dysgenesis, streak ovaries). The ovaries are essential glands for female reproductive cells (eggs) and certain female hormones. Therefore, ovarian dysgenesis may be associated with delayed or failed development of secondary sexual characteristics during puberty (e.g., breast development, the appearance of pubic hair, menstruation) and infertility.
| 819 |
Mosaic Trisomy 22
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nord_819_2
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Causes of Mosaic Trisomy 22
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There are 23 pairs of human chromosomes, or a total of 46 chromosomes. Mosaic trisomy 22 is characterized by an extra copy of the chromosome 22 (trisomy) in some of the body cell populations. This could be due to an error during the division of reproductive cells in one of the parents or during cellular division after fertilization. The disorder can also occur in association with uniparental disomy, an abnormality in which an affected individual inherits both copies of a chromosomal pair from one parent, rather than one copy from each parent. The presence of the additional chromosome 22 in some groups of cells is responsible for the symptoms and physical findings of the disorder.
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Causes of Mosaic Trisomy 22. There are 23 pairs of human chromosomes, or a total of 46 chromosomes. Mosaic trisomy 22 is characterized by an extra copy of the chromosome 22 (trisomy) in some of the body cell populations. This could be due to an error during the division of reproductive cells in one of the parents or during cellular division after fertilization. The disorder can also occur in association with uniparental disomy, an abnormality in which an affected individual inherits both copies of a chromosomal pair from one parent, rather than one copy from each parent. The presence of the additional chromosome 22 in some groups of cells is responsible for the symptoms and physical findings of the disorder.
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Mosaic Trisomy 22
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nord_819_3
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Affects of Mosaic Trisomy 22
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There have been about 20 reports of live born children with mosaic trisomy 22. It is speculated that children with mosaic trisomy 22 with minimal physical findings and normal development are under diagnosed. The condition appears to occur in females more frequently than in males (approximately 3 females: 2 males).
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Affects of Mosaic Trisomy 22. There have been about 20 reports of live born children with mosaic trisomy 22. It is speculated that children with mosaic trisomy 22 with minimal physical findings and normal development are under diagnosed. The condition appears to occur in females more frequently than in males (approximately 3 females: 2 males).
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Mosaic Trisomy 22
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nord_819_4
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Related disorders of Mosaic Trisomy 22
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Symptoms of the following disorders can be similar to those of Chromosome 22, Trisomy Mosaic. Comparisons may be useful for a differential diagnosis.Trisomy 22 (“complete” or “non-mosaic” Trisomy 22) is a rare chromosomal disorder in which all or a portion of chromosome 22 appears to be present three times (trisomy) rather than twice in all cells of the body. In contrast to mosaic trisomy 22, “complete” trisomy 22 often is incompatible with life. Survival beyond the first semester of gestation is rare. Typically, surviving children with full trisomy 22 often have delayed growth of upper jaw, cheekbones and eye sockets (midface hypoplasia) with flat/broad nasal bridge, ear malformation with pits or tags, incomplete closure of the roof of the mouth (cleft palate), increased distance between organs or bodily parts, unusually small head (microcephaly), congenital heart disease, genital abnormalities and delayed growth.The differential diagnoses for the condition also include Turner syndrome, Noonan syndrome and Russell Silver syndrome (RSS). While webbing of the neck is commonly seen mainly in Turner and Noonan syndromes, asymmetry of the body is commonly seen in RSS. In addition, Turner syndrome affects only females; Noonan and RSS affect both males and females. (For further information on these syndromes, please choose “Turner Syndrome”, “Noonan syndrome”, or “Russell Silver syndrome” as your search term in Rare Disease Database.)
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Related disorders of Mosaic Trisomy 22. Symptoms of the following disorders can be similar to those of Chromosome 22, Trisomy Mosaic. Comparisons may be useful for a differential diagnosis.Trisomy 22 (“complete” or “non-mosaic” Trisomy 22) is a rare chromosomal disorder in which all or a portion of chromosome 22 appears to be present three times (trisomy) rather than twice in all cells of the body. In contrast to mosaic trisomy 22, “complete” trisomy 22 often is incompatible with life. Survival beyond the first semester of gestation is rare. Typically, surviving children with full trisomy 22 often have delayed growth of upper jaw, cheekbones and eye sockets (midface hypoplasia) with flat/broad nasal bridge, ear malformation with pits or tags, incomplete closure of the roof of the mouth (cleft palate), increased distance between organs or bodily parts, unusually small head (microcephaly), congenital heart disease, genital abnormalities and delayed growth.The differential diagnoses for the condition also include Turner syndrome, Noonan syndrome and Russell Silver syndrome (RSS). While webbing of the neck is commonly seen mainly in Turner and Noonan syndromes, asymmetry of the body is commonly seen in RSS. In addition, Turner syndrome affects only females; Noonan and RSS affect both males and females. (For further information on these syndromes, please choose “Turner Syndrome”, “Noonan syndrome”, or “Russell Silver syndrome” as your search term in Rare Disease Database.)
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Mosaic Trisomy 22
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nord_819_5
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Diagnosis of Mosaic Trisomy 22
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The diagnosis of trisomy mosaic 22 may be suggested before birth (prenatally) by specialized tests such as ultrasound and amniocentesis. Fetal ultrasound is a non-invasive imaging technique that utilizes high-frequency sound waves to produce image of fetus in the uterus. Abnormal results during ultrasound may prompt to more invasive test such as amniocentesis. During amniocentesis, a sample amniotic fluid (AF) that surrounds the fetus is removed and analyzed. Chromosomal analysis of either AF or chorionic tissues can reveal the presence of mosaic trisomy 22. Karyotyping from AF is not sufficient to confirm a definitive diagnosis. Diagnostic confirmation may require fetal blood sampling or fetal skin biopsy (fetal fibroblast). A diagnosis of mosaic trisomy 22 may also be made or confirmed after birth (postnatally) based upon clinical assessment through physical findings and chromosomal analysis. A normal karyotype on blood does not rule out the diagnosis of mosaicism, because the trisomic cells may be present only in some tissues. In addition, specialized testing may be conducted to detect or characterize abnormalities that may be associated with the disorder (e.g., cardiovascular defects, hearing impairment, renal abnormalities, ovarian dysgenesis, etc.).
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Diagnosis of Mosaic Trisomy 22. The diagnosis of trisomy mosaic 22 may be suggested before birth (prenatally) by specialized tests such as ultrasound and amniocentesis. Fetal ultrasound is a non-invasive imaging technique that utilizes high-frequency sound waves to produce image of fetus in the uterus. Abnormal results during ultrasound may prompt to more invasive test such as amniocentesis. During amniocentesis, a sample amniotic fluid (AF) that surrounds the fetus is removed and analyzed. Chromosomal analysis of either AF or chorionic tissues can reveal the presence of mosaic trisomy 22. Karyotyping from AF is not sufficient to confirm a definitive diagnosis. Diagnostic confirmation may require fetal blood sampling or fetal skin biopsy (fetal fibroblast). A diagnosis of mosaic trisomy 22 may also be made or confirmed after birth (postnatally) based upon clinical assessment through physical findings and chromosomal analysis. A normal karyotype on blood does not rule out the diagnosis of mosaicism, because the trisomic cells may be present only in some tissues. In addition, specialized testing may be conducted to detect or characterize abnormalities that may be associated with the disorder (e.g., cardiovascular defects, hearing impairment, renal abnormalities, ovarian dysgenesis, etc.).
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Mosaic Trisomy 22
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nord_819_6
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Therapies of Mosaic Trisomy 22
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Treatment
The treatment of mosaic trisomy 22 is directed toward the specific problems that are apparent in each individual. Such treatment may require interdisciplinary efforts of health care professionals, including pediatricians, surgeons, cardiologists, ophthalmologists and other health care partners.Some infants with mosaic trisomy 22 may require surgical repair for their congenital heart defects, certain craniofacial and other physical abnormalities associated with the disorder. The surgical procedures performed will depend upon the severity of the abnormalities, their associated symptoms and other factors. Patients with hearing loss may benefit from artificial devices (prostheses) such as specialized hearing aids.Early intervention may be essential in ensuring that children with mosaic trisomy 22 reach their potential. Special services that may be beneficial include special education, speech therapy, physical therapy and/or other medical, social and/or vocational services. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Mosaic Trisomy 22. Treatment
The treatment of mosaic trisomy 22 is directed toward the specific problems that are apparent in each individual. Such treatment may require interdisciplinary efforts of health care professionals, including pediatricians, surgeons, cardiologists, ophthalmologists and other health care partners.Some infants with mosaic trisomy 22 may require surgical repair for their congenital heart defects, certain craniofacial and other physical abnormalities associated with the disorder. The surgical procedures performed will depend upon the severity of the abnormalities, their associated symptoms and other factors. Patients with hearing loss may benefit from artificial devices (prostheses) such as specialized hearing aids.Early intervention may be essential in ensuring that children with mosaic trisomy 22 reach their potential. Special services that may be beneficial include special education, speech therapy, physical therapy and/or other medical, social and/or vocational services. Genetic counseling is recommended for affected individuals and their families.
| 819 |
Mosaic Trisomy 22
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nord_820_0
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Overview of Mosaic Trisomy 9
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Mosaic trisomy 9 is a rare chromosomal disorder in which the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 9, while others have the typical chromosomal pair. Mosaic trisomy 9 may be caused by errors during the division of a parent’s egg or sperm or during the division of body tissue cells (somatic cells) early in the development of the fetus.Associated symptoms and findings may vary greatly in range and severity, depending on the percentage of cells with the extra chromosome. However, common features include growth deficiency before birth (intrauterine growth restriction or IUGR); structural malformations of the heart that are present at birth (congenital heart defects); and/or distinctive differences in the shape of the skull and facial (craniofacial) region, such as a sloping forehead, a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes and/or low-set ears. The syndrome may also be characterized by musculoskeletal, genital, kidney (renal) and/or additional physical anomalies. Intellectual disability is common and varies in severity.
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Overview of Mosaic Trisomy 9. Mosaic trisomy 9 is a rare chromosomal disorder in which the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body. The term “mosaic” indicates that some cells contain the extra chromosome 9, while others have the typical chromosomal pair. Mosaic trisomy 9 may be caused by errors during the division of a parent’s egg or sperm or during the division of body tissue cells (somatic cells) early in the development of the fetus.Associated symptoms and findings may vary greatly in range and severity, depending on the percentage of cells with the extra chromosome. However, common features include growth deficiency before birth (intrauterine growth restriction or IUGR); structural malformations of the heart that are present at birth (congenital heart defects); and/or distinctive differences in the shape of the skull and facial (craniofacial) region, such as a sloping forehead, a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes and/or low-set ears. The syndrome may also be characterized by musculoskeletal, genital, kidney (renal) and/or additional physical anomalies. Intellectual disability is common and varies in severity.
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Mosaic Trisomy 9
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nord_820_1
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Symptoms of Mosaic Trisomy 9
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As noted above, mosaic trisomy 9 is characterized by an extra 9th chromosome (trisomy 9) in some cells of the body (mosaicism). The range and severity of associated features is variable depending on the percentage of cells in the body with an extra chromosome 9 (trisomic cells). In addition, rare cases have also been reported in which all body cells have appeared to be trisomic for all of chromosome 9; such “nonmosaic” cases are sometimes referred to as full trisomy 9 syndrome. According to investigators, in such patients, characteristic clinical features and affected organs may not substantially differ from those seen with trisomy 9 mosaicism. However, symptoms and findings associated with the latter may tend to be less severe in some cases due to the percentage of cells with an extra chromosome 9. Results of testing for mosaicism can also vary depending on the type of sample (e.g., blood, saliva) and age of the individual.Mosaic trisomy 9 is generally characterized by growth deficiency beginning prenatally (IUGR), failure to gain height and weight at the expected rate during infancy (failure to thrive), and low muscle tone (hypotonia). Most infants and children with mosaic trisomy 9 have feeding difficulties and may require a feeding tube to supplement oral feeding or for all nutritional intake.Many affected individuals have intellectual disability characterized by delays in learning academic as well as functional/daily living skills. However, there have also been some reports in which individuals with the disorder exhibit typical psychomotor development (e.g., walking unaided) or only mild gross motor delay. Regression of skills is uncommon. Recent reports indicate that affected individuals possess strengths in language and communication development (particularly receptive speech, or their ability to understand language expressed to them) as well as social-emotional development.Individuals diagnosed with mosaic trisomy 9 exhibit specific differences in their facial features and the shape of their skull. Many affected infants have a small head size (microcephaly); a sloping forehead with narrow temples; a broad nose with a bulbous tip and “slit-like” nostrils and/or a small jaw (micrognathia). Additional characteristic features may include wideness of the “soft spots” (fontanels) and the fibrous joints (i.e., cranial sutures) between certain bones of the skull; a prominent upper lip covering a receding lower lip; a highly arched roof of the mouth (palate); low-set, unusually shaped ears and/or a short neck. Various eye (ocular) anomalies may also be present, such as short, upwardly slanting eyelid folds (palpebral fissures); deeply set eyes; reduction in the size of the eyes (microphthalmia); clouded corneas and/or other ocular defects that can impact vision. Some affected infants may also have a groove in the upper lip (cleft lip); incomplete closure of the palate (cleft palate); outgrowths of skin and cartilage on or before the ears (preauricular tags) and/or other craniofacial differences. Some individuals have been reported to have hearing loss requiring ear tubes or hearing aids.Previous studies have estimated that approximately 65% of affected individuals have congenital heart defects, however more recent studies report lower numbers. The most common defects include an abnormal opening in the partition (septum) that separates the two lower or upper chambers (ventricles or atria) of the heart, called ventricular septal defects (VSDs) or atrial septal defects (ASDs). Other heart defects include patent ductus arteriosus (PDA) and/or other associated defects that allow some oxygen-rich blood to recirculate through the lungs and potentially lead to rising blood pressure in the lungs (pulmonary hypertension). Some individuals with mosaic trisomy 9 will have more than one heart defect.In individuals with cardiac defects, associated symptoms and concerns may vary depending upon the size, nature, and/or combination of heart malformations present and other factors including age and respiratory function. Some individuals may show no apparent symptoms (asymptomatic), while others may develop difficulties in feeding, poor growth, difficult or labored breathing (dyspnea), profuse sweating, an impaired ability of the heart to pump blood efficiently to the lungs and other parts of the body (heart failure) and/or other problems. In severe cases, congenital heart disease may lead to potentially life-threatening complications. Individuals may require palliative or intensive surgery to correct cardiac defects. Recovery time varies.Individuals with mosaic trisomy 9 may also experience respiratory issues including central and/or obstructive apnea. There are instances of short as well as long term need for oxygen (via nasal canula) and placement of a tracheotomy to assist with the airway. A sleep study is often utilized to identify specific respiratory needs. A bronchoscopy or similar procedure may be needed to determine anatomical anomalies affecting respiration. Nebulizer treatments may be needed as well as deep suctioning to assist with mucus build-up affecting breathing. It is critical to include a pulmonologist on the medical team if these concerns persist, especially when one or more cardiac defects is also present.Mosaic trisomy 9 is also often characterized by conditions affecting muscles and bones including congenital dislocation of the hips (developmental dysplasia of the hip), atypical position and/or limited function of other joints, such as the elbows, knees and/or fingers and toes (digits) and atypical curvature of the spine. Underdevelopment (hypoplasia) of certain bones of the digits (phalanges); hypoplasia of the nails and/or a single crease across the palms (single transverse palmar crease) may also be present. Other skeletal differences have also been reported including a narrow chest, rib defects and differences in shape of specific bones of the spine (vertebral anomalies).Affected males may also have genital complications including undescended testes (cryptorchidism), a small penis (micropenis) and/or atypical placement of the urinary opening (hypospadias, such as on the underside of the penis. Kidney (renal) complications may also be present in both males and females, including renal cysts, swelling (distension) of the kidneys with urine (hydronephrosis) due to narrowing or blockage of the tubes (i.e., ureters) that carry urine from the kidneys into the bladder and/or additional renal problems.In some cases, mosaic trisomy 9 may also be associated with brain anomalies such as hydrocephalus, Dandy-Walker malformation and/or other features. Hydrocephalus involves excess cerebrospinal fluid (CSF) on the brain, resulting in increased pressure on the skull and widening of cavities (ventricles) of the brain. CSF is the watery protective fluid that circulates through the four ventricles of the brain, the canal containing the spinal cord (spinal canal) and the space between layers of the protective membranes (meninges) surrounding the brain and spinal cord (i.e., subarachnoid space). Depending on the age at symptom onset and other factors, associated symptoms may include rapid enlargement of the head, sudden episodes of uncontrolled electrical activity in the brain (seizures), feeding difficulties, vomiting, irritability, headache, loss of coordination and/or reduction in mental functioning. In severe cases, potentially life-threatening complications may result. In those with Dandy-Walker malformation, cystic malformation of the fourth ventricle of the brain may lead to hydrocephalus with increased prominence of the back region of the head (occiput), and/or additional associated anomalies. A small number of affected individuals have agenesis of the corpus callosum, or partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. Agenesis of the corpus callosum can range in severity and may result in seizures and/or developmental delays.In some instances, additional physical features have been reported in association with mosaic trisomy 9 including clouding of the cornea of the eye, presence of cysts on one or both eyeballs (epibulbar dermoids), underdevelopment of the lungs (pulmonary hypoplasia), diaphragmatic hernia and/or gastroesophageal reflux. In individuals with a diaphragmatic hernia, there is protrusion of abdominal structures into the chest cavity through an abnormal opening in the diaphragm often in addition to gastroesophageal reflux, which is characterized by backflow (reflux) of stomach acid into the esophagus. This condition can cause inflammation of and possible damage to the esophageal lining. A gastroenterologist is often necessary to monitor and treat these digestive conditions.
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Symptoms of Mosaic Trisomy 9. As noted above, mosaic trisomy 9 is characterized by an extra 9th chromosome (trisomy 9) in some cells of the body (mosaicism). The range and severity of associated features is variable depending on the percentage of cells in the body with an extra chromosome 9 (trisomic cells). In addition, rare cases have also been reported in which all body cells have appeared to be trisomic for all of chromosome 9; such “nonmosaic” cases are sometimes referred to as full trisomy 9 syndrome. According to investigators, in such patients, characteristic clinical features and affected organs may not substantially differ from those seen with trisomy 9 mosaicism. However, symptoms and findings associated with the latter may tend to be less severe in some cases due to the percentage of cells with an extra chromosome 9. Results of testing for mosaicism can also vary depending on the type of sample (e.g., blood, saliva) and age of the individual.Mosaic trisomy 9 is generally characterized by growth deficiency beginning prenatally (IUGR), failure to gain height and weight at the expected rate during infancy (failure to thrive), and low muscle tone (hypotonia). Most infants and children with mosaic trisomy 9 have feeding difficulties and may require a feeding tube to supplement oral feeding or for all nutritional intake.Many affected individuals have intellectual disability characterized by delays in learning academic as well as functional/daily living skills. However, there have also been some reports in which individuals with the disorder exhibit typical psychomotor development (e.g., walking unaided) or only mild gross motor delay. Regression of skills is uncommon. Recent reports indicate that affected individuals possess strengths in language and communication development (particularly receptive speech, or their ability to understand language expressed to them) as well as social-emotional development.Individuals diagnosed with mosaic trisomy 9 exhibit specific differences in their facial features and the shape of their skull. Many affected infants have a small head size (microcephaly); a sloping forehead with narrow temples; a broad nose with a bulbous tip and “slit-like” nostrils and/or a small jaw (micrognathia). Additional characteristic features may include wideness of the “soft spots” (fontanels) and the fibrous joints (i.e., cranial sutures) between certain bones of the skull; a prominent upper lip covering a receding lower lip; a highly arched roof of the mouth (palate); low-set, unusually shaped ears and/or a short neck. Various eye (ocular) anomalies may also be present, such as short, upwardly slanting eyelid folds (palpebral fissures); deeply set eyes; reduction in the size of the eyes (microphthalmia); clouded corneas and/or other ocular defects that can impact vision. Some affected infants may also have a groove in the upper lip (cleft lip); incomplete closure of the palate (cleft palate); outgrowths of skin and cartilage on or before the ears (preauricular tags) and/or other craniofacial differences. Some individuals have been reported to have hearing loss requiring ear tubes or hearing aids.Previous studies have estimated that approximately 65% of affected individuals have congenital heart defects, however more recent studies report lower numbers. The most common defects include an abnormal opening in the partition (septum) that separates the two lower or upper chambers (ventricles or atria) of the heart, called ventricular septal defects (VSDs) or atrial septal defects (ASDs). Other heart defects include patent ductus arteriosus (PDA) and/or other associated defects that allow some oxygen-rich blood to recirculate through the lungs and potentially lead to rising blood pressure in the lungs (pulmonary hypertension). Some individuals with mosaic trisomy 9 will have more than one heart defect.In individuals with cardiac defects, associated symptoms and concerns may vary depending upon the size, nature, and/or combination of heart malformations present and other factors including age and respiratory function. Some individuals may show no apparent symptoms (asymptomatic), while others may develop difficulties in feeding, poor growth, difficult or labored breathing (dyspnea), profuse sweating, an impaired ability of the heart to pump blood efficiently to the lungs and other parts of the body (heart failure) and/or other problems. In severe cases, congenital heart disease may lead to potentially life-threatening complications. Individuals may require palliative or intensive surgery to correct cardiac defects. Recovery time varies.Individuals with mosaic trisomy 9 may also experience respiratory issues including central and/or obstructive apnea. There are instances of short as well as long term need for oxygen (via nasal canula) and placement of a tracheotomy to assist with the airway. A sleep study is often utilized to identify specific respiratory needs. A bronchoscopy or similar procedure may be needed to determine anatomical anomalies affecting respiration. Nebulizer treatments may be needed as well as deep suctioning to assist with mucus build-up affecting breathing. It is critical to include a pulmonologist on the medical team if these concerns persist, especially when one or more cardiac defects is also present.Mosaic trisomy 9 is also often characterized by conditions affecting muscles and bones including congenital dislocation of the hips (developmental dysplasia of the hip), atypical position and/or limited function of other joints, such as the elbows, knees and/or fingers and toes (digits) and atypical curvature of the spine. Underdevelopment (hypoplasia) of certain bones of the digits (phalanges); hypoplasia of the nails and/or a single crease across the palms (single transverse palmar crease) may also be present. Other skeletal differences have also been reported including a narrow chest, rib defects and differences in shape of specific bones of the spine (vertebral anomalies).Affected males may also have genital complications including undescended testes (cryptorchidism), a small penis (micropenis) and/or atypical placement of the urinary opening (hypospadias, such as on the underside of the penis. Kidney (renal) complications may also be present in both males and females, including renal cysts, swelling (distension) of the kidneys with urine (hydronephrosis) due to narrowing or blockage of the tubes (i.e., ureters) that carry urine from the kidneys into the bladder and/or additional renal problems.In some cases, mosaic trisomy 9 may also be associated with brain anomalies such as hydrocephalus, Dandy-Walker malformation and/or other features. Hydrocephalus involves excess cerebrospinal fluid (CSF) on the brain, resulting in increased pressure on the skull and widening of cavities (ventricles) of the brain. CSF is the watery protective fluid that circulates through the four ventricles of the brain, the canal containing the spinal cord (spinal canal) and the space between layers of the protective membranes (meninges) surrounding the brain and spinal cord (i.e., subarachnoid space). Depending on the age at symptom onset and other factors, associated symptoms may include rapid enlargement of the head, sudden episodes of uncontrolled electrical activity in the brain (seizures), feeding difficulties, vomiting, irritability, headache, loss of coordination and/or reduction in mental functioning. In severe cases, potentially life-threatening complications may result. In those with Dandy-Walker malformation, cystic malformation of the fourth ventricle of the brain may lead to hydrocephalus with increased prominence of the back region of the head (occiput), and/or additional associated anomalies. A small number of affected individuals have agenesis of the corpus callosum, or partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. Agenesis of the corpus callosum can range in severity and may result in seizures and/or developmental delays.In some instances, additional physical features have been reported in association with mosaic trisomy 9 including clouding of the cornea of the eye, presence of cysts on one or both eyeballs (epibulbar dermoids), underdevelopment of the lungs (pulmonary hypoplasia), diaphragmatic hernia and/or gastroesophageal reflux. In individuals with a diaphragmatic hernia, there is protrusion of abdominal structures into the chest cavity through an abnormal opening in the diaphragm often in addition to gastroesophageal reflux, which is characterized by backflow (reflux) of stomach acid into the esophagus. This condition can cause inflammation of and possible damage to the esophageal lining. A gastroenterologist is often necessary to monitor and treat these digestive conditions.
| 820 |
Mosaic Trisomy 9
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nord_820_2
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Causes of Mosaic Trisomy 9
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In individuals with mosaic trisomy 9, the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body (mosaicism). Chromosomes are found in the nucleus, or central part, of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 9 includes bands 9p11 to 9p24, and the long arm includes bands 9q11 to 9q34.The same chromosomal makeup is usually present in all body cells. However, those with mosaicism have two or more cell lines that are chromosomally distinct. In individuals with mosaic trisomy 9, there is trisomy (three copies) of chromosome 9 in a percentage of cells, while other cells have a typical chromosomal makeup with two copies. The additional chromosome causes the symptoms and physical findings (phenotype) that are seen in the disorder. Individuals with a low percentage of affected cells (low mosaicism) may have fewer, less severe symptoms than those with a high percentage of affected cells (high mosaicism). The percentage of mosaicism can fluctuate depending on where the sample is drawn (cheek swab versus blood for example) and the age of the individual.Mosaic trisomy 9 appears to result from errors of chromosomal separation (nondisjunction) during meiosis, which is the division of reproductive cells (sperm or eggs) in the parents. It has also been shown to occur during cellular division after fertilization (mitosis). There have been some reports in which the disorder has appeared to occur due to a balanced chromosomal rearrangement (pericentric inversion) in one of the parents. A pericentric inversion is characterized by breakage of a chromosome in two places including the centromere and reunion of the segment in the reverse order. If a chromosomal rearrangement is balanced, meaning that the genetic material is in a different order but is in the correct quantity, it is usually harmless to the carrier. However, such a chromosomal rearrangement may result in a child with unbalanced genetic material.Chromosome studies and genetic counseling are typically recommended for parents with a child diagnosed with mosaic trisomy 9. These can help confirm or exclude the presence of a pericentric inversion or other chromosomal rearrangement involving chromosome 9 in one of the parents. In addition, knowing the chromosome structure of the parents can inform them of the risk for future children.
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Causes of Mosaic Trisomy 9. In individuals with mosaic trisomy 9, the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body (mosaicism). Chromosomes are found in the nucleus, or central part, of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 9 includes bands 9p11 to 9p24, and the long arm includes bands 9q11 to 9q34.The same chromosomal makeup is usually present in all body cells. However, those with mosaicism have two or more cell lines that are chromosomally distinct. In individuals with mosaic trisomy 9, there is trisomy (three copies) of chromosome 9 in a percentage of cells, while other cells have a typical chromosomal makeup with two copies. The additional chromosome causes the symptoms and physical findings (phenotype) that are seen in the disorder. Individuals with a low percentage of affected cells (low mosaicism) may have fewer, less severe symptoms than those with a high percentage of affected cells (high mosaicism). The percentage of mosaicism can fluctuate depending on where the sample is drawn (cheek swab versus blood for example) and the age of the individual.Mosaic trisomy 9 appears to result from errors of chromosomal separation (nondisjunction) during meiosis, which is the division of reproductive cells (sperm or eggs) in the parents. It has also been shown to occur during cellular division after fertilization (mitosis). There have been some reports in which the disorder has appeared to occur due to a balanced chromosomal rearrangement (pericentric inversion) in one of the parents. A pericentric inversion is characterized by breakage of a chromosome in two places including the centromere and reunion of the segment in the reverse order. If a chromosomal rearrangement is balanced, meaning that the genetic material is in a different order but is in the correct quantity, it is usually harmless to the carrier. However, such a chromosomal rearrangement may result in a child with unbalanced genetic material.Chromosome studies and genetic counseling are typically recommended for parents with a child diagnosed with mosaic trisomy 9. These can help confirm or exclude the presence of a pericentric inversion or other chromosomal rearrangement involving chromosome 9 in one of the parents. In addition, knowing the chromosome structure of the parents can inform them of the risk for future children.
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Affects of Mosaic Trisomy 9
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Mosaic trisomy 9 appears to affect males and females of all ethnicities in relatively equal numbers. Some research has found more females with this diagnosis. Since the disorder was originally described in 1973 (Haslam RH), over 100 cases have been reported in the medical literature.
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Affects of Mosaic Trisomy 9. Mosaic trisomy 9 appears to affect males and females of all ethnicities in relatively equal numbers. Some research has found more females with this diagnosis. Since the disorder was originally described in 1973 (Haslam RH), over 100 cases have been reported in the medical literature.
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Related disorders of Mosaic Trisomy 9
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Certain symptoms and findings associated with the following disorders may be similar to those of mosaic trisomy 9. Comparisons may be useful for a differential diagnosis:Oculo-auriculo-vertebral (OAV) spectrum usually appears to occur sporadically in the absence of a family history. However, in some cases, more than one family member has been affected, suggesting autosomal dominant or autosomal recessive inheritance. Some researchers indicate that the disorder may be caused by the interaction of multiple genes, possibly in association with environmental factors. (For further information, choose “OAV spectrum” as your search term in the Rare Disease Database.)Trisomy 9p is a rare chromosomal disorder in which a portion of the 9th chromosome appears three times (trisomy) rather than twice in cells of the body. The trisomy may involve a portion of the short arm (9p), the entire short arm, or the short arm and a portion of the long arm (9q) of chromosome 9. (As noted above [see “Causes”], each chromosome contains a short arm known as “p” and a long arm designated as “q,” with both arms further subdivided into bands that are numbered.) Evidence suggests that, in many cases, associated symptoms and findings may be relatively similar among affected infants despite differing lengths of the trisomic (duplicated) segment of 9p. However, in individuals with larger trisomies, such as those that extend through bands 9q22 or 9q32, additional clinical findings may also be present that appear to correlate with the extent of the duplication.Generally, according to investigators, trisomies involving part or all of 9p and, in some cases, extending to band 9q11-13 may be characterized by moderate to severe intellectual disability; psychomotor delay; short stature and distinctive craniofacial differences. Such craniofacial features may include a small head (microcephaly); a wide mouth with downturned corners; a relatively bulbous nose; low-set, “cup-shaped” ears; deeply set, widely spaced eyes; downwardly slanting eyelid folds (palpebral fissures) and/or an unusually short vertical groove in the center of the upper lip (philtrum). However, in addition to such features, congenital heart defects, other skeletal anomalies (e.g., congenital hip dislocation), intrauterine growth restriction and additional craniofacial differences (e.g., micrognathia, cleft lip and/or cleft palate) are more common with trisomies extending to band 9q22-q32. In addition, evidence indicates that in individuals with trisomies involving more of 9q, clinical features resemble those associated with mosaic trisomy 9. In some cases, trisomy 9p appears to result from a balanced chromosomal rearrangement in one of the parents. In others, it is thought to arise from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). (For further information, please choose “trisomy 9p” as your search term in the Rare Disease Database.)Tetrasomy 9p is a rare chromosomal disorder in which the short arm of chromosome 9 (9p) is present four times (tetrasomy) rather than twice in all or some cells of the body. Although many associated symptoms and findings may be similar to those seen in individuals with trisomy 9p, researchers suggest that such features may be more variable or severe in some cases. Characteristic anomalies associated with tetrasomy 9p may include growth deficiency; psychomotor delay; moderate to severe intellectual disability; and various craniofacial, skeletal, heart (cardiac), kidney (renal) and/or other physical differences. Craniofacial features may include an unusually small head (microcephaly); a bulbous nose; low-set, malformed ears; a down-slanted mouth; deeply set, widely spaced eyes; a short neck and/or other features. Tetrasomy 9p appears to result from spontaneous (de novo) errors very early in embryonic development. (For more information, choose “tetrasomy 9p” as your search term in the Rare Disease Database.)Additional chromosomal disorders may be characterized by symptoms and findings similar to those associated with mosaic trisomy 9. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Related disorders of Mosaic Trisomy 9. Certain symptoms and findings associated with the following disorders may be similar to those of mosaic trisomy 9. Comparisons may be useful for a differential diagnosis:Oculo-auriculo-vertebral (OAV) spectrum usually appears to occur sporadically in the absence of a family history. However, in some cases, more than one family member has been affected, suggesting autosomal dominant or autosomal recessive inheritance. Some researchers indicate that the disorder may be caused by the interaction of multiple genes, possibly in association with environmental factors. (For further information, choose “OAV spectrum” as your search term in the Rare Disease Database.)Trisomy 9p is a rare chromosomal disorder in which a portion of the 9th chromosome appears three times (trisomy) rather than twice in cells of the body. The trisomy may involve a portion of the short arm (9p), the entire short arm, or the short arm and a portion of the long arm (9q) of chromosome 9. (As noted above [see “Causes”], each chromosome contains a short arm known as “p” and a long arm designated as “q,” with both arms further subdivided into bands that are numbered.) Evidence suggests that, in many cases, associated symptoms and findings may be relatively similar among affected infants despite differing lengths of the trisomic (duplicated) segment of 9p. However, in individuals with larger trisomies, such as those that extend through bands 9q22 or 9q32, additional clinical findings may also be present that appear to correlate with the extent of the duplication.Generally, according to investigators, trisomies involving part or all of 9p and, in some cases, extending to band 9q11-13 may be characterized by moderate to severe intellectual disability; psychomotor delay; short stature and distinctive craniofacial differences. Such craniofacial features may include a small head (microcephaly); a wide mouth with downturned corners; a relatively bulbous nose; low-set, “cup-shaped” ears; deeply set, widely spaced eyes; downwardly slanting eyelid folds (palpebral fissures) and/or an unusually short vertical groove in the center of the upper lip (philtrum). However, in addition to such features, congenital heart defects, other skeletal anomalies (e.g., congenital hip dislocation), intrauterine growth restriction and additional craniofacial differences (e.g., micrognathia, cleft lip and/or cleft palate) are more common with trisomies extending to band 9q22-q32. In addition, evidence indicates that in individuals with trisomies involving more of 9q, clinical features resemble those associated with mosaic trisomy 9. In some cases, trisomy 9p appears to result from a balanced chromosomal rearrangement in one of the parents. In others, it is thought to arise from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). (For further information, please choose “trisomy 9p” as your search term in the Rare Disease Database.)Tetrasomy 9p is a rare chromosomal disorder in which the short arm of chromosome 9 (9p) is present four times (tetrasomy) rather than twice in all or some cells of the body. Although many associated symptoms and findings may be similar to those seen in individuals with trisomy 9p, researchers suggest that such features may be more variable or severe in some cases. Characteristic anomalies associated with tetrasomy 9p may include growth deficiency; psychomotor delay; moderate to severe intellectual disability; and various craniofacial, skeletal, heart (cardiac), kidney (renal) and/or other physical differences. Craniofacial features may include an unusually small head (microcephaly); a bulbous nose; low-set, malformed ears; a down-slanted mouth; deeply set, widely spaced eyes; a short neck and/or other features. Tetrasomy 9p appears to result from spontaneous (de novo) errors very early in embryonic development. (For more information, choose “tetrasomy 9p” as your search term in the Rare Disease Database.)Additional chromosomal disorders may be characterized by symptoms and findings similar to those associated with mosaic trisomy 9. Chromosomal testing is necessary to confirm the specific chromosomal abnormality present. (For further information on such disorders, choose the name of the specific chromosomal disorder in question or use “chromosome” as your search term in the Rare Disease Database.)
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Diagnosis of Mosaic Trisomy 9
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Mosaic trisomy 9 may be suspected based on characteristic physical findings. The diagnosis can be confirmed with chromosomal analysis. It may be necessary to use multiple testing methods and to collect samples from various tissue sites to detect low-level mosaicism.Diagnostic evaluation may require various studies, including advanced imaging techniques to help detect and/or characterize certain anomalies that may be associated with the disorder (e.g., craniofacial differences, skeletal anomalies, brain anomalies). A thorough cardiac evaluation may be advised to detect any heart defects that may be present. Such evaluation may include a thorough clinical examination, evaluation of heart and lung sounds with a stethoscope, x-ray studies, tests that record the electrical activities of the heart muscle (electrocardiography [EKG]); a technique in which sound waves are directed toward the heart, enabling evaluations of cardiac motion and structure (echocardiogram); or other measures based on concerns (e.g., feeding difficulties may require bronchoscopy).
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Diagnosis of Mosaic Trisomy 9. Mosaic trisomy 9 may be suspected based on characteristic physical findings. The diagnosis can be confirmed with chromosomal analysis. It may be necessary to use multiple testing methods and to collect samples from various tissue sites to detect low-level mosaicism.Diagnostic evaluation may require various studies, including advanced imaging techniques to help detect and/or characterize certain anomalies that may be associated with the disorder (e.g., craniofacial differences, skeletal anomalies, brain anomalies). A thorough cardiac evaluation may be advised to detect any heart defects that may be present. Such evaluation may include a thorough clinical examination, evaluation of heart and lung sounds with a stethoscope, x-ray studies, tests that record the electrical activities of the heart muscle (electrocardiography [EKG]); a technique in which sound waves are directed toward the heart, enabling evaluations of cardiac motion and structure (echocardiogram); or other measures based on concerns (e.g., feeding difficulties may require bronchoscopy).
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Therapies of Mosaic Trisomy 9
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TreatmentThe treatment of mosaic trisomy 9 is directed toward the specific symptoms in each individual. Such treatment requires the coordinated efforts of a team of medical professionals such as pediatricians; surgeons; heart specialists (cardiologists); physicians who diagnose and treat problems of the skeleton, joints, muscles, and related tissues (orthopedists); neurologists and/or other health care professionals.In affected individuals with congenital heart defects, treatment with specific medications, surgical intervention, and/or other measures may be required. For those with hydrocephalus, disease management may include administration of specific medications to help reduce the rate of cerebrospinal fluid (CSF) production, shunting, or other measures. (Shunts are specialized devices that drain excess CSF away from the brain to another part of the body for absorption into the bloodstream). In addition, in some cases, physicians may recommend surgical repair or correction of other craniofacial, musculoskeletal, genital and/or other complications associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of the anatomical differences, their associated symptoms, and other factors.Early intervention services are important in assisting affected children reach their potential. These services are provided to infants and toddlers. Services continue when the child reaches the age of three. Special services include special education services, physical therapy, occupational therapy, speech therapy, feeding therapy and/or other services to meet individual needs such as vision therapy. Upon reaching adulthood, medical, social/recreational and vocational or employment related services are often necessary.Genetic counseling is recommended for families of affected children.
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Therapies of Mosaic Trisomy 9. TreatmentThe treatment of mosaic trisomy 9 is directed toward the specific symptoms in each individual. Such treatment requires the coordinated efforts of a team of medical professionals such as pediatricians; surgeons; heart specialists (cardiologists); physicians who diagnose and treat problems of the skeleton, joints, muscles, and related tissues (orthopedists); neurologists and/or other health care professionals.In affected individuals with congenital heart defects, treatment with specific medications, surgical intervention, and/or other measures may be required. For those with hydrocephalus, disease management may include administration of specific medications to help reduce the rate of cerebrospinal fluid (CSF) production, shunting, or other measures. (Shunts are specialized devices that drain excess CSF away from the brain to another part of the body for absorption into the bloodstream). In addition, in some cases, physicians may recommend surgical repair or correction of other craniofacial, musculoskeletal, genital and/or other complications associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of the anatomical differences, their associated symptoms, and other factors.Early intervention services are important in assisting affected children reach their potential. These services are provided to infants and toddlers. Services continue when the child reaches the age of three. Special services include special education services, physical therapy, occupational therapy, speech therapy, feeding therapy and/or other services to meet individual needs such as vision therapy. Upon reaching adulthood, medical, social/recreational and vocational or employment related services are often necessary.Genetic counseling is recommended for families of affected children.
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Overview of Mowat-Wilson Syndrome
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Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or later in childhood. MWS is characterized by intellectual disability, distinctive facial features and seizures. Other congenital anomalies occur in some individuals and can include a gastrointestinal disease known as Hirschsprung disease (40-50% of individuals) in which a narrowing of a portion of the colon is present, eye (ophthalmologic) defects, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. MWS is caused by an abnormality in the ZEB2 gene that is usually the result of a new genetic change (mutation) in the affected person.
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Overview of Mowat-Wilson Syndrome. Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or later in childhood. MWS is characterized by intellectual disability, distinctive facial features and seizures. Other congenital anomalies occur in some individuals and can include a gastrointestinal disease known as Hirschsprung disease (40-50% of individuals) in which a narrowing of a portion of the colon is present, eye (ophthalmologic) defects, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. MWS is caused by an abnormality in the ZEB2 gene that is usually the result of a new genetic change (mutation) in the affected person.
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Symptoms of Mowat-Wilson Syndrome
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MWS is associated with a range of physical symptoms as well as intellectual disability. Most people with MWS have a severe intellectual disability, though a small number have milder features and only moderate intellectual disability. People who have MWS typically have a distinctive facial appearance, absent or severely limited speech, and often have seizures. Some physical problems may present at birth or infancy. These include the intestinal disorder Hirschsprung disease in about half, problems with development of the kidneys and male genitalia (hypospadias), congenital heart defects, eye problems and absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum). Later features may include small head size (microcephaly) and short stature. MWS specific growth charts now are available to track growth. Chronic constipation may occur even in those who do not have Hirschsprung disease. Constipation in people with MWS needs investigation in view of the possibility of very short segment HSCR. The distinctive facial appearance of people with MWS is the most consistent feature of this condition, and can be recognized by an experienced medical specialist. Common features include a high forehead, broad eyebrows that are wide apart centrally, widely spaced eyes (hypertelorism) that are large and deep set, uplifted ear lobes with a central depression, relatively small nose (in babies) with a prominent rounded nasal tip, prominent portion between nostrils (columella), open mouth with M-shaped upper lip, and a prominent but narrow and triangular pointed chin. These features may not all be obvious in babies. Some facial features become more apparent with time, so a diagnosis of MWS is easier to make in older children. Children with MWS make their developmental progress (such as sitting, crawling, and walking) at a significantly slower rate than average. Speech is often delayed or absent, with few exceptions (see mild Mowat-Wilson syndrome). Comprehension is usually better than speech ability and children may communicate in non-verbal ways such as signing or use of a communication device. They usually have a happy demeanor and smile frequently. Seizures are common, occurring in approximately 90% of individuals by 10 years of age. Seizures can be difficult to control in childhood but are not usually a major problem in adulthood. A small subset of individuals will have electrical status epilepticus during sleep (ESES) that can lead to loss of some developmental and physical skills if it continues untreated. Although a variety of congenital abnormalities may occur in infants with MWS, it is important to note that affected infants will not have all of the anomalies associated with the condition. One common congenital abnormality is Hirschsprung disease, a gastrointestinal condition characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, bloating or swelling (distention) of the abdomen, abnormal accumulation of feces within the colon, and widening of the colon above the affected segment (megacolon). Hirschsprung disease can eventually cause diarrhea, dehydration, and failure to grow and gain weight at the expected rate (failure to thrive). Short stature is common in MWS, although some people have normal stature. One rare finding is lack of a spleen, an organ that helps to fight certain types of infections. All individuals with MWS should be checked at the time of diagnosis to see if they have a spleen. This can be done through an ultrasound of the abdomen. Blood testing can sometimes also suggest that the spleen is absent. Mild Mowat-Wilson Syndrome A subset of individuals with MWS has been identified who have mild features. Such individuals may have no malformations or may have fewer facial features, sometimes making the diagnosis harder to appreciate based on physical findings alone. Additionally, such individuals may have intellectual disability that falls in the moderate, as opposed to severe, range. Speech capabilities are more advanced, with some able to speak in short sentences by mid-childhood. Individuals who have mild MWS typically have a missense mutation in the ZEB2 gene, leading to a protein that has decreased function as opposed to absent function (see Causes section).
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Symptoms of Mowat-Wilson Syndrome. MWS is associated with a range of physical symptoms as well as intellectual disability. Most people with MWS have a severe intellectual disability, though a small number have milder features and only moderate intellectual disability. People who have MWS typically have a distinctive facial appearance, absent or severely limited speech, and often have seizures. Some physical problems may present at birth or infancy. These include the intestinal disorder Hirschsprung disease in about half, problems with development of the kidneys and male genitalia (hypospadias), congenital heart defects, eye problems and absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum). Later features may include small head size (microcephaly) and short stature. MWS specific growth charts now are available to track growth. Chronic constipation may occur even in those who do not have Hirschsprung disease. Constipation in people with MWS needs investigation in view of the possibility of very short segment HSCR. The distinctive facial appearance of people with MWS is the most consistent feature of this condition, and can be recognized by an experienced medical specialist. Common features include a high forehead, broad eyebrows that are wide apart centrally, widely spaced eyes (hypertelorism) that are large and deep set, uplifted ear lobes with a central depression, relatively small nose (in babies) with a prominent rounded nasal tip, prominent portion between nostrils (columella), open mouth with M-shaped upper lip, and a prominent but narrow and triangular pointed chin. These features may not all be obvious in babies. Some facial features become more apparent with time, so a diagnosis of MWS is easier to make in older children. Children with MWS make their developmental progress (such as sitting, crawling, and walking) at a significantly slower rate than average. Speech is often delayed or absent, with few exceptions (see mild Mowat-Wilson syndrome). Comprehension is usually better than speech ability and children may communicate in non-verbal ways such as signing or use of a communication device. They usually have a happy demeanor and smile frequently. Seizures are common, occurring in approximately 90% of individuals by 10 years of age. Seizures can be difficult to control in childhood but are not usually a major problem in adulthood. A small subset of individuals will have electrical status epilepticus during sleep (ESES) that can lead to loss of some developmental and physical skills if it continues untreated. Although a variety of congenital abnormalities may occur in infants with MWS, it is important to note that affected infants will not have all of the anomalies associated with the condition. One common congenital abnormality is Hirschsprung disease, a gastrointestinal condition characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, bloating or swelling (distention) of the abdomen, abnormal accumulation of feces within the colon, and widening of the colon above the affected segment (megacolon). Hirschsprung disease can eventually cause diarrhea, dehydration, and failure to grow and gain weight at the expected rate (failure to thrive). Short stature is common in MWS, although some people have normal stature. One rare finding is lack of a spleen, an organ that helps to fight certain types of infections. All individuals with MWS should be checked at the time of diagnosis to see if they have a spleen. This can be done through an ultrasound of the abdomen. Blood testing can sometimes also suggest that the spleen is absent. Mild Mowat-Wilson Syndrome A subset of individuals with MWS has been identified who have mild features. Such individuals may have no malformations or may have fewer facial features, sometimes making the diagnosis harder to appreciate based on physical findings alone. Additionally, such individuals may have intellectual disability that falls in the moderate, as opposed to severe, range. Speech capabilities are more advanced, with some able to speak in short sentences by mid-childhood. Individuals who have mild MWS typically have a missense mutation in the ZEB2 gene, leading to a protein that has decreased function as opposed to absent function (see Causes section).
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Causes of Mowat-Wilson Syndrome
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MWS is an autosomal dominant genetic disorder caused by an abnormality (mutation) in the gene called ZEB2. This mutation leads to either loss of function (common) or decreased function (rare) of this gene. The ZEB2 gene (previously called ZFHX1B or SIP1) is located on chromosome 2 in the region 2q22.3. Genes provide the instructions for making a protein that plays a critical role in the formation of many organs and tissues of the body before birth. When a mutation occurs in one copy of this gene, the protein produced may be faulty, inefficient, or absent. This affects the development of many organs and tissues throughout the body especially the brain. MWS almost always occurs as a new (sporadic or de novo) mutation. This means that in nearly all cases, the gene mutation has occurred at the time of formation of the egg or sperm for that child only, and no other family member will be affected. It is usually not inherited from, or “carried” by, a healthy parent. In a very small number of families, more than one child has been affected with MWS. Of the more than 300 individuals described in the literature, recurrence of MWS has only been reported in 5 families. The chance of recurrence for parents who have a child with MWS is thus approximately 2% or less. This could happen if one parent has a proportion of cells in their ovaries or testes that have a mutation which causes MWS. This is called germ-line mosaicism. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. Due to the severity of the condition, affected persons are unlikely to have children of their own and there have been no reports of individuals with MWS reproducing. If an affected person were to reproduce, there would be a 50% chance with each pregnancy to have an affected child.
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Causes of Mowat-Wilson Syndrome. MWS is an autosomal dominant genetic disorder caused by an abnormality (mutation) in the gene called ZEB2. This mutation leads to either loss of function (common) or decreased function (rare) of this gene. The ZEB2 gene (previously called ZFHX1B or SIP1) is located on chromosome 2 in the region 2q22.3. Genes provide the instructions for making a protein that plays a critical role in the formation of many organs and tissues of the body before birth. When a mutation occurs in one copy of this gene, the protein produced may be faulty, inefficient, or absent. This affects the development of many organs and tissues throughout the body especially the brain. MWS almost always occurs as a new (sporadic or de novo) mutation. This means that in nearly all cases, the gene mutation has occurred at the time of formation of the egg or sperm for that child only, and no other family member will be affected. It is usually not inherited from, or “carried” by, a healthy parent. In a very small number of families, more than one child has been affected with MWS. Of the more than 300 individuals described in the literature, recurrence of MWS has only been reported in 5 families. The chance of recurrence for parents who have a child with MWS is thus approximately 2% or less. This could happen if one parent has a proportion of cells in their ovaries or testes that have a mutation which causes MWS. This is called germ-line mosaicism. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. Due to the severity of the condition, affected persons are unlikely to have children of their own and there have been no reports of individuals with MWS reproducing. If an affected person were to reproduce, there would be a 50% chance with each pregnancy to have an affected child.
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Affects of Mowat-Wilson Syndrome
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MWS affects both males and females. It is estimated to occur in 1 in 50,000-100,000 births. MWS has been described in many different countries and ethnic groups around the world.
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Affects of Mowat-Wilson Syndrome. MWS affects both males and females. It is estimated to occur in 1 in 50,000-100,000 births. MWS has been described in many different countries and ethnic groups around the world.
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Related disorders of Mowat-Wilson Syndrome
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Symptoms of the following disorders may overlap with those of Mowat-Wilson syndrome. Comparisons may be useful for a differential diagnosis. There are over 100 syndromes associated with Hirschsprung disease. Some MWS children have been thought to have Angelman syndrome because both conditions share features such as a happy personality, microcephaly, seizures and poor balance. The facial appearance is quite different in Angelman syndrome, and an experienced clinical geneticist should be able to recognize the difference. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.) Goldberg-Shprintzen megacolon syndrome (GOSHS) is also associated with Hirschsprung disease and intellectual disability. This condition is inherited in a different way and caused by mutations in a different gene (called the KIFIBP gene) than MWS. Individuals with GOSHS have a different facial appearance to those with MWS, which can be distinguished by an experienced geneticist. GOSHS is characterized by widely spaced eyes (hypertelorism), incomplete closure of the roof of the mouth (cleft palate), absence of tissue from the colored portion of the eye (iris coloboma), droopy eyelids (ptosis), arched eyebrows, and microcephaly. Affected individuals may also experience short stature and learning problems. GSS is inherited as an autosomal recessive condition. Smith-Lemli-Opitz syndrome is a rare genetic disorder characterized by delayed growth, developmental delays and a variety of congenital malformations. The most common malformations include facial abnormalities; genitourinary anomalies; heart defects; and microcephaly. Facial abnormalities include low-set ears, droopy eyelids (ptosis), cataracts, a small jaw (micrognathia), a small, upturned nose, and incomplete closure of the roof of the mouth (cleft palate). Genitourinary anomalies may include (hypospadias), undescended testes, and Hirschsprung disease. Affected infants may also have extra fingers or toes (polydactyly), webbing of the toes (syndactyly), and short thumbs. Smith-Lemli-Optiz syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Smith-Lemli-Optiz” as your search term in the Rare Disease Database.)
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Related disorders of Mowat-Wilson Syndrome. Symptoms of the following disorders may overlap with those of Mowat-Wilson syndrome. Comparisons may be useful for a differential diagnosis. There are over 100 syndromes associated with Hirschsprung disease. Some MWS children have been thought to have Angelman syndrome because both conditions share features such as a happy personality, microcephaly, seizures and poor balance. The facial appearance is quite different in Angelman syndrome, and an experienced clinical geneticist should be able to recognize the difference. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.) Goldberg-Shprintzen megacolon syndrome (GOSHS) is also associated with Hirschsprung disease and intellectual disability. This condition is inherited in a different way and caused by mutations in a different gene (called the KIFIBP gene) than MWS. Individuals with GOSHS have a different facial appearance to those with MWS, which can be distinguished by an experienced geneticist. GOSHS is characterized by widely spaced eyes (hypertelorism), incomplete closure of the roof of the mouth (cleft palate), absence of tissue from the colored portion of the eye (iris coloboma), droopy eyelids (ptosis), arched eyebrows, and microcephaly. Affected individuals may also experience short stature and learning problems. GSS is inherited as an autosomal recessive condition. Smith-Lemli-Opitz syndrome is a rare genetic disorder characterized by delayed growth, developmental delays and a variety of congenital malformations. The most common malformations include facial abnormalities; genitourinary anomalies; heart defects; and microcephaly. Facial abnormalities include low-set ears, droopy eyelids (ptosis), cataracts, a small jaw (micrognathia), a small, upturned nose, and incomplete closure of the roof of the mouth (cleft palate). Genitourinary anomalies may include (hypospadias), undescended testes, and Hirschsprung disease. Affected infants may also have extra fingers or toes (polydactyly), webbing of the toes (syndactyly), and short thumbs. Smith-Lemli-Optiz syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Smith-Lemli-Optiz” as your search term in the Rare Disease Database.)
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Mowat-Wilson Syndrome
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Diagnosis of Mowat-Wilson Syndrome
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MWS is usually diagnosed during infancy or childhood, based upon a thorough clinical evaluation, identification of characteristic physical findings and facial appearance, and information from a variety of specialized tests. Many of these features become more pronounced with time and so the diagnosis is easier to make in older individuals. Checking for features may include imaging techniques such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain, kidney ultrasound or heart ultrasound. The clinical diagnosis can be confirmed by molecular genetic testing for mutations in the ZEB2 gene. Standard chromosome testing may be undertaken in MWS to exclude a chromosome rearrangement involving chromosome 2q22, which is rare.
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Diagnosis of Mowat-Wilson Syndrome. MWS is usually diagnosed during infancy or childhood, based upon a thorough clinical evaluation, identification of characteristic physical findings and facial appearance, and information from a variety of specialized tests. Many of these features become more pronounced with time and so the diagnosis is easier to make in older individuals. Checking for features may include imaging techniques such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain, kidney ultrasound or heart ultrasound. The clinical diagnosis can be confirmed by molecular genetic testing for mutations in the ZEB2 gene. Standard chromosome testing may be undertaken in MWS to exclude a chromosome rearrangement involving chromosome 2q22, which is rare.
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Mowat-Wilson Syndrome
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Therapies of Mowat-Wilson Syndrome
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TreatmentThe treatment of individuals with MWS should be directed towards the needs of each individual. It may be necessary for a team of specialists to work together and plan for the best strategy to enable each individual to reach their full potential. Just like each individual will be different, the treatment plan will be unique and best discussed with the health professionals involved in the care plan. In MWS, associated conditions including Hirschsprung disease, heart abnormalities and seizures require intervention of relevant specialists, such as neurologists, cardiologists, and surgeons. Physical therapy, occupational therapy and speech therapy may all be useful in helping children with developmental delay reach their full potential. Treatment of Hirschsprung disease usually involves surgery to relieve bowel obstruction. A temporary bowel opening of the colon is made in the abdominal wall (colostomy) and a second surgery is performed later to remove the non-functioning section of the colon and rejoin the healthy sections of bowel. Other surgeries may be performed to treat specific congenital anomalies such as heart defects and urinary tract abnormalities. In some cases, seizures have been resistant to treatment in childhood but appear to be more easily managed in adolescents and adults. It is rare for an individual with MWS to regress in their cognitive or motor skills. However, a subset of individuals who have regression have been found to have electrical status epilepticus during sleep (ESES), that once treated, has resulted in improvements in skills that were lost. In individuals who do not have a functional spleen, giving specific immunizations and sometimes daily antibiotics may be considered. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Mowat-Wilson Syndrome. TreatmentThe treatment of individuals with MWS should be directed towards the needs of each individual. It may be necessary for a team of specialists to work together and plan for the best strategy to enable each individual to reach their full potential. Just like each individual will be different, the treatment plan will be unique and best discussed with the health professionals involved in the care plan. In MWS, associated conditions including Hirschsprung disease, heart abnormalities and seizures require intervention of relevant specialists, such as neurologists, cardiologists, and surgeons. Physical therapy, occupational therapy and speech therapy may all be useful in helping children with developmental delay reach their full potential. Treatment of Hirschsprung disease usually involves surgery to relieve bowel obstruction. A temporary bowel opening of the colon is made in the abdominal wall (colostomy) and a second surgery is performed later to remove the non-functioning section of the colon and rejoin the healthy sections of bowel. Other surgeries may be performed to treat specific congenital anomalies such as heart defects and urinary tract abnormalities. In some cases, seizures have been resistant to treatment in childhood but appear to be more easily managed in adolescents and adults. It is rare for an individual with MWS to regress in their cognitive or motor skills. However, a subset of individuals who have regression have been found to have electrical status epilepticus during sleep (ESES), that once treated, has resulted in improvements in skills that were lost. In individuals who do not have a functional spleen, giving specific immunizations and sometimes daily antibiotics may be considered. Genetic counseling is recommended for affected individuals and their families.
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Mowat-Wilson Syndrome
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Overview of Moyamoya Disease
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Moyamoya disease is a progressive disorder that affects the blood vessels in the brain (cerebrovascular). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. These tiny vessels are the “moyamoya” vessels for which the disease was named. Inadequate blood supply then leads to reduced oxygen delivery to the brain, and it is this oxygen deprivation that causes the signs of moyamoya. One of the symptoms is typically stroke, which results in paralysis of the face, arms or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attacks, or “TIA”). Other symptoms that may result include headaches, visual disturbances, developmental delay, and seizures. Approximately 10-30% of cases of moyamoya in Asian countries have a genetic cause. Patients with this arteriopathy that occurs either on a familial or idiopathic basis are said to have moyamoya disease. Patients in whom the artery changes occur in association with another process such as sickle cell disease or Down syndrome are said to have moyamoya disease. In this report, we use the term “moyamoya disease” as shorthand for both forms.
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Overview of Moyamoya Disease. Moyamoya disease is a progressive disorder that affects the blood vessels in the brain (cerebrovascular). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. These tiny vessels are the “moyamoya” vessels for which the disease was named. Inadequate blood supply then leads to reduced oxygen delivery to the brain, and it is this oxygen deprivation that causes the signs of moyamoya. One of the symptoms is typically stroke, which results in paralysis of the face, arms or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attacks, or “TIA”). Other symptoms that may result include headaches, visual disturbances, developmental delay, and seizures. Approximately 10-30% of cases of moyamoya in Asian countries have a genetic cause. Patients with this arteriopathy that occurs either on a familial or idiopathic basis are said to have moyamoya disease. Patients in whom the artery changes occur in association with another process such as sickle cell disease or Down syndrome are said to have moyamoya disease. In this report, we use the term “moyamoya disease” as shorthand for both forms.
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Moyamoya Disease
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Symptoms of Moyamoya Disease
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Although moyamoya disease may occur at any age, there are two peak incidence periods –between the ages of five and ten years in children, and between 30 to 50 years in adults. Children with moyamoya disease may present with a variety of symptoms, but most present with those related to reduced brain blood supply, including stroke, TIAs, headaches, seizures, involuntary movements or occasionally progressive developmental delay.Although adults with moyamoya also present with signs and symptoms of brain ischemia, they also have a greater tendency to suffer intracranial hemorrhage than children, presumably due to rupture of the tiny moyamoya blood vessels possibly in the setting of higher blood pressures seen in adulthood.
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Symptoms of Moyamoya Disease. Although moyamoya disease may occur at any age, there are two peak incidence periods –between the ages of five and ten years in children, and between 30 to 50 years in adults. Children with moyamoya disease may present with a variety of symptoms, but most present with those related to reduced brain blood supply, including stroke, TIAs, headaches, seizures, involuntary movements or occasionally progressive developmental delay.Although adults with moyamoya also present with signs and symptoms of brain ischemia, they also have a greater tendency to suffer intracranial hemorrhage than children, presumably due to rupture of the tiny moyamoya blood vessels possibly in the setting of higher blood pressures seen in adulthood.
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Moyamoya Disease
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Causes of Moyamoya Disease
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The causes of moyamoya disease are unknown in many cases. However, it is increasingly recognized that gene changes (mutations or variants) particularly variants that may impair the ability of smooth muscle cells in the walls of affected arteries, to contract normally, are present in many patients. It is also important to note that moymoya is found in association with a number of different underlying disorders, as noted above.Primary moyamoya disease may be genetically transmitted as an autosomal recessive trait, and accounts for approximately 10% of all cases in Japan. Recently, two major gene mutations (variants) have been reported to be associated with specific subpopulations of moyamoya patients. The first, R179 variants in the ACTA2 gene, correlate with a radiographically distinct subtype of moyamoya disease, identified in a very small cohort of patients related to a larger group of ACTA2 variants that cause cardiac and aortic disorders. (Munot, 2012) More significantly, variants in the RNF213 gene are strongly associated with the classic East Asian, bilateral, idiopathic familial disease presenting in adulthood and may be present in up to 70% of all East Asian familial cases of moyamoya. (Kamada, 2011)Secondary moyamoya disease occurs in association with a number of different underlying disorders or conditions, including certain infections involving the central nervous system, neurofibromatosis type I, sickle cell disease and Down syndrome, although there is a long list of conditions now published in the medical literature with which moyamoya disease is associated. In susceptible patients, the disease may occur following radiation therapy to the brain to treat certain brain tumors such as optic glioma or craniopharyngioma. Unlike primary moyamoya disease, the disease can occasionally present with angiographic changes involving only on one side. This process can remain unilateral, or – in about 30% of patients – progress to involve the other side. (For more information on these disorders, use “neurofibromatosis type I,” “sickle cell,”, etc., as your search terms in the Rare Disease Database.)
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Causes of Moyamoya Disease. The causes of moyamoya disease are unknown in many cases. However, it is increasingly recognized that gene changes (mutations or variants) particularly variants that may impair the ability of smooth muscle cells in the walls of affected arteries, to contract normally, are present in many patients. It is also important to note that moymoya is found in association with a number of different underlying disorders, as noted above.Primary moyamoya disease may be genetically transmitted as an autosomal recessive trait, and accounts for approximately 10% of all cases in Japan. Recently, two major gene mutations (variants) have been reported to be associated with specific subpopulations of moyamoya patients. The first, R179 variants in the ACTA2 gene, correlate with a radiographically distinct subtype of moyamoya disease, identified in a very small cohort of patients related to a larger group of ACTA2 variants that cause cardiac and aortic disorders. (Munot, 2012) More significantly, variants in the RNF213 gene are strongly associated with the classic East Asian, bilateral, idiopathic familial disease presenting in adulthood and may be present in up to 70% of all East Asian familial cases of moyamoya. (Kamada, 2011)Secondary moyamoya disease occurs in association with a number of different underlying disorders or conditions, including certain infections involving the central nervous system, neurofibromatosis type I, sickle cell disease and Down syndrome, although there is a long list of conditions now published in the medical literature with which moyamoya disease is associated. In susceptible patients, the disease may occur following radiation therapy to the brain to treat certain brain tumors such as optic glioma or craniopharyngioma. Unlike primary moyamoya disease, the disease can occasionally present with angiographic changes involving only on one side. This process can remain unilateral, or – in about 30% of patients – progress to involve the other side. (For more information on these disorders, use “neurofibromatosis type I,” “sickle cell,”, etc., as your search terms in the Rare Disease Database.)
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Moyamoya Disease
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Affects of Moyamoya Disease
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In Japan, moyamoya disease typically occurs in females under the age of 20. In Japan, the disease is estimated to occur in 1 per 300,000 people. Although moyamoya was originally reported in individuals of Japanese ancestry, cases have been reported from elsewhere in Asia as well as from Europe, North and South America and most series reported in the western hemisphere have a minority of patients of Asian descent. Of note, most patients in North America are isolated cases, with recent literature suggesting that less than 4% of cases in this population are familial. (Gaillard 2017)
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Affects of Moyamoya Disease. In Japan, moyamoya disease typically occurs in females under the age of 20. In Japan, the disease is estimated to occur in 1 per 300,000 people. Although moyamoya was originally reported in individuals of Japanese ancestry, cases have been reported from elsewhere in Asia as well as from Europe, North and South America and most series reported in the western hemisphere have a minority of patients of Asian descent. Of note, most patients in North America are isolated cases, with recent literature suggesting that less than 4% of cases in this population are familial. (Gaillard 2017)
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Related disorders of Moyamoya Disease
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Symptoms of the following disorders can be similar to those of moyamoya disease. Comparisons may be useful for a differential diagnosis:In children, any cause of occlusion or narrowing of blood vessels that supply the brain might present with symptoms similar to moyamoya. These conditions include dissection of neck or brain blood vessels (spontaneous or trauma-induced bleeding into the blood vessel wall, which both narrows the vessel and causes the formation of blood clot in the vessel), sickle cell disease (which causes clotting in major blood vessels in the brain) and inflammatory conditions, such as vasculitis, etc. In adults, strokes have multiple causes, including atherosclerosis of cerebral blood vessels, clots that lodge in brain blood vessels originating in the heart or from narrowed areas in the neck blood vessels, etc. Bleeding within the brain has multiple causes, and a discussion of differential diagnoses is beyond the scope of this article.
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Related disorders of Moyamoya Disease. Symptoms of the following disorders can be similar to those of moyamoya disease. Comparisons may be useful for a differential diagnosis:In children, any cause of occlusion or narrowing of blood vessels that supply the brain might present with symptoms similar to moyamoya. These conditions include dissection of neck or brain blood vessels (spontaneous or trauma-induced bleeding into the blood vessel wall, which both narrows the vessel and causes the formation of blood clot in the vessel), sickle cell disease (which causes clotting in major blood vessels in the brain) and inflammatory conditions, such as vasculitis, etc. In adults, strokes have multiple causes, including atherosclerosis of cerebral blood vessels, clots that lodge in brain blood vessels originating in the heart or from narrowed areas in the neck blood vessels, etc. Bleeding within the brain has multiple causes, and a discussion of differential diagnoses is beyond the scope of this article.
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Moyamoya Disease
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Diagnosis of Moyamoya Disease
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In most patients, the diagnosis of moyamoya can be made from a careful assessment of an MRI and MRA. Cerebral arteriography will confirm the diagnosis, establish the exact degree of blood vessel narrowing, demonstrate the existing blood flow patterns to various areas of the brain, and allow treatment decisions to be made; for these reasons, it is the standard diagnostic tool for this condition. In particular, catheter angiography can help with the identification of important blood vessels called “transdural collaterals,” which are present in some cases and can markedly influence surgical planning and prognosis. (Storey 2017)
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Diagnosis of Moyamoya Disease. In most patients, the diagnosis of moyamoya can be made from a careful assessment of an MRI and MRA. Cerebral arteriography will confirm the diagnosis, establish the exact degree of blood vessel narrowing, demonstrate the existing blood flow patterns to various areas of the brain, and allow treatment decisions to be made; for these reasons, it is the standard diagnostic tool for this condition. In particular, catheter angiography can help with the identification of important blood vessels called “transdural collaterals,” which are present in some cases and can markedly influence surgical planning and prognosis. (Storey 2017)
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Moyamoya Disease
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Therapies of Moyamoya Disease
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TreatmentMedical treatment of moyamoya disease has been utilized to treat many of the symptoms of moyamoya and is often an important part of the patient’s management. Treatment measures include aspirin (to prevent or reduce the development of small blood clots developing within the narrowed vessels) and anti-seizure medications (when indicated because of a patient’s seizure disorder). In rare instances, anticoagulants such as lovenox or coumadin are administered in very unstable patients having frequent symptoms, but because of the obvious risk of cerebral bleeding in this condition, they are rarely indicated as long-term measures. Calcium channel blockers are sometimes used to help reduce headache and, in some patients, reduce symptoms related to transient ischemic attacks, However, calcium channel blockers need to be used carefully, as they can also lower blood pressure, which may increase stroke risk. There is no medication available which will stop the progression of the cerebral artery narrowing and the disease will continue to progress in the vast majority of patients regardless of treatment.Surgical procedures are designed to reestablish blood supply to the brain by diverting scalp blood supply to the brain surface and thereby circumventing the progressive loss of brain hemisphere blood flow. There are many surgical procedures proposed to treat moyamoya, and they have been divided into so-called “indirect” and “direct” operations. Indirect procedures, usually carried out in children and younger patients, include pial synangiosis, encephalomyosynangiosis (EMS), encephaloduroarteriosynangiosis (EDAS), dural inversion, and other similar variants. These operations involve the placement of vascularized structures from the scalp and/or the membranes that surround the brain onto the brain surface, which in most moyamoya patients will induce the growth of new blood vessels into the brain. The most common direct procedure involves the direct suturing of a scalp blood vessel, the superficial temporal artery, to a middle cerebral artery branch on the brain surface. Long-term results following surgery of either type have been quite good, with long-term prevention of strokes seen in published series of both pediatric and adult patients. The current American Stroke Association Guidelines for pediatric stroke supports the use of surgical revascularization in affected children.Importantly, recent data demonstrates that the most important factor predicting a successful surgical outcome is to receive treatment at a center that cares for a high volume of moyamoya patients every year. (Titsworth 2016) Long-term results following surgery of either type have been quite good, with long-term prevention of strokes seen in published series of both pediatric and adult patients, including decades of follow-up with patients successfully giving birth and engaging in all manner of sports and employment.Genetic counseling is recommended for patients and their families if they have a hereditary form of moyamoya disease.
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Therapies of Moyamoya Disease. TreatmentMedical treatment of moyamoya disease has been utilized to treat many of the symptoms of moyamoya and is often an important part of the patient’s management. Treatment measures include aspirin (to prevent or reduce the development of small blood clots developing within the narrowed vessels) and anti-seizure medications (when indicated because of a patient’s seizure disorder). In rare instances, anticoagulants such as lovenox or coumadin are administered in very unstable patients having frequent symptoms, but because of the obvious risk of cerebral bleeding in this condition, they are rarely indicated as long-term measures. Calcium channel blockers are sometimes used to help reduce headache and, in some patients, reduce symptoms related to transient ischemic attacks, However, calcium channel blockers need to be used carefully, as they can also lower blood pressure, which may increase stroke risk. There is no medication available which will stop the progression of the cerebral artery narrowing and the disease will continue to progress in the vast majority of patients regardless of treatment.Surgical procedures are designed to reestablish blood supply to the brain by diverting scalp blood supply to the brain surface and thereby circumventing the progressive loss of brain hemisphere blood flow. There are many surgical procedures proposed to treat moyamoya, and they have been divided into so-called “indirect” and “direct” operations. Indirect procedures, usually carried out in children and younger patients, include pial synangiosis, encephalomyosynangiosis (EMS), encephaloduroarteriosynangiosis (EDAS), dural inversion, and other similar variants. These operations involve the placement of vascularized structures from the scalp and/or the membranes that surround the brain onto the brain surface, which in most moyamoya patients will induce the growth of new blood vessels into the brain. The most common direct procedure involves the direct suturing of a scalp blood vessel, the superficial temporal artery, to a middle cerebral artery branch on the brain surface. Long-term results following surgery of either type have been quite good, with long-term prevention of strokes seen in published series of both pediatric and adult patients. The current American Stroke Association Guidelines for pediatric stroke supports the use of surgical revascularization in affected children.Importantly, recent data demonstrates that the most important factor predicting a successful surgical outcome is to receive treatment at a center that cares for a high volume of moyamoya patients every year. (Titsworth 2016) Long-term results following surgery of either type have been quite good, with long-term prevention of strokes seen in published series of both pediatric and adult patients, including decades of follow-up with patients successfully giving birth and engaging in all manner of sports and employment.Genetic counseling is recommended for patients and their families if they have a hereditary form of moyamoya disease.
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Moyamoya Disease
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Overview of Mucha Habermann Disease
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Mucha-Habermann disease, also known as pityriasis lichenoides et varioliformis acuta or PLEVA, is a rare skin disorder. The lesions most often appear on the trunk and the arms and legs. Lesions tend to develop in small groups. Mucha-Habermann disease most often affects children or young adults. A more severe variant of this disorder, known as febrile ulceronecrotic Mucha-Habermann disease, can cause life-threatening complications in adults. The exact cause of Mucha-Habermann disease is unknown. Mucha-Habermannn is considered to be the acute end of a spectrum of skin disease known as pityriasis lichenoides. The more chronic end is known as pityriasis lichenoides chronica. In some cases, the term Mucha-Habermann disease may be used to denote the entire spectrum.
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Overview of Mucha Habermann Disease. Mucha-Habermann disease, also known as pityriasis lichenoides et varioliformis acuta or PLEVA, is a rare skin disorder. The lesions most often appear on the trunk and the arms and legs. Lesions tend to develop in small groups. Mucha-Habermann disease most often affects children or young adults. A more severe variant of this disorder, known as febrile ulceronecrotic Mucha-Habermann disease, can cause life-threatening complications in adults. The exact cause of Mucha-Habermann disease is unknown. Mucha-Habermannn is considered to be the acute end of a spectrum of skin disease known as pityriasis lichenoides. The more chronic end is known as pityriasis lichenoides chronica. In some cases, the term Mucha-Habermann disease may be used to denote the entire spectrum.
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Mucha Habermann Disease
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Symptoms of Mucha Habermann Disease
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The onset of Mucha-Habermann disease is usually sudden and is marked by the development of a recurrent rash consisting of rounded, elevated lesions (papules or macules) that may be itchy and burning. These lesions are usually reddish-purple to reddish-brown and may progress to develop a blackish-brown crust, tissue death (necrosis) and bleeding (hemorrhaging). The lesions eventually blister, often causing scarring or temporary discoloration upon healing.Although the trunk and the arms and legs are most often affected by Mucha-Habermann disease, any part of the body may potentially develop skin lesions. Lesions may number only a few to more than one hundred. Lesions may resolve without treatment in a few weeks, but may recur on and off for years.In most cases, affected individuals do not have any symptoms in addition to the skin findings. However, some individuals may have headaches, fever, joint pain (arthralgia), and a general feeling or poor health (malaise). In some cases, swelling of nearby lymph nodes (lymphadenopathy) may also occur.Febrile Ulceronecrotic Mucha-Haberman Disease (FUMHD)FUMHD is a rare, severe variant of Mucha-Habermann disease characterized by the rapid development of numerous black or necrotic bumps (papules) on the skin. These lesions may grow and spread rapidly, eventually combining (coalescing) into extremely painful ulcers and blisters. These lesions tend to be larger than those associated with the more common form of Mucha-Habermann disease. They may bleed, often scar upon healing, and may become infected.FUMHD is associated with additional symptoms including a high fever, joint pain (arthritis), gastrointestinal abnormalities (e.g., diarrhea, sore throat, and abdominal pain), enlargement of the spleen, inflammation of the lungs (interstitial pneumonitis), and central nervous system abnormalities. FUMHD occurs more often in children than adults. However, in adults some cases have progressed to cause life-threatening complications such as infection of the blood (sepsis). Life-threatening complications have not been reported in children with FUMHD.FUMHD usually lasts several months before resolving on its own, but recurs on and off for several years. Eventually, FUMHD may transform into the less severe form of Mucha-Habermann disease.
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Symptoms of Mucha Habermann Disease. The onset of Mucha-Habermann disease is usually sudden and is marked by the development of a recurrent rash consisting of rounded, elevated lesions (papules or macules) that may be itchy and burning. These lesions are usually reddish-purple to reddish-brown and may progress to develop a blackish-brown crust, tissue death (necrosis) and bleeding (hemorrhaging). The lesions eventually blister, often causing scarring or temporary discoloration upon healing.Although the trunk and the arms and legs are most often affected by Mucha-Habermann disease, any part of the body may potentially develop skin lesions. Lesions may number only a few to more than one hundred. Lesions may resolve without treatment in a few weeks, but may recur on and off for years.In most cases, affected individuals do not have any symptoms in addition to the skin findings. However, some individuals may have headaches, fever, joint pain (arthralgia), and a general feeling or poor health (malaise). In some cases, swelling of nearby lymph nodes (lymphadenopathy) may also occur.Febrile Ulceronecrotic Mucha-Haberman Disease (FUMHD)FUMHD is a rare, severe variant of Mucha-Habermann disease characterized by the rapid development of numerous black or necrotic bumps (papules) on the skin. These lesions may grow and spread rapidly, eventually combining (coalescing) into extremely painful ulcers and blisters. These lesions tend to be larger than those associated with the more common form of Mucha-Habermann disease. They may bleed, often scar upon healing, and may become infected.FUMHD is associated with additional symptoms including a high fever, joint pain (arthritis), gastrointestinal abnormalities (e.g., diarrhea, sore throat, and abdominal pain), enlargement of the spleen, inflammation of the lungs (interstitial pneumonitis), and central nervous system abnormalities. FUMHD occurs more often in children than adults. However, in adults some cases have progressed to cause life-threatening complications such as infection of the blood (sepsis). Life-threatening complications have not been reported in children with FUMHD.FUMHD usually lasts several months before resolving on its own, but recurs on and off for several years. Eventually, FUMHD may transform into the less severe form of Mucha-Habermann disease.
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Mucha Habermann Disease
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Causes of Mucha Habermann Disease
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The exact cause of Mucha-Habermann disease is unknown. Mucha-Habermann disease is part of the spectrum of pityriasis lichenoides, a benign group of disorders. Within this spectrum is also pityriasis lichenoides chronica, in which the lesions are more persistent and are characterized as pink scaling round patches on the trunk and extremities. Researchers have speculated that pityriasis lichenoides occurs because of an exaggerated, inflammatory reaction (hypersensitivity) of the body to an infectious agent. However, no causative infectious agent has been identified.Some researchers have suggested that Mucha-Habermann disease is a benign, self-healing lymphoproliferative disorder. Lymphoproliferative disorders are characterized by the overproduction of certain white blood cells called lymphocytes. These cells often accumulate in structures and tissues of the body potentially damaging them.
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Causes of Mucha Habermann Disease. The exact cause of Mucha-Habermann disease is unknown. Mucha-Habermann disease is part of the spectrum of pityriasis lichenoides, a benign group of disorders. Within this spectrum is also pityriasis lichenoides chronica, in which the lesions are more persistent and are characterized as pink scaling round patches on the trunk and extremities. Researchers have speculated that pityriasis lichenoides occurs because of an exaggerated, inflammatory reaction (hypersensitivity) of the body to an infectious agent. However, no causative infectious agent has been identified.Some researchers have suggested that Mucha-Habermann disease is a benign, self-healing lymphoproliferative disorder. Lymphoproliferative disorders are characterized by the overproduction of certain white blood cells called lymphocytes. These cells often accumulate in structures and tissues of the body potentially damaging them.
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Mucha Habermann Disease
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Affects of Mucha Habermann Disease
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Mucha-Habermann disease affects men more often than women. The disorder is most common in children and young adults, but can affect people of any age including newborns (with lesions present at birth) and the elderly. The incidence of Mucha-Habermann disease is unknown.
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Affects of Mucha Habermann Disease. Mucha-Habermann disease affects men more often than women. The disorder is most common in children and young adults, but can affect people of any age including newborns (with lesions present at birth) and the elderly. The incidence of Mucha-Habermann disease is unknown.
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Mucha Habermann Disease
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Related disorders of Mucha Habermann Disease
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Symptoms of the following disorders can be similar to those of Mucha-Habermann disease. Comparisons may be useful for a differential diagnosis.Lymphomatoid papulosis is a rare benign skin disorder. The disorder is characterized by groups of slightly-elevated, reddish-brown bumps (nodules or papules) that most often affect the trunk, face, and arms and legs. These lesions often become crusted or ulcerated, sometimes leaving a scar. Approximately 5-20 percent of individuals with lymphomatoid papulosis eventually develop cutaneous T-cell lymphoma (CTCL). Most researchers believe that lymphomatoid papulosis is a similar, yet distinct, “premalignant” condition and not a form of CTCL. (For more information on this disorder, choose “cutaneous T-cell lymphoma” as your search term in the Rare Disease Database.)Gianotti-Crosti syndrome is a rare skin disorder characterized by swollen red bumps on the skin that may or may not itch. Although an individual’s lesions could be confused with pityriasis lichenoides chronica, they tend to be smaller and typical in their distribution on the face, buttocks, and extensor surfaces of the arms or legs, often clustered on the elbows and knees.They represent a skin reaction to a wide variety of viruses, most commonly Epstein-Barr virus in the United States. Although many affected children otherwise feel perfectly fine, some have an associated upper respiratory tract infection.The bumps usually last from 4-6 weeks; they do not usually recur. There may be an enlargement of the lymph nodes in the trunk or neck areas of the body. (For more information on this disorder, choose “Gianotti” as your search term in the Rare Disease Database.)Psoriasis is a chronic, inflammatory skin disease characterized by dry, reddish (erythematous), thickened patches of skin that are covered with silvery-gray scales. These patches may be referred to as papules or plaques and most often affect the elbows, knees, hands, feet, buttock and/or lower back. The plaques may be intensely itchy (pruritic) or sore. In some cases, individuals with psoriasis may experience abnormalities affecting the fingernails, toenails, and the scalp. The severity of psoriasis varies from case to case. Psoriasis may be classified as mild, moderate or severe depending upon the amount of skin involved and the effect on an individual’s quality of life. In approximately one-third of cases a family history of psoriasis is present. Pityriasis rosea is a self-limited, mild, inflammatory skin disorder characterized by scaly lesions that follow a pattern on the skin. Often, a large lesion is seen initially (herald patch). Lesions are found most commonly on the trunk. The disorder is possibly due to an unidentified infectious agent. It may occur at any age but is seen most frequently in young adults. In temperate climates, incidence is highest during spring and autumn.A variety of additional general skin conditions including erythema multiforme, chicken pox, lichen planus, and leukocytoclastic vasculitis may resemble Mucha-Habermann disease. In some cases, skin lesions resulting from an abnormally heightened response to a bite from an insect or arthropod (e.g., spiders) may resemble Mucha-Habermann disease. (For more information on these disorders, choose the specific disorder name in the Rare Disease Database.)
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Related disorders of Mucha Habermann Disease. Symptoms of the following disorders can be similar to those of Mucha-Habermann disease. Comparisons may be useful for a differential diagnosis.Lymphomatoid papulosis is a rare benign skin disorder. The disorder is characterized by groups of slightly-elevated, reddish-brown bumps (nodules or papules) that most often affect the trunk, face, and arms and legs. These lesions often become crusted or ulcerated, sometimes leaving a scar. Approximately 5-20 percent of individuals with lymphomatoid papulosis eventually develop cutaneous T-cell lymphoma (CTCL). Most researchers believe that lymphomatoid papulosis is a similar, yet distinct, “premalignant” condition and not a form of CTCL. (For more information on this disorder, choose “cutaneous T-cell lymphoma” as your search term in the Rare Disease Database.)Gianotti-Crosti syndrome is a rare skin disorder characterized by swollen red bumps on the skin that may or may not itch. Although an individual’s lesions could be confused with pityriasis lichenoides chronica, they tend to be smaller and typical in their distribution on the face, buttocks, and extensor surfaces of the arms or legs, often clustered on the elbows and knees.They represent a skin reaction to a wide variety of viruses, most commonly Epstein-Barr virus in the United States. Although many affected children otherwise feel perfectly fine, some have an associated upper respiratory tract infection.The bumps usually last from 4-6 weeks; they do not usually recur. There may be an enlargement of the lymph nodes in the trunk or neck areas of the body. (For more information on this disorder, choose “Gianotti” as your search term in the Rare Disease Database.)Psoriasis is a chronic, inflammatory skin disease characterized by dry, reddish (erythematous), thickened patches of skin that are covered with silvery-gray scales. These patches may be referred to as papules or plaques and most often affect the elbows, knees, hands, feet, buttock and/or lower back. The plaques may be intensely itchy (pruritic) or sore. In some cases, individuals with psoriasis may experience abnormalities affecting the fingernails, toenails, and the scalp. The severity of psoriasis varies from case to case. Psoriasis may be classified as mild, moderate or severe depending upon the amount of skin involved and the effect on an individual’s quality of life. In approximately one-third of cases a family history of psoriasis is present. Pityriasis rosea is a self-limited, mild, inflammatory skin disorder characterized by scaly lesions that follow a pattern on the skin. Often, a large lesion is seen initially (herald patch). Lesions are found most commonly on the trunk. The disorder is possibly due to an unidentified infectious agent. It may occur at any age but is seen most frequently in young adults. In temperate climates, incidence is highest during spring and autumn.A variety of additional general skin conditions including erythema multiforme, chicken pox, lichen planus, and leukocytoclastic vasculitis may resemble Mucha-Habermann disease. In some cases, skin lesions resulting from an abnormally heightened response to a bite from an insect or arthropod (e.g., spiders) may resemble Mucha-Habermann disease. (For more information on these disorders, choose the specific disorder name in the Rare Disease Database.)
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Mucha Habermann Disease
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Diagnosis of Mucha Habermann Disease
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A diagnosis of Mucha-Habermann disease is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic skin lesions and, if needed for confirmation, microscopic examination (biopsy) of affected skin tissue.
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Diagnosis of Mucha Habermann Disease. A diagnosis of Mucha-Habermann disease is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic skin lesions and, if needed for confirmation, microscopic examination (biopsy) of affected skin tissue.
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Mucha Habermann Disease
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Therapies of Mucha Habermann Disease
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Treatment
Mucha-Habermann disease usually resolves on its own within several weeks to several months. However, in some cases various therapies to treat condition may be used. Oral antibiotics can help to clear lesions in about 50% of affected individuals, particularly erythromycin in children and a tetracycline derivative in adults. Exposure to ultraviolet light is the most effective therapy, particularly if the pityriasis lichenoides is persistent. While individuals can show considerable improvement from summer sunlight, phototherapy (light treatments) with narrow band ultraviolet light is an alternative for more controlled light delivery and during months that are not sunny. PUVA (psoralens and ultraviolet A light) is less commonly used, given its greater associated risk of the development of skin cancer and accelerated skin aging. Topical corticosteroids and systemic antihistamines have been used to ease pruritus, but do not clear the eruption. Methotrexate or dapsone may be necessary in severe cases.
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Therapies of Mucha Habermann Disease. Treatment
Mucha-Habermann disease usually resolves on its own within several weeks to several months. However, in some cases various therapies to treat condition may be used. Oral antibiotics can help to clear lesions in about 50% of affected individuals, particularly erythromycin in children and a tetracycline derivative in adults. Exposure to ultraviolet light is the most effective therapy, particularly if the pityriasis lichenoides is persistent. While individuals can show considerable improvement from summer sunlight, phototherapy (light treatments) with narrow band ultraviolet light is an alternative for more controlled light delivery and during months that are not sunny. PUVA (psoralens and ultraviolet A light) is less commonly used, given its greater associated risk of the development of skin cancer and accelerated skin aging. Topical corticosteroids and systemic antihistamines have been used to ease pruritus, but do not clear the eruption. Methotrexate or dapsone may be necessary in severe cases.
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Mucha Habermann Disease
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Overview of Muckle-Wells Syndrome
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Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash and joint pain.Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli. In most cases, Muckle-Wells syndrome (MWS) patients develop progressive hearing loss. In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient's tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated.
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Overview of Muckle-Wells Syndrome. Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash and joint pain.Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli. In most cases, Muckle-Wells syndrome (MWS) patients develop progressive hearing loss. In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient's tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated.
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Muckle-Wells Syndrome
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Symptoms of Muckle-Wells Syndrome
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Common symptoms of MWS include recurrent rashes beginning in infancy or early childhood, intermittent fevers, joint pain (usually with no apparent changes in tissue and cartilage), recurrent conjunctivitis (the inflammation of the outer most layer of the eye causing redness, discomfort and discharge from the eye), progressive hearing loss and amyloidosis. Symptoms can be unprecipitated, but can also be triggered by cold exposure as well as stress or exercise. Episodes generally last between 24 to 48 hours.
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Symptoms of Muckle-Wells Syndrome. Common symptoms of MWS include recurrent rashes beginning in infancy or early childhood, intermittent fevers, joint pain (usually with no apparent changes in tissue and cartilage), recurrent conjunctivitis (the inflammation of the outer most layer of the eye causing redness, discomfort and discharge from the eye), progressive hearing loss and amyloidosis. Symptoms can be unprecipitated, but can also be triggered by cold exposure as well as stress or exercise. Episodes generally last between 24 to 48 hours.
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Muckle-Wells Syndrome
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Causes of Muckle-Wells Syndrome
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MWS is usually inherited in an autosomal dominant condition and is caused by a heterozygous mutation in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Mutations in this gene are hypothesized to cause increased activity of a protein complex containing cryopyrin. This protein complex is known as the inflammasome and regulates inflammation in the body. Increased inflammasome activity results in increased release of a protein known as interleukin (IL) 1ß, which leads to symptoms of inflammation such as fever and joint pain.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 affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Muckle-Wells Syndrome. MWS is usually inherited in an autosomal dominant condition and is caused by a heterozygous mutation in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Mutations in this gene are hypothesized to cause increased activity of a protein complex containing cryopyrin. This protein complex is known as the inflammasome and regulates inflammation in the body. Increased inflammasome activity results in increased release of a protein known as interleukin (IL) 1ß, which leads to symptoms of inflammation such as fever and joint pain.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 affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Muckle-Wells Syndrome
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Affects of Muckle-Wells Syndrome
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Since MWS is a newly discovered condition, the actual incidence and prevalence of the disease are difficult to determine.
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Affects of Muckle-Wells Syndrome. Since MWS is a newly discovered condition, the actual incidence and prevalence of the disease are difficult to determine.
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Related disorders of Muckle-Wells Syndrome
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Symptoms of the following disorders can be similar to those of Muckle-Wells syndrome and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS occurs during infancy and early childhood and persists throughout the patient's life. FCAS is considered to be one of the cryopyrin associated periodic syndromes (CAPS) and also is caused by mutations in the CIAS1/NLRP3 gene.Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, congenital, systemic, inflammatory condition distinguished by fever, joint disease, rash and central nervous system (CNS) disease presenting during infancy. NOMID is the most severe form of the cryopyrin associated periodic syndromes (CAPS) and is often caused by mutations in the CIAS1/NLRP3 gene.
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Related disorders of Muckle-Wells Syndrome. Symptoms of the following disorders can be similar to those of Muckle-Wells syndrome and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS occurs during infancy and early childhood and persists throughout the patient's life. FCAS is considered to be one of the cryopyrin associated periodic syndromes (CAPS) and also is caused by mutations in the CIAS1/NLRP3 gene.Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, congenital, systemic, inflammatory condition distinguished by fever, joint disease, rash and central nervous system (CNS) disease presenting during infancy. NOMID is the most severe form of the cryopyrin associated periodic syndromes (CAPS) and is often caused by mutations in the CIAS1/NLRP3 gene.
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Muckle-Wells Syndrome
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Diagnosis of Muckle-Wells Syndrome
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Diagnosis of MWS is determined through an evaluation of a patient's symptoms. Confirmation of the diagnosis is achieved through genetic testing and the identification of a CIAS1/NLRP3 mutation, although not all MWS patients possess a mutation in this gene.
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Diagnosis of Muckle-Wells Syndrome. Diagnosis of MWS is determined through an evaluation of a patient's symptoms. Confirmation of the diagnosis is achieved through genetic testing and the identification of a CIAS1/NLRP3 mutation, although not all MWS patients possess a mutation in this gene.
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Muckle-Wells Syndrome
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Therapies of Muckle-Wells Syndrome
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TreatmentTo correct the hearing loss that often occurs, hearing aids may be used. Non-steroidal anti-inflammatory drugs are often used to alleviate joint pain. High doses of corticosteroids have shown to be somewhat effective, but may cause short- and long-term side effects.Arcalyst (Rilonacept) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 and older.Ilaris (Canakinumab) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta, was approved by the FDA in 2009 as a treatment for children and adults with CAPS, including FCAS and MWS.Kineret (Anakinra) by Biovitrum pharmaceuticals, an IL-1 receptor antagonist, has been used extensively in MWS patients with excellent clinical results. However, it is not currently approved by the FDA for the treatment of MWS or any of the CAPS diseases.
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Therapies of Muckle-Wells Syndrome. TreatmentTo correct the hearing loss that often occurs, hearing aids may be used. Non-steroidal anti-inflammatory drugs are often used to alleviate joint pain. High doses of corticosteroids have shown to be somewhat effective, but may cause short- and long-term side effects.Arcalyst (Rilonacept) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 and older.Ilaris (Canakinumab) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta, was approved by the FDA in 2009 as a treatment for children and adults with CAPS, including FCAS and MWS.Kineret (Anakinra) by Biovitrum pharmaceuticals, an IL-1 receptor antagonist, has been used extensively in MWS patients with excellent clinical results. However, it is not currently approved by the FDA for the treatment of MWS or any of the CAPS diseases.
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Overview of Mucolipidosis IV
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Mucolipidosis IV is a rare metabolic disorder characterized by intellectual disability; severe impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation); diminished muscle tone (hypotonia); clouding (opacity) of the clear portion of the eyes through which light passes (cornea); and progressive degeneration of the nerve-rich membrane lining the eyes (retinal degeneration). Mucolipidosis IV is inherited as an autosomal recessive genetic trait and caused by mutations in the MCOLN1 gene.
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Overview of Mucolipidosis IV. Mucolipidosis IV is a rare metabolic disorder characterized by intellectual disability; severe impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation); diminished muscle tone (hypotonia); clouding (opacity) of the clear portion of the eyes through which light passes (cornea); and progressive degeneration of the nerve-rich membrane lining the eyes (retinal degeneration). Mucolipidosis IV is inherited as an autosomal recessive genetic trait and caused by mutations in the MCOLN1 gene.
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Mucolipidosis IV
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Symptoms of Mucolipidosis IV
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The severe form of the disease is called typical mucolipidosis IV, and the mild form is called atypical mucolipidosis IV. Approximately 95 percent of individuals diagnosed with this condition have the severe form. The symptoms and physical findings associated with mucolipidosis IV are usually apparent within three to eight months following birth. The first recognized symptoms are usually clouding (opacity) of the cornea and eye movement abnormalities. In some cases, these symptoms may be overlooked until three to five years of age. Most affected infants exhibit hypotonia, moderate to severe intellectual disability, delays in reaching developmental milestones, and/or significant psychomotor retardation. In addition, individuals with mucolipidosis IV may have abnormalities affecting the eyes including crossed eyes (strabismus), puffy eyelids, degeneration of the nerve-rich membrane lining the eyes (retina), and/or visual impairment (amblyopia) in an eye that appears structurally normal. In some cases, such eye abnormalities may result in an abnormal sensitivity to light (photophobia) and/or nearsightedness (myopia). Individuals with mucolipidosis IV develop iron deficiency anemia because their stomachs do not secrete acid. They do not have enlarged livers or spleens, skeletal involvement, or mucopolysaccharides in the urine. Patients exhibit accumulation of certain fatty substances (lipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body. Those appear as large vacuoles and fluorescent vesicles in patient cells.
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Symptoms of Mucolipidosis IV. The severe form of the disease is called typical mucolipidosis IV, and the mild form is called atypical mucolipidosis IV. Approximately 95 percent of individuals diagnosed with this condition have the severe form. The symptoms and physical findings associated with mucolipidosis IV are usually apparent within three to eight months following birth. The first recognized symptoms are usually clouding (opacity) of the cornea and eye movement abnormalities. In some cases, these symptoms may be overlooked until three to five years of age. Most affected infants exhibit hypotonia, moderate to severe intellectual disability, delays in reaching developmental milestones, and/or significant psychomotor retardation. In addition, individuals with mucolipidosis IV may have abnormalities affecting the eyes including crossed eyes (strabismus), puffy eyelids, degeneration of the nerve-rich membrane lining the eyes (retina), and/or visual impairment (amblyopia) in an eye that appears structurally normal. In some cases, such eye abnormalities may result in an abnormal sensitivity to light (photophobia) and/or nearsightedness (myopia). Individuals with mucolipidosis IV develop iron deficiency anemia because their stomachs do not secrete acid. They do not have enlarged livers or spleens, skeletal involvement, or mucopolysaccharides in the urine. Patients exhibit accumulation of certain fatty substances (lipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body. Those appear as large vacuoles and fluorescent vesicles in patient cells.
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Mucolipidosis IV
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Causes of Mucolipidosis IV
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Mucolipidosis IV is inherited as an autosomal recessive genetic trait. The responsible gene has been isolated and its protein-product, as well as its chromosomal location, determined. The gene, designated MCOLN1, has been tracked to 19p13.3-p13.2 where it encodes for the mucolipin-1 protein. Mutations in this gene result in a deficiency of transport channel receptor protein. The exact function of this protein is still unknown. The effect of mutations on patient and animal model cells indicates a loss of regulation on intracellular traffic which eventually affects various tissue functions. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as p and a long arm identified by the letter q. Chromosomes are further subdivided into bands that are numbered. For example, chromosome 11p15.4 refers to band 15.4 on the short arm of chromosome 11. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Mucolipidosis IV. Mucolipidosis IV is inherited as an autosomal recessive genetic trait. The responsible gene has been isolated and its protein-product, as well as its chromosomal location, determined. The gene, designated MCOLN1, has been tracked to 19p13.3-p13.2 where it encodes for the mucolipin-1 protein. Mutations in this gene result in a deficiency of transport channel receptor protein. The exact function of this protein is still unknown. The effect of mutations on patient and animal model cells indicates a loss of regulation on intracellular traffic which eventually affects various tissue functions. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as p and a long arm identified by the letter q. Chromosomes are further subdivided into bands that are numbered. For example, chromosome 11p15.4 refers to band 15.4 on the short arm of chromosome 11. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Mucolipidosis IV
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Affects of Mucolipidosis IV
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Mucolipidosis IV is a rare inherited metabolic disorder that affects males and females in equal numbers. The disorder was first identified in 1974 and as of 2010, 70 cases have been reported in the medical literature. The precise incidence is unknown, but is estimated to be approximately 1:40,000. About 70% of those diagnosed are of Ashkenazi Jewish ancestry.
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Affects of Mucolipidosis IV. Mucolipidosis IV is a rare inherited metabolic disorder that affects males and females in equal numbers. The disorder was first identified in 1974 and as of 2010, 70 cases have been reported in the medical literature. The precise incidence is unknown, but is estimated to be approximately 1:40,000. About 70% of those diagnosed are of Ashkenazi Jewish ancestry.
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Related disorders of Mucolipidosis IV
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Symptoms of the following disorders can be similar to those of mucolipidosis IV. Comparisons may be useful for a differential diagnosis:Clinically the more severe cases of MLIV tend to be misdiagnosed as cerebral palsy, a group of developmental diseases with no known genetic cause. This can be easily corrected by testing blood gastrin level, which is increased in MLIV patient due to the inability to produce stomach acid. In milder cases the disease does not affect the development of children, but vision deteriorates with age and some aspects of eye abnormalities exist in the patients.Laboratory testing, in particular microscopic examination of patient tissues reveal accumulation of large vacuoles in patient’s cells. This would be characteristic of mucolipidoses and mucopolysaccharidoses. The mucolipidoses are a subgroup of lysosomal storage disorders and include I-cell disease, pseudo-hurler polydystrophy, and mucolipidosis IV. I-cell disease (mucolipidosis type II) is characterized by diffused deficiency of lysosomal enzymes within the cell and is not associated with excretion of mucopolysaccharides in the urine. Pseudo-Hurler polydystrophy (mucolipidosis type III) is characterized by a deficiency of multiple lysosomal enzymes needed to break down mucopolysaccharides. ML III affects males more often than females, and can be identified by such symptoms as claw-like hands, somewhat coarse facial features, short stature and pain in the hands. Intelligence tends to be normal in most individuals, but mild intellectual disability is possible. The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits. (For more information on these disorders, choose “mucopolysaccharidoses” as your search term in the Rare Disease Database.)Free sialic acid storage disorders are a group of related disorders characterized by the abnormal accumulation of sialic acid in various cells and tissues of the body. These disorders are generally broken down into three subtypes: infantile free sialic acid storage disease (ISSD), the most severe form; Salla disease, the mildest form; and intermediate Salla disease which is less severe than ISSD, but more serious than Salla disease. The specific symptoms associated with these disorders can vary greatly. All the disorders are characterized by some degree of degeneration of nerve cells (neurodegeneration) and cognitive impairment. Free sialic acid storage disorders occur because of mutations of the SLC17A5 gene and are inherited in an autosomal recessive fashion. (For more information on these disorders, choose “free sialic acid storage disorders” as your search term in the Rare Disease Database.)
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Related disorders of Mucolipidosis IV. Symptoms of the following disorders can be similar to those of mucolipidosis IV. Comparisons may be useful for a differential diagnosis:Clinically the more severe cases of MLIV tend to be misdiagnosed as cerebral palsy, a group of developmental diseases with no known genetic cause. This can be easily corrected by testing blood gastrin level, which is increased in MLIV patient due to the inability to produce stomach acid. In milder cases the disease does not affect the development of children, but vision deteriorates with age and some aspects of eye abnormalities exist in the patients.Laboratory testing, in particular microscopic examination of patient tissues reveal accumulation of large vacuoles in patient’s cells. This would be characteristic of mucolipidoses and mucopolysaccharidoses. The mucolipidoses are a subgroup of lysosomal storage disorders and include I-cell disease, pseudo-hurler polydystrophy, and mucolipidosis IV. I-cell disease (mucolipidosis type II) is characterized by diffused deficiency of lysosomal enzymes within the cell and is not associated with excretion of mucopolysaccharides in the urine. Pseudo-Hurler polydystrophy (mucolipidosis type III) is characterized by a deficiency of multiple lysosomal enzymes needed to break down mucopolysaccharides. ML III affects males more often than females, and can be identified by such symptoms as claw-like hands, somewhat coarse facial features, short stature and pain in the hands. Intelligence tends to be normal in most individuals, but mild intellectual disability is possible. The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits. (For more information on these disorders, choose “mucopolysaccharidoses” as your search term in the Rare Disease Database.)Free sialic acid storage disorders are a group of related disorders characterized by the abnormal accumulation of sialic acid in various cells and tissues of the body. These disorders are generally broken down into three subtypes: infantile free sialic acid storage disease (ISSD), the most severe form; Salla disease, the mildest form; and intermediate Salla disease which is less severe than ISSD, but more serious than Salla disease. The specific symptoms associated with these disorders can vary greatly. All the disorders are characterized by some degree of degeneration of nerve cells (neurodegeneration) and cognitive impairment. Free sialic acid storage disorders occur because of mutations of the SLC17A5 gene and are inherited in an autosomal recessive fashion. (For more information on these disorders, choose “free sialic acid storage disorders” as your search term in the Rare Disease Database.)
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Diagnosis of Mucolipidosis IV
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Mucolipidosis IV may be suspected based upon a thorough clinical examination, a detailed patient history, and a variety of specialized tests. Individuals with mucolipidosis IV present with iron deficiency anemia, high serum gastrin levels and characteristic findings on brain MRI examinations. In most cases, an electron microscope is used to visualize characteristic lysosomal storage bodies in fibroblasts obtained from biopsied tissue of the skin and/or the delicate membrane that lines the eyes (conjunctiva). Molecular genetic testing for mutations in the MCOLN1 gene is available to confirm the diagnosis.
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Diagnosis of Mucolipidosis IV. Mucolipidosis IV may be suspected based upon a thorough clinical examination, a detailed patient history, and a variety of specialized tests. Individuals with mucolipidosis IV present with iron deficiency anemia, high serum gastrin levels and characteristic findings on brain MRI examinations. In most cases, an electron microscope is used to visualize characteristic lysosomal storage bodies in fibroblasts obtained from biopsied tissue of the skin and/or the delicate membrane that lines the eyes (conjunctiva). Molecular genetic testing for mutations in the MCOLN1 gene is available to confirm the diagnosis.
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Mucolipidosis IV
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Therapies of Mucolipidosis IV
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TreatmentTreatment of mucolipidosis IV is symptomatic and supportive. Symptoms associated with clouding of the corneas may be treated by the use of contact lenses and/or artificial tears. Intense physical, occupational and speech therapy are also of benefit. Iron replacement is utilized for those with anemia.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Mucolipidosis IV. TreatmentTreatment of mucolipidosis IV is symptomatic and supportive. Symptoms associated with clouding of the corneas may be treated by the use of contact lenses and/or artificial tears. Intense physical, occupational and speech therapy are also of benefit. Iron replacement is utilized for those with anemia.Genetic counseling is recommended for affected individuals and their families.
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Mucolipidosis IV
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Overview of Mucopolysaccharidoses
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The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits.
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Overview of Mucopolysaccharidoses. The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis. These disorders, with one exception, are inherited as autosomal recessive traits.
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Mucopolysaccharidoses
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Symptoms of Mucopolysaccharidoses
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Individuals with MPS disorders share many similar symptoms such as multiple organ involvement, distinctive “coarse” facial features, and abnormalities of the skeleton especially joint problems. Additional findings include short stature, heart abnormalities, breathing irregularities, liver and spleen enlargement (hepatosplenomegaly), and/or neurological abnormalities. The severity of the different MPS disorders varies greatly among affected individuals, even among those with the same type of MPS and even among individuals of the same family.In most cases of MPS, affected infants appear normal at birth and symptoms become apparent around the age of one or two, however, in MPS VII, approximately 40% of pregnancies with an affected baby are complicated by a condition called non-immune hydrops fetalis that may be detected on routine ultrasound examination. Initial symptoms may include frequent colds, runny nose, infections, growth delays, or mild developmental delays. Mild forms of these disorders may not become apparent until childhood or adolescence. In most cases, the mucopolysaccharidoses are chronic, progressive disorders and, depending upon the type of MPS and severity, affected individuals may experience a decline in physical and mental function, sometimes resulting in life-threatening complications.There are different types of mucopolysaccharides that are not broken down due to enzyme malfunction or deficiency. Specifically, the mucopolysaccharides known as dermatan sulfate, heparan sulfate, or keratan sulfate may be involved alone or in some combination.MPS Subdivisions:
Hurler syndrome (mucopolysaccharidosis type 1-H; MPS 1-H) is the most severe form of mucopolysaccharidosis. It is characterized by a deficiency of the enzyme alpha-L-iduronidase, which results in an accumulation of dermatan and heparan sulfates. Symptoms of the disorder first become evident at six months to two years of age. Affected infants may experience developmental delays, recurrent urinary and upper respiratory tract infections, noisy breathing and persistent nasal discharge. Additional physical problems may include clouding of the cornea of the eye, an unusually large tongue, severe deformity of the spine, and joint stiffness. Mental development begins to regress at about the age of two.Scheie syndrome (mucopolysaccharidosis type I-S; MPS 1-S) is the mildest form of mucopolysaccharidosis. As in Hurler syndrome, individuals with Scheie syndrome have a deficiency of the enzyme alpha-L-iduronidase. However, in Scheie syndrome the deficiency is specific for accumulation of dermatan sulfate. Individuals with Scheie syndrome have normal intelligence, height, and life expectancy. Symptoms include stiff joints, carpal tunnel syndrome, backward flow of blood into the heart (aortic regurgitation), and clouding of the cornea that may result in the loss of visual acuity. The onset of symptoms in individuals with Scheie syndrome usually occurs around the age of five.Hurler-Scheie syndrome (mucopolysaccharidosis type I-H/S; MPS-IH/S) is an extremely rare disorder that refers to individuals who have a less severe form of Hurler syndrome, but a more severe form than Scheie syndrome. Like Scheie syndrome, affected individuals have a deficiency of the alpha-L-iduronidase specific for accumulation of dermatan sulfate. Hurler-Scheie syndrome is not as severe as Hurler syndrome, but more severe than Scheie syndrome. Affected individuals may develop coarse facial features, joint stiffness, short stature, clouding of the corneas, abnormally enlarged liver and/spleen (hepatosplenomegaly), and skeletal and cardiac abnormalities. Intelligence may be normal or mild to moderate intellectual disability may develop. Symptoms usually become apparent between three and six years of age.Hunter syndrome (mucopolysaccharidosis type II; MPS II) is the only type of MPS disorder inherited as an X-linked trait. Initial symptoms and findings associated with Hunter syndrome usually become apparent between ages two to four years. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Accumulation of heparin sulfate may occur. Two relatively distinct clinical forms of Hunter syndrome have been recognized. In the mild form of the disease (MPS IIB), intelligence may be normal or only slightly impaired. However, in the more severe form (MPS IIA), profound intellectual disability may become apparent by late childhood. In addition, slower disease progression tends to occur in those with the mild form of the disorder.Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) has four subtypes (A, B, C, and D) that are distinguished by four different enzyme deficiencies. Initial symptoms of the four types of Sanfilippo syndrome include hyperactivity, sleep disorders, and delays in attaining developmental milestones (e.g., crawling and walking). All forms of Sanfilippo syndrome are characterized by varying degrees of intellectual disability, progressive loss of previously acquired skills (e.g., language), and hearing loss. Affected individuals may experience seizures, unsteady gait, and aggressive behavior. Affected individuals may eventually lose the ability to walk. Accumulation of heparan sulfate may occur.Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively, resulting in accumulation of keratan and chondroitin sulfate in type A and keratan sulfate in type B. A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, abnormal skeletal development, and additional symptoms. In most cases, individuals with Morquio syndrome have normal intelligence. The clinical features of MPS IV-B are usually fewer and milder than those associated with MPS IV-A. Symptoms may include growth retardation, a prominent lower face, an abnormally short neck, knees that are abnormally close together (knock knees or genu valgum), flat feet, abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses), and/or a prominent breast bone (pectus carinatum). In some cases, hearing loss, weakness of the legs, and/or additional abnormalities also occurs.Mucopolysaccharidosis type V is the former designation for Scheie syndrome. However when it was discovered that both Hurler and Scheie syndromes occur due to a deficiency of the same enzyme, Scheie syndrome was reclassified as a subtype of mucopolysaccharidosis type I.Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is characterized by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase, resulting in accumulation of dermatan sulfate. This form of MPS varies greatly among affected individuals. Some affected individuals only experience a few mild symptoms, other develop a more severe form of the disorder. Possible symptoms of Maroteaux-Lamy syndrome include coarse facial features, umbilical hernia, a prominent breast bone (pectus carinatum), joint contractures, clouding of the corneas, and an abnormal enlargement of the liver and/or spleen (heptasplenomegaly). Skeletal malformations and heart disease may occur in individuals with this form of MPS. In most cases, intelligence is normal.Sly syndrome (mucopolysaccharidosis type VII; MPS VII) is characterized by a deficiency of the enzyme beta-glucuronidase, resulting in the accumulation of three glycosaminoglycans: dermatan sulfate, heparan sulfate and chondroitin sulfate. The symptoms may vary greatly from person to person. Individuals may have normal intelligence or mild to severe intellectual disability. Some skeletal abnormalities are often present. Hernias, clouding of the corneas, excessive accumulation of cerebrospinal fluid in the skull (hydrocephalus), short stature, heart disease, and coarse facial features have also been reported. In rare cases, some newborn infants with Sly syndrome may experience abnormal accumulation of fluid in various tissues of the body (hydrops fetalis). MPS VII is currently in clinical trial.DiFerrante syndrome (mucopolysaccharidosis VIII; MPS VIII) is an obsolete term for a form of MPS described in a single individual with clinical and biochemical features of Morquio and Sanfilippo syndromes. The disorder had been reported to be due to a deficiency of glucosamine-6-sulfate sulfatase. Subsequently, this disorder was called MPS VIII (DiFerrante syndrome). Dr. DiFerrante later found that the enzyme was normal in his patient, and the disorder had been misdiagnosed. Therefore, DiFerrante syndrome is not a valid medical disorder.Hyaluronidase deficiency (mucopolysaccharidosis IX; MPS IX) is an extremely rare form of MPS characterized by a deficiency of the enzyme hyaluronidase, which is needed to breakdown the mucopolysaccharides known as hyaluronan (hyaluronic acid). This form of MPS was first described in 1996. Symptoms may include mild short stature, cysts, frequent ear infections, cleft palate, and the development of soft-tissue masses. However, more cases of this form of MPS must be identified before a clear clinical picture can be established.
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Symptoms of Mucopolysaccharidoses. Individuals with MPS disorders share many similar symptoms such as multiple organ involvement, distinctive “coarse” facial features, and abnormalities of the skeleton especially joint problems. Additional findings include short stature, heart abnormalities, breathing irregularities, liver and spleen enlargement (hepatosplenomegaly), and/or neurological abnormalities. The severity of the different MPS disorders varies greatly among affected individuals, even among those with the same type of MPS and even among individuals of the same family.In most cases of MPS, affected infants appear normal at birth and symptoms become apparent around the age of one or two, however, in MPS VII, approximately 40% of pregnancies with an affected baby are complicated by a condition called non-immune hydrops fetalis that may be detected on routine ultrasound examination. Initial symptoms may include frequent colds, runny nose, infections, growth delays, or mild developmental delays. Mild forms of these disorders may not become apparent until childhood or adolescence. In most cases, the mucopolysaccharidoses are chronic, progressive disorders and, depending upon the type of MPS and severity, affected individuals may experience a decline in physical and mental function, sometimes resulting in life-threatening complications.There are different types of mucopolysaccharides that are not broken down due to enzyme malfunction or deficiency. Specifically, the mucopolysaccharides known as dermatan sulfate, heparan sulfate, or keratan sulfate may be involved alone or in some combination.MPS Subdivisions:
Hurler syndrome (mucopolysaccharidosis type 1-H; MPS 1-H) is the most severe form of mucopolysaccharidosis. It is characterized by a deficiency of the enzyme alpha-L-iduronidase, which results in an accumulation of dermatan and heparan sulfates. Symptoms of the disorder first become evident at six months to two years of age. Affected infants may experience developmental delays, recurrent urinary and upper respiratory tract infections, noisy breathing and persistent nasal discharge. Additional physical problems may include clouding of the cornea of the eye, an unusually large tongue, severe deformity of the spine, and joint stiffness. Mental development begins to regress at about the age of two.Scheie syndrome (mucopolysaccharidosis type I-S; MPS 1-S) is the mildest form of mucopolysaccharidosis. As in Hurler syndrome, individuals with Scheie syndrome have a deficiency of the enzyme alpha-L-iduronidase. However, in Scheie syndrome the deficiency is specific for accumulation of dermatan sulfate. Individuals with Scheie syndrome have normal intelligence, height, and life expectancy. Symptoms include stiff joints, carpal tunnel syndrome, backward flow of blood into the heart (aortic regurgitation), and clouding of the cornea that may result in the loss of visual acuity. The onset of symptoms in individuals with Scheie syndrome usually occurs around the age of five.Hurler-Scheie syndrome (mucopolysaccharidosis type I-H/S; MPS-IH/S) is an extremely rare disorder that refers to individuals who have a less severe form of Hurler syndrome, but a more severe form than Scheie syndrome. Like Scheie syndrome, affected individuals have a deficiency of the alpha-L-iduronidase specific for accumulation of dermatan sulfate. Hurler-Scheie syndrome is not as severe as Hurler syndrome, but more severe than Scheie syndrome. Affected individuals may develop coarse facial features, joint stiffness, short stature, clouding of the corneas, abnormally enlarged liver and/spleen (hepatosplenomegaly), and skeletal and cardiac abnormalities. Intelligence may be normal or mild to moderate intellectual disability may develop. Symptoms usually become apparent between three and six years of age.Hunter syndrome (mucopolysaccharidosis type II; MPS II) is the only type of MPS disorder inherited as an X-linked trait. Initial symptoms and findings associated with Hunter syndrome usually become apparent between ages two to four years. Such abnormalities may include progressive growth delays, resulting in short stature; joint stiffness, with associated restriction of movements; and coarsening of facial features, including thickening of the lips, tongue, and nostrils. Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly). Accumulation of heparin sulfate may occur. Two relatively distinct clinical forms of Hunter syndrome have been recognized. In the mild form of the disease (MPS IIB), intelligence may be normal or only slightly impaired. However, in the more severe form (MPS IIA), profound intellectual disability may become apparent by late childhood. In addition, slower disease progression tends to occur in those with the mild form of the disorder.Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) has four subtypes (A, B, C, and D) that are distinguished by four different enzyme deficiencies. Initial symptoms of the four types of Sanfilippo syndrome include hyperactivity, sleep disorders, and delays in attaining developmental milestones (e.g., crawling and walking). All forms of Sanfilippo syndrome are characterized by varying degrees of intellectual disability, progressive loss of previously acquired skills (e.g., language), and hearing loss. Affected individuals may experience seizures, unsteady gait, and aggressive behavior. Affected individuals may eventually lose the ability to walk. Accumulation of heparan sulfate may occur.Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively, resulting in accumulation of keratan and chondroitin sulfate in type A and keratan sulfate in type B. A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, abnormal skeletal development, and additional symptoms. In most cases, individuals with Morquio syndrome have normal intelligence. The clinical features of MPS IV-B are usually fewer and milder than those associated with MPS IV-A. Symptoms may include growth retardation, a prominent lower face, an abnormally short neck, knees that are abnormally close together (knock knees or genu valgum), flat feet, abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses), and/or a prominent breast bone (pectus carinatum). In some cases, hearing loss, weakness of the legs, and/or additional abnormalities also occurs.Mucopolysaccharidosis type V is the former designation for Scheie syndrome. However when it was discovered that both Hurler and Scheie syndromes occur due to a deficiency of the same enzyme, Scheie syndrome was reclassified as a subtype of mucopolysaccharidosis type I.Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is characterized by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase, resulting in accumulation of dermatan sulfate. This form of MPS varies greatly among affected individuals. Some affected individuals only experience a few mild symptoms, other develop a more severe form of the disorder. Possible symptoms of Maroteaux-Lamy syndrome include coarse facial features, umbilical hernia, a prominent breast bone (pectus carinatum), joint contractures, clouding of the corneas, and an abnormal enlargement of the liver and/or spleen (heptasplenomegaly). Skeletal malformations and heart disease may occur in individuals with this form of MPS. In most cases, intelligence is normal.Sly syndrome (mucopolysaccharidosis type VII; MPS VII) is characterized by a deficiency of the enzyme beta-glucuronidase, resulting in the accumulation of three glycosaminoglycans: dermatan sulfate, heparan sulfate and chondroitin sulfate. The symptoms may vary greatly from person to person. Individuals may have normal intelligence or mild to severe intellectual disability. Some skeletal abnormalities are often present. Hernias, clouding of the corneas, excessive accumulation of cerebrospinal fluid in the skull (hydrocephalus), short stature, heart disease, and coarse facial features have also been reported. In rare cases, some newborn infants with Sly syndrome may experience abnormal accumulation of fluid in various tissues of the body (hydrops fetalis). MPS VII is currently in clinical trial.DiFerrante syndrome (mucopolysaccharidosis VIII; MPS VIII) is an obsolete term for a form of MPS described in a single individual with clinical and biochemical features of Morquio and Sanfilippo syndromes. The disorder had been reported to be due to a deficiency of glucosamine-6-sulfate sulfatase. Subsequently, this disorder was called MPS VIII (DiFerrante syndrome). Dr. DiFerrante later found that the enzyme was normal in his patient, and the disorder had been misdiagnosed. Therefore, DiFerrante syndrome is not a valid medical disorder.Hyaluronidase deficiency (mucopolysaccharidosis IX; MPS IX) is an extremely rare form of MPS characterized by a deficiency of the enzyme hyaluronidase, which is needed to breakdown the mucopolysaccharides known as hyaluronan (hyaluronic acid). This form of MPS was first described in 1996. Symptoms may include mild short stature, cysts, frequent ear infections, cleft palate, and the development of soft-tissue masses. However, more cases of this form of MPS must be identified before a clear clinical picture can be established.
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Mucopolysaccharidoses
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Causes of Mucopolysaccharidoses
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All of the MPS disorders result from deficiency or malfunction of a specific lysosomal enzyme necessary in the breaking down of dermatan sulfate, heparan sulfate, or keratan sulfate, either alone or together. Failure to breakdown these mucopolysaccharides results in their accumulation in cells, tissues and organs throughout the body. All of these disorders are inherited as autosomal recessive traits except for Hunter syndrome, which is an X-linked recessive trait.Genetic diseases are determined by abnormal changes in the gene for enzyme for each disorder, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits an 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 pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. A Female who has an abnormal gene present on one of her X chromosomes is a carrier for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.
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Causes of Mucopolysaccharidoses. All of the MPS disorders result from deficiency or malfunction of a specific lysosomal enzyme necessary in the breaking down of dermatan sulfate, heparan sulfate, or keratan sulfate, either alone or together. Failure to breakdown these mucopolysaccharides results in their accumulation in cells, tissues and organs throughout the body. All of these disorders are inherited as autosomal recessive traits except for Hunter syndrome, which is an X-linked recessive trait.Genetic diseases are determined by abnormal changes in the gene for enzyme for each disorder, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits an 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 pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. A Female who has an abnormal gene present on one of her X chromosomes is a carrier for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.
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Mucopolysaccharidoses
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Affects of Mucopolysaccharidoses
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The prevalence of all forms of mucopolysaccharidosis is estimated to be one in 25,000 births. However, because mucopolysaccharidoses, especially the milder forms of the diseases, often go unrecognized, these disorders are under-diagnosed or misdiagnosed, making it difficult to determine their true frequency in the general population.Estimates for the specific types of mucopolysaccharidosis range from: one in 100,000 for Hurler syndrome; one in 500,000 for Scheie syndrome; one in 115,000 for Hurler-Scheie syndrome; one in 70,000 for Sanfilippo syndrome; one in 200,000 for Morquio syndrome; and fewer than one in 250,000 in Sly syndrome. Hunter syndrome occurs predominantly in males. In extremely rare cases, affected females have been reported. The incidence of Hunter syndrome is estimated at one in 100,000-150,000 male births.More than 40 distinct lysosomal storage diseases have been identified.
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Affects of Mucopolysaccharidoses. The prevalence of all forms of mucopolysaccharidosis is estimated to be one in 25,000 births. However, because mucopolysaccharidoses, especially the milder forms of the diseases, often go unrecognized, these disorders are under-diagnosed or misdiagnosed, making it difficult to determine their true frequency in the general population.Estimates for the specific types of mucopolysaccharidosis range from: one in 100,000 for Hurler syndrome; one in 500,000 for Scheie syndrome; one in 115,000 for Hurler-Scheie syndrome; one in 70,000 for Sanfilippo syndrome; one in 200,000 for Morquio syndrome; and fewer than one in 250,000 in Sly syndrome. Hunter syndrome occurs predominantly in males. In extremely rare cases, affected females have been reported. The incidence of Hunter syndrome is estimated at one in 100,000-150,000 male births.More than 40 distinct lysosomal storage diseases have been identified.
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Mucopolysaccharidoses
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Related disorders of Mucopolysaccharidoses
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Symptoms of the following disorders can be similar to those of mucopolysaccharidosis. Comparisons may be useful for a differential diagnosis:The mucolipidoses are another subgroup of lysosomal storage disorders and produce symptoms similar to those of the mucopolysaccharidoses. These disorders include I-cell disease, pseudo-hurler polydystrophy, and mucolipidosis (ML) type IV. I-cell disease (mucolipidosis type II) resembles Hurler syndrome and the two disorders are difficult to distinguish. I-cell disease has similar physical and mental deterioration as MPS I, but usually occurs earlier and is more severe. I-cell disease is characterized by diffused deficiency of lysosomal enzymes within the cell and is not associated with excretion of mucopolysaccharides in the urine. Pseudo-Hurler polydystrophy (mucolipidosis type III) is characterized by a deficiency of multiple lysosomal enzymes needed to break down mucopolysaccharides. ML III affects males more often than females, and can be identified by such symptoms as claw-like hands, somewhat coarse facial features, short stature and pain in the hands. Intelligence tends to be normal in most individuals, but mild intellectual disability is possible. ML type IV is thought to be caused by a deficiency of transport channel receptor protein. This deficiency may lead to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body. ML IV is characterized by intellectual disability; severe impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation); diminished muscle tone (hypotonia); clouding (opacity) of the clear portion of the eyes through which light passes (cornea); and/or degeneration of the nerve-rich membrane lining the eyes (retinal degeneration). (For more information on these disorders, choose “mucolipidosis” as your search term in the Rare Disease Database.)Lipid storage disorders are a group of disorders that include Fabry disease and Gaucher disease. Fabry disease is characterized by a deficiency of the enzyme alpha-galactosidase A. Low levels or inactivity of this enzyme leads to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various organs of the body, particularly blood vessels and the eyes. Symptoms of Fabry disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), abdominal pain, and/or visual impairment. Later in the course of the disease, kidney failure, heart irregularities, and/or progressive neurological abnormalities may cause serious complications. Gaucher disease is rare disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain fats (lipids), specifically the glycolipid glucocerebroside, throughout the body especially within the bone marrow, spleen and liver. The symptoms and physical findings associated with Gaucher disease vary greatly from person to person. Some individuals will develop few or no symptoms (asymptomatic); others may have serious complications. Common symptoms associated with Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets (thrombocytopenia), and skeletal abnormalities. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Multiple sulfatase deficiency is a rare hereditary metabolic disorder characterized by impairment of all known sulfatase enzymes. Major symptoms include coarse facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur such as abnormal curvature of the spine (lumbar kyphosis). The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak as quickly as other children (developmental delays). Multiple sulfatase deficiency is inherited as an autosomal recessive trait. (For more information on this disorder, choose “multiple sulfatase deficiency” as your search term in the Rare Disease Database.)Additional groups of disorders that have similar symptoms to the mucopolysaccharidoses include glycoprotein disorders (oligosaccharidoses), which include fucosidosis and mannosidosis; leukodystrophies, which include Krabbe’s disease and metachromatic leukodystrophy; and gangliosidoses such as Tay-Sachs disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Mucopolysaccharidoses. Symptoms of the following disorders can be similar to those of mucopolysaccharidosis. Comparisons may be useful for a differential diagnosis:The mucolipidoses are another subgroup of lysosomal storage disorders and produce symptoms similar to those of the mucopolysaccharidoses. These disorders include I-cell disease, pseudo-hurler polydystrophy, and mucolipidosis (ML) type IV. I-cell disease (mucolipidosis type II) resembles Hurler syndrome and the two disorders are difficult to distinguish. I-cell disease has similar physical and mental deterioration as MPS I, but usually occurs earlier and is more severe. I-cell disease is characterized by diffused deficiency of lysosomal enzymes within the cell and is not associated with excretion of mucopolysaccharides in the urine. Pseudo-Hurler polydystrophy (mucolipidosis type III) is characterized by a deficiency of multiple lysosomal enzymes needed to break down mucopolysaccharides. ML III affects males more often than females, and can be identified by such symptoms as claw-like hands, somewhat coarse facial features, short stature and pain in the hands. Intelligence tends to be normal in most individuals, but mild intellectual disability is possible. ML type IV is thought to be caused by a deficiency of transport channel receptor protein. This deficiency may lead to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body. ML IV is characterized by intellectual disability; severe impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation); diminished muscle tone (hypotonia); clouding (opacity) of the clear portion of the eyes through which light passes (cornea); and/or degeneration of the nerve-rich membrane lining the eyes (retinal degeneration). (For more information on these disorders, choose “mucolipidosis” as your search term in the Rare Disease Database.)Lipid storage disorders are a group of disorders that include Fabry disease and Gaucher disease. Fabry disease is characterized by a deficiency of the enzyme alpha-galactosidase A. Low levels or inactivity of this enzyme leads to the abnormal accumulation of a substance consisting of fatty material and carbohydrates (i.e., glycolipids such as glycosphingolipid) in various organs of the body, particularly blood vessels and the eyes. Symptoms of Fabry disease may include the appearance of clusters of wart-like discolorations on the skin (angiokeratomas), abdominal pain, and/or visual impairment. Later in the course of the disease, kidney failure, heart irregularities, and/or progressive neurological abnormalities may cause serious complications. Gaucher disease is rare disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain fats (lipids), specifically the glycolipid glucocerebroside, throughout the body especially within the bone marrow, spleen and liver. The symptoms and physical findings associated with Gaucher disease vary greatly from person to person. Some individuals will develop few or no symptoms (asymptomatic); others may have serious complications. Common symptoms associated with Gaucher disease include an abnormally enlarged liver and/or spleen (hepatosplenomegaly), low levels of circulating red blood cells (anemia), low levels of platelets (thrombocytopenia), and skeletal abnormalities. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Multiple sulfatase deficiency is a rare hereditary metabolic disorder characterized by impairment of all known sulfatase enzymes. Major symptoms include coarse facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur such as abnormal curvature of the spine (lumbar kyphosis). The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak as quickly as other children (developmental delays). Multiple sulfatase deficiency is inherited as an autosomal recessive trait. (For more information on this disorder, choose “multiple sulfatase deficiency” as your search term in the Rare Disease Database.)Additional groups of disorders that have similar symptoms to the mucopolysaccharidoses include glycoprotein disorders (oligosaccharidoses), which include fucosidosis and mannosidosis; leukodystrophies, which include Krabbe’s disease and metachromatic leukodystrophy; and gangliosidoses such as Tay-Sachs disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Mucopolysaccharidoses
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nord_826_5
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Diagnosis of Mucopolysaccharidoses
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A diagnosis of a mucopolysaccharidosis disorder is made based upon a thorough clinical evaluation, identification of characteristic findings (e.g., coarse facial features, skeletal malformations, hepatosplenomegaly), and a variety of specialized tests including urine analysis to detect excessive levels of mucopolysaccharides. Tests known as enzyme assays may be performed to detect deficient levels of lysosomal enzymes in cells of the body.Newborn screening for MPS I has recently been approved for inclusion in the Recommended Universal Screening Panel, although each state decides independently when or if, it will be added to its newborn screening panel MPS II is currently being screened in Illinois. After an abnormal newborn screening result, it would be necessary to follow up with a definitive diagnosis by enzyme assay.Prenatal diagnosis is possible through the use of amniocentesis and chorionic villus sampling. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During CVS, tissue samples are removed from a portion of the placenta and DNA studies may be performed, primarily in families with a previously affected child, and the abnormal gene mutations are known.
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Diagnosis of Mucopolysaccharidoses. A diagnosis of a mucopolysaccharidosis disorder is made based upon a thorough clinical evaluation, identification of characteristic findings (e.g., coarse facial features, skeletal malformations, hepatosplenomegaly), and a variety of specialized tests including urine analysis to detect excessive levels of mucopolysaccharides. Tests known as enzyme assays may be performed to detect deficient levels of lysosomal enzymes in cells of the body.Newborn screening for MPS I has recently been approved for inclusion in the Recommended Universal Screening Panel, although each state decides independently when or if, it will be added to its newborn screening panel MPS II is currently being screened in Illinois. After an abnormal newborn screening result, it would be necessary to follow up with a definitive diagnosis by enzyme assay.Prenatal diagnosis is possible through the use of amniocentesis and chorionic villus sampling. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During CVS, tissue samples are removed from a portion of the placenta and DNA studies may be performed, primarily in families with a previously affected child, and the abnormal gene mutations are known.
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Mucopolysaccharidoses
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nord_826_6
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Therapies of Mucopolysaccharidoses
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ManagementIn 2005, The U.S. Food and Drug Administration (FDA) approved galsulfase (Naglazyme) for the treatment of MPS VI, also known as Maroteaux-Lamy syndrome. Naglazyme, an orphan drug, is a product of BioMarin Pharmaceutical Inc.In 2003, The FDA approved laronidase (Aldurazyme) as a treatment for MPS I Specifically, this enzyme replacement therapy is approved for treating patients with the Hurler and Hurler-Scheie forms of MPS I and those with the Scheie form who exhibit moderate to severe symptoms. Aldurazyme is manufactured by BioMarin Pharmaceutical Inc. and distributed by Sanofi-Genzyme. It is the first treatment approved specifically for MPS I. The FDA approved idursulfase (Elaprase) for MPS II (July 2006), galsidase (Naglazyme) for MPS VI (May 2005) and elosufase alfa (Vimizin) for MPS IVA (February 2014). Elaprase is manufactured by Shire Pharmaceuticals, and Naglazyme and Vimizin by BioMarin Pharmaceutical Inc.Otherwise, treatment for the various forms of mucopolysaccharidosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat heart problems (cardiologists), specialists who assess and treat hearing problems (audiologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat skeletal problems (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Surgery may be used to treat a variety of symptoms associated with mucopolysaccharidosis, including carpal tunnel syndrome, skeletal malformations, and hernias. Corneal transplantation has been performed with mixed results. Physical therapy and exercise may improve joint stiffness. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Heart valve replacement may be necessary in some cases.Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Mucopolysaccharidoses. ManagementIn 2005, The U.S. Food and Drug Administration (FDA) approved galsulfase (Naglazyme) for the treatment of MPS VI, also known as Maroteaux-Lamy syndrome. Naglazyme, an orphan drug, is a product of BioMarin Pharmaceutical Inc.In 2003, The FDA approved laronidase (Aldurazyme) as a treatment for MPS I Specifically, this enzyme replacement therapy is approved for treating patients with the Hurler and Hurler-Scheie forms of MPS I and those with the Scheie form who exhibit moderate to severe symptoms. Aldurazyme is manufactured by BioMarin Pharmaceutical Inc. and distributed by Sanofi-Genzyme. It is the first treatment approved specifically for MPS I. The FDA approved idursulfase (Elaprase) for MPS II (July 2006), galsidase (Naglazyme) for MPS VI (May 2005) and elosufase alfa (Vimizin) for MPS IVA (February 2014). Elaprase is manufactured by Shire Pharmaceuticals, and Naglazyme and Vimizin by BioMarin Pharmaceutical Inc.Otherwise, treatment for the various forms of mucopolysaccharidosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat heart problems (cardiologists), specialists who assess and treat hearing problems (audiologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat skeletal problems (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Surgery may be used to treat a variety of symptoms associated with mucopolysaccharidosis, including carpal tunnel syndrome, skeletal malformations, and hernias. Corneal transplantation has been performed with mixed results. Physical therapy and exercise may improve joint stiffness. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Heart valve replacement may be necessary in some cases.Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Mucopolysaccharidoses
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nord_827_0
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Overview of Mucopolysaccharidosis IV
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SummaryMucopolysaccharidosis IV (MPS IV) is a mucopolysaccharide storage disease that exists in two forms (MPS IVA and MPS IVB). These are autosomal recessive genetic conditions that comprise a continuum consisting of a severe form with rapid progression and another slowly progressing form. The severe form becomes apparent between the ages of one and three and typically presents with knock-knees and breastbone prominence. The slowly progressing form, which may not become apparent until adolescence, presents with hip pain and stiffness.Although they are subtypes of the same disease, it is important to distinguish MPS IVA from MPS IVB for the purposes of effective treatment and disease management. MPS IVA can only be distinguished from MPS IVB by molecular genetic or biochemical testing because of the similarities in the symptoms they present. MPS IV occurs because of a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase (GALNS) and MPS IVB occurs due to a deficiency of beta-galactosidase.A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, abnormal skeletal development, and additional symptoms. In most cases, individuals with MPS IV have normal intelligence. The clinical features of MPS IVB are usually fewer and milder than those associated with MPS IVA. Enzyme replacement therapy is available to treat MPS IVA.IntroductionThe mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis.
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Overview of Mucopolysaccharidosis IV. SummaryMucopolysaccharidosis IV (MPS IV) is a mucopolysaccharide storage disease that exists in two forms (MPS IVA and MPS IVB). These are autosomal recessive genetic conditions that comprise a continuum consisting of a severe form with rapid progression and another slowly progressing form. The severe form becomes apparent between the ages of one and three and typically presents with knock-knees and breastbone prominence. The slowly progressing form, which may not become apparent until adolescence, presents with hip pain and stiffness.Although they are subtypes of the same disease, it is important to distinguish MPS IVA from MPS IVB for the purposes of effective treatment and disease management. MPS IVA can only be distinguished from MPS IVB by molecular genetic or biochemical testing because of the similarities in the symptoms they present. MPS IV occurs because of a deficiency of the enzyme N-acetyl-galactosamine-6-sulfatase (GALNS) and MPS IVB occurs due to a deficiency of beta-galactosidase.A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, abnormal skeletal development, and additional symptoms. In most cases, individuals with MPS IV have normal intelligence. The clinical features of MPS IVB are usually fewer and milder than those associated with MPS IVA. Enzyme replacement therapy is available to treat MPS IVA.IntroductionThe mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates (mucopolysaccharides or glycosaminoglycans) in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of mucopolysaccharidosis.
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Mucopolysaccharidosis IV
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nord_827_1
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Symptoms of Mucopolysaccharidosis IV
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Symptoms of MPS IV may include growth delays; a prominent lower face; abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis) or concern for a spine abnormality; an abnormally short neck; knees that are abnormally close together (knock knees or genu valgum); flat feet; abnormal development of the growing ends of the long bones (epiphyses); hip dislocation and arthritis and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or additional abnormalities may also occur. Affected children have a characteristic facial appearance that may include an enlarged head, broad mouth, prominent cheekbones, an unusually small nose, widely spaced and thinly enameled teeth, and widely separated eyes with subtle corneal clouding. The liver and spleen may be mildly enlarged. Children with MPS IV show marked growth abnormalities with short trunks and normal limbs from early in life. The elbows, wrists, hips, knees and other large joints are abnormally flexible, causing overall instability. Affected individuals exhibit a waddling gait with frequent falls. Early development and intelligence are typically normal, unlike other MPS storage disorders. High frequency hearing impairment is common. Skeletal X-rays typically show marked flattening of the vertebra. The long bones of the arms and legs are characteristically shorter and thicker than normal. The skull is large for the rest of the body. The connection between the first and second vertebrae in the neck is poorly developed and this abnormality can be life threatening. A trivial injury may cause the two vertebrae to slip on each other and compress the spinal cord. Surgery to stabilize the upper cervical spine, usually by spinal fusion, can be lifesaving but life expectancy is decreased somewhat despite surgery. The deformity of the chest causes a strain on the heart and lungs, which may eventually cause respiratory failure.
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Symptoms of Mucopolysaccharidosis IV. Symptoms of MPS IV may include growth delays; a prominent lower face; abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis) or concern for a spine abnormality; an abnormally short neck; knees that are abnormally close together (knock knees or genu valgum); flat feet; abnormal development of the growing ends of the long bones (epiphyses); hip dislocation and arthritis and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or additional abnormalities may also occur. Affected children have a characteristic facial appearance that may include an enlarged head, broad mouth, prominent cheekbones, an unusually small nose, widely spaced and thinly enameled teeth, and widely separated eyes with subtle corneal clouding. The liver and spleen may be mildly enlarged. Children with MPS IV show marked growth abnormalities with short trunks and normal limbs from early in life. The elbows, wrists, hips, knees and other large joints are abnormally flexible, causing overall instability. Affected individuals exhibit a waddling gait with frequent falls. Early development and intelligence are typically normal, unlike other MPS storage disorders. High frequency hearing impairment is common. Skeletal X-rays typically show marked flattening of the vertebra. The long bones of the arms and legs are characteristically shorter and thicker than normal. The skull is large for the rest of the body. The connection between the first and second vertebrae in the neck is poorly developed and this abnormality can be life threatening. A trivial injury may cause the two vertebrae to slip on each other and compress the spinal cord. Surgery to stabilize the upper cervical spine, usually by spinal fusion, can be lifesaving but life expectancy is decreased somewhat despite surgery. The deformity of the chest causes a strain on the heart and lungs, which may eventually cause respiratory failure.
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Mucopolysaccharidosis IV
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nord_827_2
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Causes of Mucopolysaccharidosis IV
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MPS IVA is an autosomal recessive genetic disorder caused by deficiency of the GALNS enzyme due to mutations in the GALNS gene.MPS IVB is an autosomal recessive genetic disorder caused by deficiency of the beta-galactosidase enzyme due to mutations in the GLB1 gene.Both lead to an accumulation of keratan sulfate (KS) in the cells and tissues of the body. The accumulation of KS in the cornea and bone leads to reduced vision and skeletal deformities, respectively. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Mucopolysaccharidosis IV. MPS IVA is an autosomal recessive genetic disorder caused by deficiency of the GALNS enzyme due to mutations in the GALNS gene.MPS IVB is an autosomal recessive genetic disorder caused by deficiency of the beta-galactosidase enzyme due to mutations in the GLB1 gene.Both lead to an accumulation of keratan sulfate (KS) in the cells and tissues of the body. The accumulation of KS in the cornea and bone leads to reduced vision and skeletal deformities, respectively. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Mucopolysaccharidosis IV
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nord_827_3
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Affects of Mucopolysaccharidosis IV
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MPS IV affects males and females equally often. Estimates of prevalence range from 1/40,000 to 1/200,000 births. MPS IVA (95% of individuals affected by MPS IV) occurs more often than MPS IVB (5% of affected individuals). As a group, lysosomal storage diseases (of which the MPS are a subgroup) are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world.
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Affects of Mucopolysaccharidosis IV. MPS IV affects males and females equally often. Estimates of prevalence range from 1/40,000 to 1/200,000 births. MPS IVA (95% of individuals affected by MPS IV) occurs more often than MPS IVB (5% of affected individuals). As a group, lysosomal storage diseases (of which the MPS are a subgroup) are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world.
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Mucopolysaccharidosis IV
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nord_827_4
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Related disorders of Mucopolysaccharidosis IV
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Mutations in the GLB1 gene can also be associated with a different lysosomal storage disease called GM1 gangliosidosis, an autosomal recessive genetic disorder that progressively destroys nerve cells in the brain and spinal cord. Signs and symptoms of MPS IVA and MPS IVB overlap with other types of MPS storage diseases and mucolipidoses, a family of similar disorders producing symptoms very much like MPS storage diseases. Information about these conditions can be located in the Rare Disease Database. Spondyleopiphyseal dysplasia (SED) is a rare, hereditary skeletal disorder that only affects males and X-ray findings are similar to those of individuals with MPS IVA, but other features are also present. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk, and premature osteoarthritis.Legg-Calve-Perthes disease may be misdiagnosed in individuals with MPS IVA if the disease initially presents only with hip pain.
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Related disorders of Mucopolysaccharidosis IV. Mutations in the GLB1 gene can also be associated with a different lysosomal storage disease called GM1 gangliosidosis, an autosomal recessive genetic disorder that progressively destroys nerve cells in the brain and spinal cord. Signs and symptoms of MPS IVA and MPS IVB overlap with other types of MPS storage diseases and mucolipidoses, a family of similar disorders producing symptoms very much like MPS storage diseases. Information about these conditions can be located in the Rare Disease Database. Spondyleopiphyseal dysplasia (SED) is a rare, hereditary skeletal disorder that only affects males and X-ray findings are similar to those of individuals with MPS IVA, but other features are also present. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk, and premature osteoarthritis.Legg-Calve-Perthes disease may be misdiagnosed in individuals with MPS IVA if the disease initially presents only with hip pain.
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Mucopolysaccharidosis IV
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nord_827_5
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Diagnosis of Mucopolysaccharidosis IV
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MPS IV diagnosis is suggested by the findings of medical history, physical examinations, skeletal X-rays, and urine glycosaminoglycans (GAG) analysis. Excessive amounts of keratan sulfate will usually be present in the urine.Diagnosis of MPS IVA is confirmed by low GALNS enzyme activity in cultured blood or skin cells and/or molecular genetic testing to identify GALNS gene mutations. MPS IVB diagnosis is confirmed by the finding of a beta-galactosidase deficiency in blood or skin cells and/or molecular genetic testing to identify GLB1 gene mutations.
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Diagnosis of Mucopolysaccharidosis IV. MPS IV diagnosis is suggested by the findings of medical history, physical examinations, skeletal X-rays, and urine glycosaminoglycans (GAG) analysis. Excessive amounts of keratan sulfate will usually be present in the urine.Diagnosis of MPS IVA is confirmed by low GALNS enzyme activity in cultured blood or skin cells and/or molecular genetic testing to identify GALNS gene mutations. MPS IVB diagnosis is confirmed by the finding of a beta-galactosidase deficiency in blood or skin cells and/or molecular genetic testing to identify GLB1 gene mutations.
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Mucopolysaccharidosis IV
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nord_827_6
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Therapies of Mucopolysaccharidosis IV
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Treatment
In 2014, the FDA approved a recombinant human GALNS enzyme replacement therapy (elosulfase alfa, or Vimizim) for the treatment of MPS IVA. Vimizim is manufactured by BioMarin Pharmaceutical Inc. Other treatment of MPS IV is symptomatic and supportive. Surgery to decompress and fuse the bones of the upper neck to the base of the skull can prevent destabilization of the cervical vertebrae and potential damage to the spinal cord. Management of affected individuals with MPS IV is best undertaken by multiple specialists, including: a physical therapist for physical rehabilitation, a psychiatrist for psychological support, educational professionals for learning optimization, and home care professionals for affected individuals with medical equipment dependence.Surgeons may also play a crucial role in treating affected individuals. The placement of a bioprosthetic or prosthetic valve may be required for affected induvial with ventricular hypertrophy (overgrowth). Enlarged tonsils and adenoids may need to be removed in order to relieve upper-airway obstruction and sleep apnea. Additionally, ventilation tubes and hearing aids may be needed for individuals with hearing loss. Penetrating keratoplasty (corneal replacement) may be needed to treat corneal opacification (scarring or clouding of the cornea), which causes impaired vision.Since children with MPS IVA are of normal intelligence, they usually attend regular classes, but they made need to sit close to the front of the classroom if they have difficulties hearing or seeing. They may also need to use a wheelchair around school grounds.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Mucopolysaccharidosis IV. Treatment
In 2014, the FDA approved a recombinant human GALNS enzyme replacement therapy (elosulfase alfa, or Vimizim) for the treatment of MPS IVA. Vimizim is manufactured by BioMarin Pharmaceutical Inc. Other treatment of MPS IV is symptomatic and supportive. Surgery to decompress and fuse the bones of the upper neck to the base of the skull can prevent destabilization of the cervical vertebrae and potential damage to the spinal cord. Management of affected individuals with MPS IV is best undertaken by multiple specialists, including: a physical therapist for physical rehabilitation, a psychiatrist for psychological support, educational professionals for learning optimization, and home care professionals for affected individuals with medical equipment dependence.Surgeons may also play a crucial role in treating affected individuals. The placement of a bioprosthetic or prosthetic valve may be required for affected induvial with ventricular hypertrophy (overgrowth). Enlarged tonsils and adenoids may need to be removed in order to relieve upper-airway obstruction and sleep apnea. Additionally, ventilation tubes and hearing aids may be needed for individuals with hearing loss. Penetrating keratoplasty (corneal replacement) may be needed to treat corneal opacification (scarring or clouding of the cornea), which causes impaired vision.Since children with MPS IVA are of normal intelligence, they usually attend regular classes, but they made need to sit close to the front of the classroom if they have difficulties hearing or seeing. They may also need to use a wheelchair around school grounds.Genetic counseling is recommended for affected individuals and their families.
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Mucopolysaccharidosis IV
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nord_828_0
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Overview of Mucopolysaccharidosis Type I
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Summary Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder that affects many parts of the body (multisystem). Children with MPS I are described as having either a severe or attenuated (meaning reduced) form of the disorder based on age of onset, severity of symptoms, rate of disease progression and whether there is early and direct involvement of the brain. The determination of whether an individual has severe or attenuated MPS I is critical as different treatment options are available. Individuals with severe MPS I usually have symptoms apparent by 6 months of age whereas individuals with attenuated MPS I may not become apparent until after the age of 3 years with many attenuated MPS I individuals not diagnosed until late childhood or even the teenage years. Individuals with severe MPS I have onset of symptoms in early infancy with evidence of early progressive intellectual decline and when untreated, die within the first decade. In contrast, individuals with attenuated MPS I have later onset of disease symptoms, more slowly progressive disease with sparing of intelligence and can have a near normal life expectancy. MPS I is caused by variations (AKA mutations or pathogenic sequence variants) in the IDUA gene and is inherited in an autosomal recessive pattern. Therefore, both parents of every affected MPS I individual are carriers of MPS I. Being a carrier for MPS I does not lead to symptoms. Introduction MPS I is member of a group of hereditary metabolic diseases known as the mucopolysaccharidoses which, in turn, are part of a larger group of diseases known as lysosomal storage disorders (LSDs). Lysosomes function as the primary digestive and recycling units within cells. Enzymes within lysosomes break down or digest particular cellular components, such carbohydrates, proteins and fats to their basic units which can then be recycled. Healthy cells and organs are constantly breaking down, recycling and building new cellular components. In individuals with MPS disorders, including MPS I, deficiency or improper functioning of lysosomal enzymes leads to an abnormal accumulation of a particular complex carbohydrate known as glycosaminoglycans. Glycosaminoglycans were once known as mucopolysaccharides and are how these disorders got their names. When cells cannot breakdown these glycosaminoglycans they then accumulate within various tissues, such as the bones, joints, brain, spinal cord, heart, spleen, or liver and lead to the symptoms that MPS I individuals have. MPS I is best thought of as a spectrum of disease that ranges from severe forms (Hurler syndrome) that are present very early in life to less severe forms that may not become apparent until much later in childhood. Individuals with MPS I were previously classified as having either a severe, mild, or intermediate form of the disorder. The severe form was known as Hurler syndrome, the mild form was known as Scheie syndrome, and the intermediate form was known as Hurler-Scheie syndrome. Although the term Hurler syndrome is still used, the term attenuated MPS I is now used in place of Hurler-Scheie and Scheie.
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Overview of Mucopolysaccharidosis Type I. Summary Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder that affects many parts of the body (multisystem). Children with MPS I are described as having either a severe or attenuated (meaning reduced) form of the disorder based on age of onset, severity of symptoms, rate of disease progression and whether there is early and direct involvement of the brain. The determination of whether an individual has severe or attenuated MPS I is critical as different treatment options are available. Individuals with severe MPS I usually have symptoms apparent by 6 months of age whereas individuals with attenuated MPS I may not become apparent until after the age of 3 years with many attenuated MPS I individuals not diagnosed until late childhood or even the teenage years. Individuals with severe MPS I have onset of symptoms in early infancy with evidence of early progressive intellectual decline and when untreated, die within the first decade. In contrast, individuals with attenuated MPS I have later onset of disease symptoms, more slowly progressive disease with sparing of intelligence and can have a near normal life expectancy. MPS I is caused by variations (AKA mutations or pathogenic sequence variants) in the IDUA gene and is inherited in an autosomal recessive pattern. Therefore, both parents of every affected MPS I individual are carriers of MPS I. Being a carrier for MPS I does not lead to symptoms. Introduction MPS I is member of a group of hereditary metabolic diseases known as the mucopolysaccharidoses which, in turn, are part of a larger group of diseases known as lysosomal storage disorders (LSDs). Lysosomes function as the primary digestive and recycling units within cells. Enzymes within lysosomes break down or digest particular cellular components, such carbohydrates, proteins and fats to their basic units which can then be recycled. Healthy cells and organs are constantly breaking down, recycling and building new cellular components. In individuals with MPS disorders, including MPS I, deficiency or improper functioning of lysosomal enzymes leads to an abnormal accumulation of a particular complex carbohydrate known as glycosaminoglycans. Glycosaminoglycans were once known as mucopolysaccharides and are how these disorders got their names. When cells cannot breakdown these glycosaminoglycans they then accumulate within various tissues, such as the bones, joints, brain, spinal cord, heart, spleen, or liver and lead to the symptoms that MPS I individuals have. MPS I is best thought of as a spectrum of disease that ranges from severe forms (Hurler syndrome) that are present very early in life to less severe forms that may not become apparent until much later in childhood. Individuals with MPS I were previously classified as having either a severe, mild, or intermediate form of the disorder. The severe form was known as Hurler syndrome, the mild form was known as Scheie syndrome, and the intermediate form was known as Hurler-Scheie syndrome. Although the term Hurler syndrome is still used, the term attenuated MPS I is now used in place of Hurler-Scheie and Scheie.
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Mucopolysaccharidosis Type I
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nord_828_1
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Symptoms of Mucopolysaccharidosis Type I
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The specific signs and symptoms seen in MPS I are highly variable and depends on numerous factors including what form of MPS I a child has, when treatment was first started, and how an individual child responds to various treatment options. It is important to note that MPS I is a progressive disorder and therefore the symptoms that a child has are also related to the age of the child at the time of diagnosis. The age of onset, disease severity, degree of intellectual disability, and rate of progression vary significantly among affected individuals.Severe Mucopolysaccharidosis Type I
Common signs and symptoms of the severe form of mucopolysaccharidosis type I are delays in the developmental of motor skills and intelligence, and skeletal deformities. Symptoms may not be present at birth and may not become apparent until several months to 1 year of age.Sometimes, affected infants have an inguinal or umbilical hernia. Inguinal hernia is when some abdominal tissue or part of the small intestine pushes through a bulge or tear in the abdominal muscles near the groin. An umbilical hernia is when some abdominal tissue or part of the small intestine pushes through a bulge or tear in the bellybutton. Affected infants often experience repeated upper respiratory tract infections in the first year of life. Because both hernias and ear infections occur commonly in children, these findings alone do not often lead to diagnosis.Within the first year to 18 months of age, affected children usuallyThe signs listed above represent the early signs of severe disease but because this disorder is progressive other potential symptoms occur as the disease progresses and children age and include:Attenuated Mucopolysaccharidosis Type I
Children described as having the attenuated form of MPS I experience similar signs and symptoms seen in severely affected patients but tend to show slower disease progression and later age of onset of symptoms. A key difference between severe and attenuated patients is that attenuated patients do not show early developmental delay and do not experience progressive decline in mental capabilities. As a group, attenuated patients show significant variability in the symptoms they have and the rate of progression. Some children are mildly affected and have a near normal lifespan, while others develop symptoms during childhood, usually around 6 or 7 years old and can develop life-threatening complications by their teen-aged years or during their 20s. These symptoms of the attenuated form are as described as above for the severe form. The symptoms can be as significant as the severe form, or can be milder. Individuals with attenuated MPS I can have their quality of life significantly affected.Intelligence is usually not affected in children with attenuated MPS I, but some children and young adults may experience learning disabilities. Affected children will have varying degrees of growth deficiency. They can develop an enlarged liver (hepatomegaly), clouding of the cornea, and heart valve abnormalities during their teen-aged years. Corneal clouding can lead to significant problems with vision. Other eye abnormalities including glaucoma, optic atrophy, and degeneration of the retina can also occur. Progressive heart valve problems can begin as early 10 or 11 years of age. Coronary heart disease can also occur.Dysostosis multiplex, skeletal malformations, carpal tunnel syndrome, and progressive joint disease can also occur in the attenuated forms. These signs and symptoms are the same as described above for the severe form. Affected individuals may also have a high arch to the feet (pes cavus) and knees that are angled in so that they rub together when the legs are straight (knock knees or genu valgum). Some children may walk on the balls of their feet so that the heels do not touch the ground (toe-walking).Moderate to severe hearing loss can also occur in the attenuated forms. Some children may develop sleep apnea. Hernias can also be present. Progressive compression of the spinal cord can also be possible and can cause problems including exercise intolerance and reduced activity.
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Symptoms of Mucopolysaccharidosis Type I. The specific signs and symptoms seen in MPS I are highly variable and depends on numerous factors including what form of MPS I a child has, when treatment was first started, and how an individual child responds to various treatment options. It is important to note that MPS I is a progressive disorder and therefore the symptoms that a child has are also related to the age of the child at the time of diagnosis. The age of onset, disease severity, degree of intellectual disability, and rate of progression vary significantly among affected individuals.Severe Mucopolysaccharidosis Type I
Common signs and symptoms of the severe form of mucopolysaccharidosis type I are delays in the developmental of motor skills and intelligence, and skeletal deformities. Symptoms may not be present at birth and may not become apparent until several months to 1 year of age.Sometimes, affected infants have an inguinal or umbilical hernia. Inguinal hernia is when some abdominal tissue or part of the small intestine pushes through a bulge or tear in the abdominal muscles near the groin. An umbilical hernia is when some abdominal tissue or part of the small intestine pushes through a bulge or tear in the bellybutton. Affected infants often experience repeated upper respiratory tract infections in the first year of life. Because both hernias and ear infections occur commonly in children, these findings alone do not often lead to diagnosis.Within the first year to 18 months of age, affected children usuallyThe signs listed above represent the early signs of severe disease but because this disorder is progressive other potential symptoms occur as the disease progresses and children age and include:Attenuated Mucopolysaccharidosis Type I
Children described as having the attenuated form of MPS I experience similar signs and symptoms seen in severely affected patients but tend to show slower disease progression and later age of onset of symptoms. A key difference between severe and attenuated patients is that attenuated patients do not show early developmental delay and do not experience progressive decline in mental capabilities. As a group, attenuated patients show significant variability in the symptoms they have and the rate of progression. Some children are mildly affected and have a near normal lifespan, while others develop symptoms during childhood, usually around 6 or 7 years old and can develop life-threatening complications by their teen-aged years or during their 20s. These symptoms of the attenuated form are as described as above for the severe form. The symptoms can be as significant as the severe form, or can be milder. Individuals with attenuated MPS I can have their quality of life significantly affected.Intelligence is usually not affected in children with attenuated MPS I, but some children and young adults may experience learning disabilities. Affected children will have varying degrees of growth deficiency. They can develop an enlarged liver (hepatomegaly), clouding of the cornea, and heart valve abnormalities during their teen-aged years. Corneal clouding can lead to significant problems with vision. Other eye abnormalities including glaucoma, optic atrophy, and degeneration of the retina can also occur. Progressive heart valve problems can begin as early 10 or 11 years of age. Coronary heart disease can also occur.Dysostosis multiplex, skeletal malformations, carpal tunnel syndrome, and progressive joint disease can also occur in the attenuated forms. These signs and symptoms are the same as described above for the severe form. Affected individuals may also have a high arch to the feet (pes cavus) and knees that are angled in so that they rub together when the legs are straight (knock knees or genu valgum). Some children may walk on the balls of their feet so that the heels do not touch the ground (toe-walking).Moderate to severe hearing loss can also occur in the attenuated forms. Some children may develop sleep apnea. Hernias can also be present. Progressive compression of the spinal cord can also be possible and can cause problems including exercise intolerance and reduced activity.
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Mucopolysaccharidosis Type I
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nord_828_2
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Causes of Mucopolysaccharidosis Type I
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Mucopolysaccharidosis type I is caused by a variation (mutation, pathogenic sequence variant) in the alpha-L-iduronidase (IDUA) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The IDUA gene regulates the production of the alpha-L-iduronidase enzyme. This enzyme is needed to break down complex carbohydrates produced in the body called glycosaminoglycans (which used to be called mucopolysaccharides). When the IDUA gene is altered, there are deficient levels of functional alpha-L-iduronidase enzyme. Without proper levels of this enzyme, these glycosaminoglycans, especially dermatan sulfate and heparan sulfate, build up in the lysosomes of all cells. This abnormal accumulation interferes with the proper functions and health of the cells and, ultimately, this leads to progressive damage of the tissues and results in symptoms. In severe MPS I there is a complete absence of the alpha-L-iduronidase enzyme, while with the attenuated forms there is likely a very, very, small amount of enzyme made in the cells. Genetic diseases are determined by the combination of genes that we receive from our father and mother. We all have 2 copies of the IDUA gene; one we have inherited from our father and one we have inherited from our mother. Disorders inherited in a recessive manner occur when an individual has 2 copies of a gene and both copies have errors in them. This is the case for all MPS I individuals; they have 2 copies of the IDUA gene that are altered; they have received one from each of their parents. The parents are therefore carriers of MPS I. Carriers have one normal copy and one altered copy of the IDUA gene. Carriers are healthy and being a carrier for MPS I will not lead to symptoms. The risk for two carrier parents to both pass the altered IDUA 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.
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Causes of Mucopolysaccharidosis Type I. Mucopolysaccharidosis type I is caused by a variation (mutation, pathogenic sequence variant) in the alpha-L-iduronidase (IDUA) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The IDUA gene regulates the production of the alpha-L-iduronidase enzyme. This enzyme is needed to break down complex carbohydrates produced in the body called glycosaminoglycans (which used to be called mucopolysaccharides). When the IDUA gene is altered, there are deficient levels of functional alpha-L-iduronidase enzyme. Without proper levels of this enzyme, these glycosaminoglycans, especially dermatan sulfate and heparan sulfate, build up in the lysosomes of all cells. This abnormal accumulation interferes with the proper functions and health of the cells and, ultimately, this leads to progressive damage of the tissues and results in symptoms. In severe MPS I there is a complete absence of the alpha-L-iduronidase enzyme, while with the attenuated forms there is likely a very, very, small amount of enzyme made in the cells. Genetic diseases are determined by the combination of genes that we receive from our father and mother. We all have 2 copies of the IDUA gene; one we have inherited from our father and one we have inherited from our mother. Disorders inherited in a recessive manner occur when an individual has 2 copies of a gene and both copies have errors in them. This is the case for all MPS I individuals; they have 2 copies of the IDUA gene that are altered; they have received one from each of their parents. The parents are therefore carriers of MPS I. Carriers have one normal copy and one altered copy of the IDUA gene. Carriers are healthy and being a carrier for MPS I will not lead to symptoms. The risk for two carrier parents to both pass the altered IDUA 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.
| 828 |
Mucopolysaccharidosis Type I
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nord_828_3
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Affects of Mucopolysaccharidosis Type I
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Mucopolysaccharidosis type I affects males and females in equal numbers, with an incidence of about 1 in 100,000 live births for the severe type, and an incidence of about 1in 500,000 live births for the attenuated type. Incidence is the number of people who develop a disorder over a given period of time (e.g. one year). The incidence for MPS disorders collectively is about 1 in 25,000. However, rare disorders, especially milder forms of MPS, often go misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population.
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Affects of Mucopolysaccharidosis Type I. Mucopolysaccharidosis type I affects males and females in equal numbers, with an incidence of about 1 in 100,000 live births for the severe type, and an incidence of about 1in 500,000 live births for the attenuated type. Incidence is the number of people who develop a disorder over a given period of time (e.g. one year). The incidence for MPS disorders collectively is about 1 in 25,000. However, rare disorders, especially milder forms of MPS, often go misdiagnosed or undiagnosed, making it difficult to determine the true frequency in the general population.
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Mucopolysaccharidosis Type I
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