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nord_1142_6
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Therapies of Spastic Paraplegia 51
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Management of Symptoms
Ages 0-3 years
Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators and sensory-impairment specialists.Ages 3-5 years
In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social and/or cognitive delay. The early intervention program typically assists with this transition.Ages 5-21 years
In the United States, an IEP based on the individual’s level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at the age of 12 years. Developmental pediatricians can help with transition to adulthood.Motor Dysfunction
Gross motor dysfunction
• Physical therapy is recommended to maximize mobility.
• Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing and writing.Oral-motor dysfunction
Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained.Communication issues
Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.Multidisciplinary Care
Care should be provided by a multidisciplinary care team that includes input from neurology, physiatry, orthopedics, developmental medicine and others is recommended.
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Therapies of Spastic Paraplegia 51. Management of Symptoms
Ages 0-3 years
Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators and sensory-impairment specialists.Ages 3-5 years
In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social and/or cognitive delay. The early intervention program typically assists with this transition.Ages 5-21 years
In the United States, an IEP based on the individual’s level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at the age of 12 years. Developmental pediatricians can help with transition to adulthood.Motor Dysfunction
Gross motor dysfunction
• Physical therapy is recommended to maximize mobility.
• Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing and writing.Oral-motor dysfunction
Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained.Communication issues
Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.Multidisciplinary Care
Care should be provided by a multidisciplinary care team that includes input from neurology, physiatry, orthopedics, developmental medicine and others is recommended.
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Spastic Paraplegia 51
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nord_1143_0
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Overview of Spastic Paraplegia 52
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Summary
Spastic paraplegia 52 (SPG52) is a slowly-progressing neurodegenerative disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures, and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to non-ambulation and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of all four limbs and torso (tetraplegia).
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Overview of Spastic Paraplegia 52. Summary
Spastic paraplegia 52 (SPG52) is a slowly-progressing neurodegenerative disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures, and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to non-ambulation and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of all four limbs and torso (tetraplegia).
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Spastic Paraplegia 52
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nord_1143_1
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Symptoms of Spastic Paraplegia 52
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Most children with SPG52 have:• a “floppy” appearance in infancy due to low muscle tone
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• intellectual disability
• microcephaly
• delayed motor development
• poor or absent speech developmentOther known features of SPG52 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of feverSome children may also have facial differences that can include:• high palate
• wide nasal bridge
• bulbous nose
• wide mouth
• protruding tongue
• short philtrum (the groove between the bottom of the nose and top of the lips)
• narrow forehead
• flat feet or club feet
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Symptoms of Spastic Paraplegia 52. Most children with SPG52 have:• a “floppy” appearance in infancy due to low muscle tone
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• intellectual disability
• microcephaly
• delayed motor development
• poor or absent speech developmentOther known features of SPG52 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of feverSome children may also have facial differences that can include:• high palate
• wide nasal bridge
• bulbous nose
• wide mouth
• protruding tongue
• short philtrum (the groove between the bottom of the nose and top of the lips)
• narrow forehead
• flat feet or club feet
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Spastic Paraplegia 52
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nord_1143_2
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Causes of Spastic Paraplegia 52
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SPG52 is inherited in an autosomal recessive manner. The gene that is involved is AP4S1. A gene with a disease-causing (pathogenic) mutation must be inherited from each parent to result in manifestations of symptoms. Parents carrying a mutated gene have a 25% chance of having an affected child, a 50% chance of having an unaffected carrier child and a 25% chance of having a child who is unaffected and does not carry a mutated gene.
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Causes of Spastic Paraplegia 52. SPG52 is inherited in an autosomal recessive manner. The gene that is involved is AP4S1. A gene with a disease-causing (pathogenic) mutation must be inherited from each parent to result in manifestations of symptoms. Parents carrying a mutated gene have a 25% chance of having an affected child, a 50% chance of having an unaffected carrier child and a 25% chance of having a child who is unaffected and does not carry a mutated gene.
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Spastic Paraplegia 52
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nord_1143_3
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Affects of Spastic Paraplegia 52
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SPG52 affects males and females of ethnic groups from around the world.
The prevalence of SPG52 is unknown. SPG52 is likely under-recognized since the phenotypic spectrum largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be misdiagnosed as having cerebral palsy.
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Affects of Spastic Paraplegia 52. SPG52 affects males and females of ethnic groups from around the world.
The prevalence of SPG52 is unknown. SPG52 is likely under-recognized since the phenotypic spectrum largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be misdiagnosed as having cerebral palsy.
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Spastic Paraplegia 52
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nord_1143_4
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Related disorders of Spastic Paraplegia 52
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AP-4-associated hereditary spastic paraplegia (HSP) is a group of slowly-progressing neurodegenerative disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures, and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by mutations in genes that result in production of an abnormal adaptor protein complex 4.
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Related disorders of Spastic Paraplegia 52. AP-4-associated hereditary spastic paraplegia (HSP) is a group of slowly-progressing neurodegenerative disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures, and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by mutations in genes that result in production of an abnormal adaptor protein complex 4.
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Spastic Paraplegia 52
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nord_1143_5
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Diagnosis of Spastic Paraplegia 52
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Since many of the initial clinical manifestations of SPG52 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability, and seizure, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
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Diagnosis of Spastic Paraplegia 52. Since many of the initial clinical manifestations of SPG52 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability, and seizure, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
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Spastic Paraplegia 52
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nord_1143_6
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Therapies of Spastic Paraplegia 52
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Treatment: management of symptomsAges 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators, and sensory-impairment specialists. Ages 3-5 years. In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, and/or cognitive delay. The early intervention program typically assists with this transition. Ages 5-21 years. In the United States, an IEP based on the individual's level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.Motor DysfunctionGross motor dysfunction• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.Oral-motor dysfunction. Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Communication issues. Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
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Therapies of Spastic Paraplegia 52. Treatment: management of symptomsAges 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators, and sensory-impairment specialists. Ages 3-5 years. In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, and/or cognitive delay. The early intervention program typically assists with this transition. Ages 5-21 years. In the United States, an IEP based on the individual's level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.Motor DysfunctionGross motor dysfunction• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.Oral-motor dysfunction. Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Communication issues. Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
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Spastic Paraplegia 52
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nord_1144_0
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Overview of Spina Bifida
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Spina bifida is characterized by incomplete closure of certain bones of the spinal column (vertebrae), leaving a portion of the spinal cord exposed. Part of the contents of the spinal canal may protrude through this opening. In the most severe form, rachischisis, the opening is extensive. Spina bifida may cause difficulties with bladder control, walking and/or other functions, depending on the severity of associated symptoms.
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Overview of Spina Bifida. Spina bifida is characterized by incomplete closure of certain bones of the spinal column (vertebrae), leaving a portion of the spinal cord exposed. Part of the contents of the spinal canal may protrude through this opening. In the most severe form, rachischisis, the opening is extensive. Spina bifida may cause difficulties with bladder control, walking and/or other functions, depending on the severity of associated symptoms.
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Spina Bifida
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nord_1144_1
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Symptoms of Spina Bifida
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Patients with spina bifida have a wide variety of symptoms and physical findings, depending on the extent of the defect in the spine. The mildest form of the condition, spina bifida occulta, causes few if any symptoms, and may go undetected. In this mild form, the lack of closure of the neural tube affects only a small area of the spine and is found on X-rays. The disorder may be suspected because of a dimple or tuft of hair on the back overlying the affected area. Impaired bladder control is a common finding, even with relatively mild forms of the condition.In more severe forms of spina bifida, a sac (meningocele or myelomeningocele) may push its way out through the opening. A meningocele involves the meninges, the tough membrane that covers and protects the brain and cord. This sac may be small or it may be as large as a grapefruit. The meningocele may be covered with skin, or the nerve tissue may be exposed. Generally the sac contains cerebrospinal fluid (CSF). A myelomeningocele represents the most severe form of spina bifida and indicates that a portion of the spinal cord itself has pushed through the spinal (vertebral) opening into the sac in the back of the torso.The malformation of the lower spinal cord causes abnormalities of the lower trunk and extremities of varying severity. If the condition is mild, the person may only experience some muscle weakness and impaired skin sensations. In patients with meningocele, accumulation of cerebrospinal fluid in the brain results in enlargement of the head (hydrocephalus) and possible brain damage.Although spina bifida is usually present at birth, it occasionally is first seen during adolescence. The rapid growth during this time stretches the shortened nerves and may cause progressive weakness. Prenatal testing for spina bifida is available. However, this test is not absolutely reliable.
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Symptoms of Spina Bifida. Patients with spina bifida have a wide variety of symptoms and physical findings, depending on the extent of the defect in the spine. The mildest form of the condition, spina bifida occulta, causes few if any symptoms, and may go undetected. In this mild form, the lack of closure of the neural tube affects only a small area of the spine and is found on X-rays. The disorder may be suspected because of a dimple or tuft of hair on the back overlying the affected area. Impaired bladder control is a common finding, even with relatively mild forms of the condition.In more severe forms of spina bifida, a sac (meningocele or myelomeningocele) may push its way out through the opening. A meningocele involves the meninges, the tough membrane that covers and protects the brain and cord. This sac may be small or it may be as large as a grapefruit. The meningocele may be covered with skin, or the nerve tissue may be exposed. Generally the sac contains cerebrospinal fluid (CSF). A myelomeningocele represents the most severe form of spina bifida and indicates that a portion of the spinal cord itself has pushed through the spinal (vertebral) opening into the sac in the back of the torso.The malformation of the lower spinal cord causes abnormalities of the lower trunk and extremities of varying severity. If the condition is mild, the person may only experience some muscle weakness and impaired skin sensations. In patients with meningocele, accumulation of cerebrospinal fluid in the brain results in enlargement of the head (hydrocephalus) and possible brain damage.Although spina bifida is usually present at birth, it occasionally is first seen during adolescence. The rapid growth during this time stretches the shortened nerves and may cause progressive weakness. Prenatal testing for spina bifida is available. However, this test is not absolutely reliable.
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Spina Bifida
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nord_1144_2
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Causes of Spina Bifida
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The exact cause of spina bifida is not known. A combination of hereditary and environmental factors may be involved. Studies have also indicated that a lack of folic acid in the mother's diet during pregnancy heightens the risk of spina bifida and other neural tube defects. In most cases, babies with spina bifida and other neural tube defects are born into families with no history of these disorders. However, if a child in a family has spina bifida, the likelihood of the parents having another child with this disorder in the future is increased.
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Causes of Spina Bifida. The exact cause of spina bifida is not known. A combination of hereditary and environmental factors may be involved. Studies have also indicated that a lack of folic acid in the mother's diet during pregnancy heightens the risk of spina bifida and other neural tube defects. In most cases, babies with spina bifida and other neural tube defects are born into families with no history of these disorders. However, if a child in a family has spina bifida, the likelihood of the parents having another child with this disorder in the future is increased.
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Spina Bifida
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nord_1144_3
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Affects of Spina Bifida
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Spina bifida is the most common neural tube defect in the United States. Between 1,500 and 2,000 babies out of about 4 million births are born with this disorder each year in the United States.
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Affects of Spina Bifida. Spina bifida is the most common neural tube defect in the United States. Between 1,500 and 2,000 babies out of about 4 million births are born with this disorder each year in the United States.
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Spina Bifida
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nord_1144_4
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Related disorders of Spina Bifida
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Spina bifida is usually an isolated birth defect but it can also occur as part of a syndrome with other birth defects. It is one of a group of disorders known as neural tube defects.
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Related disorders of Spina Bifida. Spina bifida is usually an isolated birth defect but it can also occur as part of a syndrome with other birth defects. It is one of a group of disorders known as neural tube defects.
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Spina Bifida
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nord_1144_5
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Diagnosis of Spina Bifida
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Diagnosis of Spina Bifida.
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Spina Bifida
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nord_1144_6
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Therapies of Spina Bifida
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PreventionThe U.S. Public Health Service (PHS) advises women of childbearing age to take 0.4 mg of folic acid daily, either through diet or low dose supplements. Women are urged not to take more than 1.0 mg of folic acid daily unless advised by a physician because high doses of folic acid can mask other vitamin deficiencies.TreatmentThe mildest cases of spina bifida may not require treatment. The moderate cases require a decision as to whether or not surgery is advisable. Surgery may prevent the worsening of the condition in some instances, but cannot restore the lost function. In those extreme cases where the sac (meningocele) breaks or appears about to break, immediate surgery becomes essential.The family doctor or the orthopedist may prescribe corrective shoes, braces, crutches, or other devices. These help the affected individual to make the most effective use of the weakened muscles, and to prevent the arms and legs from being maintained in an improper or awkward position. Range of motion exercises may also be helpful.
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Therapies of Spina Bifida. PreventionThe U.S. Public Health Service (PHS) advises women of childbearing age to take 0.4 mg of folic acid daily, either through diet or low dose supplements. Women are urged not to take more than 1.0 mg of folic acid daily unless advised by a physician because high doses of folic acid can mask other vitamin deficiencies.TreatmentThe mildest cases of spina bifida may not require treatment. The moderate cases require a decision as to whether or not surgery is advisable. Surgery may prevent the worsening of the condition in some instances, but cannot restore the lost function. In those extreme cases where the sac (meningocele) breaks or appears about to break, immediate surgery becomes essential.The family doctor or the orthopedist may prescribe corrective shoes, braces, crutches, or other devices. These help the affected individual to make the most effective use of the weakened muscles, and to prevent the arms and legs from being maintained in an improper or awkward position. Range of motion exercises may also be helpful.
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Spina Bifida
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nord_1145_0
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Overview of Spinal Muscular Atrophy
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Spinal muscular atrophy (SMA) is a group of inherited neuromuscular disorders characterized by loss of nerve cells in the spinal cord called lower motor neurons or anterior horn cells. Lower motor neurons originate in the brainstem or the spinal cord and relay nerve impulses from upper motor neurons, located in the brain, to the muscles they control. The loss of lower motor neurons leads to progressive muscle weakness, muscle wasting (atrophy) and low muscle tone (hypotonia) that is typically more pronounced in muscles closest to the trunk of the body (proximal muscles) such as the shoulders, hips and back. However, neurons controlling most voluntary muscles can be affected, including those that control muscles involved in feeding, swallowing and breathing.SMA is divided into subtypes (SMA types 0 to 4) based on age of symptom onset and maximum motor function achieved, with a lower number representing a younger age of onset and more severe disease. SMA is inherited as an autosomal recessive genetic disorder and is associated with mutations in the survivor motor neuron 1 (SMN1) gene. SMN1 is located on chromosome 5 in the long arm (q) region. Thus, SMA with a SMN1 gene deletion is often referred to as 5q SMA, distinguishing this form of SMA from other genetic forms of SMA.Newborn screening facilitates early identification of infants with SMA and thus early implementation of treatment. Infants identified by SMA newborn screening are urgently referred for confirmatory testing, discussion of treatments and care. Early treatment prior to the onset of symptoms provides the best outcomes.Although the management of SMA was previously centered around symptom management and supportive care, since 2016, therapies that can improve the course of the disease (disease-modifying therapies) have emerged and have shown promising results. Currently three SMN-enhancing treatments have U.S. Food and Drug Administration (FDA) approval.
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Overview of Spinal Muscular Atrophy. Spinal muscular atrophy (SMA) is a group of inherited neuromuscular disorders characterized by loss of nerve cells in the spinal cord called lower motor neurons or anterior horn cells. Lower motor neurons originate in the brainstem or the spinal cord and relay nerve impulses from upper motor neurons, located in the brain, to the muscles they control. The loss of lower motor neurons leads to progressive muscle weakness, muscle wasting (atrophy) and low muscle tone (hypotonia) that is typically more pronounced in muscles closest to the trunk of the body (proximal muscles) such as the shoulders, hips and back. However, neurons controlling most voluntary muscles can be affected, including those that control muscles involved in feeding, swallowing and breathing.SMA is divided into subtypes (SMA types 0 to 4) based on age of symptom onset and maximum motor function achieved, with a lower number representing a younger age of onset and more severe disease. SMA is inherited as an autosomal recessive genetic disorder and is associated with mutations in the survivor motor neuron 1 (SMN1) gene. SMN1 is located on chromosome 5 in the long arm (q) region. Thus, SMA with a SMN1 gene deletion is often referred to as 5q SMA, distinguishing this form of SMA from other genetic forms of SMA.Newborn screening facilitates early identification of infants with SMA and thus early implementation of treatment. Infants identified by SMA newborn screening are urgently referred for confirmatory testing, discussion of treatments and care. Early treatment prior to the onset of symptoms provides the best outcomes.Although the management of SMA was previously centered around symptom management and supportive care, since 2016, therapies that can improve the course of the disease (disease-modifying therapies) have emerged and have shown promising results. Currently three SMN-enhancing treatments have U.S. Food and Drug Administration (FDA) approval.
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Spinal Muscular Atrophy
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nord_1145_1
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Symptoms of Spinal Muscular Atrophy
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The signs and symptoms of SMA are a consequence of lower motor neuron loss. The features of lower motor neuron disease include muscle weakness and atrophy, hypotonia, decreased or absent reflexes (hypo- or areflexia) and twitching of muscle fibers (fasciculations). Although SMA is a disease spectrum, the five subtypes are determined based on their age of symptom onset and maximum motor function achieved. This classification for SMA was established prior to the availability of genetic testing and prior to the availability of disease modifying treatments.SMA type 0, also known as prenatal SMA, is the most severe form of the disease and develops before birth. The first sign may be a decrease or loss of fetal movement during late pregnancy. Symptoms of SMA type 0 are apparent at birth and include severe weakness and hypotonia. In addition, joint deformity and tightening (contractures) and congenital heart defects are common. As a result, infants do not achieve developmental motor milestones. Because of severe respiratory muscle weakness, affected infants rapidly progress to respiratory failure often by the first month of life.SMA type 1, also known as infantile SMA or Werdnig-Hoffmann disease, is the most common type of SMA affecting approximately 60% of infants born with SMA and is also a severe form of the disease. Infants with SMA type 1 usually appear normal at birth but experience severe weakness before 6 months of age. Developmentally they do not achieve independent sitting and may achieve very few developmental motor milestones. Because of lower motor neuron loss, affected infants have poor suck and swallow reflexes and respiratory muscle weakness. Historically without intervention, affected children die before two years of age due to progressive respiratory muscle weakness and respiratory failure.SMA type 2, also known as intermediate SMA or Dubowitz disease, comprises about 30% of infants born with SMA. The disease usually manifests between 6 and 18 months of age. Affected children can sit independently at some point in their development. However, this ability is usually lost by the mid-teens or later and affected individuals never achieve independent standing and walking. Additional associated symptoms include difficulty swallowing (dysphagia) and respiratory difficulties. Trembling (tremor) of the fingers is also common. In addition, weakness of the muscles supporting the spine leads to curvature of the spine (scoliosis). Historically, life expectancy is reduced in patients with SMA type 2 but many reach adulthood.SMA type 3, also known as juvenile SMA or Kugelberg-Welander disease, accounts for about 10% of infants born with SMA. The age of onset is variable and can be as early as 18 months or as late as teenage years. Although affected individuals have hip and leg weakness and may fall frequently, they are able to walk independently at some point in their development. However, the ability to walk and stand may be lost as they grow and with disease progression, and many become wheelchair dependent. Long-term prognosis depends on the degree of motor function attained as a child, and respiratory muscle weakness is typically mild or absent. SMA type 3 is associated with a normal life expectancy.SMA type 4, also known as late-onset SMA, occurs in less than 1% of people with SMA. Symptoms are less severe than in other subtypes and onset typically occurs in adulthood and most commonly after 35 years of age. All motor developmental milestones are achieved and most individuals with SMA type 4 can walk throughout their life. Patients with SMA type 4 have a normal life expectancy.The following resources from Cure SMA provides a description of symptoms, as well as videos to assist with early diagnosis:https://smartmoves.curesma.org/https://www.curesma.org/types-of-sma/
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Symptoms of Spinal Muscular Atrophy. The signs and symptoms of SMA are a consequence of lower motor neuron loss. The features of lower motor neuron disease include muscle weakness and atrophy, hypotonia, decreased or absent reflexes (hypo- or areflexia) and twitching of muscle fibers (fasciculations). Although SMA is a disease spectrum, the five subtypes are determined based on their age of symptom onset and maximum motor function achieved. This classification for SMA was established prior to the availability of genetic testing and prior to the availability of disease modifying treatments.SMA type 0, also known as prenatal SMA, is the most severe form of the disease and develops before birth. The first sign may be a decrease or loss of fetal movement during late pregnancy. Symptoms of SMA type 0 are apparent at birth and include severe weakness and hypotonia. In addition, joint deformity and tightening (contractures) and congenital heart defects are common. As a result, infants do not achieve developmental motor milestones. Because of severe respiratory muscle weakness, affected infants rapidly progress to respiratory failure often by the first month of life.SMA type 1, also known as infantile SMA or Werdnig-Hoffmann disease, is the most common type of SMA affecting approximately 60% of infants born with SMA and is also a severe form of the disease. Infants with SMA type 1 usually appear normal at birth but experience severe weakness before 6 months of age. Developmentally they do not achieve independent sitting and may achieve very few developmental motor milestones. Because of lower motor neuron loss, affected infants have poor suck and swallow reflexes and respiratory muscle weakness. Historically without intervention, affected children die before two years of age due to progressive respiratory muscle weakness and respiratory failure.SMA type 2, also known as intermediate SMA or Dubowitz disease, comprises about 30% of infants born with SMA. The disease usually manifests between 6 and 18 months of age. Affected children can sit independently at some point in their development. However, this ability is usually lost by the mid-teens or later and affected individuals never achieve independent standing and walking. Additional associated symptoms include difficulty swallowing (dysphagia) and respiratory difficulties. Trembling (tremor) of the fingers is also common. In addition, weakness of the muscles supporting the spine leads to curvature of the spine (scoliosis). Historically, life expectancy is reduced in patients with SMA type 2 but many reach adulthood.SMA type 3, also known as juvenile SMA or Kugelberg-Welander disease, accounts for about 10% of infants born with SMA. The age of onset is variable and can be as early as 18 months or as late as teenage years. Although affected individuals have hip and leg weakness and may fall frequently, they are able to walk independently at some point in their development. However, the ability to walk and stand may be lost as they grow and with disease progression, and many become wheelchair dependent. Long-term prognosis depends on the degree of motor function attained as a child, and respiratory muscle weakness is typically mild or absent. SMA type 3 is associated with a normal life expectancy.SMA type 4, also known as late-onset SMA, occurs in less than 1% of people with SMA. Symptoms are less severe than in other subtypes and onset typically occurs in adulthood and most commonly after 35 years of age. All motor developmental milestones are achieved and most individuals with SMA type 4 can walk throughout their life. Patients with SMA type 4 have a normal life expectancy.The following resources from Cure SMA provides a description of symptoms, as well as videos to assist with early diagnosis:https://smartmoves.curesma.org/https://www.curesma.org/types-of-sma/
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Causes of Spinal Muscular Atrophy
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SMA is caused by deletion or mutation in the SMN1 gene, which encodes a protein known as survival motor neuron (SMN). This protein plays an important role in the functioning and maintenance of motor neurons. Approximately 95-98% of affected individuals have deletions in the SMN1 gene and 2-5% have a point mutation in the SMN1 gene that results in a decreased production of the SMN protein.The SMN2 gene is a paralog of SMN1 and also encodes the SMN protein and can partially compensate for the loss of the SMN1 gene. However, most SMN protein produced by the SMN2 gene is not functional, which means that the SMN2 gene can only partially compensate for the loss of the SMN1 gene. For this reason, an individual with SMA who has more copies of the SMN2 gene will produce more functional SMN protein and may be better able to compensate for the loss of the SMN1 gene, therefore leading to less severe disease. Generally, more copies of SMN2 are associated with milder SMA disease, although there are exceptions.SMA is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a pathogenic gene variant for the disease from each parent. If an individual receives one normal gene and one variant 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 variant 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.Parents who are close blood relative (consanguineous) are more likely to have the same harmful gene variant and, therefore, to have an affected child.
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Causes of Spinal Muscular Atrophy. SMA is caused by deletion or mutation in the SMN1 gene, which encodes a protein known as survival motor neuron (SMN). This protein plays an important role in the functioning and maintenance of motor neurons. Approximately 95-98% of affected individuals have deletions in the SMN1 gene and 2-5% have a point mutation in the SMN1 gene that results in a decreased production of the SMN protein.The SMN2 gene is a paralog of SMN1 and also encodes the SMN protein and can partially compensate for the loss of the SMN1 gene. However, most SMN protein produced by the SMN2 gene is not functional, which means that the SMN2 gene can only partially compensate for the loss of the SMN1 gene. For this reason, an individual with SMA who has more copies of the SMN2 gene will produce more functional SMN protein and may be better able to compensate for the loss of the SMN1 gene, therefore leading to less severe disease. Generally, more copies of SMN2 are associated with milder SMA disease, although there are exceptions.SMA is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a pathogenic gene variant for the disease from each parent. If an individual receives one normal gene and one variant 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 variant 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.Parents who are close blood relative (consanguineous) are more likely to have the same harmful gene variant and, therefore, to have an affected child.
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Affects of Spinal Muscular Atrophy
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The incidence of SMA is approximately 1 in 10,000 live births. SMA affects females and males equally.
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Affects of Spinal Muscular Atrophy. The incidence of SMA is approximately 1 in 10,000 live births. SMA affects females and males equally.
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Related disorders of Spinal Muscular Atrophy
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Symptoms of the following disorders can be similar to those of SMA. Comparisons may be useful for a differential diagnosis.Several other forms of SMA exist beyond those caused by anomalies in the SMN1 gene. These other forms of SMA affect lower motor neurons, although they might preferentially affect certain parts of the body and may be associated with other symptoms. These types of SMA notably include scapuloperoneal SMA, SMA with pontocerebellar hypoplasia, X-linked infantile SMA with arthrogryposis, SMA with respiratory distress type I (SMARD1), congenital distal SMA, distal SMA-V/CMT2d and Finkel type SMA.Congenital myasthenic syndromes are caused by genetic defects of muscle and nerve communication (neuromuscular transmission). These conditions usually occur in infants but may become evident in adulthood. Associated features may vary in severity from person to person. Symptoms may include feeding difficulties, sudden episodes of absence of spontaneous breathing (apnea), failure to grow and gain weight at the expected rate (failure to thrive), muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia) and other abnormalities. (For more information on these disorders, choose “Congenital Myasthenic Syndromes” as your search term in the Rare Disease Database.)Congenital myopathies are a group of inherited diseases that affect the muscles (myopathy) and are characterized by weakness and hypotonia, often present at birth. There are several different subtypes of congenital myopathies, and many are caused by pathogenic variants in specific genes. They differ in severity and onset of symptoms, cellular characteristics under a microscope and prognosis. Symptoms can be present from birth or slowly progress throughout infancy and childhood, but these disorders do not typically get more severe in adulthood. (For more information on these disorders, choose “Congenital Myopathy” as your search term in the Rare Disease Database.)Congenital muscular dystrophy (CMD) is a general term for another group of genetic muscle diseases that occur at birth or early during infancy. CMDs are generally characterized by hypotonia, progressive muscle weakness and atrophy, contractures, spinal rigidity and delays in reaching motor milestones. Feeding difficulties and respiratory complications can develop in some patients. Muscle weakness may improve, remain stable or worsen. Some forms of CMD may be associated with structural brain abnormalities and intellectual disability. The severity, specific symptoms and progression of these disorders vary greatly. Duchenne and Becker muscular dystrophies are two other types of muscular dystrophies that are usually classified separately. (For more information on these disorders, choose the specific disease name as your search term in the Rare Disease Database.)
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Related disorders of Spinal Muscular Atrophy. Symptoms of the following disorders can be similar to those of SMA. Comparisons may be useful for a differential diagnosis.Several other forms of SMA exist beyond those caused by anomalies in the SMN1 gene. These other forms of SMA affect lower motor neurons, although they might preferentially affect certain parts of the body and may be associated with other symptoms. These types of SMA notably include scapuloperoneal SMA, SMA with pontocerebellar hypoplasia, X-linked infantile SMA with arthrogryposis, SMA with respiratory distress type I (SMARD1), congenital distal SMA, distal SMA-V/CMT2d and Finkel type SMA.Congenital myasthenic syndromes are caused by genetic defects of muscle and nerve communication (neuromuscular transmission). These conditions usually occur in infants but may become evident in adulthood. Associated features may vary in severity from person to person. Symptoms may include feeding difficulties, sudden episodes of absence of spontaneous breathing (apnea), failure to grow and gain weight at the expected rate (failure to thrive), muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia) and other abnormalities. (For more information on these disorders, choose “Congenital Myasthenic Syndromes” as your search term in the Rare Disease Database.)Congenital myopathies are a group of inherited diseases that affect the muscles (myopathy) and are characterized by weakness and hypotonia, often present at birth. There are several different subtypes of congenital myopathies, and many are caused by pathogenic variants in specific genes. They differ in severity and onset of symptoms, cellular characteristics under a microscope and prognosis. Symptoms can be present from birth or slowly progress throughout infancy and childhood, but these disorders do not typically get more severe in adulthood. (For more information on these disorders, choose “Congenital Myopathy” as your search term in the Rare Disease Database.)Congenital muscular dystrophy (CMD) is a general term for another group of genetic muscle diseases that occur at birth or early during infancy. CMDs are generally characterized by hypotonia, progressive muscle weakness and atrophy, contractures, spinal rigidity and delays in reaching motor milestones. Feeding difficulties and respiratory complications can develop in some patients. Muscle weakness may improve, remain stable or worsen. Some forms of CMD may be associated with structural brain abnormalities and intellectual disability. The severity, specific symptoms and progression of these disorders vary greatly. Duchenne and Becker muscular dystrophies are two other types of muscular dystrophies that are usually classified separately. (For more information on these disorders, choose the specific disease name as your search term in the Rare Disease Database.)
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Diagnosis of Spinal Muscular Atrophy
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The evaluation of a patient with suspected SMA, such as an infant with unexplained weakness and hypotonia while appearing bright eyed and socially engaging, begins with a complete patient history and physical examination. If the clinical evaluation shows signs of lower motor neuron disease (see Signs & Symptoms section) and suggests SMA, the diagnosis is confirmed with genetic testing to detect pathogenic variants in the SMN1 gene and if there are no copies of SMN1, then reflex testing for SMN2 copy number should be competed. If the patient is symptomatic and one copy of SMN1 is identified, then gene sequence analysis should be obtained to evaluate for a possible SMN1 point mutation.No other tests are needed to diagnose SMA, although additional testing may be initially performed to exclude other conditions that could have a similar clinical presentation. This can include genetic testing associated with other diseases, metabolic or biochemical tests or evaluation of the transmission of electrical signals from nerves to muscles (electromyography; EMG). Muscle biopsy may be considered when the above testing does not reveal a diagnosis.Newborn screening for SMA is being implemented throughout the United States. As of January 2021, 39 states screen for SMA representing 86% of all infants born in the U.S. Newborn screening facilitates early identification of infants with SMA and thus early implementation of treatment. Infants identified by SMA newborn screening are urgently referred for confirmatory testing, discussion of treatments and care. Early treatment prior to the onset of symptoms provides the best outcomes. Newborn screening will not identify 3-5% of infants with SMA due to having a point mutation in the SMN1 gene. These infants will progress to develop symptoms and require rapid diagnosis and treatment.Carrier testing for SMA is also available using a molecular genetic test in which the number of copies of the SMN1 gene is determined. The American College of Obstetricians and Gynecologists recommends offering carrier screening for SMA to all women who are considering pregnancy or are currently pregnant.
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Diagnosis of Spinal Muscular Atrophy. The evaluation of a patient with suspected SMA, such as an infant with unexplained weakness and hypotonia while appearing bright eyed and socially engaging, begins with a complete patient history and physical examination. If the clinical evaluation shows signs of lower motor neuron disease (see Signs & Symptoms section) and suggests SMA, the diagnosis is confirmed with genetic testing to detect pathogenic variants in the SMN1 gene and if there are no copies of SMN1, then reflex testing for SMN2 copy number should be competed. If the patient is symptomatic and one copy of SMN1 is identified, then gene sequence analysis should be obtained to evaluate for a possible SMN1 point mutation.No other tests are needed to diagnose SMA, although additional testing may be initially performed to exclude other conditions that could have a similar clinical presentation. This can include genetic testing associated with other diseases, metabolic or biochemical tests or evaluation of the transmission of electrical signals from nerves to muscles (electromyography; EMG). Muscle biopsy may be considered when the above testing does not reveal a diagnosis.Newborn screening for SMA is being implemented throughout the United States. As of January 2021, 39 states screen for SMA representing 86% of all infants born in the U.S. Newborn screening facilitates early identification of infants with SMA and thus early implementation of treatment. Infants identified by SMA newborn screening are urgently referred for confirmatory testing, discussion of treatments and care. Early treatment prior to the onset of symptoms provides the best outcomes. Newborn screening will not identify 3-5% of infants with SMA due to having a point mutation in the SMN1 gene. These infants will progress to develop symptoms and require rapid diagnosis and treatment.Carrier testing for SMA is also available using a molecular genetic test in which the number of copies of the SMN1 gene is determined. The American College of Obstetricians and Gynecologists recommends offering carrier screening for SMA to all women who are considering pregnancy or are currently pregnant.
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Therapies of Spinal Muscular Atrophy
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The treatment of SMA requires a multidisciplinary team approach and should notably include neurologists, medical geneticists, physical therapists, speech pathologists, pulmonologists, respiratory therapists, medical social workers, nutritionists, psychologists and specialized nurses. There are two main components to SMA management: treatment that slows the progression of the disease (disease-modifying therapy) and therapy that helps manage symptoms and improves quality of life (supportive therapy). Genetic counseling is recommended for affected individuals and their families.Symptomatic therapyThe symptomatic management of SMA includes physical therapy, occupational therapy, monitoring respiratory function and intervening as clinically indicated, nutritional status monitoring and intervention, spine curvature monitoring and intervention and use of orthotics and adaptive equipment as needed. Respiratory support for SMA type 1 (infants symptomatic prior to 6 months of age) includes providing breathing support called BiPAP (bi-level positive airway pressure) to manage hypoventilation and a mechanical insufflation-exsufflation device to support weak cough. Supportive management has been shown to increase comfort and life expectancy. Earlier in the disease, some affected infants might only require ventilation support at night. Children with progressive respiratory insufficiency might require more invasive interventions to breathe, such as surgical placement of a breathing tube through the neck (tracheostomy). For infants and children with dysphagia, nutrition support may require gastrostomy tube placement to provide nutrition safely. Children with SMA may also require surgical intervention for musculoskeletal issues such as scoliosis and/or hip dislocation.Disease-modifying therapyResearch efforts have led to therapies that can improve the course of SMA. The first disease-modifying therapy was approved by the U.S. Food and Drug Administration (FDA) in 2016. These therapies have shown promising results, notably developmental motor milestone achievement and improved survival in treated individuals. As the impact of these treatments are being studied, keep in mind that these treatments are not cures.In 2016, nusinersen (Spinraza) was approved by the FDA as the first drug to treat children and adults with SMA. Nusinersen is an injection administered into the fluid surrounding the spinal cord (intrathecal administration). Nusinersen acts by modifying the splicing of the SMN2 gene product, mRNA, so that more full length and functional SMN protein is produced.In 2019, the FDA approved onasemnogene abeparvovec-xioi (Zolgensma) for the treatment of children less than two years of age with SMA. Onasemnogene abeparvovec-xioi is a gene therapy that delivers a fully functional copy of human SMN1 gene into the target motor neuron cells via a viral vector, AAV9. A one-time intravenous administration of the medication results in increased SMN protein in all cells including motor neurons.In 2020, the FDA approved risdiplam (Evrysdi) to treat patients two months of age and older with SMA. Risdiplam is the first orally administered drug approved for the treatment of SMA. It has a mechanism of action is also to modify splicing of the SMN2 mRNA resulting in increased SMN protein.
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Therapies of Spinal Muscular Atrophy. The treatment of SMA requires a multidisciplinary team approach and should notably include neurologists, medical geneticists, physical therapists, speech pathologists, pulmonologists, respiratory therapists, medical social workers, nutritionists, psychologists and specialized nurses. There are two main components to SMA management: treatment that slows the progression of the disease (disease-modifying therapy) and therapy that helps manage symptoms and improves quality of life (supportive therapy). Genetic counseling is recommended for affected individuals and their families.Symptomatic therapyThe symptomatic management of SMA includes physical therapy, occupational therapy, monitoring respiratory function and intervening as clinically indicated, nutritional status monitoring and intervention, spine curvature monitoring and intervention and use of orthotics and adaptive equipment as needed. Respiratory support for SMA type 1 (infants symptomatic prior to 6 months of age) includes providing breathing support called BiPAP (bi-level positive airway pressure) to manage hypoventilation and a mechanical insufflation-exsufflation device to support weak cough. Supportive management has been shown to increase comfort and life expectancy. Earlier in the disease, some affected infants might only require ventilation support at night. Children with progressive respiratory insufficiency might require more invasive interventions to breathe, such as surgical placement of a breathing tube through the neck (tracheostomy). For infants and children with dysphagia, nutrition support may require gastrostomy tube placement to provide nutrition safely. Children with SMA may also require surgical intervention for musculoskeletal issues such as scoliosis and/or hip dislocation.Disease-modifying therapyResearch efforts have led to therapies that can improve the course of SMA. The first disease-modifying therapy was approved by the U.S. Food and Drug Administration (FDA) in 2016. These therapies have shown promising results, notably developmental motor milestone achievement and improved survival in treated individuals. As the impact of these treatments are being studied, keep in mind that these treatments are not cures.In 2016, nusinersen (Spinraza) was approved by the FDA as the first drug to treat children and adults with SMA. Nusinersen is an injection administered into the fluid surrounding the spinal cord (intrathecal administration). Nusinersen acts by modifying the splicing of the SMN2 gene product, mRNA, so that more full length and functional SMN protein is produced.In 2019, the FDA approved onasemnogene abeparvovec-xioi (Zolgensma) for the treatment of children less than two years of age with SMA. Onasemnogene abeparvovec-xioi is a gene therapy that delivers a fully functional copy of human SMN1 gene into the target motor neuron cells via a viral vector, AAV9. A one-time intravenous administration of the medication results in increased SMN protein in all cells including motor neurons.In 2020, the FDA approved risdiplam (Evrysdi) to treat patients two months of age and older with SMA. Risdiplam is the first orally administered drug approved for the treatment of SMA. It has a mechanism of action is also to modify splicing of the SMN2 mRNA resulting in increased SMN protein.
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Overview of Spinal Muscular Atrophy with Respiratory Distress
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SummarySpinal muscular atrophy with respiratory distress type 1 (SMARD1) is an extremely rare type of spinal muscular atrophy (SMA) that results from irreversible deterioration of alpha motor neurons of the spinal cord. Alpha motor neurons supply nerves to skeletal muscle and stimulate muscle contraction. The symptoms of SMARD1 primarily presents as infants having trouble breathing between the ages of 6 weeks and 6 months of age. Unless they are not supported with mechanical ventilation, most affected children die from respiratory failure before 13 months of age. Progression of muscle weakness typically stops within two years, but, in a young child, the consequences of severe neuromuscular weakness are progressive. SMARD1 is known to be caused by changes (called mutations or variants) in the IGHMBP2 gene and is inherited in an autosomal recessive pattern. A majority of children with SMARD1 have early onset in infancy, but there have been many children reported with a later onset juvenile form of SMARD1.IntroductionSMARD1 was first reported in medical literature in 1974 by Mellins, et al, who described two newborns presenting with an atypical variant of SMA type 1 (Wernig-Hoffmann disease). However, SMARD1 was not recognized as a separate disease from SMA until 1996. The first research showing IGHMBP2 gene mutations in relation to the characteristics of SMARD1 was reported in 2001 by Grohmann, et al.
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Overview of Spinal Muscular Atrophy with Respiratory Distress. SummarySpinal muscular atrophy with respiratory distress type 1 (SMARD1) is an extremely rare type of spinal muscular atrophy (SMA) that results from irreversible deterioration of alpha motor neurons of the spinal cord. Alpha motor neurons supply nerves to skeletal muscle and stimulate muscle contraction. The symptoms of SMARD1 primarily presents as infants having trouble breathing between the ages of 6 weeks and 6 months of age. Unless they are not supported with mechanical ventilation, most affected children die from respiratory failure before 13 months of age. Progression of muscle weakness typically stops within two years, but, in a young child, the consequences of severe neuromuscular weakness are progressive. SMARD1 is known to be caused by changes (called mutations or variants) in the IGHMBP2 gene and is inherited in an autosomal recessive pattern. A majority of children with SMARD1 have early onset in infancy, but there have been many children reported with a later onset juvenile form of SMARD1.IntroductionSMARD1 was first reported in medical literature in 1974 by Mellins, et al, who described two newborns presenting with an atypical variant of SMA type 1 (Wernig-Hoffmann disease). However, SMARD1 was not recognized as a separate disease from SMA until 1996. The first research showing IGHMBP2 gene mutations in relation to the characteristics of SMARD1 was reported in 2001 by Grohmann, et al.
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Symptoms of Spinal Muscular Atrophy with Respiratory Distress
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Symptoms of SMARD1 generally begin during infancy. Early features of SMARD1 include a weak cry, feeding problems, difficult and noisy breathing- especially when inhaling (inspiratory stridor) and recurrent pneumonia. Between 6 weeks and 6 months of age, affected infants typically experience sudden onset of shortness of breath with progressive respiratory distress. This is due to paralysis of the diaphragm, (primary inspiratory muscle) and abdomen resulting in ineffective breathing with an increased respiratory rate (tachypnea) and eventual inability to breathe (respiratory failure). Diaphragmatic paralysis can result from a dysfunction of the phrenic nerve that supplies the diaphragm. This paralysis (phrenic nerve palsy) usually starts on the right side although it can affect one or both halves of the diaphragm.Following respiratory failure, muscle weakness occurs in muscles farther from the midline of the body (distal), usually beginning in the lower limbs, spreading to all muscles. The decline of muscle weakness stabilizes within two years. The retention of muscle function following this period is variable among individuals. Patients often experience complete paralysis of all limbs and trunk muscles.Most affected individuals lose their deep tendon reflexes (areflexia) by the age of one. Children may also develop an abnormal sideways curvature of the spine (scoliosis), an excessive outward curvature of the spine (kyphosis), or both (kyphoscoliosis). Other features include a loss of bladder and bowel control (incontinence), irregular heartbeat (arrhythmia), low muscle tone (hypotonia), excessive sweating (hyperhidrosis), a reduced pain sensitivity, and deformities of feet and hands.A variety of other symptoms and physical findings can develop in individuals with SMARD1:Prenatal/Natal Features• Intrauterine growth retardation (unborn not growing as expected)
• Premature birth
• Reduced fetal movements
• Birth weight, length and head circumference values less than the 10th percentile (small for their gestational age)
• Inability to gain weight or grow at the expected rate (failure to thrive)Respiratory Abnormalities• Respiratory paradox due to diaphragmatic weakness/paralysis
• Respiratory failure
• Persistent or recurrent atelectasis (collapse of lung segments or lobes) due to weak cough and reduced ability to clear respiratory secretions even without an illness.
• Spine and chest wall deformities due to chest wall muscle involvement that further reduce respiratory efficiencyOrthopedic abnormalities• Distal extremity deformities, such as clubfoot (talipes equinovarus)
• Permanent flexion of the finger (camptodactyly of finger)
• Front half of the foot turning inward (metatarsus varus)
• Limitation of the range of motion of joints (joint contractures) in hands or feet (hand/foot arthrogryposis)
o Wrist retraction
o Elbow, ankle, and knee stiffness
• Curved/bent fingers or toes (claw hands or toes)
• Elbow, ankle, and knee stiffness.Gastrointestinal features• Excessive production of saliva (hyper salivation)
• Difficulty swallowing (dysphagia)
• Gastroesophageal reflux (persistent spitting up)
• Inability of the stomach to empty food in the usual way (gastroparesis)
• Inability to empty the bladder (urinary retention)
• ConstipationNeuromuscular features• Fatty finger pads
• Loss of nerve supply to the diaphragm (denervation of the diaphragm)
• Abnormal elevation of the diaphragm (diaphragmatic eventration)
• Muscle wasting of arms and legs
• Spinal muscle deterioration (spinal muscular atrophy)
• Decreased nerve conduction velocity (slowed ability for nerves to send messages to parts of body)
• Involuntary twitching of the tongue and weakness of facial muscles
• Decreased degree of facial expression (hypomimia)Other Characteristics• Thoracospinal deformities (scoliosis, thoracic dystrophy)
• Seizures occurring during or after a hypoxic or anoxic (little to no oxygen) episode
• High blood pressure
• Dislocated hipSymptoms of SMARD1 is typically present in infancy, but there is a significant amount of variability in the timing of the onset, and numerous SMARD1 patients have been diagnosed later in childhood. Only a few have been reported with late onset or mild presentation.
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Symptoms of Spinal Muscular Atrophy with Respiratory Distress. Symptoms of SMARD1 generally begin during infancy. Early features of SMARD1 include a weak cry, feeding problems, difficult and noisy breathing- especially when inhaling (inspiratory stridor) and recurrent pneumonia. Between 6 weeks and 6 months of age, affected infants typically experience sudden onset of shortness of breath with progressive respiratory distress. This is due to paralysis of the diaphragm, (primary inspiratory muscle) and abdomen resulting in ineffective breathing with an increased respiratory rate (tachypnea) and eventual inability to breathe (respiratory failure). Diaphragmatic paralysis can result from a dysfunction of the phrenic nerve that supplies the diaphragm. This paralysis (phrenic nerve palsy) usually starts on the right side although it can affect one or both halves of the diaphragm.Following respiratory failure, muscle weakness occurs in muscles farther from the midline of the body (distal), usually beginning in the lower limbs, spreading to all muscles. The decline of muscle weakness stabilizes within two years. The retention of muscle function following this period is variable among individuals. Patients often experience complete paralysis of all limbs and trunk muscles.Most affected individuals lose their deep tendon reflexes (areflexia) by the age of one. Children may also develop an abnormal sideways curvature of the spine (scoliosis), an excessive outward curvature of the spine (kyphosis), or both (kyphoscoliosis). Other features include a loss of bladder and bowel control (incontinence), irregular heartbeat (arrhythmia), low muscle tone (hypotonia), excessive sweating (hyperhidrosis), a reduced pain sensitivity, and deformities of feet and hands.A variety of other symptoms and physical findings can develop in individuals with SMARD1:Prenatal/Natal Features• Intrauterine growth retardation (unborn not growing as expected)
• Premature birth
• Reduced fetal movements
• Birth weight, length and head circumference values less than the 10th percentile (small for their gestational age)
• Inability to gain weight or grow at the expected rate (failure to thrive)Respiratory Abnormalities• Respiratory paradox due to diaphragmatic weakness/paralysis
• Respiratory failure
• Persistent or recurrent atelectasis (collapse of lung segments or lobes) due to weak cough and reduced ability to clear respiratory secretions even without an illness.
• Spine and chest wall deformities due to chest wall muscle involvement that further reduce respiratory efficiencyOrthopedic abnormalities• Distal extremity deformities, such as clubfoot (talipes equinovarus)
• Permanent flexion of the finger (camptodactyly of finger)
• Front half of the foot turning inward (metatarsus varus)
• Limitation of the range of motion of joints (joint contractures) in hands or feet (hand/foot arthrogryposis)
o Wrist retraction
o Elbow, ankle, and knee stiffness
• Curved/bent fingers or toes (claw hands or toes)
• Elbow, ankle, and knee stiffness.Gastrointestinal features• Excessive production of saliva (hyper salivation)
• Difficulty swallowing (dysphagia)
• Gastroesophageal reflux (persistent spitting up)
• Inability of the stomach to empty food in the usual way (gastroparesis)
• Inability to empty the bladder (urinary retention)
• ConstipationNeuromuscular features• Fatty finger pads
• Loss of nerve supply to the diaphragm (denervation of the diaphragm)
• Abnormal elevation of the diaphragm (diaphragmatic eventration)
• Muscle wasting of arms and legs
• Spinal muscle deterioration (spinal muscular atrophy)
• Decreased nerve conduction velocity (slowed ability for nerves to send messages to parts of body)
• Involuntary twitching of the tongue and weakness of facial muscles
• Decreased degree of facial expression (hypomimia)Other Characteristics• Thoracospinal deformities (scoliosis, thoracic dystrophy)
• Seizures occurring during or after a hypoxic or anoxic (little to no oxygen) episode
• High blood pressure
• Dislocated hipSymptoms of SMARD1 is typically present in infancy, but there is a significant amount of variability in the timing of the onset, and numerous SMARD1 patients have been diagnosed later in childhood. Only a few have been reported with late onset or mild presentation.
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Causes of Spinal Muscular Atrophy with Respiratory Distress
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SMARD1 is caused by variants (mutations) in the IGHMBP2 gene. Researchers have found more than 60 different mutations in the IGHMBP2 gene that cause SMARD1. The IGHMBP2 gene is responsible for providing instructions necessary for making the IGHMBP2 protein that is involved in DNA replication and production of RNA and proteins. However, the exact role of the IGHMBP2 protein is currently unknown.The abnormal IGHMBP2 protein leads to damage and death of the alpha-motor neurons of the brain stem and spinal cord. These neurons are responsible for controlling muscle movements. The mechanism as to how the abnormal IGHMP2 proteins lead to damage and death of the alpha neurons is currently unknown. Affected individuals with some functional protein are more likely to have a higher level of muscle function and a later onset of SMARD1 symptoms.SMARD1 is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Spinal Muscular Atrophy with Respiratory Distress. SMARD1 is caused by variants (mutations) in the IGHMBP2 gene. Researchers have found more than 60 different mutations in the IGHMBP2 gene that cause SMARD1. The IGHMBP2 gene is responsible for providing instructions necessary for making the IGHMBP2 protein that is involved in DNA replication and production of RNA and proteins. However, the exact role of the IGHMBP2 protein is currently unknown.The abnormal IGHMBP2 protein leads to damage and death of the alpha-motor neurons of the brain stem and spinal cord. These neurons are responsible for controlling muscle movements. The mechanism as to how the abnormal IGHMP2 proteins lead to damage and death of the alpha neurons is currently unknown. Affected individuals with some functional protein are more likely to have a higher level of muscle function and a later onset of SMARD1 symptoms.SMARD1 is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Spinal Muscular Atrophy with Respiratory Distress
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Affects of Spinal Muscular Atrophy with Respiratory Distress
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The exact prevalence of SMARD1 is currently unknown. Studies show that diaphragmatic paralysis affects about 1% percent of individuals diagnosed with early onset spinal muscular atrophy. As of 2015, greater than 60 cases of SMARD1 have been described in scientific literature.
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Affects of Spinal Muscular Atrophy with Respiratory Distress. The exact prevalence of SMARD1 is currently unknown. Studies show that diaphragmatic paralysis affects about 1% percent of individuals diagnosed with early onset spinal muscular atrophy. As of 2015, greater than 60 cases of SMARD1 have been described in scientific literature.
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Related disorders of Spinal Muscular Atrophy with Respiratory Distress
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Symptoms of the following disorders may have characteristics like SMARD1. Comparing the clinical features of these disorders could be helpful in obtaining an accurate diagnosis.Werdnig-Hoffmann disease (SMA1) is an autosomal recessive disorder characterized by extreme muscle weakness, poor muscle tone (hypotonia), and lack of motor development that typically manifest prior to 6 months of age. Other features that may develop include trouble breathing, sucking, and swallowing; constipation; and an increased likelihood of respiratory infections. Respiratory failure may occur. There appears to be a variability in the rate of progression of SMA1 in patients. About 80% of patients with spinal muscular atrophy (SMA) are diagnosed with SMA1. In SMA1, features seem to present in an order opposite of that in SMARD1. Individuals affected with SMA1 will experience hypotonia and muscle weakness before being affected with respiratory failure. The early presentation of diaphragm paralysis and distal muscle weakness in SMARD1 clinically distinguishes it from SMA1.Charcot Marie Tooth disease (CMT) is a group of disorders characterized by muscle weakness and atrophy (wasting), and sensory loss that begins in the distal legs and progresses to include the hands. This disorder results from irregularities of the nerve axon or myelin sheath (the fatty substance surrounding some axons that is responsible for protection). These abnormalities affect motor and/or sensory peripheral nerves that provide communication from the brain and spinal cord to the rest of the body. CMT is a slow progressive disease and often begins with decreased sensitivity to heat, touch and pain followed by muscle weakness.Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) has an autosomal recessive inheritance and is caused by mutations in the MEG10 gene. It is characterized by a disorder of the skeletal muscles at birth (congenital). Signs of EMARDD include muscle weakness, respiratory distress caused by paralysis of the diaphragm, joint contractures, scoliosis, absent reflexes and difficulty swallowing. Other symptoms include a cleft palate and difficulty feeding. Electromyography (EMG) results indicate abnormalities of the muscle cells (myopathic changes), while nerve conduction velocities appeared normal. On the contrary, a significant slowing in nerve conduction velocities is common in SMARD1. There seems to be variability in the severity of the disorder in EMARDD patients.Brown-Vialetto-van Laere and Fazio Londe syndrome (BVvL) is a neurological disorder for which the characteristic features are bulbar palsy (symptoms due to impaired function of cranial nerves 9-12) and sensory deafness. This is caused by mutations in the C20ORF54 gene. More females than males are affected by this disorder, with a ratio of 3:1. The age of onset is highly variable as BVvL may present from infancy to the third decade of life. Other features of BVvL include deterioration of respiratory function, distal muscle weakness, facial weakness, autonomic dysfunction (unable to control automatic functions such as heartrate), and epilepsy. The respiratory failure and muscular weakness are the major similarity between BVvL and SMARD1 when considering a diagnosis.Transient neonatal myasthenia gravis, congenital myopathy, and Pompe disease (glycogenosis type II) are other possible related disorders in which the abnormal elevation of the diaphragm (eventration) present in SMARD1 does not occur.Transient neonatal myasthenia gravis usually only lasts a few weeks and occurs when antibodies cross the placenta from the mother to the fetus and destroy neuromuscular connections. Common features include muscle weakness, poor sucking ability, and respiratory distress. Severely affected patients require mechanical ventilation if respiratory muscles are too weak to enable the infant to breathe on their own.Pompe disease is an autosomal recessive, multisystem disorder that results from variations in the acid alpha-glucosidase (GAA) gene. This causes a buildup of glycogen in cells of the body, which impedes the ability of some organs and tissues- particularly muscles- to function regularly. The disease onset of the classic infantile-onset form is usually within the first three months of life with symptoms of muscle weakness, low muscle tone (hypotonia), heart failure and breathing problems. It is also characterized by a thickening of the walls of the heart (hypertrophic cardiomyopathy) and a moderately enlarged liver (hepatomegaly). Feeding and swallowing difficulties as well as respiratory tract infections are typical.Congenital myopathy is a group of genetic muscle diseases that occur at birth. Common signs include muscle weakness, a lack of muscle tone, facial weakness, and drooping eyelids. Other features may include feeding problems, respiratory difficulty, scoliosis, osteopenia, or hip problems.
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Related disorders of Spinal Muscular Atrophy with Respiratory Distress. Symptoms of the following disorders may have characteristics like SMARD1. Comparing the clinical features of these disorders could be helpful in obtaining an accurate diagnosis.Werdnig-Hoffmann disease (SMA1) is an autosomal recessive disorder characterized by extreme muscle weakness, poor muscle tone (hypotonia), and lack of motor development that typically manifest prior to 6 months of age. Other features that may develop include trouble breathing, sucking, and swallowing; constipation; and an increased likelihood of respiratory infections. Respiratory failure may occur. There appears to be a variability in the rate of progression of SMA1 in patients. About 80% of patients with spinal muscular atrophy (SMA) are diagnosed with SMA1. In SMA1, features seem to present in an order opposite of that in SMARD1. Individuals affected with SMA1 will experience hypotonia and muscle weakness before being affected with respiratory failure. The early presentation of diaphragm paralysis and distal muscle weakness in SMARD1 clinically distinguishes it from SMA1.Charcot Marie Tooth disease (CMT) is a group of disorders characterized by muscle weakness and atrophy (wasting), and sensory loss that begins in the distal legs and progresses to include the hands. This disorder results from irregularities of the nerve axon or myelin sheath (the fatty substance surrounding some axons that is responsible for protection). These abnormalities affect motor and/or sensory peripheral nerves that provide communication from the brain and spinal cord to the rest of the body. CMT is a slow progressive disease and often begins with decreased sensitivity to heat, touch and pain followed by muscle weakness.Early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) has an autosomal recessive inheritance and is caused by mutations in the MEG10 gene. It is characterized by a disorder of the skeletal muscles at birth (congenital). Signs of EMARDD include muscle weakness, respiratory distress caused by paralysis of the diaphragm, joint contractures, scoliosis, absent reflexes and difficulty swallowing. Other symptoms include a cleft palate and difficulty feeding. Electromyography (EMG) results indicate abnormalities of the muscle cells (myopathic changes), while nerve conduction velocities appeared normal. On the contrary, a significant slowing in nerve conduction velocities is common in SMARD1. There seems to be variability in the severity of the disorder in EMARDD patients.Brown-Vialetto-van Laere and Fazio Londe syndrome (BVvL) is a neurological disorder for which the characteristic features are bulbar palsy (symptoms due to impaired function of cranial nerves 9-12) and sensory deafness. This is caused by mutations in the C20ORF54 gene. More females than males are affected by this disorder, with a ratio of 3:1. The age of onset is highly variable as BVvL may present from infancy to the third decade of life. Other features of BVvL include deterioration of respiratory function, distal muscle weakness, facial weakness, autonomic dysfunction (unable to control automatic functions such as heartrate), and epilepsy. The respiratory failure and muscular weakness are the major similarity between BVvL and SMARD1 when considering a diagnosis.Transient neonatal myasthenia gravis, congenital myopathy, and Pompe disease (glycogenosis type II) are other possible related disorders in which the abnormal elevation of the diaphragm (eventration) present in SMARD1 does not occur.Transient neonatal myasthenia gravis usually only lasts a few weeks and occurs when antibodies cross the placenta from the mother to the fetus and destroy neuromuscular connections. Common features include muscle weakness, poor sucking ability, and respiratory distress. Severely affected patients require mechanical ventilation if respiratory muscles are too weak to enable the infant to breathe on their own.Pompe disease is an autosomal recessive, multisystem disorder that results from variations in the acid alpha-glucosidase (GAA) gene. This causes a buildup of glycogen in cells of the body, which impedes the ability of some organs and tissues- particularly muscles- to function regularly. The disease onset of the classic infantile-onset form is usually within the first three months of life with symptoms of muscle weakness, low muscle tone (hypotonia), heart failure and breathing problems. It is also characterized by a thickening of the walls of the heart (hypertrophic cardiomyopathy) and a moderately enlarged liver (hepatomegaly). Feeding and swallowing difficulties as well as respiratory tract infections are typical.Congenital myopathy is a group of genetic muscle diseases that occur at birth. Common signs include muscle weakness, a lack of muscle tone, facial weakness, and drooping eyelids. Other features may include feeding problems, respiratory difficulty, scoliosis, osteopenia, or hip problems.
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Diagnosis of Spinal Muscular Atrophy with Respiratory Distress
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A diagnosis of SMARD1 is based upon the presence of characteristic features. Diagnosis usually follows severe and rapidly progressive respiratory distress caused by diaphragm paralysis, which often requires mechanical ventilation. An abnormally high position of the diaphragm can be indicative of SMARD1 if this occurs with one or more of the following signs: an infant with respiratory distress; family history of sudden infant death syndrome; close familial relation (consanguinity) of parents; and foot and hand muscle weakness and/or distal articular retractions. Genetic testing can detect the presence of mutations in the IGHMBP2 gene and confirm a clinical diagnosis. Further testing- such as an x-ray, electromyogram (EMG), and nerve conduction study (NCS), or muscle biopsy- may be performed to rule out related disorders.
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Diagnosis of Spinal Muscular Atrophy with Respiratory Distress. A diagnosis of SMARD1 is based upon the presence of characteristic features. Diagnosis usually follows severe and rapidly progressive respiratory distress caused by diaphragm paralysis, which often requires mechanical ventilation. An abnormally high position of the diaphragm can be indicative of SMARD1 if this occurs with one or more of the following signs: an infant with respiratory distress; family history of sudden infant death syndrome; close familial relation (consanguinity) of parents; and foot and hand muscle weakness and/or distal articular retractions. Genetic testing can detect the presence of mutations in the IGHMBP2 gene and confirm a clinical diagnosis. Further testing- such as an x-ray, electromyogram (EMG), and nerve conduction study (NCS), or muscle biopsy- may be performed to rule out related disorders.
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Therapies of Spinal Muscular Atrophy with Respiratory Distress
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TreatmentThe evaluation for respiratory insufficiency is of critical importance for overall successful management. This evaluation should include the measurements of random and early morning (prior to awakening) blood gas data to evaluate for alveolar hypoventilation/respiratory insufficiency (elevated levels of carbon dioxide or CO2). The features of respiratory insufficiency of neuromuscular disease include frequent nighttime awakening or arousals, REM (dream) sleep suppression, reduction in airflow from shallow or obstructed breathing, rapid breathing, respiratory paradox (see saw moments of the chest and abdomen), low saturations with or without apneas (respiratory pauses) and elevated CO2 levels. The gold standard for such evaluation is the sleep study (polysomnogram or PSG). The interpretation of this study should be done in light of the global diagnosis and needs to be done (ideally) by a sleep medicine specialist with expertise in the management of neuromuscular disease.There is currently no effective treatment available for SMARD1. Treatment is primarily supportive, focusing on the symptoms present in the affected individual. Patients with urinary retention need catheterization. Patients with diaphragm paralysis require early initiation of adequate support with mechanical ventilation to reduce the likelihood or degree of thoracic dystrophy. Unless they receive mechanical ventilation, most affected individuals will die from respiratory failure before 13 months of age. Recurrent airway infections are treated with antibiotic therapy and other preventative measures (prophylaxis).Ventilation strategies include the goals of reducing work of breathing and providing optimal respiratory muscle rest during sleep. Maintenance of appropriate resting lung volumes will lead to stabilization of ventilation (CO2 levels) and saturations (oxygen levels). Optimizing pulmonary care includes the incorporation of airway clearance therapies. Suctioning is needed to clear the secretions from the upper airways. In addition, the use of cough augmentation devices (for example the Cough Assist machine) assists patients with producing an effective cough. The machine provides positive pressure when the patient breathes in to expand the lungs. When the patient breathes out, the machine exerts negative pressure that pulls the air back and out of the lungs. This change in pressure elicits a stronger effective cough, thereby removing secretions. The use of such a machine requires patient interaction and cooperation and may therefore prove to be a little more challenging to use in infants and toddlers. It is essential to remove mucous from the lungs to prevent obstruction as well as infections such as bronchitis and pneumonia.Treatment also focuses on nutrition for these patients because of difficulty swallowing and digesting food due to muscle weakness and gastrointestinal dysfunction. If necessary, nutrition is given through a nasogastric tube (tube through the nose to the stomach) or gastrostomy tube that is surgically placed through wall of abdomen directly into stomach. Other vital aspects of treatment include physical and occupational therapy.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Spinal Muscular Atrophy with Respiratory Distress. TreatmentThe evaluation for respiratory insufficiency is of critical importance for overall successful management. This evaluation should include the measurements of random and early morning (prior to awakening) blood gas data to evaluate for alveolar hypoventilation/respiratory insufficiency (elevated levels of carbon dioxide or CO2). The features of respiratory insufficiency of neuromuscular disease include frequent nighttime awakening or arousals, REM (dream) sleep suppression, reduction in airflow from shallow or obstructed breathing, rapid breathing, respiratory paradox (see saw moments of the chest and abdomen), low saturations with or without apneas (respiratory pauses) and elevated CO2 levels. The gold standard for such evaluation is the sleep study (polysomnogram or PSG). The interpretation of this study should be done in light of the global diagnosis and needs to be done (ideally) by a sleep medicine specialist with expertise in the management of neuromuscular disease.There is currently no effective treatment available for SMARD1. Treatment is primarily supportive, focusing on the symptoms present in the affected individual. Patients with urinary retention need catheterization. Patients with diaphragm paralysis require early initiation of adequate support with mechanical ventilation to reduce the likelihood or degree of thoracic dystrophy. Unless they receive mechanical ventilation, most affected individuals will die from respiratory failure before 13 months of age. Recurrent airway infections are treated with antibiotic therapy and other preventative measures (prophylaxis).Ventilation strategies include the goals of reducing work of breathing and providing optimal respiratory muscle rest during sleep. Maintenance of appropriate resting lung volumes will lead to stabilization of ventilation (CO2 levels) and saturations (oxygen levels). Optimizing pulmonary care includes the incorporation of airway clearance therapies. Suctioning is needed to clear the secretions from the upper airways. In addition, the use of cough augmentation devices (for example the Cough Assist machine) assists patients with producing an effective cough. The machine provides positive pressure when the patient breathes in to expand the lungs. When the patient breathes out, the machine exerts negative pressure that pulls the air back and out of the lungs. This change in pressure elicits a stronger effective cough, thereby removing secretions. The use of such a machine requires patient interaction and cooperation and may therefore prove to be a little more challenging to use in infants and toddlers. It is essential to remove mucous from the lungs to prevent obstruction as well as infections such as bronchitis and pneumonia.Treatment also focuses on nutrition for these patients because of difficulty swallowing and digesting food due to muscle weakness and gastrointestinal dysfunction. If necessary, nutrition is given through a nasogastric tube (tube through the nose to the stomach) or gastrostomy tube that is surgically placed through wall of abdomen directly into stomach. Other vital aspects of treatment include physical and occupational therapy.Genetic counseling is recommended for affected individuals and their families.
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Spinal Muscular Atrophy with Respiratory Distress
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nord_1147_0
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Overview of Spinocerebellar Ataxia with Axonal Neuropathy
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Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a neurodegenerative disorder that is inherited in an autosomal recessive pattern. SCAN1 is characterized by late childhood-onset of a slowly progressive cerebellar ataxia, followed by areflexia and signs of peripheral neuropathy. Gaze nystagmus and cerebellar dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation become impaired in the hands and legs; vibration sense disappears in hands and lower thigh. Individuals with advanced disease develop a steppage gait and pes cavus; and later become wheelchair dependent. Affected individuals have normal intellect and longevity.
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Overview of Spinocerebellar Ataxia with Axonal Neuropathy. Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a neurodegenerative disorder that is inherited in an autosomal recessive pattern. SCAN1 is characterized by late childhood-onset of a slowly progressive cerebellar ataxia, followed by areflexia and signs of peripheral neuropathy. Gaze nystagmus and cerebellar dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation become impaired in the hands and legs; vibration sense disappears in hands and lower thigh. Individuals with advanced disease develop a steppage gait and pes cavus; and later become wheelchair dependent. Affected individuals have normal intellect and longevity.
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Spinocerebellar Ataxia with Axonal Neuropathy
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Symptoms of Spinocerebellar Ataxia with Axonal Neuropathy
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SCAN1 is suspected in individuals with the following clinical features:– Cerebellar ataxia and areflexia of late childhood (13 – 15 years)-onset followed by signs of peripheral neuropathy– Slow progression– Absence of oculomotor apraxia– Absence of extra-neurological findings common in ataxia-telangiectasia (telangiectasias, immunodeficiency and cancer predisposition)– Family history consistent with autosomal recessive inheritance– MRI: Cerebellar atrophy especially of the vermis is present in all affected individuals– Nerve conduction studies: Signs of axonal neuropathy– Nerve biopsy: axonal loss– Blood tests: Decreased serum concentration of albumin and increased serum concentration of cholesterol
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Symptoms of Spinocerebellar Ataxia with Axonal Neuropathy. SCAN1 is suspected in individuals with the following clinical features:– Cerebellar ataxia and areflexia of late childhood (13 – 15 years)-onset followed by signs of peripheral neuropathy– Slow progression– Absence of oculomotor apraxia– Absence of extra-neurological findings common in ataxia-telangiectasia (telangiectasias, immunodeficiency and cancer predisposition)– Family history consistent with autosomal recessive inheritance– MRI: Cerebellar atrophy especially of the vermis is present in all affected individuals– Nerve conduction studies: Signs of axonal neuropathy– Nerve biopsy: axonal loss– Blood tests: Decreased serum concentration of albumin and increased serum concentration of cholesterol
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Spinocerebellar Ataxia with Axonal Neuropathy
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nord_1147_2
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Causes of Spinocerebellar Ataxia with Axonal Neuropathy
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SCAN1 is inherited as an autosomal recessive disorder. 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.Biallelic mutations in the tyrosyl-DNA phosphodiesterase 1 (TDP1) gene are found in all individuals with SCAN1. The TDP1 gene encodes tyrosyl-DNA phosphodiesterase 1 (Tdp1) a DNA repair enzyme that is involved in correction of the DNA strand breaks in which the 3′ end is blocked by stalled topoisomerase I or phosphoglycolate. The histidine at amino acid residue 493 (His493) is a key residue in the active site of Tdp1 and its mutation impairs enzymatic activity. In particular, the p.His493Arg mutation identified in SCAN1 reduces enzymatic activity 25-fold and results in accumulation of topoisomerase I DNA complexes. Also, the mutant Tdp1 forms a prolonged covalent intermediate with the DNA.Consistent with these in vitro studies, lymphoblastoid cells from persons with SCAN1 are more sensitive to the camptothecins and radiation. Despite these findings, SCAN1 does not appear to arise solely from deficient functional Tdp1 because Tdp1-deficient mice have normal growth and survival under ideal growth conditions although they are highly sensitive to the camptothecins and bleomycin. This suggests that, at least in mice and yeast, redundant pathways exist for Tdp1 and that this redundancy is sufficient under ideal conditions.Further analysis suggests that the pathology of SCAN1 can be partially attributed to the prolonged covalent intermediate state formed by the p.His493Arg Tdp1 because murine and yeast cells expressing the ortholog of the human p.His493Arg Tdp1 are more sensitive to DNA damaging agents than are Tdp1-deficientl cells. This latter observation would also provide an explanation for the rarity of SCAN1 because recurrence of the disease would require recurrence of the p.His493Arg mutation or a functionally equivalent mutation. The autosomal recessive inheritance of a neomorphic mutation is explained by the finding that the covalent intermediate formed by p.His493Arg Tdp1 is rapidly repaired by wild type Tdp1.
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Causes of Spinocerebellar Ataxia with Axonal Neuropathy. SCAN1 is inherited as an autosomal recessive disorder. 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.Biallelic mutations in the tyrosyl-DNA phosphodiesterase 1 (TDP1) gene are found in all individuals with SCAN1. The TDP1 gene encodes tyrosyl-DNA phosphodiesterase 1 (Tdp1) a DNA repair enzyme that is involved in correction of the DNA strand breaks in which the 3′ end is blocked by stalled topoisomerase I or phosphoglycolate. The histidine at amino acid residue 493 (His493) is a key residue in the active site of Tdp1 and its mutation impairs enzymatic activity. In particular, the p.His493Arg mutation identified in SCAN1 reduces enzymatic activity 25-fold and results in accumulation of topoisomerase I DNA complexes. Also, the mutant Tdp1 forms a prolonged covalent intermediate with the DNA.Consistent with these in vitro studies, lymphoblastoid cells from persons with SCAN1 are more sensitive to the camptothecins and radiation. Despite these findings, SCAN1 does not appear to arise solely from deficient functional Tdp1 because Tdp1-deficient mice have normal growth and survival under ideal growth conditions although they are highly sensitive to the camptothecins and bleomycin. This suggests that, at least in mice and yeast, redundant pathways exist for Tdp1 and that this redundancy is sufficient under ideal conditions.Further analysis suggests that the pathology of SCAN1 can be partially attributed to the prolonged covalent intermediate state formed by the p.His493Arg Tdp1 because murine and yeast cells expressing the ortholog of the human p.His493Arg Tdp1 are more sensitive to DNA damaging agents than are Tdp1-deficientl cells. This latter observation would also provide an explanation for the rarity of SCAN1 because recurrence of the disease would require recurrence of the p.His493Arg mutation or a functionally equivalent mutation. The autosomal recessive inheritance of a neomorphic mutation is explained by the finding that the covalent intermediate formed by p.His493Arg Tdp1 is rapidly repaired by wild type Tdp1.
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Spinocerebellar Ataxia with Axonal Neuropathy
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Affects of Spinocerebellar Ataxia with Axonal Neuropathy
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SCAN1 has been identified in a single Saudi Arabian family. It has not been identified in other ataxic individuals.
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Affects of Spinocerebellar Ataxia with Axonal Neuropathy. SCAN1 has been identified in a single Saudi Arabian family. It has not been identified in other ataxic individuals.
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Spinocerebellar Ataxia with Axonal Neuropathy
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Related disorders of Spinocerebellar Ataxia with Axonal Neuropathy
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Partial symptomatic overlap with SCAN1 can be seen in several spinocerebellar ataxias including ataxia oculomotor apraxia 1 (AOA1), ataxia oculomotor apraxia 2 (AOA2), Friedreich ataxia (FRDA) and ataxia with vitamin E deficiency (AVED). AOA1 is characterized by early onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia and chorea or dystonia. Serum concentration of albumin is decreased and total cholesterol is increased. The presence of oculomotor apraxia (80% of individuals with AOA1) differentiates AOA1 from SCAN1; however, this sign is not obvious in the early stages of the disease. AOA1 is caused by mutations of APTX.AOA2 is characterized by early onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia and chorea or dystonia. Serum concentration of alpha-fetoprotein (AFP) is increased. AOA2 is caused by mutations of SETX.FRDA is characterized by slowly progressive ataxia of gait and limbs, extensor plantar responses, and is regularly accompanied by dysarthria and axonal (predominantly sensory) neuropathy. Areflexia and reduced vibration or position sense of the lower limbs are frequent signs. Progressive scoliosis and sensorineural hearing loss are common. The onset is usually before age 25 years (mean ranging between 11 and 20 years). FRDA can be distinguished from SCAN1 by the presence of extensor plantar responses, cardiomyopathy (detected by ECG or echocardiography), and/or the usual absence of cerebellar atrophy on CT/MRI. Molecular genetic testing of FRDA is helpful for diagnostic confirmation.AVED is characterized by cerebellar ataxia, loss of proprioception and areflexia associated with markedly reduced plasma vitamin E (alpha-tocopherol) concentration. AVED can be treated by vitamin E supplementation. The diagnosis can be confirmed by identification of mutations in TTPA, the gene encoding the alpha-tocopherol transfer protein.
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Related disorders of Spinocerebellar Ataxia with Axonal Neuropathy. Partial symptomatic overlap with SCAN1 can be seen in several spinocerebellar ataxias including ataxia oculomotor apraxia 1 (AOA1), ataxia oculomotor apraxia 2 (AOA2), Friedreich ataxia (FRDA) and ataxia with vitamin E deficiency (AVED). AOA1 is characterized by early onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia and chorea or dystonia. Serum concentration of albumin is decreased and total cholesterol is increased. The presence of oculomotor apraxia (80% of individuals with AOA1) differentiates AOA1 from SCAN1; however, this sign is not obvious in the early stages of the disease. AOA1 is caused by mutations of APTX.AOA2 is characterized by early onset cerebellar ataxia, axonal neuropathy, oculomotor apraxia and chorea or dystonia. Serum concentration of alpha-fetoprotein (AFP) is increased. AOA2 is caused by mutations of SETX.FRDA is characterized by slowly progressive ataxia of gait and limbs, extensor plantar responses, and is regularly accompanied by dysarthria and axonal (predominantly sensory) neuropathy. Areflexia and reduced vibration or position sense of the lower limbs are frequent signs. Progressive scoliosis and sensorineural hearing loss are common. The onset is usually before age 25 years (mean ranging between 11 and 20 years). FRDA can be distinguished from SCAN1 by the presence of extensor plantar responses, cardiomyopathy (detected by ECG or echocardiography), and/or the usual absence of cerebellar atrophy on CT/MRI. Molecular genetic testing of FRDA is helpful for diagnostic confirmation.AVED is characterized by cerebellar ataxia, loss of proprioception and areflexia associated with markedly reduced plasma vitamin E (alpha-tocopherol) concentration. AVED can be treated by vitamin E supplementation. The diagnosis can be confirmed by identification of mutations in TTPA, the gene encoding the alpha-tocopherol transfer protein.
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Spinocerebellar Ataxia with Axonal Neuropathy
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Diagnosis of Spinocerebellar Ataxia with Axonal Neuropathy
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The diagnosis of SCAN1 is made on history and clinical signs as listed above. DNA testing for mutations in TDP1 is only available on a research basis.
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Diagnosis of Spinocerebellar Ataxia with Axonal Neuropathy. The diagnosis of SCAN1 is made on history and clinical signs as listed above. DNA testing for mutations in TDP1 is only available on a research basis.
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Spinocerebellar Ataxia with Axonal Neuropathy
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nord_1147_6
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Therapies of Spinocerebellar Ataxia with Axonal Neuropathy
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TreatmentTreatments are selected to address individual symptoms as they develop. Prostheses, walking aids, and wheelchairs are helpful for mobility depending on disabilities. Physical therapy may be helpful to maintain a more active lifestyle. Based on the proposed mechanism of disease, decreasing the predisposition of topoisomerase I to become trapped on the DNA might slow the progression of disease. Since oxidative damage of DNA is one factor that increases the amount of topoisomerase I stalled on the DNA, antioxidants may prove efficacious in affected individuals although this therapy has not been tried yet.
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Therapies of Spinocerebellar Ataxia with Axonal Neuropathy. TreatmentTreatments are selected to address individual symptoms as they develop. Prostheses, walking aids, and wheelchairs are helpful for mobility depending on disabilities. Physical therapy may be helpful to maintain a more active lifestyle. Based on the proposed mechanism of disease, decreasing the predisposition of topoisomerase I to become trapped on the DNA might slow the progression of disease. Since oxidative damage of DNA is one factor that increases the amount of topoisomerase I stalled on the DNA, antioxidants may prove efficacious in affected individuals although this therapy has not been tried yet.
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Spinocerebellar Ataxia with Axonal Neuropathy
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nord_1148_0
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Overview of Split Hand/Split Foot Malformation
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Split hand/foot malformation (SHFM) is a limb abnormality that is present at birth. It is characterized by absence of certain fingers and toes (ectrodactyly) that suggest a claw-like appearance and webbing of fingers and toes may also be present. SHFM can be inherited as a single abnormality or as a part of syndrome that includes other characteristics. There is a wide variety of symptoms and genetic causes of SHFM, and there can be varying levels of severity in people who are affected. Severity can vary even among members of the same family.
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Overview of Split Hand/Split Foot Malformation. Split hand/foot malformation (SHFM) is a limb abnormality that is present at birth. It is characterized by absence of certain fingers and toes (ectrodactyly) that suggest a claw-like appearance and webbing of fingers and toes may also be present. SHFM can be inherited as a single abnormality or as a part of syndrome that includes other characteristics. There is a wide variety of symptoms and genetic causes of SHFM, and there can be varying levels of severity in people who are affected. Severity can vary even among members of the same family.
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Split Hand/Split Foot Malformation
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Symptoms of Split Hand/Split Foot Malformation
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Symptom presentation varies from person to person. Most people with SHFM have fewer than five fingers or toes on a hand or foot (oligodactyly). A smaller proportion of individuals affected by SFHM have finger fusing (syndactyly) of multiple fingers on the hands. This is often referred to as the “lobster claw” variety where the third digit is absent and replaced with a cone-shaped cleft that tapers in toward the wrist and divides the hand into two parts resembling a lobster claw. The remaining fingers or parts of fingers on each side of the cleft are often joined or webbed together. A cleft, or the absence of bones in the hands before the fingers, usually occurs in both hands. A similar deformity commonly occurs in the feet.In the second variety of finger fusing associated with split-hand deformity, there is the presence of only the fifth digit (monodactyly) and no cleft. There are varying levels of severity between these types, and cases of each type can occasionally be found within the same family.A smaller proportion of individuals with SHFM may exhibit additional symptoms including complete absence of a hand, absence of the iris in the eye (aniridia), and deafness.Individuals with split-hand deformity usually have a normal lifespan and intelligence. Difficulties in physical functioning are related to the severity of the deformity.
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Symptoms of Split Hand/Split Foot Malformation. Symptom presentation varies from person to person. Most people with SHFM have fewer than five fingers or toes on a hand or foot (oligodactyly). A smaller proportion of individuals affected by SFHM have finger fusing (syndactyly) of multiple fingers on the hands. This is often referred to as the “lobster claw” variety where the third digit is absent and replaced with a cone-shaped cleft that tapers in toward the wrist and divides the hand into two parts resembling a lobster claw. The remaining fingers or parts of fingers on each side of the cleft are often joined or webbed together. A cleft, or the absence of bones in the hands before the fingers, usually occurs in both hands. A similar deformity commonly occurs in the feet.In the second variety of finger fusing associated with split-hand deformity, there is the presence of only the fifth digit (monodactyly) and no cleft. There are varying levels of severity between these types, and cases of each type can occasionally be found within the same family.A smaller proportion of individuals with SHFM may exhibit additional symptoms including complete absence of a hand, absence of the iris in the eye (aniridia), and deafness.Individuals with split-hand deformity usually have a normal lifespan and intelligence. Difficulties in physical functioning are related to the severity of the deformity.
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Split Hand/Split Foot Malformation
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nord_1148_2
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Causes of Split Hand/Split Foot Malformation
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There are multiple genetic causes (genetic heterogeneity) of split hand/foot malformation which makes it difficult to pinpoint a single causative mutation that leads to the condition.Split hand/foot malformation can be inherited in an autosomal dominant pattern in some families, autosomal recessive in some families, and X-linked in others. SHFM also occurs as a result of a random (sporadic) mutation during fertilization or embryonic development. When one limb is affected, the cause is often a new gene mutation. However, when four limbs are affected, the cause is often an inherited gene mutation.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.SHFM may occur by itself (isolated) or it may be part of a syndrome with abnormalities in other parts of the body. Twelve different types of SHFM have been mapped to different human chromosomes with new gene locations (loci) continually being identified by researchers. The first eight types of SHFM include the type 1 isolated split hand/foot malformation symptoms whereas other subtypes are type 2 with long-bone deficiencies. SHFM1 has been mapped to chromosome 7q21, SHFM2 to Xq32, SHFM3 located to 10q24, SHFM4 to 3q27, SHFM5 to 2q31, SHFM6 to 12q13.11q13, and other loci in the 8q21.11q22.3 region. There are additional types of SHFM with long bone deficiency that map to chromosomes 1q42.2q43, 6q14.1 and 17p13.3.There are other subtypes of SHFM with long bone deficiency (SHFLD) that typically follow autosomal dominant inheritance and have specific genetic causes. Individuals with SHFLD often have deformities in their tibia and fibula and this has been associated with three loci. SHFLD1 has been mapped to a region spanning 1q42.4q43, SHFLD2 to 6q14.1, and SHFLD3 to a region in 17p13.1p13.3. Researchers have narrowed down the association of SHFLD3 to the BHLHA9 gene in a single family, but more validation is required.SHFM1 has also been associated with mutations in the DLX5 and DLX6 genes, both members of the WNt signaling pathway, which is known to be important for limb development in embryogenesis. The role of these genes in causing ectrodactyly (the absence of fingers and/or toes) has been shown in knockout mice with no DLX5 and DLX6 genes. These mice presented with significant forms of ectrodactyly.SHFM2 shows a unique X-linked inheritance of ectrodactyly that has only been recorded in one family related by blood (consanguineous). Further linkage analysis mapped this association to Xp26, and possible gene candidates are FGF13 and TONDU.SHFM3 ectrodactyly maps to the 10q24 region of chromosome 10, and the responsible genetic mutation found here is a tandem duplication. This duplication actually accounts for 20% of SHFM cases. There are several genes affected by the duplication: DACTYLIN (SFHM3), BTRC, POLL, FGF8, and LBX1.SHFM4 is caused by a loss of function mutation in the TP63 gene. TP63 has been shown to be important in tissue layering (epithelial stratification). It is uniquely inherited in an autosomal dominant fashion. Mice lacking p63 protein have been shown to have significant defects in proper limb development and/or limb shortening.SHFM5 is seen in individuals who have deletions of the entire HOXD cluster. HOX genes are important for limb development and proper growth. Deletions of HOX genes can be causative for many growth aberrations including ectrodactyly and monodactyly.SHFM6 is another subtype of ectrodactyly and is caused by mutations in the 12q13 locus. It is uniquely caused by autosomal recessive mutations in the DLX5 and Wnt genes, and has been only seen in three reported families. Mutations in Wnt genes have been shown to be necessary, but not sufficient in producing SHMF.SHFM7 with mesoaxial polydactyly, the addition of another finger or toe, (SHFMMP) has been shown to be caused by mutations in the ZAK gene. Mesoaxial polydactyly is the presence of more than 5 digits not including the thumb or toe with the associated fusing of some bones. Homozygous missense mutations and homozygous intragenic deletions have also been shown in affected patientsSHFM8 is another form of ectrodactyly with mild-to-severe symptoms that is caused by mutations in the EPS15L1 gene. Some of the mutations reported include frameshift deletions, nonsense mutations, and other variants that lead to decreased amounts of EPS15L1 protein. The EPS15L1 protein has a unique role in embryonic development and neurogenesis.
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Causes of Split Hand/Split Foot Malformation. There are multiple genetic causes (genetic heterogeneity) of split hand/foot malformation which makes it difficult to pinpoint a single causative mutation that leads to the condition.Split hand/foot malformation can be inherited in an autosomal dominant pattern in some families, autosomal recessive in some families, and X-linked in others. SHFM also occurs as a result of a random (sporadic) mutation during fertilization or embryonic development. When one limb is affected, the cause is often a new gene mutation. However, when four limbs are affected, the cause is often an inherited gene mutation.Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.SHFM may occur by itself (isolated) or it may be part of a syndrome with abnormalities in other parts of the body. Twelve different types of SHFM have been mapped to different human chromosomes with new gene locations (loci) continually being identified by researchers. The first eight types of SHFM include the type 1 isolated split hand/foot malformation symptoms whereas other subtypes are type 2 with long-bone deficiencies. SHFM1 has been mapped to chromosome 7q21, SHFM2 to Xq32, SHFM3 located to 10q24, SHFM4 to 3q27, SHFM5 to 2q31, SHFM6 to 12q13.11q13, and other loci in the 8q21.11q22.3 region. There are additional types of SHFM with long bone deficiency that map to chromosomes 1q42.2q43, 6q14.1 and 17p13.3.There are other subtypes of SHFM with long bone deficiency (SHFLD) that typically follow autosomal dominant inheritance and have specific genetic causes. Individuals with SHFLD often have deformities in their tibia and fibula and this has been associated with three loci. SHFLD1 has been mapped to a region spanning 1q42.4q43, SHFLD2 to 6q14.1, and SHFLD3 to a region in 17p13.1p13.3. Researchers have narrowed down the association of SHFLD3 to the BHLHA9 gene in a single family, but more validation is required.SHFM1 has also been associated with mutations in the DLX5 and DLX6 genes, both members of the WNt signaling pathway, which is known to be important for limb development in embryogenesis. The role of these genes in causing ectrodactyly (the absence of fingers and/or toes) has been shown in knockout mice with no DLX5 and DLX6 genes. These mice presented with significant forms of ectrodactyly.SHFM2 shows a unique X-linked inheritance of ectrodactyly that has only been recorded in one family related by blood (consanguineous). Further linkage analysis mapped this association to Xp26, and possible gene candidates are FGF13 and TONDU.SHFM3 ectrodactyly maps to the 10q24 region of chromosome 10, and the responsible genetic mutation found here is a tandem duplication. This duplication actually accounts for 20% of SHFM cases. There are several genes affected by the duplication: DACTYLIN (SFHM3), BTRC, POLL, FGF8, and LBX1.SHFM4 is caused by a loss of function mutation in the TP63 gene. TP63 has been shown to be important in tissue layering (epithelial stratification). It is uniquely inherited in an autosomal dominant fashion. Mice lacking p63 protein have been shown to have significant defects in proper limb development and/or limb shortening.SHFM5 is seen in individuals who have deletions of the entire HOXD cluster. HOX genes are important for limb development and proper growth. Deletions of HOX genes can be causative for many growth aberrations including ectrodactyly and monodactyly.SHFM6 is another subtype of ectrodactyly and is caused by mutations in the 12q13 locus. It is uniquely caused by autosomal recessive mutations in the DLX5 and Wnt genes, and has been only seen in three reported families. Mutations in Wnt genes have been shown to be necessary, but not sufficient in producing SHMF.SHFM7 with mesoaxial polydactyly, the addition of another finger or toe, (SHFMMP) has been shown to be caused by mutations in the ZAK gene. Mesoaxial polydactyly is the presence of more than 5 digits not including the thumb or toe with the associated fusing of some bones. Homozygous missense mutations and homozygous intragenic deletions have also been shown in affected patientsSHFM8 is another form of ectrodactyly with mild-to-severe symptoms that is caused by mutations in the EPS15L1 gene. Some of the mutations reported include frameshift deletions, nonsense mutations, and other variants that lead to decreased amounts of EPS15L1 protein. The EPS15L1 protein has a unique role in embryonic development and neurogenesis.
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Split Hand/Split Foot Malformation
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nord_1148_3
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Affects of Split Hand/Split Foot Malformation
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Split hand/foot malformation affects males and females at similar rates, due to the nature of SHFM being inherited in an autosomal dominant, autosomal recessive or X-linked manner. The X-linked SHFM cases typically manifest in males. The total frequency of all SHFM cases is approximately 1 out of every 90,000-100,000 live births, worldwide.
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Affects of Split Hand/Split Foot Malformation. Split hand/foot malformation affects males and females at similar rates, due to the nature of SHFM being inherited in an autosomal dominant, autosomal recessive or X-linked manner. The X-linked SHFM cases typically manifest in males. The total frequency of all SHFM cases is approximately 1 out of every 90,000-100,000 live births, worldwide.
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Split Hand/Split Foot Malformation
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nord_1148_4
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Related disorders of Split Hand/Split Foot Malformation
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This disorder falls under the category of “ectodermal dysplasia”. Related disorders in this category are characterized by ectrodactyly; the absence of tear ducts; cleft lip and/or palate; and sparse scalp hair, lashes and eyebrows.For more information on these disorders, search for “ectodermal dysplasia” in the Rare Disease Database.
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Related disorders of Split Hand/Split Foot Malformation. This disorder falls under the category of “ectodermal dysplasia”. Related disorders in this category are characterized by ectrodactyly; the absence of tear ducts; cleft lip and/or palate; and sparse scalp hair, lashes and eyebrows.For more information on these disorders, search for “ectodermal dysplasia” in the Rare Disease Database.
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Split Hand/Split Foot Malformation
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nord_1148_5
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Diagnosis of Split Hand/Split Foot Malformation
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SHFM is usually diagnosed by physical features present at birth. The presence of abnormal number of toes and finger dysplasia is usually obvious during initial evaluations. Genetic testing for the genes previously discussed is available to further support the initial diagnosis.
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Diagnosis of Split Hand/Split Foot Malformation. SHFM is usually diagnosed by physical features present at birth. The presence of abnormal number of toes and finger dysplasia is usually obvious during initial evaluations. Genetic testing for the genes previously discussed is available to further support the initial diagnosis.
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Split Hand/Split Foot Malformation
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nord_1148_6
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Therapies of Split Hand/Split Foot Malformation
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Treatment
Reconstructive surgery can be performed to improve function and appearance when applicable. Prosthetics are also available for patients.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Split Hand/Split Foot Malformation. Treatment
Reconstructive surgery can be performed to improve function and appearance when applicable. Prosthetics are also available for patients.Genetic counseling is recommended for affected individuals and their families.
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Split Hand/Split Foot Malformation
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nord_1149_0
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Overview of Spondylocostal Dysplasia
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SummarySpondylocostal dysplasia is a rare genetic disorder characterized by defects of the bones of the spine (vertebrae) and abnormalities of the ribs. Ribs can be fused or missing in chaotic patterns. These malformations are present at birth (congenital). The severity and specific symptoms can vary among affected individuals, even among members of the same family. Some infants may have difficulty breathing because of a reduced size of the thorax. The thorax is the middle portion of the body extending from the neck to the abdomen and including the chest cavity. Sometimes, breathing difficulties can be severe and life-threatening. Most times, spondylocostal dysplasia is inherited in an autosomal recessive manner and is caused by a change (mutation) in one of four genes, DLL3, MESP2, LFNG, HES7. Rarely, spondylocostal dysplasia can be inherited in an autosomal dominant manner. One gene, TBX6, is known to cause autosomal dominant spondylocostal dysplasia. Many individuals do not have a mutation in any of these genes. With treatment, most individuals survive well into adulthood. IntroductionThere is significant confusion in the medical literature regarding names for spondylocostal dysplasia. For years, this disorder and a similar disorder, spondylothoracic dysplasia, were considered the same disorder and referred to as Jarcho-Levin syndrome. Researchers now know that these disorders are separate entities with different causes and associated malformations. The term Jarcho-Levin syndrome is still used for both disorders, and sometimes it is used as an “umbrella” term to describe a broad range of conditions associated with spinal and rib defects. This has led to confusion for individuals and families who receive a diagnosis of Jarcho-Levin syndrome. Some researchers have advocated that Jarcho-Levin syndrome be reserved for people with spondylocostal dysplasia. Other researchers believe the widespread, inconsistent use of Jarcho-Levin syndrome has rendered the term obsolete and that its use should be discontinued. Jarcho and Levin were two doctors who first described what is now known as spondylothoracic dysplasia in the medical literature in 1938.
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Overview of Spondylocostal Dysplasia. SummarySpondylocostal dysplasia is a rare genetic disorder characterized by defects of the bones of the spine (vertebrae) and abnormalities of the ribs. Ribs can be fused or missing in chaotic patterns. These malformations are present at birth (congenital). The severity and specific symptoms can vary among affected individuals, even among members of the same family. Some infants may have difficulty breathing because of a reduced size of the thorax. The thorax is the middle portion of the body extending from the neck to the abdomen and including the chest cavity. Sometimes, breathing difficulties can be severe and life-threatening. Most times, spondylocostal dysplasia is inherited in an autosomal recessive manner and is caused by a change (mutation) in one of four genes, DLL3, MESP2, LFNG, HES7. Rarely, spondylocostal dysplasia can be inherited in an autosomal dominant manner. One gene, TBX6, is known to cause autosomal dominant spondylocostal dysplasia. Many individuals do not have a mutation in any of these genes. With treatment, most individuals survive well into adulthood. IntroductionThere is significant confusion in the medical literature regarding names for spondylocostal dysplasia. For years, this disorder and a similar disorder, spondylothoracic dysplasia, were considered the same disorder and referred to as Jarcho-Levin syndrome. Researchers now know that these disorders are separate entities with different causes and associated malformations. The term Jarcho-Levin syndrome is still used for both disorders, and sometimes it is used as an “umbrella” term to describe a broad range of conditions associated with spinal and rib defects. This has led to confusion for individuals and families who receive a diagnosis of Jarcho-Levin syndrome. Some researchers have advocated that Jarcho-Levin syndrome be reserved for people with spondylocostal dysplasia. Other researchers believe the widespread, inconsistent use of Jarcho-Levin syndrome has rendered the term obsolete and that its use should be discontinued. Jarcho and Levin were two doctors who first described what is now known as spondylothoracic dysplasia in the medical literature in 1938.
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Spondylocostal Dysplasia
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nord_1149_1
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Symptoms of Spondylocostal Dysplasia
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The signs and symptoms of spondylocostal dysplasia can vary greatly from one person to another, even among members of the same family. Affected individuals have abnormalities in the development of the spine and ribs. The bones of the spine (vertebrae) may be fused together or misshapen. Sometimes, they are underdeveloped and wedge-shaped (hemivertebrae). Multiple vertebrae are always affected, usually at least 10 segments in a row (contiguously). The ribs may be fused together, misaligned, broadened, split or forked (bifid), and sometimes some of the ribs are missing. Boys have an increased risk of developing inguinal hernia, a condition characterized by protrusion of parts of the large intestine through an opening in the abdominal wall near the groin. The trunk, which is the part of the body that extends from the neck to the abdomen, may be disproportionately smaller in comparison to their height. In addition, affected individuals may be shorter than would otherwise be expected for their age and gender (short stature). Affected individuals may have a short neck with limited mobility. Some individuals have abnormal sideways curvature of the spine, a condition called scoliosis. Scoliosis is usually mild, but, in rare instances, can be severe. Scoliosis usually does not get worse, but should be carefully followed with spine x-raysBecause of the malformation of the spine and ribs, the lungs of affected individuals may not be able to grow and develop properly. This is known as thoracic insufficiency syndrome. Affected infants and children cannot expand their chests sufficiently with causes reduced lung capacity, which means the lungs can hold less air than they normally would. Consequently, they can have difficulties breathing and experience repeated respiratory infections. Breathing problems are usually mild or moderate, but sometimes can become life-threatening and be fatal. Some children may develop high blood pressure of the pulmonary artery, which is the main artery that delivers blood to the lungs (pulmonary hypertension). Pulmonary hypertension is a chronic and, if not treated, life-threatening complication. Reduced lung capacity also increases the risk of heart failure another life-threatening complication.Despite the potential for serious complications, most individuals with spondylocostal dysplasia live until adulthood. They may experience chronic back pain. Intelligence is usually unaffected, and neurological complications are rare. Researchers are studying spondylocostal dysplasia to determine whether there are any genotype-phenotype correlations. Genotype is the distinct set of genes a person carries. Phenotype refers to the observable characteristics of a person. People with an altered LFNG gene usually have the most severe shortening of the spine. People with an altered HES7 gene have improper separation (malsegmentation) of the bones of the entire spine. People with an altered DLL3 gene usually (but not always) have mild scoliosis that does not require surgical intervention.
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Symptoms of Spondylocostal Dysplasia. The signs and symptoms of spondylocostal dysplasia can vary greatly from one person to another, even among members of the same family. Affected individuals have abnormalities in the development of the spine and ribs. The bones of the spine (vertebrae) may be fused together or misshapen. Sometimes, they are underdeveloped and wedge-shaped (hemivertebrae). Multiple vertebrae are always affected, usually at least 10 segments in a row (contiguously). The ribs may be fused together, misaligned, broadened, split or forked (bifid), and sometimes some of the ribs are missing. Boys have an increased risk of developing inguinal hernia, a condition characterized by protrusion of parts of the large intestine through an opening in the abdominal wall near the groin. The trunk, which is the part of the body that extends from the neck to the abdomen, may be disproportionately smaller in comparison to their height. In addition, affected individuals may be shorter than would otherwise be expected for their age and gender (short stature). Affected individuals may have a short neck with limited mobility. Some individuals have abnormal sideways curvature of the spine, a condition called scoliosis. Scoliosis is usually mild, but, in rare instances, can be severe. Scoliosis usually does not get worse, but should be carefully followed with spine x-raysBecause of the malformation of the spine and ribs, the lungs of affected individuals may not be able to grow and develop properly. This is known as thoracic insufficiency syndrome. Affected infants and children cannot expand their chests sufficiently with causes reduced lung capacity, which means the lungs can hold less air than they normally would. Consequently, they can have difficulties breathing and experience repeated respiratory infections. Breathing problems are usually mild or moderate, but sometimes can become life-threatening and be fatal. Some children may develop high blood pressure of the pulmonary artery, which is the main artery that delivers blood to the lungs (pulmonary hypertension). Pulmonary hypertension is a chronic and, if not treated, life-threatening complication. Reduced lung capacity also increases the risk of heart failure another life-threatening complication.Despite the potential for serious complications, most individuals with spondylocostal dysplasia live until adulthood. They may experience chronic back pain. Intelligence is usually unaffected, and neurological complications are rare. Researchers are studying spondylocostal dysplasia to determine whether there are any genotype-phenotype correlations. Genotype is the distinct set of genes a person carries. Phenotype refers to the observable characteristics of a person. People with an altered LFNG gene usually have the most severe shortening of the spine. People with an altered HES7 gene have improper separation (malsegmentation) of the bones of the entire spine. People with an altered DLL3 gene usually (but not always) have mild scoliosis that does not require surgical intervention.
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Causes of Spondylocostal Dysplasia
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Spondylocostal dysplasia is caused by a change (mutation) in one of at least five different genes, specifically the DLL3, MESP2, LFNG, HES7, and TBX6 genes. An altered DLL3 gene is the most common cause. Many people do not have a mutation in any of these genes, suggesting that as-yet-unidentified genes also cause spondylocostal dysplasia. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.The DLL3, MESP2, LFNG, and HES7 genes are inherited in an autosomal recessive manner. There are reports of the TBX6 gene being inherited in an autosomal dominant as well as in a recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, an autosomal dominant disorder is due to spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. The altered genes that cause spondylocostal dysplasia produce proteins that are involved in the NOTCH signaling pathway. This pathway is a series of chemical reactions that are vital to the health and function of the body, particularly with the development of the spine and ribs. The protein produced by the altered gene is inefficient or defective, or the gene does not produce enough of the protein. Without the protein in question, the normal chemical reactions that occur in the NOTCH signaling pathway are impaired, leading to the signs and symptoms of spondylocostal dysplasia.
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Causes of Spondylocostal Dysplasia. Spondylocostal dysplasia is caused by a change (mutation) in one of at least five different genes, specifically the DLL3, MESP2, LFNG, HES7, and TBX6 genes. An altered DLL3 gene is the most common cause. Many people do not have a mutation in any of these genes, suggesting that as-yet-unidentified genes also cause spondylocostal dysplasia. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.The DLL3, MESP2, LFNG, and HES7 genes are inherited in an autosomal recessive manner. There are reports of the TBX6 gene being inherited in an autosomal dominant as well as in a recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, an autosomal dominant disorder is due to spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. The altered genes that cause spondylocostal dysplasia produce proteins that are involved in the NOTCH signaling pathway. This pathway is a series of chemical reactions that are vital to the health and function of the body, particularly with the development of the spine and ribs. The protein produced by the altered gene is inefficient or defective, or the gene does not produce enough of the protein. Without the protein in question, the normal chemical reactions that occur in the NOTCH signaling pathway are impaired, leading to the signs and symptoms of spondylocostal dysplasia.
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Affects of Spondylocostal Dysplasia
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Spondylocostal dysplasia is a rare disorder. The exact prevalence or incidence of the disorder is unknown. Because it is a rare disorder, some people may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Spondylocostal dysplasia affects both men and women, and is seen in all ethnic groups (panethnic).
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Affects of Spondylocostal Dysplasia. Spondylocostal dysplasia is a rare disorder. The exact prevalence or incidence of the disorder is unknown. Because it is a rare disorder, some people may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Spondylocostal dysplasia affects both men and women, and is seen in all ethnic groups (panethnic).
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Related disorders of Spondylocostal Dysplasia
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Symptoms of the following disorders can be similar to those of spondylocostal dysplasia. Comparisons may be useful for a differential diagnosis.Spondylothoracic dysplasia is a rare disorder in which there are malformations affecting the spine and ribs. These malformations are present at birth (congenital). The bones of the spine called the vertebrae do not develop properly, often fused together in the thoracic spine, and many of the ribs are fused together. On x-ray this gives the thorax a crab-like shape. The thorax is the portion of the body extending from the neck to the abdomen and including the cavity surrounded by the ribs, breastbone and certain vertebrae. Spondylothoracic dysplasia can cause severe breathing (respiratory) problems and infants are at risk of life-threatening respiratory failure. Affected individuals are shorter than would otherwise be expected based on their age and gender (short stature) and have an abnormal curvature to the spine (scoliosis). Many people with spondylothoracic dysplasia have a change (mutation) in the MESP2 gene. (For more information on this disorder, choose “spondylothoracic dysplasia” as your search term in the Rare Disease Database.)There are numerous disorders that have malformations of the spine and ribs, which are similar to those seen in spondylocostal dysplasia. A partial list of these disorders includes Alagille syndrome, camptomelic dysplasia, oculo-auriculo-vertebral spectrum, Klippel-Feil syndrome Robinow syndrome, multiple pterygium syndrome, sirenomelia, and VACTERL syndrome. Casamassima-Morton-Nance syndrome is characterized by the spinal and rib malformations of spondylocostal dysplasia combined with urogenital abnormalities. Urogenital refers to both the urinary and genital organs. (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 Spondylocostal Dysplasia. Symptoms of the following disorders can be similar to those of spondylocostal dysplasia. Comparisons may be useful for a differential diagnosis.Spondylothoracic dysplasia is a rare disorder in which there are malformations affecting the spine and ribs. These malformations are present at birth (congenital). The bones of the spine called the vertebrae do not develop properly, often fused together in the thoracic spine, and many of the ribs are fused together. On x-ray this gives the thorax a crab-like shape. The thorax is the portion of the body extending from the neck to the abdomen and including the cavity surrounded by the ribs, breastbone and certain vertebrae. Spondylothoracic dysplasia can cause severe breathing (respiratory) problems and infants are at risk of life-threatening respiratory failure. Affected individuals are shorter than would otherwise be expected based on their age and gender (short stature) and have an abnormal curvature to the spine (scoliosis). Many people with spondylothoracic dysplasia have a change (mutation) in the MESP2 gene. (For more information on this disorder, choose “spondylothoracic dysplasia” as your search term in the Rare Disease Database.)There are numerous disorders that have malformations of the spine and ribs, which are similar to those seen in spondylocostal dysplasia. A partial list of these disorders includes Alagille syndrome, camptomelic dysplasia, oculo-auriculo-vertebral spectrum, Klippel-Feil syndrome Robinow syndrome, multiple pterygium syndrome, sirenomelia, and VACTERL syndrome. Casamassima-Morton-Nance syndrome is characterized by the spinal and rib malformations of spondylocostal dysplasia combined with urogenital abnormalities. Urogenital refers to both the urinary and genital organs. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Spondylocostal Dysplasia
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A diagnosis of spondylocostal dysplasia is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
X-rays (radiographs) of the spine can show characteristic changes to the spine and ribs that characterized spondylocostal dysplasia. A diagnosis of spondylocostal dysplasia can be confirmed through molecular genetic testing in some individuals. Molecular genetic testing can detect alterations in the specific genes known to cause spondylocostal dysplasia, but is available only as a diagnostic service at specialized laboratories. Also, many people do not have a mutation in any of the genes known to cause this disorder and their diagnosis cannot be confirmed through molecular genetic testing. Prenatal diagnosis of spondylocostal dysplasia is possible by fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can reveal some of the defects associated with spondylocostal dysplasia.
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Diagnosis of Spondylocostal Dysplasia. A diagnosis of spondylocostal dysplasia is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
X-rays (radiographs) of the spine can show characteristic changes to the spine and ribs that characterized spondylocostal dysplasia. A diagnosis of spondylocostal dysplasia can be confirmed through molecular genetic testing in some individuals. Molecular genetic testing can detect alterations in the specific genes known to cause spondylocostal dysplasia, but is available only as a diagnostic service at specialized laboratories. Also, many people do not have a mutation in any of the genes known to cause this disorder and their diagnosis cannot be confirmed through molecular genetic testing. Prenatal diagnosis of spondylocostal dysplasia is possible by fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can reveal some of the defects associated with spondylocostal dysplasia.
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Therapies of Spondylocostal Dysplasia
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Treatment
The treatment of spondylocostal dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic surgeons, specialists who diagnose and assess heart disorders (cardiologists), specialists who diagnose and treat lung disorders (pulmonologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Infants who experience breathing difficulties can require some form of respiratory support. This can include the use of a machine or device to help an infant breath. Some infants may require intensive care, which involves constant monitoring in a hospital. Surgery is used to repair an inguinal hernia. If scoliosis is severe enough, surgery may be required to straighten the spine. Antibiotics may be necessary to treat recurrent respiratory infections. The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. For treatment of spondylocostal dysplasia, ribs are separated and VEPTRs are placed on the concave side of the chest. It is manufactured by DePuy Synthes Spine Co. in Raynham Mass.
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Therapies of Spondylocostal Dysplasia. Treatment
The treatment of spondylocostal dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic surgeons, specialists who diagnose and assess heart disorders (cardiologists), specialists who diagnose and treat lung disorders (pulmonologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Infants who experience breathing difficulties can require some form of respiratory support. This can include the use of a machine or device to help an infant breath. Some infants may require intensive care, which involves constant monitoring in a hospital. Surgery is used to repair an inguinal hernia. If scoliosis is severe enough, surgery may be required to straighten the spine. Antibiotics may be necessary to treat recurrent respiratory infections. The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. For treatment of spondylocostal dysplasia, ribs are separated and VEPTRs are placed on the concave side of the chest. It is manufactured by DePuy Synthes Spine Co. in Raynham Mass.
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Overview of Spondyloepiphyseal Dysplasia Tarda
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SummarySpondyloepiphyseal dysplasia tarda (SEDT; SEDL) is a rare, hereditary skeletal disorder. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk and premature osteoarthritis. It is inherited as an X-linked recessive disorder and typically only males will develop SEDT.Introduction
SEDT commonly refers to the X-linked recessive form of the disorder, although rare autosomal dominant and autosomal recessive “tarda” forms have been described. In the 2023 revision of the Nosology of Genetic Skeletal Disorders, X-linked SEDT is referred to as TRAPPC2-related X-linked spondyloepiphyseal dysplasia tarda and included in the group of conditions called spondyloepi(meta)physeal dysplasias.
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Overview of Spondyloepiphyseal Dysplasia Tarda. SummarySpondyloepiphyseal dysplasia tarda (SEDT; SEDL) is a rare, hereditary skeletal disorder. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk and premature osteoarthritis. It is inherited as an X-linked recessive disorder and typically only males will develop SEDT.Introduction
SEDT commonly refers to the X-linked recessive form of the disorder, although rare autosomal dominant and autosomal recessive “tarda” forms have been described. In the 2023 revision of the Nosology of Genetic Skeletal Disorders, X-linked SEDT is referred to as TRAPPC2-related X-linked spondyloepiphyseal dysplasia tarda and included in the group of conditions called spondyloepi(meta)physeal dysplasias.
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Symptoms of Spondyloepiphyseal Dysplasia Tarda
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Young boys with SEDT do not typically show signs of the condition and have otherwise normal height and body proportions until the age of 6 to 8 years old. Around this time, symptoms of the disorder begin to develop, hence the word “tarda” in SEDT which refers to the later onset of this condition. At ages 6 to 8 years, the following symptoms may be seen: spine growth slows and eventually stops while the arms and legs continue to grow. This results in a disproportionately short trunk (the part of the body containing the chest, stomach and back) as well as height below normal for age (short stature). Arm growth can result in an arm span that exceeds the child’s height by 4 to 8 inches. The chest can become rounded and protrude outwards in a bulging manner (barrel-shaped chest). Around puberty other symptoms may develop, but some of these may develop before puberty. These symptoms include a short neck and skeletal abnormalities of the spine that can cause rounding of the upper back (dorsal kyphosis) or an excessive inward curvature of the lower spine (lumbar hyperlordosis). These skeletal abnormalities can also cause a wearing down of the cartilage at the ends of the bones (osteoarthritis), often seen earliest in the hips but also in the joints of the back, knees, ankles and shoulders. Osteoarthritis can cause discomfort and pain. Where and when osteoarthritis develops varies between boys affected with SEDT.Regarding the face, some boys may have a flatter appearance to their face (midface retrusion), but the head shape is usually normal.By adulthood, men with SEDT tend to have normal sized head, hands and feet and normal limb lengths. However, a barrel-shaped chest, short stature and short trunk are more readily apparent. The final height of adults with SEDT typically ranges from 4’10” to 5’6”. Males with SEDT reach normal motor and cognitive milestones and are expected to have a normal lifespan. While SEDT mostly affects males, rare cases of females with SEDT have been seen though they typically have mild symptoms.
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Symptoms of Spondyloepiphyseal Dysplasia Tarda. Young boys with SEDT do not typically show signs of the condition and have otherwise normal height and body proportions until the age of 6 to 8 years old. Around this time, symptoms of the disorder begin to develop, hence the word “tarda” in SEDT which refers to the later onset of this condition. At ages 6 to 8 years, the following symptoms may be seen: spine growth slows and eventually stops while the arms and legs continue to grow. This results in a disproportionately short trunk (the part of the body containing the chest, stomach and back) as well as height below normal for age (short stature). Arm growth can result in an arm span that exceeds the child’s height by 4 to 8 inches. The chest can become rounded and protrude outwards in a bulging manner (barrel-shaped chest). Around puberty other symptoms may develop, but some of these may develop before puberty. These symptoms include a short neck and skeletal abnormalities of the spine that can cause rounding of the upper back (dorsal kyphosis) or an excessive inward curvature of the lower spine (lumbar hyperlordosis). These skeletal abnormalities can also cause a wearing down of the cartilage at the ends of the bones (osteoarthritis), often seen earliest in the hips but also in the joints of the back, knees, ankles and shoulders. Osteoarthritis can cause discomfort and pain. Where and when osteoarthritis develops varies between boys affected with SEDT.Regarding the face, some boys may have a flatter appearance to their face (midface retrusion), but the head shape is usually normal.By adulthood, men with SEDT tend to have normal sized head, hands and feet and normal limb lengths. However, a barrel-shaped chest, short stature and short trunk are more readily apparent. The final height of adults with SEDT typically ranges from 4’10” to 5’6”. Males with SEDT reach normal motor and cognitive milestones and are expected to have a normal lifespan. While SEDT mostly affects males, rare cases of females with SEDT have been seen though they typically have mild symptoms.
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Causes of Spondyloepiphyseal Dysplasia Tarda
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SEDT is caused by changes (mutations) in a gene on the short arm of the X chromosome at Xp22.2-p22.1. The gene, known as SEDL or TRAPPC2, is widely expressed in tissues throughout the body, but mutations in this gene appear to only affect cartilage. Mutations have been found to be distributed throughout the gene [Gedeon et al., 2001]. The TRAPPC2 gene encodes the instructions for a protein product called sedlin, which is thought to help transport proteins within the cell. There are no other disorders linked to TRAPPC2.Chromosomes, which are present in the nucleus of all cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xp22.2-p22.1” refers to a region between bands 22.1 and 22.2 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.SEDT is inherited in an X-linked recessive pattern. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Spondyloepiphyseal Dysplasia Tarda. SEDT is caused by changes (mutations) in a gene on the short arm of the X chromosome at Xp22.2-p22.1. The gene, known as SEDL or TRAPPC2, is widely expressed in tissues throughout the body, but mutations in this gene appear to only affect cartilage. Mutations have been found to be distributed throughout the gene [Gedeon et al., 2001]. The TRAPPC2 gene encodes the instructions for a protein product called sedlin, which is thought to help transport proteins within the cell. There are no other disorders linked to TRAPPC2.Chromosomes, which are present in the nucleus of all cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xp22.2-p22.1” refers to a region between bands 22.1 and 22.2 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.SEDT is inherited in an X-linked recessive pattern. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Affects of Spondyloepiphyseal Dysplasia Tarda
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SEDT affects individuals of many different ancestral groups. Individuals with SEDT have been reported in European, American, Asian and Australian populations (but not in populations of African ancestry to date). SEDT is estimated to occur in 2 persons per million.
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Affects of Spondyloepiphyseal Dysplasia Tarda. SEDT affects individuals of many different ancestral groups. Individuals with SEDT have been reported in European, American, Asian and Australian populations (but not in populations of African ancestry to date). SEDT is estimated to occur in 2 persons per million.
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Related disorders of Spondyloepiphyseal Dysplasia Tarda
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Symptoms of the following disorders can be similar to those of spondyloepiphyseal dysplasia tarda. Comparisons may be useful for a differential diagnosis.Morquio syndrome (mucopolysaccharidosis IV) is an autosomal recessive metabolic disorder that is usually diagnosed by 18 months of age. Patients have marked disproportionate short stature, clouding of the cornea, hearing loss, enlarged liver and spleen, and excretion of excessive mucopolysaccharides in the urine. Unlike SEDT, this disorder affects males and females equally. (For more information, choose “mucopolysaccharidosis IV” as your search term in the Rare Disease Database.)Autosomal dominant multiple epiphyseal dysplasia (MED) is a disorder with autosomal dominant inheritance and variable severity of symptoms. Unlike SEDT, it affects males and females equally. Symptoms of MED appear between two and five years of age and include a waddling gait and short stature. Individuals with MED may experience pain because of osteoarthritis in the joints. Dysfunction of one of at least five possible genes are responsible for MED. (For more information, choose “dominant multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Progressive pseudorheumatoid dysplasia (PPD or PPAC) is a disorder with autosomal recessive inheritance that is usually diagnosed between three and six years of age. Patients have stiff joints, short stature, abnormal walking pattern and widening of the ends of fingers, toes and other bones. Unlike SEDT, this disorder affects males and females equally.Spondyloepiphyseal dysplasia congenita (SED or SEDC) is a disorder with autosomal dominant inheritance and considerable variability in the severity of symptoms. It is characterized by flat facial profile, marked nearsightedness, short stature, waddling gait, normally sized hands and feet and increased incidence of retinal detachment, cleft palate and clubfoot. Unlike SEDT, this disorder is often diagnosed at birth and affects males and females equally. (For more information, choose “SEDC” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of connective tissue disorders. Mutations in one of at least six possible genes are responsible for Stickler syndrome. Some types of Stickler syndrome have autosomal dominant inheritance and others have autosomal recessive inheritance, depending on what gene is involved. The symptoms of this disorder vary greatly from one individual to another. Most often the eyes, ears, skeleton and joints are affected. Individuals with Stickler syndrome can have nearsightedness, retinal holes and detachments, hearing loss, facial flatness, musculoskeletal problems or other issues. Unlike SEDT, this disorder affects males and females equally. (For more information, choose “Stickler” as your search term in the Rare Disease Database.)
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Related disorders of Spondyloepiphyseal Dysplasia Tarda. Symptoms of the following disorders can be similar to those of spondyloepiphyseal dysplasia tarda. Comparisons may be useful for a differential diagnosis.Morquio syndrome (mucopolysaccharidosis IV) is an autosomal recessive metabolic disorder that is usually diagnosed by 18 months of age. Patients have marked disproportionate short stature, clouding of the cornea, hearing loss, enlarged liver and spleen, and excretion of excessive mucopolysaccharides in the urine. Unlike SEDT, this disorder affects males and females equally. (For more information, choose “mucopolysaccharidosis IV” as your search term in the Rare Disease Database.)Autosomal dominant multiple epiphyseal dysplasia (MED) is a disorder with autosomal dominant inheritance and variable severity of symptoms. Unlike SEDT, it affects males and females equally. Symptoms of MED appear between two and five years of age and include a waddling gait and short stature. Individuals with MED may experience pain because of osteoarthritis in the joints. Dysfunction of one of at least five possible genes are responsible for MED. (For more information, choose “dominant multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Progressive pseudorheumatoid dysplasia (PPD or PPAC) is a disorder with autosomal recessive inheritance that is usually diagnosed between three and six years of age. Patients have stiff joints, short stature, abnormal walking pattern and widening of the ends of fingers, toes and other bones. Unlike SEDT, this disorder affects males and females equally.Spondyloepiphyseal dysplasia congenita (SED or SEDC) is a disorder with autosomal dominant inheritance and considerable variability in the severity of symptoms. It is characterized by flat facial profile, marked nearsightedness, short stature, waddling gait, normally sized hands and feet and increased incidence of retinal detachment, cleft palate and clubfoot. Unlike SEDT, this disorder is often diagnosed at birth and affects males and females equally. (For more information, choose “SEDC” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of connective tissue disorders. Mutations in one of at least six possible genes are responsible for Stickler syndrome. Some types of Stickler syndrome have autosomal dominant inheritance and others have autosomal recessive inheritance, depending on what gene is involved. The symptoms of this disorder vary greatly from one individual to another. Most often the eyes, ears, skeleton and joints are affected. Individuals with Stickler syndrome can have nearsightedness, retinal holes and detachments, hearing loss, facial flatness, musculoskeletal problems or other issues. Unlike SEDT, this disorder affects males and females equally. (For more information, choose “Stickler” as your search term in the Rare Disease Database.)
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Diagnosis of Spondyloepiphyseal Dysplasia Tarda
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A diagnosis of SEDT is usually made through radiological findings (X-ray), but a diagnosis can also be made through molecular genetic testing. In radiological diagnosis of SEDT, X-ray is used to look for characteristic skeletal abnormalities that are usually seen in late childhood but before puberty. These features include abnormal growth at the ends of bones (multiple epiphyseal dysplasia), flattened bones in the spine (platyspondyly), excessive curvature (“humping”) of the upper or lower spine, a sideways curvature of the spine (scoliosis), shortened bones of the thighs and structural deformities in the round ball of the hip bone (coxa vara). By adulthood, some other radiological findings that can lead to a diagnosis of SEDT include an abnormal narrowing of the space between the spinal discs and evidence of early osteoarthritis in the skeletal system, especially in the hip joints. For a molecular diagnosis of SEDT, a genetic test can be used to look for specific mutations in the TRAPPC2 gene that are known or expected to be disease-causing (pathogenic).
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Diagnosis of Spondyloepiphyseal Dysplasia Tarda. A diagnosis of SEDT is usually made through radiological findings (X-ray), but a diagnosis can also be made through molecular genetic testing. In radiological diagnosis of SEDT, X-ray is used to look for characteristic skeletal abnormalities that are usually seen in late childhood but before puberty. These features include abnormal growth at the ends of bones (multiple epiphyseal dysplasia), flattened bones in the spine (platyspondyly), excessive curvature (“humping”) of the upper or lower spine, a sideways curvature of the spine (scoliosis), shortened bones of the thighs and structural deformities in the round ball of the hip bone (coxa vara). By adulthood, some other radiological findings that can lead to a diagnosis of SEDT include an abnormal narrowing of the space between the spinal discs and evidence of early osteoarthritis in the skeletal system, especially in the hip joints. For a molecular diagnosis of SEDT, a genetic test can be used to look for specific mutations in the TRAPPC2 gene that are known or expected to be disease-causing (pathogenic).
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Therapies of Spondyloepiphyseal Dysplasia Tarda
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TreatmentTreatment is supportive and directed towards the specific symptoms that are apparent in each person. Individuals with abnormal sideways curving of the spine (scoliosis) or a rounded, hunched back (kyphoscoliosis) may need to meet with a specialist who can help assess and treat problems of the skeleton and associated muscles and joints (an orthopedic surgeon). In some patients, spine surgery might be recommended to help correct the spine. Some individuals may also need to have hip, knee or shoulder replacement surgeries later in life. Genetic counseling is recommended for affected individuals and their families.
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Therapies of Spondyloepiphyseal Dysplasia Tarda. TreatmentTreatment is supportive and directed towards the specific symptoms that are apparent in each person. Individuals with abnormal sideways curving of the spine (scoliosis) or a rounded, hunched back (kyphoscoliosis) may need to meet with a specialist who can help assess and treat problems of the skeleton and associated muscles and joints (an orthopedic surgeon). In some patients, spine surgery might be recommended to help correct the spine. Some individuals may also need to have hip, knee or shoulder replacement surgeries later in life. Genetic counseling is recommended for affected individuals and their families.
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Overview of Spondyloepiphyseal Dysplasia, Congenital
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SummarySpondyloepiphyseal dysplasia congenita (SEDC) is a rare genetic disorder characterized by deformities that begin before birth (prenatally), including skeletal and joint malformations involving the spine, hips and knees, and abnormalities affecting the eyes. Such growth deformities lead to children being shorter than normally would be expected based upon their age and gender (short stature or dwarfism). Some individuals may develop hearing and vision problems. Additional findings can occur in some cases. Intelligence is unaffected. SEDC is caused by mutations in the type II collagen (COL2A1) gene. The disorder is inherited in an autosomal dominant manner, but most cases occur due to a new (de novo) mutation with no previous family history.IntroductionSpondyloepiphyseal dysplasia is a form of skeletal dysplasia (osteochondrodysplasia), a broad term for a group of disorders characterized by abnormal growth or development of cartilage or bone. SEDC is characterized by distinctive skeletal malformations affecting the long bones of the arms and legs as well as the bones of the spine (vertebrae). Characteristic involvement includes underdevelopment and fragmentation of the bone and cartilage of the epiphyses, which are the rounded ends or “heads” of the long bones, and underdevelopment or malformation of the vertebrae. There are two main forms of spondyloepiphyseal dysplasia, SEDC and spondyloepiphyseal dysplasia tarda (SEDT).
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Overview of Spondyloepiphyseal Dysplasia, Congenital. SummarySpondyloepiphyseal dysplasia congenita (SEDC) is a rare genetic disorder characterized by deformities that begin before birth (prenatally), including skeletal and joint malformations involving the spine, hips and knees, and abnormalities affecting the eyes. Such growth deformities lead to children being shorter than normally would be expected based upon their age and gender (short stature or dwarfism). Some individuals may develop hearing and vision problems. Additional findings can occur in some cases. Intelligence is unaffected. SEDC is caused by mutations in the type II collagen (COL2A1) gene. The disorder is inherited in an autosomal dominant manner, but most cases occur due to a new (de novo) mutation with no previous family history.IntroductionSpondyloepiphyseal dysplasia is a form of skeletal dysplasia (osteochondrodysplasia), a broad term for a group of disorders characterized by abnormal growth or development of cartilage or bone. SEDC is characterized by distinctive skeletal malformations affecting the long bones of the arms and legs as well as the bones of the spine (vertebrae). Characteristic involvement includes underdevelopment and fragmentation of the bone and cartilage of the epiphyses, which are the rounded ends or “heads” of the long bones, and underdevelopment or malformation of the vertebrae. There are two main forms of spondyloepiphyseal dysplasia, SEDC and spondyloepiphyseal dysplasia tarda (SEDT).
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Symptoms of Spondyloepiphyseal Dysplasia, Congenital
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The specific symptoms and severity of spondyloepiphyseal dysplasia congenita can vary greatly from one person to another. Affected individuals may not have all of the symptoms discussed below. In most cases, certain symptoms are noticeable at birth (congenital).Growth deficiency that occurs before birth is a characteristic finding. Growth deficiency continues through childhood and results in disproportionate short stature. Short stature is when a child is below the average height for a person of the same age and gender. Disproportionate means that the arms appear long in relation to the torso. Affected individuals may also have a disproportionately short neck. The head, hands and feet are average-sized. Final adult height usually ranges between 2.8 and 4.2 feet (84-128cm).In most cases, affected individuals have spinal malformations including abnormal forward curvature of the spine (lumbar lordosis) and/or abnormal roundback (kyphosis). Kyphosis may be accompanied by sideways curvature of the spine (scoliosis). Abnormal spinal curvature may worsen with age. Some individuals may have instability of the spine in the neck (cervical vertebrae), which can increase the risk of spinal injury in that area (cervical myelopathy). An individual with a stable cervical spine may develop instability later during life.Stiffness and diminished joint mobility at the knees, elbows, and hips may develop over time. Joint abnormalities may lead to the development of hip deformity in which the thigh bone is angled toward the center of the body (coxa vara) and/or knee deformities, including bow legs (genu varum) and ‘knock knees’ (genu valgum). Individuals with SEDC are more likely to develop pain, inflammation and damage in affected joints at an early age (early-onset osteoarthritis). Dislocation of affect joints (e.g. dislocation of the hips) can also occur.Affected individuals are prone to dislocation of neck bones, back pain, and compression of the sciatic nerve (sciatica), which runs from the lower back, behind the hips and buttocks and down each leg. Sciatica can cause pain, tingling and numbness along the sciatic nerve. A broad, barrel-shaped chest is common. Protrusion of the breastbone (sternum) and ribs may also occur (pectus carinatum). Children are more likely to have clubfeet at birth. Some affected individuals may experience difficulty straightening the arms and legs (limited extension).Affected children may also exhibit diminished muscle tone (hypotonia) and muscle weakness, which, along with the spinal malformations, can result in delays in affected children learning to walk. In some cases, affected children may exhibit an unusual “waddling” manner of walking (abnormal gait).In some cases, affected individuals also have an abnormally flat face, underdevelopment of the cheek bone (malar hypoplasia), and/or incomplete closure of the roof of the mouth (cleft palate). Eye abnormalities can also occur including widely spaced eyes (hypertelorism), progressive nearsightedness (myopia) and, degeneration of the thick transparent substance that fills the center of the eyes (vitreous humor) and of the nerve-rich membrane lining the eye (retina), a condition known as vitreoretinal degeneration. Less often, affected individuals may develop detachment of the retina from the underlying tissue of the eye. Flashing lights or eye “floaters” may be the initial symptoms of retinal detachment. Individuals with severe nearsightedness (“high” myopia) are at a greater risk for retinal detachment than those without high myopia.Children may develop progressive sensorineural hearing loss, in which sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve. Although intelligence is usually unaffected, there may be delay in children attaining certain developmental milestones.Some infants with SEDC may experience breathing difficulties shortly after birth, particularly if they have an underdeveloped or extremely small rib cage. Breathing difficulties usually decrease as an infant grows older. In certain cases, abnormal curvature of the spine and an abnormally developed chest can lead to breathing difficulties by preventing the lungs to fully fill with air (restrictive lung disease). This can lead to chronic breathing issues, sleep apnea, chronic respiratory infections, and potentially heart failure in middle age. Prompt and appropriate treatment can reduce this risk.
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Symptoms of Spondyloepiphyseal Dysplasia, Congenital. The specific symptoms and severity of spondyloepiphyseal dysplasia congenita can vary greatly from one person to another. Affected individuals may not have all of the symptoms discussed below. In most cases, certain symptoms are noticeable at birth (congenital).Growth deficiency that occurs before birth is a characteristic finding. Growth deficiency continues through childhood and results in disproportionate short stature. Short stature is when a child is below the average height for a person of the same age and gender. Disproportionate means that the arms appear long in relation to the torso. Affected individuals may also have a disproportionately short neck. The head, hands and feet are average-sized. Final adult height usually ranges between 2.8 and 4.2 feet (84-128cm).In most cases, affected individuals have spinal malformations including abnormal forward curvature of the spine (lumbar lordosis) and/or abnormal roundback (kyphosis). Kyphosis may be accompanied by sideways curvature of the spine (scoliosis). Abnormal spinal curvature may worsen with age. Some individuals may have instability of the spine in the neck (cervical vertebrae), which can increase the risk of spinal injury in that area (cervical myelopathy). An individual with a stable cervical spine may develop instability later during life.Stiffness and diminished joint mobility at the knees, elbows, and hips may develop over time. Joint abnormalities may lead to the development of hip deformity in which the thigh bone is angled toward the center of the body (coxa vara) and/or knee deformities, including bow legs (genu varum) and ‘knock knees’ (genu valgum). Individuals with SEDC are more likely to develop pain, inflammation and damage in affected joints at an early age (early-onset osteoarthritis). Dislocation of affect joints (e.g. dislocation of the hips) can also occur.Affected individuals are prone to dislocation of neck bones, back pain, and compression of the sciatic nerve (sciatica), which runs from the lower back, behind the hips and buttocks and down each leg. Sciatica can cause pain, tingling and numbness along the sciatic nerve. A broad, barrel-shaped chest is common. Protrusion of the breastbone (sternum) and ribs may also occur (pectus carinatum). Children are more likely to have clubfeet at birth. Some affected individuals may experience difficulty straightening the arms and legs (limited extension).Affected children may also exhibit diminished muscle tone (hypotonia) and muscle weakness, which, along with the spinal malformations, can result in delays in affected children learning to walk. In some cases, affected children may exhibit an unusual “waddling” manner of walking (abnormal gait).In some cases, affected individuals also have an abnormally flat face, underdevelopment of the cheek bone (malar hypoplasia), and/or incomplete closure of the roof of the mouth (cleft palate). Eye abnormalities can also occur including widely spaced eyes (hypertelorism), progressive nearsightedness (myopia) and, degeneration of the thick transparent substance that fills the center of the eyes (vitreous humor) and of the nerve-rich membrane lining the eye (retina), a condition known as vitreoretinal degeneration. Less often, affected individuals may develop detachment of the retina from the underlying tissue of the eye. Flashing lights or eye “floaters” may be the initial symptoms of retinal detachment. Individuals with severe nearsightedness (“high” myopia) are at a greater risk for retinal detachment than those without high myopia.Children may develop progressive sensorineural hearing loss, in which sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve. Although intelligence is usually unaffected, there may be delay in children attaining certain developmental milestones.Some infants with SEDC may experience breathing difficulties shortly after birth, particularly if they have an underdeveloped or extremely small rib cage. Breathing difficulties usually decrease as an infant grows older. In certain cases, abnormal curvature of the spine and an abnormally developed chest can lead to breathing difficulties by preventing the lungs to fully fill with air (restrictive lung disease). This can lead to chronic breathing issues, sleep apnea, chronic respiratory infections, and potentially heart failure in middle age. Prompt and appropriate treatment can reduce this risk.
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Causes of Spondyloepiphyseal Dysplasia, Congenital
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Spondyloepiphyseal dysplasia congenital is caused by a mutation in the COL2A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
SEDC can occur as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The mutation is then inherited as an autosomal dominant trait (i.e. is transmitted from either an affected mother or father to their child).
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent (autosomal), 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.
Investigators have determined that the COL2A1 gene is located on the long arm (q) of chromosome 12 (12q13.11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.The COL2A1 contains instructions for creating (encoding) type II collagen. Collagen is one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength. There are many different types of collagen, which are indicated by Roman numerals. Type II collagen is most prevalent in cartilage and the jelly-like fluid that fills the center of the eyes (vitreous humor). Collagen is also found in bone. Mutations to the COL2A1 gene result in diminished levels of functional type II collagen. Changes in the composition of this collagen ultimately lead to abnormal skeletal growth in SEDC and related disorders.
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Causes of Spondyloepiphyseal Dysplasia, Congenital. Spondyloepiphyseal dysplasia congenital is caused by a mutation in the COL2A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
SEDC can occur as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The mutation is then inherited as an autosomal dominant trait (i.e. is transmitted from either an affected mother or father to their child).
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent (autosomal), 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.
Investigators have determined that the COL2A1 gene is located on the long arm (q) of chromosome 12 (12q13.11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.The COL2A1 contains instructions for creating (encoding) type II collagen. Collagen is one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength. There are many different types of collagen, which are indicated by Roman numerals. Type II collagen is most prevalent in cartilage and the jelly-like fluid that fills the center of the eyes (vitreous humor). Collagen is also found in bone. Mutations to the COL2A1 gene result in diminished levels of functional type II collagen. Changes in the composition of this collagen ultimately lead to abnormal skeletal growth in SEDC and related disorders.
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Affects of Spondyloepiphyseal Dysplasia, Congenital
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Males and females are affected in equal numbers. The exact incidence or prevalence is unknown, but spondyloepiphyseal dysplasia congenita is estimated to occur in approximately 1 in 100,000 live births. Collectively, the skeletal dysplasias are estimated to occur in approximately 1 in 5,000 individuals in the general population.
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Affects of Spondyloepiphyseal Dysplasia, Congenital. Males and females are affected in equal numbers. The exact incidence or prevalence is unknown, but spondyloepiphyseal dysplasia congenita is estimated to occur in approximately 1 in 100,000 live births. Collectively, the skeletal dysplasias are estimated to occur in approximately 1 in 5,000 individuals in the general population.
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Related disorders of Spondyloepiphyseal Dysplasia, Congenital
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Symptoms of the following disorders can be similar to those of spondyloepiphyseal dysplasia congenita. Comparisons may be useful for a differential diagnosis.Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others may or may not cause life-threatening complications. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities may be present depending upon the specific disorder. There are approximately 500 types of recognized skeletal dysplasias with more than 300 causative genes. Several dysplasias are not yet recognized or their responsible genes are not yet discovered.There are several disorders that occur due to a mutation in the same gene that causes SEDC. These are known as allelic disorders and are caused by a different mutation in the COL2A1 gene. These disorders often share several, overlapping symptoms with one another. These disorders are inherited in an autosomal dominant manner and include Kniest dysplasia, Stickler syndrome type I, achondrogenesis type II, otospondylomegaepiphyseal dysplasia (OSMED), spondyloperipheral dysplasia, and spondyloepimetaphyseal dysplasia, Strudwick type. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Spondyloepiphyseal dysplasia tarda (SEDT; SEDL) is a rare, hereditary skeletal disorder that primarily affects males. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk, and premature osteoarthritis. Symptoms of SEDT are usually not apparent until six to eight years of age, hence the distinction “tarda” or “late.” SEDT is caused by a mutation in the TRAPPC2 (or SEDL) gene and is inherited as an X-linked recessive genetic trait. (For more information on this disorder, choose “spondyloepiphyseal dysplasia tarda” as your search term in the Rare Disease Database.)Multiple epiphyseal dysplasia is a broad term for a group of disorders characterized by abnormal development of the bone and cartilage of the epiphyses. There are at least six disorders that are separated by the underlying genetic mutation that causes each subtype. Most subtypes are inherited in an autosomal dominant manner. One form is inherited in an autosomal recessive manner. These disorders are characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. Joint pain, particularly of the hips or knees, is also common and often develops during childhood. Initial signs may include pain in the hips and knees. Clubfoot and cleft palate may occur in recessive multiple epiphyseal dysplasia. (For more information on this disorder, choose “multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) is a mucopolysaccharide storage disease that exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzymes N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively. 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 curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses), and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or additional abnormalities may also occur. Morquio syndrome is inherited in an autosomal recessive trait and is due to a mutation in either the GALNS gene (type A) or the GLB1 gene (type B). (For more information on this disorder, choose “morquio” as your search term in the Rare Disease Database.)
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Related disorders of Spondyloepiphyseal Dysplasia, Congenital. Symptoms of the following disorders can be similar to those of spondyloepiphyseal dysplasia congenita. Comparisons may be useful for a differential diagnosis.Skeletal dysplasias (osteochondrodysplasias) are a general term for a group of disorders characterized by abnormal growth or development or cartilage and bone. Some forms cause life-threatening complications shortly after birth, while others may or may not cause life-threatening complications. Skeletal dysplasias can be associated with short-limbed short stature or with more proportional shortening of the trunk and limbs. Various additional abnormalities may be present depending upon the specific disorder. There are approximately 500 types of recognized skeletal dysplasias with more than 300 causative genes. Several dysplasias are not yet recognized or their responsible genes are not yet discovered.There are several disorders that occur due to a mutation in the same gene that causes SEDC. These are known as allelic disorders and are caused by a different mutation in the COL2A1 gene. These disorders often share several, overlapping symptoms with one another. These disorders are inherited in an autosomal dominant manner and include Kniest dysplasia, Stickler syndrome type I, achondrogenesis type II, otospondylomegaepiphyseal dysplasia (OSMED), spondyloperipheral dysplasia, and spondyloepimetaphyseal dysplasia, Strudwick type. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Spondyloepiphyseal dysplasia tarda (SEDT; SEDL) is a rare, hereditary skeletal disorder that primarily affects males. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk, and premature osteoarthritis. Symptoms of SEDT are usually not apparent until six to eight years of age, hence the distinction “tarda” or “late.” SEDT is caused by a mutation in the TRAPPC2 (or SEDL) gene and is inherited as an X-linked recessive genetic trait. (For more information on this disorder, choose “spondyloepiphyseal dysplasia tarda” as your search term in the Rare Disease Database.)Multiple epiphyseal dysplasia is a broad term for a group of disorders characterized by abnormal development of the bone and cartilage of the epiphyses. There are at least six disorders that are separated by the underlying genetic mutation that causes each subtype. Most subtypes are inherited in an autosomal dominant manner. One form is inherited in an autosomal recessive manner. These disorders are characterized by skeletal malformations (dysplasia) including those affecting bones of the hands, feet, and knees. Joint pain, particularly of the hips or knees, is also common and often develops during childhood. Initial signs may include pain in the hips and knees. Clubfoot and cleft palate may occur in recessive multiple epiphyseal dysplasia. (For more information on this disorder, choose “multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) is a mucopolysaccharide storage disease that exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzymes N-acetyl-galactosamine-6-sulfatase and beta-galactosidase, respectively. 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 curvature of the spine (kyphoscoliosis), abnormal development of the growing ends of the long bones (epiphyses), and/or a prominent breast bone (pectus carinatum). Hearing loss, weakness of the legs, and/or additional abnormalities may also occur. Morquio syndrome is inherited in an autosomal recessive trait and is due to a mutation in either the GALNS gene (type A) or the GLB1 gene (type B). (For more information on this disorder, choose “morquio” as your search term in the Rare Disease Database.)
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Diagnosis of Spondyloepiphyseal Dysplasia, Congenital
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A diagnosis of spondyloepiphyseal dysplasia congenita is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected at birth because of characteristic findings.Clinical Testing and Workup
Basic x-rays (radiography) can be used to provide a thorough, careful examination of the entire bone system (complete skeletal survey) in order to detect changes in the skeleton that are characteristic of SEDC.More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used to assess skeletal health, particularly prior to surgery to correct skeletal malformations. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the gene known to cause of SEDC, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Spondyloepiphyseal Dysplasia, Congenital. A diagnosis of spondyloepiphyseal dysplasia congenita is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected at birth because of characteristic findings.Clinical Testing and Workup
Basic x-rays (radiography) can be used to provide a thorough, careful examination of the entire bone system (complete skeletal survey) in order to detect changes in the skeleton that are characteristic of SEDC.More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used to assess skeletal health, particularly prior to surgery to correct skeletal malformations. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the gene known to cause of SEDC, but is available only as a diagnostic service at specialized laboratories.
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Therapies of Spondyloepiphyseal Dysplasia, Congenital
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Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating musculoskeletal disorders (orthopedic surgeons), specialists in diagnosing and treating eye disorders (ophthalmologists), rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Specific therapies are symptomatic and supportive. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate prevention or corrective treatment of breathing (respiratory) difficulties. Regular eye (ophthalmologic) exams are required to detect and assess nearsightedness and to prevent retinal detachment. Retinal detachment can be repaired surgically. Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), can be beneficial.In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgery or bracing may be able to treat abnormal curvature of the spine. Surgical procedures may be recommended to correct other abnormalities of the spine and knee as well as to close a cleft palate. Clubfoot may also be treated with splinting or surgery.In children with cervical instability, spinal fusion surgery or the implanting of a rod to stabilize the spine may be necessary. This rod known as a ‘growing rod’ treats spinal deformity in a child, but allows for the continued and controlled growth of the spine.Specific physical findings associated with SEDC, specifically a short neck, cervical spine instability, reduced lung capacity, and small airways, can complicate the use of anesthesia. Affected individuals need to be evaluated before undergoing procedures that require anesthesia.Affected individuals should avoid activities that can cause trauma to the head or neck such as contact sports. SEDC while causing physical issues does not usually reduce life expectancy. Intelligence is usually unaffected and most individuals raise families and lead productive, active and full lives.
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Therapies of Spondyloepiphyseal Dysplasia, Congenital. Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating musculoskeletal disorders (orthopedic surgeons), specialists in diagnosing and treating eye disorders (ophthalmologists), rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Specific therapies are symptomatic and supportive. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate prevention or corrective treatment of breathing (respiratory) difficulties. Regular eye (ophthalmologic) exams are required to detect and assess nearsightedness and to prevent retinal detachment. Retinal detachment can be repaired surgically. Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), can be beneficial.In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgery or bracing may be able to treat abnormal curvature of the spine. Surgical procedures may be recommended to correct other abnormalities of the spine and knee as well as to close a cleft palate. Clubfoot may also be treated with splinting or surgery.In children with cervical instability, spinal fusion surgery or the implanting of a rod to stabilize the spine may be necessary. This rod known as a ‘growing rod’ treats spinal deformity in a child, but allows for the continued and controlled growth of the spine.Specific physical findings associated with SEDC, specifically a short neck, cervical spine instability, reduced lung capacity, and small airways, can complicate the use of anesthesia. Affected individuals need to be evaluated before undergoing procedures that require anesthesia.Affected individuals should avoid activities that can cause trauma to the head or neck such as contact sports. SEDC while causing physical issues does not usually reduce life expectancy. Intelligence is usually unaffected and most individuals raise families and lead productive, active and full lives.
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Overview of Spondyloepiphyseal Dysplasia, Kondo-Fu Type
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SummarySpondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF) is a rare genetic skeletal disorder caused by changes (mutations) in a gene named membrane bound transcription factor peptidase, site 1 (MBTPS1). MBTPS1 contains the information for the body to make a protein called site-1 protease (S1P), which is considered a master regulator of various cellular functions. Affected individuals have low birth weight and their growth milestones are delayed. Abnormal bone development progresses through childhood which results in short stature, curvature of the spine and characteristic facial features. Common non-skeletal symptoms include early onset of cataracts, inguinal hernia and feeding difficulties in early childhood. The skeletal abnormalities of SEDKF overlap with some other rare bone diseases. Normal intelligence and an increased level of lysosomal enzymes in the blood can differentiate SEDKF from similar bone diseases. However, the final diagnosis should be based on genetic testing demonstrating mutations in the MBTPS1 gene. There are currently no therapies that target the cause of SEDKF. Patients can be managed with symptomatic and supportive treatment. Please note that SEDKF was only recently discovered and only a few patients have been identified so far. Thus, the symptoms described here are based on limited information, and understanding of this disease is still evolving.IntroductionThe first child with a MBTPS1 gene mutation was reported in 2018 by a group of doctors and scientists in Oklahoma, US. This patient showed signs of spondyloepiphyseal dysplasia (SED, conditions that primarily affect the development of bones in the spine and the ends of long bones in legs and arms). Thus, the disease was named SED, Kondo-Fu type, after Drs. Yuji Kondo and Jianxin Fu, two scientists who authored the published report. Since then, a total of seven patients with SEDFK have been identified in the US, Brazil and Germany.
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Overview of Spondyloepiphyseal Dysplasia, Kondo-Fu Type. SummarySpondyloepiphyseal dysplasia, Kondo-Fu type (SEDKF) is a rare genetic skeletal disorder caused by changes (mutations) in a gene named membrane bound transcription factor peptidase, site 1 (MBTPS1). MBTPS1 contains the information for the body to make a protein called site-1 protease (S1P), which is considered a master regulator of various cellular functions. Affected individuals have low birth weight and their growth milestones are delayed. Abnormal bone development progresses through childhood which results in short stature, curvature of the spine and characteristic facial features. Common non-skeletal symptoms include early onset of cataracts, inguinal hernia and feeding difficulties in early childhood. The skeletal abnormalities of SEDKF overlap with some other rare bone diseases. Normal intelligence and an increased level of lysosomal enzymes in the blood can differentiate SEDKF from similar bone diseases. However, the final diagnosis should be based on genetic testing demonstrating mutations in the MBTPS1 gene. There are currently no therapies that target the cause of SEDKF. Patients can be managed with symptomatic and supportive treatment. Please note that SEDKF was only recently discovered and only a few patients have been identified so far. Thus, the symptoms described here are based on limited information, and understanding of this disease is still evolving.IntroductionThe first child with a MBTPS1 gene mutation was reported in 2018 by a group of doctors and scientists in Oklahoma, US. This patient showed signs of spondyloepiphyseal dysplasia (SED, conditions that primarily affect the development of bones in the spine and the ends of long bones in legs and arms). Thus, the disease was named SED, Kondo-Fu type, after Drs. Yuji Kondo and Jianxin Fu, two scientists who authored the published report. Since then, a total of seven patients with SEDFK have been identified in the US, Brazil and Germany.
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Symptoms of Spondyloepiphyseal Dysplasia, Kondo-Fu Type
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The specific symptoms and severity of SEDKF can vary from one person to another, possibly depending on where the change happens in the MBTPS1 gene. In addition, affected individuals may not have all possible symptoms discussed here. Some common manifestations are delayed growth, short stature, curvature of the spine, dysmorphic face, early onset of cataracts, bilateral inguinal hernia and gastrointestinal problems. Please note that prior to 2021, only eight patients had been identified as having mutations in MBTPS1. Thus, the relative frequency of the described symptoms is based on a small number of patients.Patients can be born at full term but with relatively low birth weight. Delayed growth and gross motor milestones are noticeable soon after birth, and deformity of spine and face progress through childhood. Patients exhibit short stature with curvature of the spine, bulging of chest (pectus carinatum) and characteristic dysmorphic facial features including prominent forehead, prominent cheekbones, small lower jaw which is set further back than the upper jaw (retromicrognathia) and large ears. Due to weak bones and, in some cases, low muscle tone, patients may complain of back pain and fatigue, and display waddling gait. Some uncommon musculoskeletal changes have been recorded, including funnel chest, outward turning of the heel or inversion of the foot (pes valgus), expanded gap between the great toe and the rest of the toes (sandal grooves), joint hypermobility and hip joint inflammation.Some patients experience digestive system problems and have difficulties in nutrition absorption. They require feeding support for survival in early childhood and suffer from chronic constipation.Patients usually have normal speech, hearing and intelligence. Some relatively rare symptoms include seizures, temporary vision loss caused by reduced blood flow in the eye (ocular migraines), ovarian cysts, mild bluish coloration of the whites of the eyes (blue sclerae), reduced sweating, dry skin, skin follicular papules, brittle hair and hair loss.
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Symptoms of Spondyloepiphyseal Dysplasia, Kondo-Fu Type. The specific symptoms and severity of SEDKF can vary from one person to another, possibly depending on where the change happens in the MBTPS1 gene. In addition, affected individuals may not have all possible symptoms discussed here. Some common manifestations are delayed growth, short stature, curvature of the spine, dysmorphic face, early onset of cataracts, bilateral inguinal hernia and gastrointestinal problems. Please note that prior to 2021, only eight patients had been identified as having mutations in MBTPS1. Thus, the relative frequency of the described symptoms is based on a small number of patients.Patients can be born at full term but with relatively low birth weight. Delayed growth and gross motor milestones are noticeable soon after birth, and deformity of spine and face progress through childhood. Patients exhibit short stature with curvature of the spine, bulging of chest (pectus carinatum) and characteristic dysmorphic facial features including prominent forehead, prominent cheekbones, small lower jaw which is set further back than the upper jaw (retromicrognathia) and large ears. Due to weak bones and, in some cases, low muscle tone, patients may complain of back pain and fatigue, and display waddling gait. Some uncommon musculoskeletal changes have been recorded, including funnel chest, outward turning of the heel or inversion of the foot (pes valgus), expanded gap between the great toe and the rest of the toes (sandal grooves), joint hypermobility and hip joint inflammation.Some patients experience digestive system problems and have difficulties in nutrition absorption. They require feeding support for survival in early childhood and suffer from chronic constipation.Patients usually have normal speech, hearing and intelligence. Some relatively rare symptoms include seizures, temporary vision loss caused by reduced blood flow in the eye (ocular migraines), ovarian cysts, mild bluish coloration of the whites of the eyes (blue sclerae), reduced sweating, dry skin, skin follicular papules, brittle hair and hair loss.
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Causes of Spondyloepiphyseal Dysplasia, Kondo-Fu Type
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SEDKF is inherited as an autosomal recessive genetic disorder, which means that an affected individual, either male or female, receives one altered MBTPS1 gene from the mother and one from the father. Changes in the MBTPS1 gene result in an abnormal level or dysfunction of S1P, which is required for various functions in the body, and, of those, the three primary ones are: intracellular transportation of large molecules such as collagen II (major component of cartilage); lipid metabolism such as cholesterol production and uptake; and targeting lysosomal enzymes to lysosomes, an organelle inside the cell where the enzymes digest complex molecules. Defects in S1P cause problems in the three functions, and for most patients, these are more so in bone development and less so in the other two.Cartilage is a connective tissue found in areas such as joints between bones, ends of the ribs and between the vertebrae in the spine. In babies, cartilage is more widespread and is gradually replaced with bones during normal development. Collagen II is the major component of cartilage which is made and released to the cartilage by chondrocytes, the major cells in cartilage. Collagen II is a very large molecule, and defects in S1P hinder its transportation inside the cells. When collagen II is abnormally accumulated in chondrocytes, cartilage lacks collagen, and sick chondrocytes die, leading to abnormal bone development and delayed body growth.S1P is involved in the regulation of a protein that adds a unique tag, mannose-6-phosphate (M6P), to lysosomal enzymes so that these enzymes can be recognized and delivered to the lysosomes. Without this tag, some of these enzymes will end up outside of the cells. Therefore, a higher than normal level of lysosomal enzymes is detected in the blood of SEDKF patients. Extracellular lysosomal enzymes in cartilage further weaken the bone by breaking down bone material.Because S1P affects many proteins that play various roles not just in chondrocytes, SEDKF patients also exhibit non-skeletal symptoms, which could vary depending on which part of the MBTPS1 gene is changed. Correlation between the MBTPS1 mutations and the diverse symptoms are under investigation.
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Causes of Spondyloepiphyseal Dysplasia, Kondo-Fu Type. SEDKF is inherited as an autosomal recessive genetic disorder, which means that an affected individual, either male or female, receives one altered MBTPS1 gene from the mother and one from the father. Changes in the MBTPS1 gene result in an abnormal level or dysfunction of S1P, which is required for various functions in the body, and, of those, the three primary ones are: intracellular transportation of large molecules such as collagen II (major component of cartilage); lipid metabolism such as cholesterol production and uptake; and targeting lysosomal enzymes to lysosomes, an organelle inside the cell where the enzymes digest complex molecules. Defects in S1P cause problems in the three functions, and for most patients, these are more so in bone development and less so in the other two.Cartilage is a connective tissue found in areas such as joints between bones, ends of the ribs and between the vertebrae in the spine. In babies, cartilage is more widespread and is gradually replaced with bones during normal development. Collagen II is the major component of cartilage which is made and released to the cartilage by chondrocytes, the major cells in cartilage. Collagen II is a very large molecule, and defects in S1P hinder its transportation inside the cells. When collagen II is abnormally accumulated in chondrocytes, cartilage lacks collagen, and sick chondrocytes die, leading to abnormal bone development and delayed body growth.S1P is involved in the regulation of a protein that adds a unique tag, mannose-6-phosphate (M6P), to lysosomal enzymes so that these enzymes can be recognized and delivered to the lysosomes. Without this tag, some of these enzymes will end up outside of the cells. Therefore, a higher than normal level of lysosomal enzymes is detected in the blood of SEDKF patients. Extracellular lysosomal enzymes in cartilage further weaken the bone by breaking down bone material.Because S1P affects many proteins that play various roles not just in chondrocytes, SEDKF patients also exhibit non-skeletal symptoms, which could vary depending on which part of the MBTPS1 gene is changed. Correlation between the MBTPS1 mutations and the diverse symptoms are under investigation.
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Affects of Spondyloepiphyseal Dysplasia, Kondo-Fu Type
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Affects of Spondyloepiphyseal Dysplasia, Kondo-Fu Type.
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Related disorders of Spondyloepiphyseal Dysplasia, Kondo-Fu Type
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Spondyloepiphyseal Dysplasia, CongenitalSpondyloepiphyseal dysplasia congenita (SEDC) is a rare genetic disorder characterized by deformities that begin before birth (prenatally), including skeletal and joint malformations involving the spine, hips and knees and abnormalities affecting the eyes. These growth deformities lead to children being shorter than normally would be expected based upon their age and gender. Some individuals may develop hearing and vision problems. Additional findings can occur in some patients. Intelligence is unaffected. SEDC is caused by mutations in the type II collagen (COL2A1) gene. The disorder is inherited in an autosomal dominant manner, but most cases occur due to a new (de novo) mutation with no previous family history. (For more information on this disorder, choose “spondyloepiphyseal dysplasia, congenital” as your search term in the Rare Disease Database.)Silver-Russell Syndrome (SRS)These patients usually have low birth weight, relatively large head size at birth, struggle to gain weight during early childhood due to feeding difficulties and share some overlapping facial features with SEDKF such as large ears and prominent forehead. They display skeletal asymmetry, may have minor hand and/or foot anomalies and their motor development skills may be delayed due to low muscle tone. However, unlike SEDKF, delay in speech development is common. About 60% of clinically diagnosed SRS patients have genetic abnormalities in chromosome 7 or 11, yet the underlying cause of the remaining 40% is still unknown. With the discovery of SEDKF, future targeted genetic testing of the MBTPS1 gene for patients with a clinical presentation of SRS is in discussion. (For more information on this disorder, choose “Silver-Russell syndrome” as your search term in the Rare Disease Database.)Mucolipidosis II/IIIMucolipidosis II and III are autosomal recessive lysosomal storage disorders caused by abnormal GlcNAc-1-phosphotransferase. The deficiency of this protein disrupts the addition of the M6P tag to lysosomal enzymes for their delivery to lysosomes. If these enzymes cannot be delivered to the right place, they won’t be able to do their job of breaking down molecules such as complex lipids and carbohydrates inside the lysosomes. As a result, these molecules build up within the cells of many tissues of the body and causing problems in critical cellular functions. Mucolipidosis II is caused by mutations in the GNPTAB gene which provides instructions for making the α- and β-subunits of the GlcNAc-1-phosphotransferase. In these patients, the GlcNAc-1-phosphotransferase is completely nonfunctional leading to severe clinical symptoms. Affected individuals have bone abnormalities at birth, coarse facial features, weak muscle tone, hernia, delayed speech and motor skill development, hearing impairment and cardiac valvular defects. Unlike SEDKF, patients with mucolipidosis II have severe intellectual disability, and many die during early childhood. Patients have a high level of lysosomal enzymes in their blood with very low activity of GlcNAc-1-phosphotransferase. A characteristic finding is abnormal vacuolization or inclusion bodies that appear in certain types of cells of the patients; thus, mucolipidosis II is also called I-Cell disease. In comparison, inclusion bodies were not detected in patients with SEDKF. Mucolipidosis III, previously known as pseudo-Hurler polydystrophy, is caused by mutations either in the GNPTAB gene (MLIII alpha/beta) or the GNPTG gene which provides instructions for making the γ-subunits of the GlcNAc-1-phosphotransferase (MLIII gamma). In these patients, the GlcNAc-1-phosphotransferase is partially functional, and therefore, their symptoms are milder compared with mucolipidosis II patients. Affected individuals have a late onset with symptoms appearing between 2 to 4 years of age. Joint stiffness, carpal tunnel syndrome, pain in hips, shoulders, hands, and/or ankles, waddling gait, as well as spinal deformities are common features of MLIII. However, coarse facial features, growth delays and heart problems are often absent or mild. Biochemical analysis shows defects in M6P modification of proteins, which is not seen in SEDKF patients. (For more information on this disorder, choose “I cell Disease” and “pseudo-Hurler polydystrophy” as your search terms in the Rare Disease Database.)
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Related disorders of Spondyloepiphyseal Dysplasia, Kondo-Fu Type. Spondyloepiphyseal Dysplasia, CongenitalSpondyloepiphyseal dysplasia congenita (SEDC) is a rare genetic disorder characterized by deformities that begin before birth (prenatally), including skeletal and joint malformations involving the spine, hips and knees and abnormalities affecting the eyes. These growth deformities lead to children being shorter than normally would be expected based upon their age and gender. Some individuals may develop hearing and vision problems. Additional findings can occur in some patients. Intelligence is unaffected. SEDC is caused by mutations in the type II collagen (COL2A1) gene. The disorder is inherited in an autosomal dominant manner, but most cases occur due to a new (de novo) mutation with no previous family history. (For more information on this disorder, choose “spondyloepiphyseal dysplasia, congenital” as your search term in the Rare Disease Database.)Silver-Russell Syndrome (SRS)These patients usually have low birth weight, relatively large head size at birth, struggle to gain weight during early childhood due to feeding difficulties and share some overlapping facial features with SEDKF such as large ears and prominent forehead. They display skeletal asymmetry, may have minor hand and/or foot anomalies and their motor development skills may be delayed due to low muscle tone. However, unlike SEDKF, delay in speech development is common. About 60% of clinically diagnosed SRS patients have genetic abnormalities in chromosome 7 or 11, yet the underlying cause of the remaining 40% is still unknown. With the discovery of SEDKF, future targeted genetic testing of the MBTPS1 gene for patients with a clinical presentation of SRS is in discussion. (For more information on this disorder, choose “Silver-Russell syndrome” as your search term in the Rare Disease Database.)Mucolipidosis II/IIIMucolipidosis II and III are autosomal recessive lysosomal storage disorders caused by abnormal GlcNAc-1-phosphotransferase. The deficiency of this protein disrupts the addition of the M6P tag to lysosomal enzymes for their delivery to lysosomes. If these enzymes cannot be delivered to the right place, they won’t be able to do their job of breaking down molecules such as complex lipids and carbohydrates inside the lysosomes. As a result, these molecules build up within the cells of many tissues of the body and causing problems in critical cellular functions. Mucolipidosis II is caused by mutations in the GNPTAB gene which provides instructions for making the α- and β-subunits of the GlcNAc-1-phosphotransferase. In these patients, the GlcNAc-1-phosphotransferase is completely nonfunctional leading to severe clinical symptoms. Affected individuals have bone abnormalities at birth, coarse facial features, weak muscle tone, hernia, delayed speech and motor skill development, hearing impairment and cardiac valvular defects. Unlike SEDKF, patients with mucolipidosis II have severe intellectual disability, and many die during early childhood. Patients have a high level of lysosomal enzymes in their blood with very low activity of GlcNAc-1-phosphotransferase. A characteristic finding is abnormal vacuolization or inclusion bodies that appear in certain types of cells of the patients; thus, mucolipidosis II is also called I-Cell disease. In comparison, inclusion bodies were not detected in patients with SEDKF. Mucolipidosis III, previously known as pseudo-Hurler polydystrophy, is caused by mutations either in the GNPTAB gene (MLIII alpha/beta) or the GNPTG gene which provides instructions for making the γ-subunits of the GlcNAc-1-phosphotransferase (MLIII gamma). In these patients, the GlcNAc-1-phosphotransferase is partially functional, and therefore, their symptoms are milder compared with mucolipidosis II patients. Affected individuals have a late onset with symptoms appearing between 2 to 4 years of age. Joint stiffness, carpal tunnel syndrome, pain in hips, shoulders, hands, and/or ankles, waddling gait, as well as spinal deformities are common features of MLIII. However, coarse facial features, growth delays and heart problems are often absent or mild. Biochemical analysis shows defects in M6P modification of proteins, which is not seen in SEDKF patients. (For more information on this disorder, choose “I cell Disease” and “pseudo-Hurler polydystrophy” as your search terms in the Rare Disease Database.)
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Diagnosis of Spondyloepiphyseal Dysplasia, Kondo-Fu Type
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Skeletal dysplasia is a group of disorders comprised of more than 450 types characterized by abnormal growth or development of cartilage and bone. Among those are SED disorders sharing many overlapping symptoms with one another. The diagnosis of SEDKF should be based on characteristic symptoms, patient history, clinical evaluation and laboratory tests and confirmed by whole-genome sequencing. X-ray, magnetic resonance imaging (MRI) and computed tomography (CT) can be used to examine the bone system and to identify characteristic spondylo-epiphyseal abnormalities. Laboratory tests should demonstrate normal blood cell count, generally normal organ functions and elevated plasma lysosomal enzymes. Detection of mutations in the MBTPS1 gene via genomic sequencing confirms the diagnosis.
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Diagnosis of Spondyloepiphyseal Dysplasia, Kondo-Fu Type. Skeletal dysplasia is a group of disorders comprised of more than 450 types characterized by abnormal growth or development of cartilage and bone. Among those are SED disorders sharing many overlapping symptoms with one another. The diagnosis of SEDKF should be based on characteristic symptoms, patient history, clinical evaluation and laboratory tests and confirmed by whole-genome sequencing. X-ray, magnetic resonance imaging (MRI) and computed tomography (CT) can be used to examine the bone system and to identify characteristic spondylo-epiphyseal abnormalities. Laboratory tests should demonstrate normal blood cell count, generally normal organ functions and elevated plasma lysosomal enzymes. Detection of mutations in the MBTPS1 gene via genomic sequencing confirms the diagnosis.
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Therapies of Spondyloepiphyseal Dysplasia, Kondo-Fu Type
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Treatment
There are currently no therapies that target the cause of SEDKF. Patients can be managed with symptomatic/supportive treatment.
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Therapies of Spondyloepiphyseal Dysplasia, Kondo-Fu Type. Treatment
There are currently no therapies that target the cause of SEDKF. Patients can be managed with symptomatic/supportive treatment.
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Overview of Spondylothoracic Dysplasia
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SummarySpondylothoracic dysplasia (STD) is a rare disorder in which there are malformations affecting the spine and ribs. The portion of the spine supporting the chest is extremely shortened. These malformations are present at birth (congenital). The bones of the spine called the vertebrae do not develop properly, and commonly fuse together with the adjacent ribs fusing to the spine. On an x-ray this gives the thorax a crab-like shape. The thorax is the portion of the body extending from the neck to the abdomen and includes the cavity surrounded by the ribs, breastbone and certain vertebrae. The shortened chest can restrict the size of the lungs, causing thoracic insufficiency syndrome. Spondylothoracic dysplasia can cause severe breathing (respiratory) problems and infants are at risk of life-threatening respiratory failure. Affected individuals are shorter than would otherwise be expected based on their age and gender (short stature) and may have an abnormal curvature to the spine. Many people with spondylothoracic dysplasia have a change (mutation) in the MESP2 gene. This gene change is inherited in an autosomal recessive manner.IntroductionThere is significant confusion in the medical literature regarding names for spondylothoracic dysplasia. For years, this disorder and a similar disorder, spondylocostal dysplasia (were considered the same disorder and referred to as Jarcho-Levin syndrome. Researchers now know that these disorders are separate entities with different causes and associated malformations. The term Jarcho-Levin syndrome is still used for both disorders, and sometimes it is used as an “umbrella” term to describe a broad range of conditions associated with spinal and rib defects. This has led to confusion for individuals and families who receive a diagnosis of Jarcho-Levin syndrome. Some researchers have advocated that Jarcho-Levin syndrome be reserved for people with spondylocostal dysplasia and the eponym Lavy-Moseley syndrome be used for spondylothoracic dysplasia. Other researchers believe the widespread, inconsistent use of Jarcho-Levin syndrome has rendered the term obsolete and that its use should be discontinued. Jarcho and Levin were two doctors who first described what is now known as spondylothoracic dysplasia in the medical literature in 1938.
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Overview of Spondylothoracic Dysplasia. SummarySpondylothoracic dysplasia (STD) is a rare disorder in which there are malformations affecting the spine and ribs. The portion of the spine supporting the chest is extremely shortened. These malformations are present at birth (congenital). The bones of the spine called the vertebrae do not develop properly, and commonly fuse together with the adjacent ribs fusing to the spine. On an x-ray this gives the thorax a crab-like shape. The thorax is the portion of the body extending from the neck to the abdomen and includes the cavity surrounded by the ribs, breastbone and certain vertebrae. The shortened chest can restrict the size of the lungs, causing thoracic insufficiency syndrome. Spondylothoracic dysplasia can cause severe breathing (respiratory) problems and infants are at risk of life-threatening respiratory failure. Affected individuals are shorter than would otherwise be expected based on their age and gender (short stature) and may have an abnormal curvature to the spine. Many people with spondylothoracic dysplasia have a change (mutation) in the MESP2 gene. This gene change is inherited in an autosomal recessive manner.IntroductionThere is significant confusion in the medical literature regarding names for spondylothoracic dysplasia. For years, this disorder and a similar disorder, spondylocostal dysplasia (were considered the same disorder and referred to as Jarcho-Levin syndrome. Researchers now know that these disorders are separate entities with different causes and associated malformations. The term Jarcho-Levin syndrome is still used for both disorders, and sometimes it is used as an “umbrella” term to describe a broad range of conditions associated with spinal and rib defects. This has led to confusion for individuals and families who receive a diagnosis of Jarcho-Levin syndrome. Some researchers have advocated that Jarcho-Levin syndrome be reserved for people with spondylocostal dysplasia and the eponym Lavy-Moseley syndrome be used for spondylothoracic dysplasia. Other researchers believe the widespread, inconsistent use of Jarcho-Levin syndrome has rendered the term obsolete and that its use should be discontinued. Jarcho and Levin were two doctors who first described what is now known as spondylothoracic dysplasia in the medical literature in 1938.
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Symptoms of Spondylothoracic Dysplasia
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The spine and ribs do not develop properly in spondylothoracic dysplasia. The bones of the spine are malformed and may be fused together. This fusion occurs where the head of the rib bones connects to the bones of the thoracic spine. The thoracic spine is the portion of the spinal column that makes up the upper and lower back. Because of the abnormal fusion of these bones, the affected area has a crab-like shape on x-rays. The spine can be markedly shorter than normal. Some individuals with STD may have an abnormal curve to the spine. The spine may be s-shaped (scoliosis), abnormally curved inward (lordosis), or abnormally curved outward (kyphosis), causing the back to appear rounded. Most patients with STD have a short straight spine.The trunk, which is the part of the body that extends from the neck to the abdomen, may be disproportionately smaller in comparison to height. In addition, affected individuals may be shorter than would otherwise be expected for their age and gender (short stature). Affected individuals may have a short neck with limited mobility.Because of the malformation of the spine and ribs, the lungs of affected infants and children may not be able to grow and develop properly. Affected infants and children cannot expand their chests sufficiently, causing reduced lung capacity, which means the lungs can hold less air than they normally would. Consequently, people with this condition can have difficulties breathing and experience repeated respiratory infections. Breathing problems can be severe and can become life-threatening and be fatal. Reduced lung capacity can also increase the risk of heart failure.There is an increased risk of developing inguinal hernia, a condition characterized by protrusion of parts of the large intestine through an opening in the abdominal wall near the groin as well as protrusion of parts of the large intestine through an opening near the belly button (umbilical hernia).
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Symptoms of Spondylothoracic Dysplasia. The spine and ribs do not develop properly in spondylothoracic dysplasia. The bones of the spine are malformed and may be fused together. This fusion occurs where the head of the rib bones connects to the bones of the thoracic spine. The thoracic spine is the portion of the spinal column that makes up the upper and lower back. Because of the abnormal fusion of these bones, the affected area has a crab-like shape on x-rays. The spine can be markedly shorter than normal. Some individuals with STD may have an abnormal curve to the spine. The spine may be s-shaped (scoliosis), abnormally curved inward (lordosis), or abnormally curved outward (kyphosis), causing the back to appear rounded. Most patients with STD have a short straight spine.The trunk, which is the part of the body that extends from the neck to the abdomen, may be disproportionately smaller in comparison to height. In addition, affected individuals may be shorter than would otherwise be expected for their age and gender (short stature). Affected individuals may have a short neck with limited mobility.Because of the malformation of the spine and ribs, the lungs of affected infants and children may not be able to grow and develop properly. Affected infants and children cannot expand their chests sufficiently, causing reduced lung capacity, which means the lungs can hold less air than they normally would. Consequently, people with this condition can have difficulties breathing and experience repeated respiratory infections. Breathing problems can be severe and can become life-threatening and be fatal. Reduced lung capacity can also increase the risk of heart failure.There is an increased risk of developing inguinal hernia, a condition characterized by protrusion of parts of the large intestine through an opening in the abdominal wall near the groin as well as protrusion of parts of the large intestine through an opening near the belly button (umbilical hernia).
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Causes of Spondylothoracic Dysplasia
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Spondylothoracic dysplasia is caused by a change (mutation) in the MESP2 gene. Most affected people have a mutation in this gene, but sometimes people with this disorder do not have a mutation in the MESP2 gene, suggesting that as-yet-unidentified gene(s) also cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body. Spondylothoracic dysplasia is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. The MESP2 gene that causes spondylothoracic dysplasia produces a protein that is involved in the NOTCH signaling pathway. This pathway is a series of chemical reactions that are vital to the health and function of the body, particularly with the development of the spine and ribs. The protein produced by the altered MESP2 gene is inefficient or defective, or the gene does not produce enough of the protein. Without the protein in question, the normal chemical reactions that occur in the NOTCH signaling pathway are impaired, leading to the signs and symptoms of spondylothoracic dysplasia.
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Causes of Spondylothoracic Dysplasia. Spondylothoracic dysplasia is caused by a change (mutation) in the MESP2 gene. Most affected people have a mutation in this gene, but sometimes people with this disorder do not have a mutation in the MESP2 gene, suggesting that as-yet-unidentified gene(s) also cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body. Spondylothoracic dysplasia is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. The MESP2 gene that causes spondylothoracic dysplasia produces a protein that is involved in the NOTCH signaling pathway. This pathway is a series of chemical reactions that are vital to the health and function of the body, particularly with the development of the spine and ribs. The protein produced by the altered MESP2 gene is inefficient or defective, or the gene does not produce enough of the protein. Without the protein in question, the normal chemical reactions that occur in the NOTCH signaling pathway are impaired, leading to the signs and symptoms of spondylothoracic dysplasia.
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Affects of Spondylothoracic Dysplasia
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Spondylothoracic dysplasia occurs with greater frequency in Puerto Rico and in individuals of Puerto Rican heritage, accounting for about half of all affected individuals reported in the medical literature.
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Affects of Spondylothoracic Dysplasia. Spondylothoracic dysplasia occurs with greater frequency in Puerto Rico and in individuals of Puerto Rican heritage, accounting for about half of all affected individuals reported in the medical literature.
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Related disorders of Spondylothoracic Dysplasia
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Symptoms of the following disorders can be similar to those of spondylothoracic dysplasia. Comparisons may be useful for a differential diagnosis.Spondylocostal dysplasia is a rare genetic disorder characterized by defects of the bones of the spine (vertebrae) and abnormalities of the ribs. These malformations are present at birth (congenital). The severity and specific symptoms can vary among affected individuals, even among members of the same family. Some infants may have difficulty breathing because of a reduced size of the thorax. The thorax is the middle portion of the body extending from the neck to the abdomen and including the chest cavity. Sometimes, breathing difficulties can be severe and life-threatening. Most times, spondylocostal dysplasia is inherited in an autosomal recessive manner and is caused by a change (mutation) in one of four genes, DLL3, MESP2, LFNG, HES7. Rarely, spondylocostal dysplasia can be inherited in an autosomal dominant manner. One gene, TBX6, is known to cause autosomal dominant spondylocostal dysplasia. Many individuals do not have a mutation in any of these genes. With treatment, most individuals survive well into adulthood. (For more information on this disorder, choose “spondylocostal dysplasia” as your search term in the Rare Disease Database.)There are numerous disorders that have malformations of the spines and ribs, which are similar to those seen in spondylothoracic dysplasia. A partial list of these disorders includes Alagille syndrome, camptomelic dysplasia, oculo-auriculo-vertebral spectrum, Klippel-Feil syndrome Robinow syndrome, multiple pterygium syndrome, sirenomelia, and VACTERL syndrome. Casamassima-Morton-Nance syndrome is characterized by similar spinal and rib malformations of spondylothoracic dysplasia combined with urogenital abnormalities. Urogenital refers to both the urinary and genital organs. (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 Spondylothoracic Dysplasia. Symptoms of the following disorders can be similar to those of spondylothoracic dysplasia. Comparisons may be useful for a differential diagnosis.Spondylocostal dysplasia is a rare genetic disorder characterized by defects of the bones of the spine (vertebrae) and abnormalities of the ribs. These malformations are present at birth (congenital). The severity and specific symptoms can vary among affected individuals, even among members of the same family. Some infants may have difficulty breathing because of a reduced size of the thorax. The thorax is the middle portion of the body extending from the neck to the abdomen and including the chest cavity. Sometimes, breathing difficulties can be severe and life-threatening. Most times, spondylocostal dysplasia is inherited in an autosomal recessive manner and is caused by a change (mutation) in one of four genes, DLL3, MESP2, LFNG, HES7. Rarely, spondylocostal dysplasia can be inherited in an autosomal dominant manner. One gene, TBX6, is known to cause autosomal dominant spondylocostal dysplasia. Many individuals do not have a mutation in any of these genes. With treatment, most individuals survive well into adulthood. (For more information on this disorder, choose “spondylocostal dysplasia” as your search term in the Rare Disease Database.)There are numerous disorders that have malformations of the spines and ribs, which are similar to those seen in spondylothoracic dysplasia. A partial list of these disorders includes Alagille syndrome, camptomelic dysplasia, oculo-auriculo-vertebral spectrum, Klippel-Feil syndrome Robinow syndrome, multiple pterygium syndrome, sirenomelia, and VACTERL syndrome. Casamassima-Morton-Nance syndrome is characterized by similar spinal and rib malformations of spondylothoracic dysplasia combined with urogenital abnormalities. Urogenital refers to both the urinary and genital organs. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Spondylothoracic Dysplasia
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A diagnosis of spondylothoracic dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
X-rays (radiographs) of the spine can show characteristic changes to the spine and ribs that characterized spondylothoracic dysplasia. A diagnosis of spondylothoracic dysplasia can be confirmed through molecular genetic testing in some individuals. Molecular genetic testing can detect alterations in the MESP2 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Also, some people may not have a mutation in this gene, and their diagnosis cannot be confirmed through molecular genetic testing. Prenatal diagnosis of spondylothoracic dysplasia is possible by fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can reveal some of the defects associated with spondylothoracic dysplasia.
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Diagnosis of Spondylothoracic Dysplasia. A diagnosis of spondylothoracic dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Clinical Testing and Workup
X-rays (radiographs) of the spine can show characteristic changes to the spine and ribs that characterized spondylothoracic dysplasia. A diagnosis of spondylothoracic dysplasia can be confirmed through molecular genetic testing in some individuals. Molecular genetic testing can detect alterations in the MESP2 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Also, some people may not have a mutation in this gene, and their diagnosis cannot be confirmed through molecular genetic testing. Prenatal diagnosis of spondylothoracic dysplasia is possible by fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can reveal some of the defects associated with spondylothoracic dysplasia.
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Therapies of Spondylothoracic Dysplasia
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Treatment
The treatment of spondylothoracic dysplasia is directed toward the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic surgeons, specialists who diagnose and assess heart disorders (cardiologists), specialists who diagnose and treat lung disorders (pulmonologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Infants who experience breathing difficulties can require some form of respiratory support. This can include the use of a machine or device to help an infant breath. Some infants may require intensive care, which involves constant monitoring in a hospital. Surgery is used to repair an inguinal hernia. Scoliosis is rare in STD, but VEPTR thoracic surgery may be beneficial in increasing chest size to maximize lung growth potential. Antibiotics may be necessary to treat recurrent respiratory infections. The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. For treatment of spondylothoracic dysplasia, ribs are separated on each side of the chest and VEPTRs are placed on each side of the chest. It is manufactured by DePuy Synthes Spine Co. in Raynham Mass.
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Therapies of Spondylothoracic Dysplasia. Treatment
The treatment of spondylothoracic dysplasia is directed toward the specific symptoms that are apparent in an individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic surgeons, specialists who diagnose and assess heart disorders (cardiologists), specialists who diagnose and treat lung disorders (pulmonologists), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.Infants who experience breathing difficulties can require some form of respiratory support. This can include the use of a machine or device to help an infant breath. Some infants may require intensive care, which involves constant monitoring in a hospital. Surgery is used to repair an inguinal hernia. Scoliosis is rare in STD, but VEPTR thoracic surgery may be beneficial in increasing chest size to maximize lung growth potential. Antibiotics may be necessary to treat recurrent respiratory infections. The vertical expandable prosthetic titanium rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. For treatment of spondylothoracic dysplasia, ribs are separated on each side of the chest and VEPTRs are placed on each side of the chest. It is manufactured by DePuy Synthes Spine Co. in Raynham Mass.
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Overview of Spontaneous Intracranial Hypotension
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SummarySpontaneous intracranial hypotension is secondary to a cerebrospinal fluid (CSF) leak at the level of the spine and the resulting loss of CSF volume that bathes the brain and spinal cord. Males and females of all ages are affected, but the diagnosis is more common in females. Annual incidence of 5 per 100,000 is likely an underestimate, and the overall prevalence is unknown. It most often results in a new-onset headache that is worse with upright posture, along with other neurologic signs and symptoms. Variability in presenting signs and symptoms, along with low awareness of the disorder, contribute to delayed diagnosis, although this is improving with a growing volume of publications. Diagnostic imaging is quite specialized, both in techniques and in interpretation. Because there is a structural cause, a hole or defect in the spinal dura (a tough layer of connective tissue) that normally holds cerebrospinal fluid in, it is both treatable and curable. The most common treatment is epidural patching with blood or fibrin sealant, though surgery is sometimes needed. Outcomes are good for most patients.
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Overview of Spontaneous Intracranial Hypotension. SummarySpontaneous intracranial hypotension is secondary to a cerebrospinal fluid (CSF) leak at the level of the spine and the resulting loss of CSF volume that bathes the brain and spinal cord. Males and females of all ages are affected, but the diagnosis is more common in females. Annual incidence of 5 per 100,000 is likely an underestimate, and the overall prevalence is unknown. It most often results in a new-onset headache that is worse with upright posture, along with other neurologic signs and symptoms. Variability in presenting signs and symptoms, along with low awareness of the disorder, contribute to delayed diagnosis, although this is improving with a growing volume of publications. Diagnostic imaging is quite specialized, both in techniques and in interpretation. Because there is a structural cause, a hole or defect in the spinal dura (a tough layer of connective tissue) that normally holds cerebrospinal fluid in, it is both treatable and curable. The most common treatment is epidural patching with blood or fibrin sealant, though surgery is sometimes needed. Outcomes are good for most patients.
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Symptoms of Spontaneous Intracranial Hypotension
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Onset of symptoms and signs may be relatively abrupt or more gradual. Patients may be minimally affected or profoundly disabled with limited ability to function while upright.The hallmark of intracranial hypotension is a positional headache. This headache is worse when upright and improves when lying down. It usually occurs within 15 minutes of assuming the upright position and is relieved after lying down within 15-30 minutes, however it may take hours to worsen or improve with change of position. Over time, the positional aspect of the headache tends to lessen and may even disappear. The location of the headache is most often in the back of the head or base of the skull, but can also occur in the front, sides or all over the head. The headache is rarely on just one side of the head. The quality of the headache is often described as a “pulling sensation” from the back of the head to the neck. The severity of the headache can range from mild to very severe and disabling.Other characteristic symptoms include neck pain, neck stiffness, nausea, vomiting, sensitivity to light and/or sound, sense of imbalance, ringing in the ears, changes in hearing, and profound fatigue. Pain between the shoulder blades and into the upper arms is commonly reported. Patients may also experience visual changes, dizziness or vertigo, facial numbness or pain, or changes in taste. Specific signs are often seen on brain MRI and are described below under the diagnosis section.Atypical and serious neurologic complications do occur, so prompt recognition and treatment in such cases is important. Rarely, patients can present with signs and symptoms typical of behavioral variant frontotemporal dementia, Parkinsonism, superficial siderosis, ataxia (very unsteady gait) or quadriplegia. Cerebral venous thrombosis, stupor or coma, seizures, stroke and death have also been reported.
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Symptoms of Spontaneous Intracranial Hypotension. Onset of symptoms and signs may be relatively abrupt or more gradual. Patients may be minimally affected or profoundly disabled with limited ability to function while upright.The hallmark of intracranial hypotension is a positional headache. This headache is worse when upright and improves when lying down. It usually occurs within 15 minutes of assuming the upright position and is relieved after lying down within 15-30 minutes, however it may take hours to worsen or improve with change of position. Over time, the positional aspect of the headache tends to lessen and may even disappear. The location of the headache is most often in the back of the head or base of the skull, but can also occur in the front, sides or all over the head. The headache is rarely on just one side of the head. The quality of the headache is often described as a “pulling sensation” from the back of the head to the neck. The severity of the headache can range from mild to very severe and disabling.Other characteristic symptoms include neck pain, neck stiffness, nausea, vomiting, sensitivity to light and/or sound, sense of imbalance, ringing in the ears, changes in hearing, and profound fatigue. Pain between the shoulder blades and into the upper arms is commonly reported. Patients may also experience visual changes, dizziness or vertigo, facial numbness or pain, or changes in taste. Specific signs are often seen on brain MRI and are described below under the diagnosis section.Atypical and serious neurologic complications do occur, so prompt recognition and treatment in such cases is important. Rarely, patients can present with signs and symptoms typical of behavioral variant frontotemporal dementia, Parkinsonism, superficial siderosis, ataxia (very unsteady gait) or quadriplegia. Cerebral venous thrombosis, stupor or coma, seizures, stroke and death have also been reported.
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Causes of Spontaneous Intracranial Hypotension
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The underlying cause of spontaneous intracranial hypotension is a loss of cerebrospinal fluid (CSF) volume through a hole or tear in the spinal dura. The dura is the tough outermost layer of the meninges (connective tissues that surround the brain and spinal cord) that holds in the CSF. When this fluid volume is reduced, there is less fluid available to cushion the brain inside the skull. This loss of CSF causes headache and other neurological signs and symptoms and may result in a range of complications. With upright posture, the loss of CSF volume has a greater effect on the brain.There is evidence that an underlying weakness of the spinal dura is present in a subset of cases. Several heritable (genetic) disorders of connective tissue (HDCT) have been associated with spontaneous intracranial hypotension. See related disorders below.Also, many cases are associated with calcified discs and bone spurs of the spine that can tear the dura on the front side of the spinal cord.The etiology of the CSF-venous fistula type of leak, first recognized in 2014, is not yet understood.CSF leaks that occur spontaneously in the head (base of the skull) are not causally associated with intracranial hypotension.
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Causes of Spontaneous Intracranial Hypotension. The underlying cause of spontaneous intracranial hypotension is a loss of cerebrospinal fluid (CSF) volume through a hole or tear in the spinal dura. The dura is the tough outermost layer of the meninges (connective tissues that surround the brain and spinal cord) that holds in the CSF. When this fluid volume is reduced, there is less fluid available to cushion the brain inside the skull. This loss of CSF causes headache and other neurological signs and symptoms and may result in a range of complications. With upright posture, the loss of CSF volume has a greater effect on the brain.There is evidence that an underlying weakness of the spinal dura is present in a subset of cases. Several heritable (genetic) disorders of connective tissue (HDCT) have been associated with spontaneous intracranial hypotension. See related disorders below.Also, many cases are associated with calcified discs and bone spurs of the spine that can tear the dura on the front side of the spinal cord.The etiology of the CSF-venous fistula type of leak, first recognized in 2014, is not yet understood.CSF leaks that occur spontaneously in the head (base of the skull) are not causally associated with intracranial hypotension.
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Affects of Spontaneous Intracranial Hypotension
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Males and females of any age may develop spontaneous intracranial hypotension, although this is diagnosed more often in females. The peak age of diagnosis is age 40.The prevalence of spontaneous intracranial hypotension is unknown. It is suspected that many cases never present for medical care, or resolve without treatment. The best estimate that we have of annual incidence is from an emergency department study done in Los Angeles, California. In this retrospective study, spontaneous intracranial hypotension was diagnosed half as frequently as subarachnoid hemorrhage (brain bleeding from an aneurysm), with an estimated incidence of about 5 cases per 100,000 per year. This is almost certainly an underestimate because the study was single-center and retrospective, and many patients likely remained undiagnosed.
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Affects of Spontaneous Intracranial Hypotension. Males and females of any age may develop spontaneous intracranial hypotension, although this is diagnosed more often in females. The peak age of diagnosis is age 40.The prevalence of spontaneous intracranial hypotension is unknown. It is suspected that many cases never present for medical care, or resolve without treatment. The best estimate that we have of annual incidence is from an emergency department study done in Los Angeles, California. In this retrospective study, spontaneous intracranial hypotension was diagnosed half as frequently as subarachnoid hemorrhage (brain bleeding from an aneurysm), with an estimated incidence of about 5 cases per 100,000 per year. This is almost certainly an underestimate because the study was single-center and retrospective, and many patients likely remained undiagnosed.
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Related disorders of Spontaneous Intracranial Hypotension
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In addition to spontaneous cases, intracranial hypotension may also occur as a result of medical procedures such as a lumbar puncture, epidural injection, over-drainage of CSF shunts, or spinal or other surgery. It may also occur as a result of an injury, such as a motor vehicle accident, sports injury, or penetrating trauma. Cases related to medical procedures and injuries are usually more readily identified than cases of spontaneous intracranial hypotension.Several HDCT are evident more often in patients with spontaneous intracranial hypotension than in the general population. These include classic and hypermobile Ehlers-Danlos syndromes (EDS), Marfan syndrome, as well as autosomal dominant polycystic disease. Many patients have evidence on history, examination, or previous testing to suggest an HDCT without meeting the criteria for a specific disorder. These HDCT have been associated with areas of thin or weak dura and spinal meningeal diverticula (outpouching of meningeal layers) or cysts that may predispose to CSF leaks.Several cardiovascular findings appear to be more common in patients with spontaneous intracranial hypotension. These include bicuspid aortic valve, other heart valve abnormalities, intracranial (brain) aneurysms, dilatation (enlargement) of the aortic root (the first part of aorta as it arises from the heart) and thoracic aortic aneurysms. These patients may or may not have a recognized HDCT. It is suspected that similar mechanisms may be involved in both vascular and dural abnormalities.Pathology along the spine is very common in the general population. Calcified discs and bone spurs can slice the dura. These leaks are often rapid, large-volume leaks.Because postural orthostatic tachycardia syndrome (POTS) also has symptoms that are worse with upright posture, often including headache, it may be confused with spontaneous intracranial hypotension. To complicate matters, POTS may also coexist in a patient with spontaneous intracranial hypotension.The cerebellar tonsils (part of the brain at the lower back part of the head) may descend into the spinal canal in intracranial hypotension and may be mistaken for Chiari malformation, which involves a congenitally small lower back section of the skull known as the posterior fossa. In intracranial hypotension, this descent of part of the brain is usually reversible with treatment. In patients with Chiari malformation that later develop intracranial hypotension, the descent of the cerebellar tonsils may worsen.EDS patients have a higher prevalence of other types of headaches (such as migraine), as well as postural orthostatic tachycardia syndrome (POTS) and congenital Chiari malformation, any or all of which may coexist in the same patient.When brain imaging reveals subdural fluid collections, spontaneous intracranial hypotension may not be recognized or considered as a potential cause.Misdiagnosis or delayed diagnosis is less common with rising familiarity among health care professionals but still occurs frequently. Patients are often treated unsuccessfully for migraine headache, tension headache, or other disorders before spontaneous intracranial hypotension is considered.
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Related disorders of Spontaneous Intracranial Hypotension. In addition to spontaneous cases, intracranial hypotension may also occur as a result of medical procedures such as a lumbar puncture, epidural injection, over-drainage of CSF shunts, or spinal or other surgery. It may also occur as a result of an injury, such as a motor vehicle accident, sports injury, or penetrating trauma. Cases related to medical procedures and injuries are usually more readily identified than cases of spontaneous intracranial hypotension.Several HDCT are evident more often in patients with spontaneous intracranial hypotension than in the general population. These include classic and hypermobile Ehlers-Danlos syndromes (EDS), Marfan syndrome, as well as autosomal dominant polycystic disease. Many patients have evidence on history, examination, or previous testing to suggest an HDCT without meeting the criteria for a specific disorder. These HDCT have been associated with areas of thin or weak dura and spinal meningeal diverticula (outpouching of meningeal layers) or cysts that may predispose to CSF leaks.Several cardiovascular findings appear to be more common in patients with spontaneous intracranial hypotension. These include bicuspid aortic valve, other heart valve abnormalities, intracranial (brain) aneurysms, dilatation (enlargement) of the aortic root (the first part of aorta as it arises from the heart) and thoracic aortic aneurysms. These patients may or may not have a recognized HDCT. It is suspected that similar mechanisms may be involved in both vascular and dural abnormalities.Pathology along the spine is very common in the general population. Calcified discs and bone spurs can slice the dura. These leaks are often rapid, large-volume leaks.Because postural orthostatic tachycardia syndrome (POTS) also has symptoms that are worse with upright posture, often including headache, it may be confused with spontaneous intracranial hypotension. To complicate matters, POTS may also coexist in a patient with spontaneous intracranial hypotension.The cerebellar tonsils (part of the brain at the lower back part of the head) may descend into the spinal canal in intracranial hypotension and may be mistaken for Chiari malformation, which involves a congenitally small lower back section of the skull known as the posterior fossa. In intracranial hypotension, this descent of part of the brain is usually reversible with treatment. In patients with Chiari malformation that later develop intracranial hypotension, the descent of the cerebellar tonsils may worsen.EDS patients have a higher prevalence of other types of headaches (such as migraine), as well as postural orthostatic tachycardia syndrome (POTS) and congenital Chiari malformation, any or all of which may coexist in the same patient.When brain imaging reveals subdural fluid collections, spontaneous intracranial hypotension may not be recognized or considered as a potential cause.Misdiagnosis or delayed diagnosis is less common with rising familiarity among health care professionals but still occurs frequently. Patients are often treated unsuccessfully for migraine headache, tension headache, or other disorders before spontaneous intracranial hypotension is considered.
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Diagnosis of Spontaneous Intracranial Hypotension
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The diagnosis of spontaneous intracranial hypotension is initially suspected based on presenting signs and symptoms. Many physician specialties may be involved in the care of patients, including primary care physicians, emergency medicine physicians, neurologists, neuroradiologists, pain management physicians, anesthesiologists, neurosurgeons, and geneticists.Effective October 1, 2020, the specific diagnostic code for spontaneous intracranial hypotension is G96.811, and the specific code for spontaneous spinal CSF leak is G96.02.When this diagnosis is suspected, magnetic resonance imaging (MRI) study of the brain with contrast should be done to look for several specific findings. These findings may be absent in up to 20% of cases, more often when this imaging is done weeks or months after onset. The mnemonic SEEPS is used by physicians to recall the findings:S – subdural fluid collections
E – enhancement of the meninges (layers around the brain)
E – engorgement of venous structures
P – pituitary hyperemia (swelling)
S – sagging of the brainA lumbar puncture may be done to measure the CSF opening pressure, but because this often falls in the normal range, it has limited value.For many patients, spinal imaging to localize their spinal CSF leak may not be necessary, because one or more epidural blood patch procedures will be curative. See the treatment section below.
Different types of spinal CSF leaks have been observed based on findings of spinal imaging and at surgery. Treatment approaches are then tailored to the type and location of the leak. Type 1 CSF leaks are caused by a dural tear located ventral to (in front of) the spinal cord (type 1a) or posterolateral to (behind and to the side of) the spinal cord (type 1b). Type 2 CSF leaks are associated with simple (type 2a) or complex (type 2b [dural ectasia]) meningeal diverticula. Type 3 CSF leaks are CSF-venous fistulas. Type 4 CSF leaks are of indeterminate origin. Noninvasive imaging in the form of a full spine MRI is preferred as the initial spinal imaging. The findings on spinal MRI guide the need for additional specialized spinal imaging techniques, including standard or dynamic computed tomography (CT), digital subtraction, and intrathecal gadolinium-enhanced MR myelography. The yield of imaging can be impacted by patient positioning and respiratory phase. The identification of the type and location of the spinal CSF leak is needed for further treatment planning. Current imaging techniques are not sensitive enough to identify a spinal CSF leak in all cases, thus negative imaging does not rule out the disorder. This limited sensitivity also impacts treatment options.When there are findings on history, clinical exam, or imaging that suggest the presence of a heritable disorder of connective tissue, referral to a physician with expertise in these disorders may be of value. These patients may be at higher risk of cardiovascular abnormalities noted above under “related disorders”. Screening with echocardiography and/or other tests may be considered on a case by case basis.
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Diagnosis of Spontaneous Intracranial Hypotension. The diagnosis of spontaneous intracranial hypotension is initially suspected based on presenting signs and symptoms. Many physician specialties may be involved in the care of patients, including primary care physicians, emergency medicine physicians, neurologists, neuroradiologists, pain management physicians, anesthesiologists, neurosurgeons, and geneticists.Effective October 1, 2020, the specific diagnostic code for spontaneous intracranial hypotension is G96.811, and the specific code for spontaneous spinal CSF leak is G96.02.When this diagnosis is suspected, magnetic resonance imaging (MRI) study of the brain with contrast should be done to look for several specific findings. These findings may be absent in up to 20% of cases, more often when this imaging is done weeks or months after onset. The mnemonic SEEPS is used by physicians to recall the findings:S – subdural fluid collections
E – enhancement of the meninges (layers around the brain)
E – engorgement of venous structures
P – pituitary hyperemia (swelling)
S – sagging of the brainA lumbar puncture may be done to measure the CSF opening pressure, but because this often falls in the normal range, it has limited value.For many patients, spinal imaging to localize their spinal CSF leak may not be necessary, because one or more epidural blood patch procedures will be curative. See the treatment section below.
Different types of spinal CSF leaks have been observed based on findings of spinal imaging and at surgery. Treatment approaches are then tailored to the type and location of the leak. Type 1 CSF leaks are caused by a dural tear located ventral to (in front of) the spinal cord (type 1a) or posterolateral to (behind and to the side of) the spinal cord (type 1b). Type 2 CSF leaks are associated with simple (type 2a) or complex (type 2b [dural ectasia]) meningeal diverticula. Type 3 CSF leaks are CSF-venous fistulas. Type 4 CSF leaks are of indeterminate origin. Noninvasive imaging in the form of a full spine MRI is preferred as the initial spinal imaging. The findings on spinal MRI guide the need for additional specialized spinal imaging techniques, including standard or dynamic computed tomography (CT), digital subtraction, and intrathecal gadolinium-enhanced MR myelography. The yield of imaging can be impacted by patient positioning and respiratory phase. The identification of the type and location of the spinal CSF leak is needed for further treatment planning. Current imaging techniques are not sensitive enough to identify a spinal CSF leak in all cases, thus negative imaging does not rule out the disorder. This limited sensitivity also impacts treatment options.When there are findings on history, clinical exam, or imaging that suggest the presence of a heritable disorder of connective tissue, referral to a physician with expertise in these disorders may be of value. These patients may be at higher risk of cardiovascular abnormalities noted above under “related disorders”. Screening with echocardiography and/or other tests may be considered on a case by case basis.
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Therapies of Spontaneous Intracranial Hypotension
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TreatmentAn uncertain percentage of patients with spontaneous intracranial hypotension have milder symptoms and/or symptoms that may resolve without any treatment. Simple measures including bed rest, fluids for hydration and caffeine intake may help to reduce the severity of symptoms.In the setting of serious complications, such as coma or large subdural hematomas, urgent treatment will be needed. For less emergent cases, when symptoms are significant or persistent, the most common initial treatment is a non-targeted epidural blood patch. In this procedure, some blood is taken from the patient’s arm vein and is injected into the spinal canal in the space outside the dura. Epidural patching procedures may also include the use of fibrin sealant and may be targeted to specific spinal levels. Neuroradiologists and anesthesiologists are physician subspecialties that perform these procedures most often. These procedures may be repeated several times if the improvement is incomplete or does not last.When non-surgical procedures are ineffective or symptoms relapse, a neurosurgical repair may be necessary but relies upon imaging localization of the spinal CSF leak.Following treatment, it is not uncommon for patients to develop rebound intracranial hypertension (elevated CSF pressure), which may persist for a variable length of time. The natural history and optimal treatment for this complication have not yet been well studied. Currently, acetazolamide is the most commonly used medication.Most patients do very well, although some patients do have relapsing or persistent symptoms and disability.
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Therapies of Spontaneous Intracranial Hypotension. TreatmentAn uncertain percentage of patients with spontaneous intracranial hypotension have milder symptoms and/or symptoms that may resolve without any treatment. Simple measures including bed rest, fluids for hydration and caffeine intake may help to reduce the severity of symptoms.In the setting of serious complications, such as coma or large subdural hematomas, urgent treatment will be needed. For less emergent cases, when symptoms are significant or persistent, the most common initial treatment is a non-targeted epidural blood patch. In this procedure, some blood is taken from the patient’s arm vein and is injected into the spinal canal in the space outside the dura. Epidural patching procedures may also include the use of fibrin sealant and may be targeted to specific spinal levels. Neuroradiologists and anesthesiologists are physician subspecialties that perform these procedures most often. These procedures may be repeated several times if the improvement is incomplete or does not last.When non-surgical procedures are ineffective or symptoms relapse, a neurosurgical repair may be necessary but relies upon imaging localization of the spinal CSF leak.Following treatment, it is not uncommon for patients to develop rebound intracranial hypertension (elevated CSF pressure), which may persist for a variable length of time. The natural history and optimal treatment for this complication have not yet been well studied. Currently, acetazolamide is the most commonly used medication.Most patients do very well, although some patients do have relapsing or persistent symptoms and disability.
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Overview of Sporadic Inclusion Body Myositis
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Sporadic inclusion body myositis (sIBM) is an acquired progressive muscle disorder that becomes apparent during adulthood. The symptoms and progression of sIBM vary from one person to another. In most cases, sIBM is characterized by progressive weakness and degeneration (atrophy) of the muscles especially those of the arms and the legs. sIBM can progress to cause severe disability. sIBM is an autoimmune disease mediated by cytotoxic T cells, but the exact cause of the disorder is unknown. sIBM, like all autoimmune diseases, is a complex disorder and, most likely, multiple factors including genetic, immunological and environmental ones in combination all play a role in its development.
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Overview of Sporadic Inclusion Body Myositis. Sporadic inclusion body myositis (sIBM) is an acquired progressive muscle disorder that becomes apparent during adulthood. The symptoms and progression of sIBM vary from one person to another. In most cases, sIBM is characterized by progressive weakness and degeneration (atrophy) of the muscles especially those of the arms and the legs. sIBM can progress to cause severe disability. sIBM is an autoimmune disease mediated by cytotoxic T cells, but the exact cause of the disorder is unknown. sIBM, like all autoimmune diseases, is a complex disorder and, most likely, multiple factors including genetic, immunological and environmental ones in combination all play a role in its development.
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Symptoms of Sporadic Inclusion Body Myositis
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The distribution, severity and progression of muscle weakness vary from one person to another. In some patients, sIBM may affect one arm or leg more than the other. In most cases, the progression is very slow. The muscles of the anterior thighs (quadriceps) and wrist and finger flexors are usually affected more severely than other muscles. Many individuals with sIBM first present with a tendency to trip or fall or with difficulty with handgrip, or with difficulty swallowing.Muscles in the wrists, fingers, and neck are commonly affected. Weakness in the hands may be the first noticeable symptoms in some people. Muscle weakness in the fingers can affect the grip making it difficult to perform functions such as gripping a golf club. Eventually, affected individuals may have difficulty manipulating objects with their hands such as turning a key, buttoning a shirt, or writing with a pen or pencil. In rare cases, muscle weakness in the neck can cause the head to drop.Weakness of the muscles below the knees can cause the toes to catch when walking or the foot to drop increasing an affected individual’s tendency to fall. Affected individuals may also have trouble walking up stairs and or rising from a sitting position.Difficulty swallowing (dysphagia) due to weakness of throat muscles may occur in individuals with sIBM. Dysphagia can potentially cause choking episodes. Facial muscle weakness occurs in some patients as well.Muscle cramping, pain (myalgia) or tenderness do not usually occur, but has been reported. Although sIBM progresses slowly, it can eventually cause significant disability and many affected individuals eventually require an assistive device such as a cane, walker or wheelchair.
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Symptoms of Sporadic Inclusion Body Myositis. The distribution, severity and progression of muscle weakness vary from one person to another. In some patients, sIBM may affect one arm or leg more than the other. In most cases, the progression is very slow. The muscles of the anterior thighs (quadriceps) and wrist and finger flexors are usually affected more severely than other muscles. Many individuals with sIBM first present with a tendency to trip or fall or with difficulty with handgrip, or with difficulty swallowing.Muscles in the wrists, fingers, and neck are commonly affected. Weakness in the hands may be the first noticeable symptoms in some people. Muscle weakness in the fingers can affect the grip making it difficult to perform functions such as gripping a golf club. Eventually, affected individuals may have difficulty manipulating objects with their hands such as turning a key, buttoning a shirt, or writing with a pen or pencil. In rare cases, muscle weakness in the neck can cause the head to drop.Weakness of the muscles below the knees can cause the toes to catch when walking or the foot to drop increasing an affected individual’s tendency to fall. Affected individuals may also have trouble walking up stairs and or rising from a sitting position.Difficulty swallowing (dysphagia) due to weakness of throat muscles may occur in individuals with sIBM. Dysphagia can potentially cause choking episodes. Facial muscle weakness occurs in some patients as well.Muscle cramping, pain (myalgia) or tenderness do not usually occur, but has been reported. Although sIBM progresses slowly, it can eventually cause significant disability and many affected individuals eventually require an assistive device such as a cane, walker or wheelchair.
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Causes of Sporadic Inclusion Body Myositis
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The cause of sIBM is unknown and complex. Researchers believe multiple immunological, genetic and environmental factors and factors related to aging all play a role in the development of the disorder. Researchers have identified two distinct processes – one autoimmune and one degenerative – that occur in individuals with sIBM. It appears likely that autoimmunity drives the disease and accounts for the minor “degenerative” pathological changes seen in sIBM skeletal muscle.Numerous factors support that sIBM is an autoimmune disorder, especially the presence of certain inflammatory white blood cells in the muscle tissue of affected individuals. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. The inflammatory findings associated with sIBM led to it to be classified as an autoimmune inflammatory muscle disease along with other prominent inflammatory muscle diseases such as dermatomyositis and polymyositis. The identification of an autoantigen (NT5C1A) has confirmed IBM’s status as an autoimmune disease. However, sIBM, like a number of other autorimmune diseases, has not responded to some of the conventional therapies normally used to treat autoimmune disorders suggesting that distinct factors account for its refractory nature. In particular, cytotoxic T cells in sIBM muscle are highly differentiated and their phenotype overlaps with those of T cells in T-cell large granular lymphocytic leukemia, a similarly refractory disease.In addition to the inflammatory process, researchers have emphasized that some muscle tissue of individuals with sIBM shows degenerative changes. Specifically, the muscle tissue of affected individuals sometimes contains sub-cellular compartments called vacuoles. These compartments have been reported to contain abnormal clumps of many different proteins. These clumps, often called “inclusion bodies”, give the disorder its name. This significant degenerative component has led some researchers to argue that sIBM is primarily a degenerative muscle disorder and not an inflammatory one. However, these changes are seen in other refractory autoimmune diseases (e.g., Sjogren syndrome and primary biliary cholangigits) and appear to be reflective of chronic exposure of tissues to highly T cell rich inflammatory environments.It is unknown what triggers or underlies the inflammatory or degenerative changes that characterize sIBM, a feature shared by all other autoimmune diseases. Some individuals with sIBM may have a genetic predisposition that makes them more susceptible to developing sIBM. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease.
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Causes of Sporadic Inclusion Body Myositis. The cause of sIBM is unknown and complex. Researchers believe multiple immunological, genetic and environmental factors and factors related to aging all play a role in the development of the disorder. Researchers have identified two distinct processes – one autoimmune and one degenerative – that occur in individuals with sIBM. It appears likely that autoimmunity drives the disease and accounts for the minor “degenerative” pathological changes seen in sIBM skeletal muscle.Numerous factors support that sIBM is an autoimmune disorder, especially the presence of certain inflammatory white blood cells in the muscle tissue of affected individuals. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue. The inflammatory findings associated with sIBM led to it to be classified as an autoimmune inflammatory muscle disease along with other prominent inflammatory muscle diseases such as dermatomyositis and polymyositis. The identification of an autoantigen (NT5C1A) has confirmed IBM’s status as an autoimmune disease. However, sIBM, like a number of other autorimmune diseases, has not responded to some of the conventional therapies normally used to treat autoimmune disorders suggesting that distinct factors account for its refractory nature. In particular, cytotoxic T cells in sIBM muscle are highly differentiated and their phenotype overlaps with those of T cells in T-cell large granular lymphocytic leukemia, a similarly refractory disease.In addition to the inflammatory process, researchers have emphasized that some muscle tissue of individuals with sIBM shows degenerative changes. Specifically, the muscle tissue of affected individuals sometimes contains sub-cellular compartments called vacuoles. These compartments have been reported to contain abnormal clumps of many different proteins. These clumps, often called “inclusion bodies”, give the disorder its name. This significant degenerative component has led some researchers to argue that sIBM is primarily a degenerative muscle disorder and not an inflammatory one. However, these changes are seen in other refractory autoimmune diseases (e.g., Sjogren syndrome and primary biliary cholangigits) and appear to be reflective of chronic exposure of tissues to highly T cell rich inflammatory environments.It is unknown what triggers or underlies the inflammatory or degenerative changes that characterize sIBM, a feature shared by all other autoimmune diseases. Some individuals with sIBM may have a genetic predisposition that makes them more susceptible to developing sIBM. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease.
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Affects of Sporadic Inclusion Body Myositis
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sIBM affects males slightly more often than females. Its prevalence is estimated to be between 10-112 people per 1,000,000 in the general population. It occurs with greater frequency in individuals more than 50 years of age. The prevalence is estimated to be 51-139 per 1,000,000 individuals in the general population over 50, making sIBM the most common acquired muscle disorder (myopathy) in that age group. Despite growing awareness of this disorder, many researchers believe it remains underdiagnosed.Although sIBM does not occur with greater frequency in any specific ethnic or racial group, it apparently occurs less often in individuals of African descent.
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Affects of Sporadic Inclusion Body Myositis. sIBM affects males slightly more often than females. Its prevalence is estimated to be between 10-112 people per 1,000,000 in the general population. It occurs with greater frequency in individuals more than 50 years of age. The prevalence is estimated to be 51-139 per 1,000,000 individuals in the general population over 50, making sIBM the most common acquired muscle disorder (myopathy) in that age group. Despite growing awareness of this disorder, many researchers believe it remains underdiagnosed.Although sIBM does not occur with greater frequency in any specific ethnic or racial group, it apparently occurs less often in individuals of African descent.
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Related disorders of Sporadic Inclusion Body Myositis
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Symptoms of the following disorders can be similar to those of sIBM. Comparisons may be useful for a differential diagnosis.Familial inflammatory inclusion body myositis (fIBM) is an extremely rare condition that has been reported in multiple members of several different families. The symptoms of this disorder closely resemble those of sIBM including a later age of onset and a similar pattern of muscle involvement, especially the prominent involvement of the quadriceps muscle and the muscles of the fingers and hands. fIBM is likely the same disease as sIBM, but with some familial occurrence related to the presence of a common autoimmune HLA haplotype, as occurs with occasional familiarl clustering of other autoimmune diseases.Hereditary inclusion body myopathies (hIBM) are a rare group of genetic muscle disorders. As with individuals with sIBM, the muscle tissue of affected individuals contains numerous sub-cellular compartments called vacuoles. The age of onset of these disorders is generally between 20 and 40 years of age. Although the underlying damage to the muscles is similar among these disorders, the specific muscles involved, the progression, and associated symptoms vary. The severity of these disorders also varies even among individuals with the same disorder. The hereditary inclusion body myopathies may be inherited as autosomal dominant or recessive traits and are caused by mutations of specific genes. These heterogeneous diseases have no real resemblance to sIBM, and their naming as “inclusion body myopathies” is unfortunate and gives the mistaken impression that “sIBM” and “hIBM” are somehow similar diseases but with “sporadic” vs “hereditary” causes. In fact, sIBM is not a “sporadic” form of “hIBM”, but rather an entirely distinct autoimmune disease with nothing more than superficial relationships to the various forms of hIBM.Polymyositis is a rare inflammatory disease characterized by degenerative changes in muscles and supporting connective tissue. Muscle weakness may occur rapidly and affect the neck, trunk, and upper arms and legs. Joint pain, swelling, and tenderness may be present. Eventually, it becomes difficult for affected individuals to rise from a sitting position. Some individuals may have difficulty climbing stairs, lifting objects, and reaching overhead. The exact cause of polymyositis is unknown, although the interaction of genetic, viral, and environmental factors may play a role. (For more information on this disorder, choose “polymyositis” as your search term in the Rare Disease Database.)A wide variety of disorders are characterized by progressive muscle wasting and weakness that can potentially resemble sIBM. These disorders include dermatomyositis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDN), myofibrillar myopathies, amyotrophic lateral sclerosis, myotonic dystrophy, motor neuron disease, metabolic disorders such as Pompe disease, and the muscular dystrophies including oculopharyngeal muscular dystrophy and the distal myopathies. (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 Sporadic Inclusion Body Myositis. Symptoms of the following disorders can be similar to those of sIBM. Comparisons may be useful for a differential diagnosis.Familial inflammatory inclusion body myositis (fIBM) is an extremely rare condition that has been reported in multiple members of several different families. The symptoms of this disorder closely resemble those of sIBM including a later age of onset and a similar pattern of muscle involvement, especially the prominent involvement of the quadriceps muscle and the muscles of the fingers and hands. fIBM is likely the same disease as sIBM, but with some familial occurrence related to the presence of a common autoimmune HLA haplotype, as occurs with occasional familiarl clustering of other autoimmune diseases.Hereditary inclusion body myopathies (hIBM) are a rare group of genetic muscle disorders. As with individuals with sIBM, the muscle tissue of affected individuals contains numerous sub-cellular compartments called vacuoles. The age of onset of these disorders is generally between 20 and 40 years of age. Although the underlying damage to the muscles is similar among these disorders, the specific muscles involved, the progression, and associated symptoms vary. The severity of these disorders also varies even among individuals with the same disorder. The hereditary inclusion body myopathies may be inherited as autosomal dominant or recessive traits and are caused by mutations of specific genes. These heterogeneous diseases have no real resemblance to sIBM, and their naming as “inclusion body myopathies” is unfortunate and gives the mistaken impression that “sIBM” and “hIBM” are somehow similar diseases but with “sporadic” vs “hereditary” causes. In fact, sIBM is not a “sporadic” form of “hIBM”, but rather an entirely distinct autoimmune disease with nothing more than superficial relationships to the various forms of hIBM.Polymyositis is a rare inflammatory disease characterized by degenerative changes in muscles and supporting connective tissue. Muscle weakness may occur rapidly and affect the neck, trunk, and upper arms and legs. Joint pain, swelling, and tenderness may be present. Eventually, it becomes difficult for affected individuals to rise from a sitting position. Some individuals may have difficulty climbing stairs, lifting objects, and reaching overhead. The exact cause of polymyositis is unknown, although the interaction of genetic, viral, and environmental factors may play a role. (For more information on this disorder, choose “polymyositis” as your search term in the Rare Disease Database.)A wide variety of disorders are characterized by progressive muscle wasting and weakness that can potentially resemble sIBM. These disorders include dermatomyositis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDN), myofibrillar myopathies, amyotrophic lateral sclerosis, myotonic dystrophy, motor neuron disease, metabolic disorders such as Pompe disease, and the muscular dystrophies including oculopharyngeal muscular dystrophy and the distal myopathies. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Sporadic Inclusion Body Myositis
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The diagnosis of sIBM is made based upon a thorough clinical evaluation, a careful patient history, and a variety of specialized tests, such as a muscle biopsy. A muscle biopsy is a procedure in which a tiny amount of muscle tissue is surgically removed and studied under a microscope to detect characteristic changes that indicate sIBM. Additional tests that can be used to aid in a diagnosis include electromyography and blood tests that measure the amount of certain enzymes in muscle tissue. A blood test specifically for IBM was developed in 2013 and is now commercially available for diagnostic use.During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Elevated CK levels occur in some, but not all individuals affected with sIBM. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of sIBM. It is typically used to exclude a diagnosis of sIBM.
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Diagnosis of Sporadic Inclusion Body Myositis. The diagnosis of sIBM is made based upon a thorough clinical evaluation, a careful patient history, and a variety of specialized tests, such as a muscle biopsy. A muscle biopsy is a procedure in which a tiny amount of muscle tissue is surgically removed and studied under a microscope to detect characteristic changes that indicate sIBM. Additional tests that can be used to aid in a diagnosis include electromyography and blood tests that measure the amount of certain enzymes in muscle tissue. A blood test specifically for IBM was developed in 2013 and is now commercially available for diagnostic use.During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Elevated CK levels occur in some, but not all individuals affected with sIBM. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of sIBM. It is typically used to exclude a diagnosis of sIBM.
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Therapies of Sporadic Inclusion Body Myositis
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TreatmentThere is no cure for sIBM and the disorder generally does not respond to conventional therapies for autoimmune disorders such as corticosteroids or drugs that suppress the immune system (immunosuppressive drugs). Some individuals have responded to these therapies for a short period of time or to a minor degree (i.e., there is not a full recovery of muscle strength). The specific types of immunosuppressive drugs that have been used to treat individuals with sIBM include azathioprine, methotrexate, cyclosporine, and cyclophosphamide.Specific treatment options for affected individuals may include physical and occupational therapy to improve muscle strength and, when necessary, the use of various devices including braces, walkers or wheelchairs to assist with walking (ambulation).
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Therapies of Sporadic Inclusion Body Myositis. TreatmentThere is no cure for sIBM and the disorder generally does not respond to conventional therapies for autoimmune disorders such as corticosteroids or drugs that suppress the immune system (immunosuppressive drugs). Some individuals have responded to these therapies for a short period of time or to a minor degree (i.e., there is not a full recovery of muscle strength). The specific types of immunosuppressive drugs that have been used to treat individuals with sIBM include azathioprine, methotrexate, cyclosporine, and cyclophosphamide.Specific treatment options for affected individuals may include physical and occupational therapy to improve muscle strength and, when necessary, the use of various devices including braces, walkers or wheelchairs to assist with walking (ambulation).
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Overview of Sporadic Porencephaly
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Sporadic porencephaly is a rare disorder affecting the central nervous system. In porencephaly, cysts or cavities form on the surface of the brain. These cysts or cavities may become filled with cerebrospinal fluid, a colorless fluid that normally surrounds the brain and spinal cord to provide protection and nourishment. The severity and associated symptoms of porencephaly vary dramatically from one person to another based upon the size and exact locations of the fluid-filled cavities or cysts. Some infants develop serious complications shortly after birth; other individuals may have mild symptoms that may go undetected.Porencephaly may be classified as sporadic or familial. Sporadic porencephaly can have many different causes including infection just before or just after birth (perinatal infection), trauma, maternal disease or sickness, maternal diabetes, or maternal use of alcohol or drugs such as cocaine during pregnancy. A distinct genetic form of porencephaly (not covered in this report) occurs due to changes (variants or mutations) of the COL4A1 gene.The terminology regarding porencephaly used in the medical literature has caused confusion. Some researchers break down porencephaly into type I (also known as encephaloclastic porencephaly) and porencephaly type II (also known as schizencephaly).
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Overview of Sporadic Porencephaly. Sporadic porencephaly is a rare disorder affecting the central nervous system. In porencephaly, cysts or cavities form on the surface of the brain. These cysts or cavities may become filled with cerebrospinal fluid, a colorless fluid that normally surrounds the brain and spinal cord to provide protection and nourishment. The severity and associated symptoms of porencephaly vary dramatically from one person to another based upon the size and exact locations of the fluid-filled cavities or cysts. Some infants develop serious complications shortly after birth; other individuals may have mild symptoms that may go undetected.Porencephaly may be classified as sporadic or familial. Sporadic porencephaly can have many different causes including infection just before or just after birth (perinatal infection), trauma, maternal disease or sickness, maternal diabetes, or maternal use of alcohol or drugs such as cocaine during pregnancy. A distinct genetic form of porencephaly (not covered in this report) occurs due to changes (variants or mutations) of the COL4A1 gene.The terminology regarding porencephaly used in the medical literature has caused confusion. Some researchers break down porencephaly into type I (also known as encephaloclastic porencephaly) and porencephaly type II (also known as schizencephaly).
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Symptoms of Sporadic Porencephaly
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The symptoms and severity of sporadic porencephaly vary greatly from one individual to another based on the size and exact location of the fluid-filled cyst or cavity. Some individuals may only have minor physical complications and intelligence may be unaffected; others can have severe, disabling complications.Symptoms that can potentially develop in association with porencephaly include delays in growth and development, diminished muscle tone (hypotonia), seizures, and microcephaly or macrocephaly, conditions in which head circumference is either smaller (micro) or larger (macro) than would be expected in a child based upon age and weight.Additional findings that have been reported with porencephaly include poor speech development or absent speech, paralysis of one side of the body (hemiplegia), abnormal tightening or shortening of certain muscles, resulting in restricted or stiff movements (contractures) and varying degrees of intellectual disability. Some individuals develop hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms.
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Symptoms of Sporadic Porencephaly. The symptoms and severity of sporadic porencephaly vary greatly from one individual to another based on the size and exact location of the fluid-filled cyst or cavity. Some individuals may only have minor physical complications and intelligence may be unaffected; others can have severe, disabling complications.Symptoms that can potentially develop in association with porencephaly include delays in growth and development, diminished muscle tone (hypotonia), seizures, and microcephaly or macrocephaly, conditions in which head circumference is either smaller (micro) or larger (macro) than would be expected in a child based upon age and weight.Additional findings that have been reported with porencephaly include poor speech development or absent speech, paralysis of one side of the body (hemiplegia), abnormal tightening or shortening of certain muscles, resulting in restricted or stiff movements (contractures) and varying degrees of intellectual disability. Some individuals develop hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms.
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Causes of Sporadic Porencephaly
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Sporadic porencephaly is caused by damage to the cerebral hemispheres of the brain, which results in the formation of fluid-filled cavities or cysts on the surface of the brain. Researchers believe that the damage or loss of brain tissue that characterizes porencephaly results from infection, interrupted or obstructed blood flow (ischemia) to the brain, or bleeding (hemorrhaging) in the brain.A variety of different conditions can potentially cause the localized brain tissue degeneration that ultimately leads to sporadic porencephaly. Such conditions include infection just before or shortly after birth (perinatal infection), too little oxygen in the body just before or shortly after birth (perinatal asphyxia), birth trauma, drug or alcohol use by the mother during pregnancy, maternal sickness or infection, maternal diabetes, or injury or trauma (particularly to the abdominal area) to the mother during pregnancy.Rarely, porencephaly has associated with performance of diagnostic techniques known as amniocentesis and chorionic villus sampling. Amniocentesis and chorionic villus sampling may be performed during pregnancy to detect certain problems in a fetus such as chromosomal abnormalities or certain genetic disorders. During an amniocentesis procedure, a small amount of amniotic fluid is removed from the sac that surrounds the fetus and studied. During chorionic villus sampling, tissue is removed from the placenta and certain cells called chorionic villi are studied.Disorders that increase the bleeding tendency in newborns have also been linked to porencephaly. These disorders include neonatal alloimmune thrombocytopenia, von Willebrand’s disease, and maternal use of the drug warfarin (a blood thinner). Neonatal alloimmune thrombocytopenia is a disorder in which antibodies from the mother attack a newborn’s platelets (cells that assist in forming blood clots). Von Willebrand’s disease is an inherited bleeding disorder that results in prolonged bleeding.Porencephaly is usually sporadic and the risk of recurrence in subsequent pregnancies is unlikely. However, in some patients, genetic factors may play a role in the development of porencephaly. For example, porencephaly is believed to occur with greater frequency than in the general population in individuals with disorders that promote excess blood clotting (thrombophilia). Such disorders include factor V Leiden or protein C deficiency.A specific form of porencephaly, known as autosomal dominant porencephaly type I, is a rare disorder caused by variants of the COL4A1 gene.
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Causes of Sporadic Porencephaly. Sporadic porencephaly is caused by damage to the cerebral hemispheres of the brain, which results in the formation of fluid-filled cavities or cysts on the surface of the brain. Researchers believe that the damage or loss of brain tissue that characterizes porencephaly results from infection, interrupted or obstructed blood flow (ischemia) to the brain, or bleeding (hemorrhaging) in the brain.A variety of different conditions can potentially cause the localized brain tissue degeneration that ultimately leads to sporadic porencephaly. Such conditions include infection just before or shortly after birth (perinatal infection), too little oxygen in the body just before or shortly after birth (perinatal asphyxia), birth trauma, drug or alcohol use by the mother during pregnancy, maternal sickness or infection, maternal diabetes, or injury or trauma (particularly to the abdominal area) to the mother during pregnancy.Rarely, porencephaly has associated with performance of diagnostic techniques known as amniocentesis and chorionic villus sampling. Amniocentesis and chorionic villus sampling may be performed during pregnancy to detect certain problems in a fetus such as chromosomal abnormalities or certain genetic disorders. During an amniocentesis procedure, a small amount of amniotic fluid is removed from the sac that surrounds the fetus and studied. During chorionic villus sampling, tissue is removed from the placenta and certain cells called chorionic villi are studied.Disorders that increase the bleeding tendency in newborns have also been linked to porencephaly. These disorders include neonatal alloimmune thrombocytopenia, von Willebrand’s disease, and maternal use of the drug warfarin (a blood thinner). Neonatal alloimmune thrombocytopenia is a disorder in which antibodies from the mother attack a newborn’s platelets (cells that assist in forming blood clots). Von Willebrand’s disease is an inherited bleeding disorder that results in prolonged bleeding.Porencephaly is usually sporadic and the risk of recurrence in subsequent pregnancies is unlikely. However, in some patients, genetic factors may play a role in the development of porencephaly. For example, porencephaly is believed to occur with greater frequency than in the general population in individuals with disorders that promote excess blood clotting (thrombophilia). Such disorders include factor V Leiden or protein C deficiency.A specific form of porencephaly, known as autosomal dominant porencephaly type I, is a rare disorder caused by variants of the COL4A1 gene.
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Sporadic Porencephaly
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Affects of Sporadic Porencephaly
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The prevalence of sporadic porencephaly in the general population is unknown. Some researchers believe that some patients may go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. Sporadic porencephaly affects males and females in equal numbers.
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Affects of Sporadic Porencephaly. The prevalence of sporadic porencephaly in the general population is unknown. Some researchers believe that some patients may go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. Sporadic porencephaly affects males and females in equal numbers.
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Related disorders of Sporadic Porencephaly
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Symptoms of the following disorders can be similar to those of sporadic porencephaly. Comparisons may be useful for a differential diagnosis.Arachnoid cysts are fluid-filled sacs that occur on the arachnoid membrane that covers the brain (intracranial) and the spinal cord (spinal). There are three membranes covering these components of the central nervous system: dura mater, arachnoid and pia mater. Arachnoid cysts appear on the arachnoid membrane, and they may also expand into the space between the pia mater and arachnoid membranes (subarachnoid space). The most common locations for intracranial arachnoid cysts are the middle fossa (near the temporal lobe), the suprasellar region (near the third ventricle) and the posterior fossa, which contains the cerebellum, pons and medulla oblongata. In many cases, arachnoid cysts do not cause symptoms (asymptomatic). In cases in which symptoms occur, headaches, seizures and abnormal accumulation of excessive cerebrospinal fluid in the brain (hydrocephalus) are common. The exact cause of arachnoid cysts is unknown. (For more information on this disorder, choose “arachnoid cysts” as your search term in the Rare Disease Database.)Cephalic disorders are a group of disorders characterized by damage to or abnormal development of the central nervous system. Cephalic disorders include anencephaly, holoprosencephaly, hydranencephaly, lissencephaly, megalencephaly and schizencephaly. Schizencephaly is sometimes called porencephaly type II. In most patients, cephalic disorders occur during the development of the fetal central nervous system. A variety of different factors may play a role in the development of cephalic disorders including genetic and environmental factors. The symptoms and severity of cephalic disorders vary greatly from one person to another based upon the size and exact location of cephalic disorders. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)Autosomal dominant porencephaly type I is a rare genetic disorder in which the characteristic fluid-filled cysts and cavities are caused by variants of the COL4A1 gene. The specific symptoms and severity of autosomal dominant porencephaly type I vary greatly from one person to another based on the size and location of a porencepahlic cyst or cavity. The symptoms are similar to those associated with sporadic porencephaly. Some individuals with autosomal dominant porencephaly type I have additional symptoms related to two other disorders, brain small vessel disease and hereditary angiopathy with neuropathy, aneurysms and muscle cramps, which are also caused by variants of the COL4A1 gene. These three disorders represent a spectrum or continuum of disease with overlapping features. (For more information on this disorder, choose “porencephaly” as your search term in the Rare Disease Database.)
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Related disorders of Sporadic Porencephaly. Symptoms of the following disorders can be similar to those of sporadic porencephaly. Comparisons may be useful for a differential diagnosis.Arachnoid cysts are fluid-filled sacs that occur on the arachnoid membrane that covers the brain (intracranial) and the spinal cord (spinal). There are three membranes covering these components of the central nervous system: dura mater, arachnoid and pia mater. Arachnoid cysts appear on the arachnoid membrane, and they may also expand into the space between the pia mater and arachnoid membranes (subarachnoid space). The most common locations for intracranial arachnoid cysts are the middle fossa (near the temporal lobe), the suprasellar region (near the third ventricle) and the posterior fossa, which contains the cerebellum, pons and medulla oblongata. In many cases, arachnoid cysts do not cause symptoms (asymptomatic). In cases in which symptoms occur, headaches, seizures and abnormal accumulation of excessive cerebrospinal fluid in the brain (hydrocephalus) are common. The exact cause of arachnoid cysts is unknown. (For more information on this disorder, choose “arachnoid cysts” as your search term in the Rare Disease Database.)Cephalic disorders are a group of disorders characterized by damage to or abnormal development of the central nervous system. Cephalic disorders include anencephaly, holoprosencephaly, hydranencephaly, lissencephaly, megalencephaly and schizencephaly. Schizencephaly is sometimes called porencephaly type II. In most patients, cephalic disorders occur during the development of the fetal central nervous system. A variety of different factors may play a role in the development of cephalic disorders including genetic and environmental factors. The symptoms and severity of cephalic disorders vary greatly from one person to another based upon the size and exact location of cephalic disorders. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)Autosomal dominant porencephaly type I is a rare genetic disorder in which the characteristic fluid-filled cysts and cavities are caused by variants of the COL4A1 gene. The specific symptoms and severity of autosomal dominant porencephaly type I vary greatly from one person to another based on the size and location of a porencepahlic cyst or cavity. The symptoms are similar to those associated with sporadic porencephaly. Some individuals with autosomal dominant porencephaly type I have additional symptoms related to two other disorders, brain small vessel disease and hereditary angiopathy with neuropathy, aneurysms and muscle cramps, which are also caused by variants of the COL4A1 gene. These three disorders represent a spectrum or continuum of disease with overlapping features. (For more information on this disorder, choose “porencephaly” as your search term in the Rare Disease Database.)
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Diagnosis of Sporadic Porencephaly
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A diagnosis of sporadic porencephaly can be made before or after birth through a variety of specialized imaging tests such as an ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI). During an ultrasound, reflected sound waves are used to make an image of the developing fetus. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues.
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Diagnosis of Sporadic Porencephaly. A diagnosis of sporadic porencephaly can be made before or after birth through a variety of specialized imaging tests such as an ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI). During an ultrasound, reflected sound waves are used to make an image of the developing fetus. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues.
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Therapies of Sporadic Porencephaly
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Treatment
The treatment of sporadic porencephaly is geared toward the specific symptoms that are present in each individual. Treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures and a shunt to treat hydrocephalus by draining excess fluid from the skull.Early intervention is important in ensuring that children with sporadic porencephaly reach their highest potential. Services that may be beneficial for some affected individuals include medical, social and/or vocational services such as special remedial education.
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Therapies of Sporadic Porencephaly. Treatment
The treatment of sporadic porencephaly is geared toward the specific symptoms that are present in each individual. Treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures and a shunt to treat hydrocephalus by draining excess fluid from the skull.Early intervention is important in ensuring that children with sporadic porencephaly reach their highest potential. Services that may be beneficial for some affected individuals include medical, social and/or vocational services such as special remedial education.
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Overview of Sprengel Deformity
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Sprengel deformity is a rare congenital disorder in which the shoulder blade (scapula) is too high on one side of the body. The affected abnormal shoulder blade is also abnormally connected to the spine, often restricting movement of the shoulder. The affected shoulder blade may also be underdeveloped and smaller than normal and rotated toward the middle of the body. In some cases, the shoulder blade may be irregularly-shaped (dysplastic). In addition, a lump may develop at the base of the neck. Sprengel deformity can occur as an isolated, single defect or in association with other abnormalities. The disorder is typically present at birth (congenital), although it may not become apparent until an affected individual grows older. The exact, underlying cause of Sprengel deformity is unknown. The disorder appears to occur randomly, for no apparent reason (sporadically), although some rare cases have run in families.
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Overview of Sprengel Deformity. Sprengel deformity is a rare congenital disorder in which the shoulder blade (scapula) is too high on one side of the body. The affected abnormal shoulder blade is also abnormally connected to the spine, often restricting movement of the shoulder. The affected shoulder blade may also be underdeveloped and smaller than normal and rotated toward the middle of the body. In some cases, the shoulder blade may be irregularly-shaped (dysplastic). In addition, a lump may develop at the base of the neck. Sprengel deformity can occur as an isolated, single defect or in association with other abnormalities. The disorder is typically present at birth (congenital), although it may not become apparent until an affected individual grows older. The exact, underlying cause of Sprengel deformity is unknown. The disorder appears to occur randomly, for no apparent reason (sporadically), although some rare cases have run in families.
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Sprengel Deformity
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