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nord_842_6
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Therapies of Multiple Sulfatase Deficiency
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There are currently no targeted therapies for MSD, and treatment is supportive and based upon symptoms. Care for patients with MSD requires a multidisciplinary team to evaluate the many body systems that may be affected by this disease. Due to the very broad spectrum of clinical problems a comprehensive approach is recommended. Depending on the needs of the child, important members of the team may include neurology and/or metabolism, complex care pediatrics, gastroenterology, nutrition, urology, orthopedics, and physiatry.The neurologic delay and regression is the most common symptom shared by patients with MSD. Early evaluation and intervention by physical, occupational, and speech therapy can be helpful to manage the symptoms of MSD and maximize mobility and communication.
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Therapies of Multiple Sulfatase Deficiency. There are currently no targeted therapies for MSD, and treatment is supportive and based upon symptoms. Care for patients with MSD requires a multidisciplinary team to evaluate the many body systems that may be affected by this disease. Due to the very broad spectrum of clinical problems a comprehensive approach is recommended. Depending on the needs of the child, important members of the team may include neurology and/or metabolism, complex care pediatrics, gastroenterology, nutrition, urology, orthopedics, and physiatry.The neurologic delay and regression is the most common symptom shared by patients with MSD. Early evaluation and intervention by physical, occupational, and speech therapy can be helpful to manage the symptoms of MSD and maximize mobility and communication.
| 842 |
Multiple Sulfatase Deficiency
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nord_843_0
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Overview of Multiple System Atrophy
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Multiple system atrophy (MSA) is a rare sporadic progressive neurological disorder characterized by a varying combination of symptoms and signs. Onset is during adulthood (>30 years). Affected individuals may experience symptoms similar to those found in Parkinson’s disease (parkinsonism); cerebellar signs such as progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia); and impaired functioning of the portion of the nervous system (autonomic nervous system) that regulates certain involuntary body functions (autonomic failure) such as heart rate, blood pressure, sweating, and bowel and bladder control. When parkinsonian symptoms predominate, the disorder may be referred to as MSA-P (parkinsonian phenotype); when the cerebellar symptoms predominate the disorder may be referred to as MSA-C (cerebellar phenotype). The exact cause of MSA is unknown.The term multiple system atrophy was first introduced in the medical literature in 1969. It encompasses three presentations of a single disease formerly thought to be separate disorders, specifically Shy-Drager syndrome (which emphasized autonomic dysfunction), striatonigral degeneration (which emphasized parkinsonian symptoms), and sporadic olivopontocerebellar atrophy (which emphasized cerebellar symptoms), although the cases of each of these that were originally described presented a combination of all three clinical features, and brain pathology was found in both the striatonigral and olivopontocerebellar structures. Additionally, there is a hereditary form of olivopontocerebellar atrophy that is not part of the multiple system atrophy spectrum.
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Overview of Multiple System Atrophy. Multiple system atrophy (MSA) is a rare sporadic progressive neurological disorder characterized by a varying combination of symptoms and signs. Onset is during adulthood (>30 years). Affected individuals may experience symptoms similar to those found in Parkinson’s disease (parkinsonism); cerebellar signs such as progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia); and impaired functioning of the portion of the nervous system (autonomic nervous system) that regulates certain involuntary body functions (autonomic failure) such as heart rate, blood pressure, sweating, and bowel and bladder control. When parkinsonian symptoms predominate, the disorder may be referred to as MSA-P (parkinsonian phenotype); when the cerebellar symptoms predominate the disorder may be referred to as MSA-C (cerebellar phenotype). The exact cause of MSA is unknown.The term multiple system atrophy was first introduced in the medical literature in 1969. It encompasses three presentations of a single disease formerly thought to be separate disorders, specifically Shy-Drager syndrome (which emphasized autonomic dysfunction), striatonigral degeneration (which emphasized parkinsonian symptoms), and sporadic olivopontocerebellar atrophy (which emphasized cerebellar symptoms), although the cases of each of these that were originally described presented a combination of all three clinical features, and brain pathology was found in both the striatonigral and olivopontocerebellar structures. Additionally, there is a hereditary form of olivopontocerebellar atrophy that is not part of the multiple system atrophy spectrum.
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Multiple System Atrophy
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nord_843_1
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Symptoms of Multiple System Atrophy
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The range, severity, and distribution of symptoms vary greatly among affected individuals. For example, some may initially have only mild symptoms for several years; others may experience severe symptoms early in the course of the disease. Symptoms of MSA may vary depending upon which form of MSA predominates. The disorder can cause the progressive loss of motor skills and approximately 50% of individuals are wheelchair-bound within 5-6 years of the onset of motor symptoms. Eventually, affected individuals may become confined to bed and experience life-threatening complications.Some affected individuals experience fatigue; a complaint of weakness, especially of the legs; blurred vision; and impaired bladder and bowel control including involuntary urination or defecation (urinary and rectal incontinence). Additional bladder disturbances may occur including the need to pass water at night, increased daytime frequency of urinating, an increased urgency to urinate, and incomplete bladder emptying. Erectile dysfunction is almost universal, and typically early, in affected males. Constipation may also be present. The skin may become extremely dry as a result of a decreased ability to sweat (anhidrosis). All cases of MSA will eventually develop some form of autonomic dysfunction (urogenital, cardiovascular, or both).The symptoms mentioned above may be preceded or followed by neurological findings that are similar to those found in individuals with Parkinson’s disease (parkinsonism). Approximately 90 percent of individuals with MSA will experience parkinsonism symptoms including slowness of voluntary movements (bradykinesia), muscle stiffness (rigidity) which may make it difficult to bend the arms and/or legs, and impaired balance (postural instability). Two thirds of patients have a tremor or jerky movements (myoclonus) of the hands or fingers, but rarely (<10%) the classical “pill-rolling” rest tremor characteristic of most cases of Parkinson’s disease..In approximately 20 percent of MSA cases, cerebellar signs may be the initial findings. These comprise progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), progressive balance problems (disequilibrium), slurred speech (dysarthria), and jerkiness of following eye movements (nystagmus).Additional neurological findings may include exaggerated reflexes (hyperreflexia); and increased muscle tone (spasticity), collectively called pyramidal signs, that can contribute to slowness and stiffness; and involuntary sustained muscle spasms (dystonia) of face, jaw, neck, trunk or limbs causing abnormal, sometimes painful, movements and postures, often involving neck flexion (antecollis) and flexion (“camptocormi”) or curvature (“Pisa syndrome”) of the spine.When divided into the predominance of parkinsonism and cerebellar features, in most parts of the world MSA-P predominates, with 60-80% of cases in different series. However, for unknown reasons MSA-C predominates in Japan with a ratio to MSA-P of about 4:1. As regards initial symptoms, 20-40% of subjects develop autonomic symptoms before other neurological features are detected.As MSA progresses, functions controlled by the autonomic nervous system become increasingly impaired. Individuals with MSA may develop vocal cord paralysis resulting in hoarseness and high-pitched, noisy respiration (stridor). In some cases, periodic episodes in which breathing is interrupted during sleep (apnea) may develop. (For more information on apnea, choose “sleep apnea” as your search term in the Rare Disease Database.) Irregular heart rhythms may also develop. Some individuals may develop painfully cold fingers and toes caused by constriction of small vessels in response to cold (Raynaud's phenomenon).Additional sleep disorders such as REM sleep behavior disorder (RBD) occur in many individuals with MSA, but RBD is also common, but less so, in PD. Normally, people cannot move during REM sleep, but in RBD they can move and often act out their dreams potentially resulting in self-injury, or injuring their bed-partner.In some cases, individuals with MSA experience a mild loss of cognitive ability although, unlike Parkinson’s disease, frank dementia is uncommon. In addition, chewing, swallowing, and speaking may become more difficult as the disorder progresses. The symptoms associated with MSA are progressive so that affected individuals may ultimately become unable to walk unassisted, or require a wheelchair, lose the ability to speak or swallow, or develop severe respiratory complications. Continued neurological degeneration can potentially result in severe, life-threatening complications such as aspiration pneumonia or deep vein thrombosis and pulmonary embolism, secondary to immobility.
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Symptoms of Multiple System Atrophy. The range, severity, and distribution of symptoms vary greatly among affected individuals. For example, some may initially have only mild symptoms for several years; others may experience severe symptoms early in the course of the disease. Symptoms of MSA may vary depending upon which form of MSA predominates. The disorder can cause the progressive loss of motor skills and approximately 50% of individuals are wheelchair-bound within 5-6 years of the onset of motor symptoms. Eventually, affected individuals may become confined to bed and experience life-threatening complications.Some affected individuals experience fatigue; a complaint of weakness, especially of the legs; blurred vision; and impaired bladder and bowel control including involuntary urination or defecation (urinary and rectal incontinence). Additional bladder disturbances may occur including the need to pass water at night, increased daytime frequency of urinating, an increased urgency to urinate, and incomplete bladder emptying. Erectile dysfunction is almost universal, and typically early, in affected males. Constipation may also be present. The skin may become extremely dry as a result of a decreased ability to sweat (anhidrosis). All cases of MSA will eventually develop some form of autonomic dysfunction (urogenital, cardiovascular, or both).The symptoms mentioned above may be preceded or followed by neurological findings that are similar to those found in individuals with Parkinson’s disease (parkinsonism). Approximately 90 percent of individuals with MSA will experience parkinsonism symptoms including slowness of voluntary movements (bradykinesia), muscle stiffness (rigidity) which may make it difficult to bend the arms and/or legs, and impaired balance (postural instability). Two thirds of patients have a tremor or jerky movements (myoclonus) of the hands or fingers, but rarely (<10%) the classical “pill-rolling” rest tremor characteristic of most cases of Parkinson’s disease..In approximately 20 percent of MSA cases, cerebellar signs may be the initial findings. These comprise progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), progressive balance problems (disequilibrium), slurred speech (dysarthria), and jerkiness of following eye movements (nystagmus).Additional neurological findings may include exaggerated reflexes (hyperreflexia); and increased muscle tone (spasticity), collectively called pyramidal signs, that can contribute to slowness and stiffness; and involuntary sustained muscle spasms (dystonia) of face, jaw, neck, trunk or limbs causing abnormal, sometimes painful, movements and postures, often involving neck flexion (antecollis) and flexion (“camptocormi”) or curvature (“Pisa syndrome”) of the spine.When divided into the predominance of parkinsonism and cerebellar features, in most parts of the world MSA-P predominates, with 60-80% of cases in different series. However, for unknown reasons MSA-C predominates in Japan with a ratio to MSA-P of about 4:1. As regards initial symptoms, 20-40% of subjects develop autonomic symptoms before other neurological features are detected.As MSA progresses, functions controlled by the autonomic nervous system become increasingly impaired. Individuals with MSA may develop vocal cord paralysis resulting in hoarseness and high-pitched, noisy respiration (stridor). In some cases, periodic episodes in which breathing is interrupted during sleep (apnea) may develop. (For more information on apnea, choose “sleep apnea” as your search term in the Rare Disease Database.) Irregular heart rhythms may also develop. Some individuals may develop painfully cold fingers and toes caused by constriction of small vessels in response to cold (Raynaud's phenomenon).Additional sleep disorders such as REM sleep behavior disorder (RBD) occur in many individuals with MSA, but RBD is also common, but less so, in PD. Normally, people cannot move during REM sleep, but in RBD they can move and often act out their dreams potentially resulting in self-injury, or injuring their bed-partner.In some cases, individuals with MSA experience a mild loss of cognitive ability although, unlike Parkinson’s disease, frank dementia is uncommon. In addition, chewing, swallowing, and speaking may become more difficult as the disorder progresses. The symptoms associated with MSA are progressive so that affected individuals may ultimately become unable to walk unassisted, or require a wheelchair, lose the ability to speak or swallow, or develop severe respiratory complications. Continued neurological degeneration can potentially result in severe, life-threatening complications such as aspiration pneumonia or deep vein thrombosis and pulmonary embolism, secondary to immobility.
| 843 |
Multiple System Atrophy
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nord_843_2
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Causes of Multiple System Atrophy
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The exact underlying cause of MSA is unknown. It appears to occur randomly for unknown reasons (sporadically). Researchers have suggested that multiple environmental or genetic factors are important, but more research is needed.PathologyMSA is characterized by progressive loss of nerve cells (neurons) in various structures of the brain. Gliosis is present and structures or “bodies” known as glial cytoplasmic inclusions (GCIs) develop which are always present in the MSA brain, and are unique to this disease. Gliosis is characterized by the proliferation of astrocytes in damaged areas of the central nervous system. Astrocytes are star-shaped cells that form the supportive tissue of the brain. The proliferation of astrocytes causes scarring in the affected areas of the brain.GCIs are abnormal structures within the brain that contain clumps of proteins. These GCIs accumulate a specific protein known as alpha-synuclein. Although the exact function of alpha-synuclein is not fully understood, researchers believe that this protein is overexpressed in individuals with MSA and may have a toxic effect on the brain, so it is believed to play a central role in the development of MSA.Researchers have been searching for variations in the alpha-synuclein (SNCA) gene that may lead to an increased risk of developing MSA. Accumulation of alpha-synuclein in the brain has also been seen in other neurological disorders such as Parkinson’s disease and dementia with Lewy bodies. These disorders are sometimes collectively referred to as “synucleinopathies”.More research is necessary to determine the exact role that alpha-synuclein plays in the development of MSA and to fully understand the complex, underlying mechanisms that ultimately lead to the disorder.Evolution of TerminologyThe older names for MSA, specifically striatonigral degeneration and olivopontocerebellar atrophy, referred to the areas of the brain that were most affected.Striatonigral degeneration refers to a disruption of communication between nerve cells within two structures of the brain involved with movement and balance known as the substantia nigra and the striatum.Olivopontocerebellar atrophy refers to specific structures of the brain known as the olives, pons and cerebellum. The inferior olives are two small round structures in the medulla, the lowest part of the brainstem. The pons is part of the brainstem and contains important neuronal pathways between the cerebrum, spinal cord, and cerebellum, and serves as a relay point for messages between these structures. The cerebellum is a part of the brain that controls balance and posture as well as coordinating voluntary movement.The term Shy-Drager syndrome was used to refer to cases of SND or OPCA in which autonomic failure was prominent, and there was associated neuronal loss in intermediolateral cell columns and Onuf’s nucleus in the spinal cord.The combination of parkinsonism with autonomic failure is present in a very high proportion of MSA cases. It is seen in a much lower proportion of Parkinson’s disease (PD) patients but, because PD is 40 times commoner than MSA in total, PD is the more common cause of this combination.
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Causes of Multiple System Atrophy. The exact underlying cause of MSA is unknown. It appears to occur randomly for unknown reasons (sporadically). Researchers have suggested that multiple environmental or genetic factors are important, but more research is needed.PathologyMSA is characterized by progressive loss of nerve cells (neurons) in various structures of the brain. Gliosis is present and structures or “bodies” known as glial cytoplasmic inclusions (GCIs) develop which are always present in the MSA brain, and are unique to this disease. Gliosis is characterized by the proliferation of astrocytes in damaged areas of the central nervous system. Astrocytes are star-shaped cells that form the supportive tissue of the brain. The proliferation of astrocytes causes scarring in the affected areas of the brain.GCIs are abnormal structures within the brain that contain clumps of proteins. These GCIs accumulate a specific protein known as alpha-synuclein. Although the exact function of alpha-synuclein is not fully understood, researchers believe that this protein is overexpressed in individuals with MSA and may have a toxic effect on the brain, so it is believed to play a central role in the development of MSA.Researchers have been searching for variations in the alpha-synuclein (SNCA) gene that may lead to an increased risk of developing MSA. Accumulation of alpha-synuclein in the brain has also been seen in other neurological disorders such as Parkinson’s disease and dementia with Lewy bodies. These disorders are sometimes collectively referred to as “synucleinopathies”.More research is necessary to determine the exact role that alpha-synuclein plays in the development of MSA and to fully understand the complex, underlying mechanisms that ultimately lead to the disorder.Evolution of TerminologyThe older names for MSA, specifically striatonigral degeneration and olivopontocerebellar atrophy, referred to the areas of the brain that were most affected.Striatonigral degeneration refers to a disruption of communication between nerve cells within two structures of the brain involved with movement and balance known as the substantia nigra and the striatum.Olivopontocerebellar atrophy refers to specific structures of the brain known as the olives, pons and cerebellum. The inferior olives are two small round structures in the medulla, the lowest part of the brainstem. The pons is part of the brainstem and contains important neuronal pathways between the cerebrum, spinal cord, and cerebellum, and serves as a relay point for messages between these structures. The cerebellum is a part of the brain that controls balance and posture as well as coordinating voluntary movement.The term Shy-Drager syndrome was used to refer to cases of SND or OPCA in which autonomic failure was prominent, and there was associated neuronal loss in intermediolateral cell columns and Onuf’s nucleus in the spinal cord.The combination of parkinsonism with autonomic failure is present in a very high proportion of MSA cases. It is seen in a much lower proportion of Parkinson’s disease (PD) patients but, because PD is 40 times commoner than MSA in total, PD is the more common cause of this combination.
| 843 |
Multiple System Atrophy
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nord_843_3
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Affects of Multiple System Atrophy
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MSA appears to affect males and females in equal numbers. The peak onset of MSA is between 55-60 years of age, with a range from 30 to over 90 years. The incidence of MSA in the United States is estimated at 0.6 cases per 100,000 people per year in the general population giving a current estimate of about 1,900 new cases per year in the USA. A prevalence study in London, UK, gave an age-adjusted figure of 4.4 living cases per 100,000 population at any one time, which would currently translate to about 14,000 living cases in the USA. There is about 1 living case of MSA in the population for every 40 cases of Parkinson’s disease, but because survival in MSA is shorter than for PD, about 1 new MSA case presents every year for about every 20 who present with PD.
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Affects of Multiple System Atrophy. MSA appears to affect males and females in equal numbers. The peak onset of MSA is between 55-60 years of age, with a range from 30 to over 90 years. The incidence of MSA in the United States is estimated at 0.6 cases per 100,000 people per year in the general population giving a current estimate of about 1,900 new cases per year in the USA. A prevalence study in London, UK, gave an age-adjusted figure of 4.4 living cases per 100,000 population at any one time, which would currently translate to about 14,000 living cases in the USA. There is about 1 living case of MSA in the population for every 40 cases of Parkinson’s disease, but because survival in MSA is shorter than for PD, about 1 new MSA case presents every year for about every 20 who present with PD.
| 843 |
Multiple System Atrophy
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nord_843_4
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Related disorders of Multiple System Atrophy
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Symptoms of the following disorders can be similar to those of MSA. Comparisons may be useful for a differential diagnosis:Parkinson’s disease (PD) is a slowly progressive neurologic movement disorder characterized by involuntary, resting tremor, muscular stiffness or lack of flexibility (rigidity), slowness of movement (bradykinesia) and difficulty controlling voluntary movements. It also commonly causes autonomic symptoms and, in advanced, older, patients, dementia. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), resulting in decreasing levels of the neurotransmitter dopamine in the brain. Dopamine is a highly specialized brain chemical that sends a signal to other nerve cells, and participates in the regulation of body movements. Parkinson’s disease usually begins in late adulthood. It is slowly progressive; however, it may not become incapacitating for many years. (For more information on this disorder, choose “Parkinson’s disease” as your search term in the Rare Disease Database.)Symptoms similar to those of PD (parkinsonian symptoms) may also develop secondary to hydrocephalus (a condition in which excessive cerebrospinal fluid accumulates the spaces in the brain [ventricles], increasing pressure in the brain. Parkinsonian symptoms may also occur as a result of head trauma, inflammation of the brain (encephalitis), strokes (infarcts), or tumors deep within the cerebral hemispheres (cerebrum) and base of the brain (i.e., basal ganglia), or exposure to certain drugs and toxins.Progressive supranuclear palsy (PSP) is a rare degenerative neurological disorder characterized by postural instability and falls, often backwards, loss of control of voluntary eye movement (supranuclear gaze palsy, or SNGP), impaired voluntary muscle activity (akinesia), abnormal stiffness (rigidity), speech difficulties (dysarthria), and problems related to swallowing and eating (dysphagia). Affected individuals frequently experience personality changes and some degree of cognitive impairment. The exact cause of progressive supranuclear palsy is unknown. Unlike MSA, in which alpha-synuclein accumulates in the brain, a different protein called tau accumulates in PSP (and also CBD – see below), so they are known as “tauopathies”. Prevalence is a bit higher than MSA, at about 6 per 100,000. Mean onset age is 60-65 years. (For more information on this disorder, choose “progressive supranuclear palsy” as your search term in the Rare Disease Database.)Corticobasal degeneration (CBD) is an even rarer progressive neurological disorder characterized by cell loss and shrinkage (atrophy) in certain areas of the brain (cerebral cortex and substantia nigra). Affected individuals may have sufficient muscle power for manual tasks but often have difficulty directing their movements appropriately (apraxia). Initial symptoms typically appear in people during the seventh decade, and may include poor coordination, difficulty accomplishing goal-directed tasks (e.g., buttoning a shirt), and/or difficulty pantomiming actions. Symptoms usually begin on one side of the body (unilateral), but both sides are affected as the disease progresses. Cognitive impairment (e.g., memory loss) and/or visual-spatial impairments often develop. The exact cause of corticobasal degeneration is unknown. (For more information on this disorder, choose “corticobasal degeneration” as your search term in the Rare Disease Database.)Hereditary olivopontocerebellar atrophy (OPCA) describes a rare group of disorders characterized by progressive balance problems (disequilibrium), progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), and difficulty speaking or slurred speech (dysarthria). Additional symptoms may include generalized weakness, difficulty swallowing (dysphagia), and/or the progressive loss of intellectual abilities and mental deterioration (dementia). There are at least five distinct forms of hereditary OPCA. All forms of hereditary OPCA, except one, are inherited as autosomal dominant traits. (For more information on this disorder, choose “olivopontocerebellar atrophy” as your search term in the Rare Disease Database.)Pure autonomic failure (PAF) is very rare, and characterized by orthostatic hypotension that has been present for 5 years or more without other evidence of a neurological condition. Orthostatic hypotension is a condition in which an excessive decrease in blood pressure occurs upon standing potentially resulting in dizziness or momentary loss of consciousness (syncope). Additional symptoms associated with autonomic failure include fatigue; blurred vision; impaired bladder and bowel control; and impotence. In some cases, the skin may become extremely dry as a result of decreased ability to sweat. The exact cause of PAF is usually due to Lewy body pathology in the brainstem and autonomic ganglia.
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Related disorders of Multiple System Atrophy. Symptoms of the following disorders can be similar to those of MSA. Comparisons may be useful for a differential diagnosis:Parkinson’s disease (PD) is a slowly progressive neurologic movement disorder characterized by involuntary, resting tremor, muscular stiffness or lack of flexibility (rigidity), slowness of movement (bradykinesia) and difficulty controlling voluntary movements. It also commonly causes autonomic symptoms and, in advanced, older, patients, dementia. Degenerative changes occur in areas deep within the brain (substantia nigra and other pigmented regions of the brain), resulting in decreasing levels of the neurotransmitter dopamine in the brain. Dopamine is a highly specialized brain chemical that sends a signal to other nerve cells, and participates in the regulation of body movements. Parkinson’s disease usually begins in late adulthood. It is slowly progressive; however, it may not become incapacitating for many years. (For more information on this disorder, choose “Parkinson’s disease” as your search term in the Rare Disease Database.)Symptoms similar to those of PD (parkinsonian symptoms) may also develop secondary to hydrocephalus (a condition in which excessive cerebrospinal fluid accumulates the spaces in the brain [ventricles], increasing pressure in the brain. Parkinsonian symptoms may also occur as a result of head trauma, inflammation of the brain (encephalitis), strokes (infarcts), or tumors deep within the cerebral hemispheres (cerebrum) and base of the brain (i.e., basal ganglia), or exposure to certain drugs and toxins.Progressive supranuclear palsy (PSP) is a rare degenerative neurological disorder characterized by postural instability and falls, often backwards, loss of control of voluntary eye movement (supranuclear gaze palsy, or SNGP), impaired voluntary muscle activity (akinesia), abnormal stiffness (rigidity), speech difficulties (dysarthria), and problems related to swallowing and eating (dysphagia). Affected individuals frequently experience personality changes and some degree of cognitive impairment. The exact cause of progressive supranuclear palsy is unknown. Unlike MSA, in which alpha-synuclein accumulates in the brain, a different protein called tau accumulates in PSP (and also CBD – see below), so they are known as “tauopathies”. Prevalence is a bit higher than MSA, at about 6 per 100,000. Mean onset age is 60-65 years. (For more information on this disorder, choose “progressive supranuclear palsy” as your search term in the Rare Disease Database.)Corticobasal degeneration (CBD) is an even rarer progressive neurological disorder characterized by cell loss and shrinkage (atrophy) in certain areas of the brain (cerebral cortex and substantia nigra). Affected individuals may have sufficient muscle power for manual tasks but often have difficulty directing their movements appropriately (apraxia). Initial symptoms typically appear in people during the seventh decade, and may include poor coordination, difficulty accomplishing goal-directed tasks (e.g., buttoning a shirt), and/or difficulty pantomiming actions. Symptoms usually begin on one side of the body (unilateral), but both sides are affected as the disease progresses. Cognitive impairment (e.g., memory loss) and/or visual-spatial impairments often develop. The exact cause of corticobasal degeneration is unknown. (For more information on this disorder, choose “corticobasal degeneration” as your search term in the Rare Disease Database.)Hereditary olivopontocerebellar atrophy (OPCA) describes a rare group of disorders characterized by progressive balance problems (disequilibrium), progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), and difficulty speaking or slurred speech (dysarthria). Additional symptoms may include generalized weakness, difficulty swallowing (dysphagia), and/or the progressive loss of intellectual abilities and mental deterioration (dementia). There are at least five distinct forms of hereditary OPCA. All forms of hereditary OPCA, except one, are inherited as autosomal dominant traits. (For more information on this disorder, choose “olivopontocerebellar atrophy” as your search term in the Rare Disease Database.)Pure autonomic failure (PAF) is very rare, and characterized by orthostatic hypotension that has been present for 5 years or more without other evidence of a neurological condition. Orthostatic hypotension is a condition in which an excessive decrease in blood pressure occurs upon standing potentially resulting in dizziness or momentary loss of consciousness (syncope). Additional symptoms associated with autonomic failure include fatigue; blurred vision; impaired bladder and bowel control; and impotence. In some cases, the skin may become extremely dry as a result of decreased ability to sweat. The exact cause of PAF is usually due to Lewy body pathology in the brainstem and autonomic ganglia.
| 843 |
Multiple System Atrophy
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nord_843_5
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Diagnosis of Multiple System Atrophy
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The diagnosis of MSA may be suspected based upon a detailed patient history, identification of specific symptoms, and a thorough clinical evaluation that includes a comprehensive history of neurological and other symptoms. Various specialized laboratory tests may assist in diagnosis. Obtaining a diagnosis can be difficult because no specific test can make or confirm a diagnosis of MSA.Clinical Testing and WorkupSpecialized tests that can aid in the diagnosis of MSA include:Magnetic resonance imaging (MRI), which may demonstrate changes in certain brain areas.Positron emission tomography (PET), using fluorodeoxyglucose (FDG) to measure regional brain glucose metabolism, is being developed as a tool to differentiate between degenerative parkinsonian conditions.Single photon emission computed tomography (SPECT) using a tracer for the dopamine transporter (DaT) in the brain can provide evidence of neuron loss in the substantia nigra, which is affected in all MSA subjects with parkinsonism, but will not differentiate between MSA, PD, PSP and CBD.In some cases a 123I-metaiodobenzylguanidine (MIBG) SPECT scan of the heart can be helpful to distinguish between Lewy body diseases (PD, LBD and PAF), in which the scan is typically very abnormal, and MSA, where it is usually normal.In individuals with symptoms of faintness it is important to take the blood pressure first lying (supine) and then after 2 and 3 minutes standing, and to record the drop in the upper (systolic) and lower (diastolic) figure. An otherwise unexplained systolic drop of more than 20 mm is abnormal, and one of over 30 mm more so.If there is suspicion of orthostatic hypotension (OH, excessive BP drop on standing), but this simple testing does not show an excessive fall, it may be necessary to do a tilt table test. During this test, a patient lies down flat on a table. Straps are placed around the body to hold the patient in place. Then, the table is raised with the person’s head in the upward position. This simulates the action of a person standing from a sitting or lying down position. This test allows a physician to measure your heart rate and blood pressure in such situations.Many people with MSA may originally be misdiagnosed with Parkinson’s disease. Specialized tests that measure the function of the autonomic nervous system may be performed, including pupillary and sweating responses, cardiovascular responses (e.g., orthostatic challenge and cold pressor test), and genitourinary and rectal responses (e.g., cremasteric, anal wink, and bulbocavernosus reflexes). A variety of tests may be conducted to assess the function of the autonomic nervous system including blood tests, sweat tests, tests to assess bladder and bowel function, and an electrocardiogram to assess the function of the heart.Some individuals may be evaluated in a sleep laboratory to undergo a sleep study to assess the presence and extent of sleep abnormalities that are sometimes associated with MSA.
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Diagnosis of Multiple System Atrophy. The diagnosis of MSA may be suspected based upon a detailed patient history, identification of specific symptoms, and a thorough clinical evaluation that includes a comprehensive history of neurological and other symptoms. Various specialized laboratory tests may assist in diagnosis. Obtaining a diagnosis can be difficult because no specific test can make or confirm a diagnosis of MSA.Clinical Testing and WorkupSpecialized tests that can aid in the diagnosis of MSA include:Magnetic resonance imaging (MRI), which may demonstrate changes in certain brain areas.Positron emission tomography (PET), using fluorodeoxyglucose (FDG) to measure regional brain glucose metabolism, is being developed as a tool to differentiate between degenerative parkinsonian conditions.Single photon emission computed tomography (SPECT) using a tracer for the dopamine transporter (DaT) in the brain can provide evidence of neuron loss in the substantia nigra, which is affected in all MSA subjects with parkinsonism, but will not differentiate between MSA, PD, PSP and CBD.In some cases a 123I-metaiodobenzylguanidine (MIBG) SPECT scan of the heart can be helpful to distinguish between Lewy body diseases (PD, LBD and PAF), in which the scan is typically very abnormal, and MSA, where it is usually normal.In individuals with symptoms of faintness it is important to take the blood pressure first lying (supine) and then after 2 and 3 minutes standing, and to record the drop in the upper (systolic) and lower (diastolic) figure. An otherwise unexplained systolic drop of more than 20 mm is abnormal, and one of over 30 mm more so.If there is suspicion of orthostatic hypotension (OH, excessive BP drop on standing), but this simple testing does not show an excessive fall, it may be necessary to do a tilt table test. During this test, a patient lies down flat on a table. Straps are placed around the body to hold the patient in place. Then, the table is raised with the person’s head in the upward position. This simulates the action of a person standing from a sitting or lying down position. This test allows a physician to measure your heart rate and blood pressure in such situations.Many people with MSA may originally be misdiagnosed with Parkinson’s disease. Specialized tests that measure the function of the autonomic nervous system may be performed, including pupillary and sweating responses, cardiovascular responses (e.g., orthostatic challenge and cold pressor test), and genitourinary and rectal responses (e.g., cremasteric, anal wink, and bulbocavernosus reflexes). A variety of tests may be conducted to assess the function of the autonomic nervous system including blood tests, sweat tests, tests to assess bladder and bowel function, and an electrocardiogram to assess the function of the heart.Some individuals may be evaluated in a sleep laboratory to undergo a sleep study to assess the presence and extent of sleep abnormalities that are sometimes associated with MSA.
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Multiple System Atrophy
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Therapies of Multiple System Atrophy
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TreatmentThere is no specific treatment for MSA. Treatment is aimed at controlling the symptoms of the disease. Drugs that are used to treat people with Parkinson’s disease, most notably levodopa (given in tablets of Sinemet), may also be prescribed for individuals with MSA. However, the effectiveness of such medications varies greatly among affected individuals. In many cases, individuals do not respond or respond poorly to such therapy. Approximately 1/3 of affected individuals respond to levodopa therapy. However, in most cases, the effectiveness of this therapy decreases over time. In addition, these drugs must be used with caution because they may lower blood pressure.In addition to levodopa, other drugs used to treat Parkinson’s disease may be used to treat individuals with MSA. These include dopamine agonists such as ropinirole (Requip) and pramipexole (Mirapexin) and an antiviral drug known as amantadine (Symmetrel).Low blood pressure upon standing (orthostatic hypotension) may be treated by dietary increases in salt consumption, using a head-up tilt of the bed at night, by ingestion of 500mls water before exertion, rising slowly, and avoiding heavy carbohydrate meals.If non-drug methods fail to sufficiently control OH symptoms, the drug fludrocortisone (Florinef), a corticosteroid derivative, can be used. This drug must be used with caution and monitored carefully by a physician for possible side effects.The drug midodrine hydrochloride (ProAmatine) has been approved by the Food and Drug Administration (FDA) for the treatment of low blood pressure sometimes associated with MSA.Adrenergic drugs such as ephedrine may be used to treat low blood pressure. The drug L-threo-dihydroxyphenylserine (L-DOPS or L-threo-DOPS) can also be used to treat low blood pressure.Urinary incontinence may be treated with drugs such as oxybutynin (Ditropan) or catheterization. The drug desmopressin may be used to treat the abnormally large production and passage of urine at night (nocturnal polyuria) but caution is advised in the elderly, and blood electrolytes need periodic monitoring. Constipation may improve along with increases in dietary fiber or the use of laxatives. Continuous positive pressure ventilation (CPAP) may be used to treat sleep apnea and anti-convulsant drugs such as clonazepam may be used to treat REM sleep behavior disorder or myoclonus. Dystonia may be treated by injections of botulinum toxin.Drugs such as sildenafil (Viagra), tadalfil (Cialis) or vardenafil (Levitra) may be used to treat impotence. In some cases, these drugs may worsen low blood pressure and faintness.A speech pathology evaluation and therapy may be helpful with swallowing or speech difficulties. Affected individuals may also benefit from physiotherapy, physical therapy, occupational therapy, and speech therapy.In later stages of MSA, where there is a risk of aspiration due to swallowing difficulty, a feeding tube may be inserted directly into the stomach (gastrostomy tube). A tracheostomy may be required for life-threatening breathing complications, daytime stridor, or abnormal vocal cord mobility. A tracheostomy is a procedure during which a tube is placed through a surgical opening in the throat to prevent breathing difficulties. In addition, affected individuals may be unable to walk unassisted or may require a wheelchair.
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Therapies of Multiple System Atrophy. TreatmentThere is no specific treatment for MSA. Treatment is aimed at controlling the symptoms of the disease. Drugs that are used to treat people with Parkinson’s disease, most notably levodopa (given in tablets of Sinemet), may also be prescribed for individuals with MSA. However, the effectiveness of such medications varies greatly among affected individuals. In many cases, individuals do not respond or respond poorly to such therapy. Approximately 1/3 of affected individuals respond to levodopa therapy. However, in most cases, the effectiveness of this therapy decreases over time. In addition, these drugs must be used with caution because they may lower blood pressure.In addition to levodopa, other drugs used to treat Parkinson’s disease may be used to treat individuals with MSA. These include dopamine agonists such as ropinirole (Requip) and pramipexole (Mirapexin) and an antiviral drug known as amantadine (Symmetrel).Low blood pressure upon standing (orthostatic hypotension) may be treated by dietary increases in salt consumption, using a head-up tilt of the bed at night, by ingestion of 500mls water before exertion, rising slowly, and avoiding heavy carbohydrate meals.If non-drug methods fail to sufficiently control OH symptoms, the drug fludrocortisone (Florinef), a corticosteroid derivative, can be used. This drug must be used with caution and monitored carefully by a physician for possible side effects.The drug midodrine hydrochloride (ProAmatine) has been approved by the Food and Drug Administration (FDA) for the treatment of low blood pressure sometimes associated with MSA.Adrenergic drugs such as ephedrine may be used to treat low blood pressure. The drug L-threo-dihydroxyphenylserine (L-DOPS or L-threo-DOPS) can also be used to treat low blood pressure.Urinary incontinence may be treated with drugs such as oxybutynin (Ditropan) or catheterization. The drug desmopressin may be used to treat the abnormally large production and passage of urine at night (nocturnal polyuria) but caution is advised in the elderly, and blood electrolytes need periodic monitoring. Constipation may improve along with increases in dietary fiber or the use of laxatives. Continuous positive pressure ventilation (CPAP) may be used to treat sleep apnea and anti-convulsant drugs such as clonazepam may be used to treat REM sleep behavior disorder or myoclonus. Dystonia may be treated by injections of botulinum toxin.Drugs such as sildenafil (Viagra), tadalfil (Cialis) or vardenafil (Levitra) may be used to treat impotence. In some cases, these drugs may worsen low blood pressure and faintness.A speech pathology evaluation and therapy may be helpful with swallowing or speech difficulties. Affected individuals may also benefit from physiotherapy, physical therapy, occupational therapy, and speech therapy.In later stages of MSA, where there is a risk of aspiration due to swallowing difficulty, a feeding tube may be inserted directly into the stomach (gastrostomy tube). A tracheostomy may be required for life-threatening breathing complications, daytime stridor, or abnormal vocal cord mobility. A tracheostomy is a procedure during which a tube is placed through a surgical opening in the throat to prevent breathing difficulties. In addition, affected individuals may be unable to walk unassisted or may require a wheelchair.
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Multiple System Atrophy
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Overview of Mulvihill-Smith Syndrome
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SummaryMulvihill-Smith syndrome is an extremely rare and complex disorder that is clinically diagnosed based on the following characteristics: abnormally small head (microcephaly), multiple non-cancerous moles (pigmented nevi), short height, reoccurring infections due to an impaired immune system, impaired hearing, dental anomalies (hypodontia), intellectual disability and decreased fat in the face that causes “bird-like” facial features. Affected individuals appear more aged and can develop illness associated with older age such as tumors, and this is why Mulvihill-Smith syndrome has been categorized as a premature aging disease (progeroid syndrome). Mulvihill-Smith syndrome is an extremely rare disorder with only 11 cases documented in the scientific literature worldwide.IntroductionMulvihill-Smith syndrome was first described by Dr. Mulvihill and Dr. Smith in 1971, when they observed a 17 old patient with a cluster of symptoms never seen in one individual, including premature aging, reoccurring infections, microcephaly, deafness, numerous moles, short stature and decreased facial fat. Subsequently, 10 other people with Mulvihill-Smith syndrome have been reported in the scientific literature. With only 11 documented cases, Mulvihill-Smith syndrome is extremely rare and has been very difficult to study. No gene(s) that cause Mulvihill-Smith syndrome has been identified, consequently the disease is diagnosed based on the symptoms. People with Mulvihill-Smith syndrome have been diagnosed as isolated cases suggesting it arises from a new spontaneous mutation in a gene or gene(s). Because of the rarity of the disorder, most physicians are unlikely to be familiar with Mulvihill-Smith syndrome. Most individuals have been diagnosed between 5-30 years of age.
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Overview of Mulvihill-Smith Syndrome. SummaryMulvihill-Smith syndrome is an extremely rare and complex disorder that is clinically diagnosed based on the following characteristics: abnormally small head (microcephaly), multiple non-cancerous moles (pigmented nevi), short height, reoccurring infections due to an impaired immune system, impaired hearing, dental anomalies (hypodontia), intellectual disability and decreased fat in the face that causes “bird-like” facial features. Affected individuals appear more aged and can develop illness associated with older age such as tumors, and this is why Mulvihill-Smith syndrome has been categorized as a premature aging disease (progeroid syndrome). Mulvihill-Smith syndrome is an extremely rare disorder with only 11 cases documented in the scientific literature worldwide.IntroductionMulvihill-Smith syndrome was first described by Dr. Mulvihill and Dr. Smith in 1971, when they observed a 17 old patient with a cluster of symptoms never seen in one individual, including premature aging, reoccurring infections, microcephaly, deafness, numerous moles, short stature and decreased facial fat. Subsequently, 10 other people with Mulvihill-Smith syndrome have been reported in the scientific literature. With only 11 documented cases, Mulvihill-Smith syndrome is extremely rare and has been very difficult to study. No gene(s) that cause Mulvihill-Smith syndrome has been identified, consequently the disease is diagnosed based on the symptoms. People with Mulvihill-Smith syndrome have been diagnosed as isolated cases suggesting it arises from a new spontaneous mutation in a gene or gene(s). Because of the rarity of the disorder, most physicians are unlikely to be familiar with Mulvihill-Smith syndrome. Most individuals have been diagnosed between 5-30 years of age.
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Symptoms of Mulvihill-Smith Syndrome
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Mulvihill-Smith syndrome is diagnosed based on a series of symptoms described in the scientific literature. There can be some variation of symptoms between affected individuals. The core symptoms include the following:Abnormally small head (microcephaly) – Microcephaly is a rare condition in which a child’s head size is significantly smaller compared to children of the same age and sex. Microcephaly is usually caused by abnormal brain development in the womb or failure of the brain to grow after birth. This characteristic has been reported in a 100% of individuals diagnosed with Mulvihill-Smith syndrome. Intellectual disabilities – Children with microcephaly tend to have intellectual disabilities that range from mild to severe. 82% of individuals diagnosed with Mulvihill-Smith syndrome had some type of intellectual disabilities. In most patients, intellectual disabilities result from slower brain development during childhood, but in a few patients, some cognitive deterioration in adulthood has also been reported. Psychological symptoms – Individuals diagnosed with Mulvihill-Smith syndrome have been reported to have various psychological symptoms such as major mood swings, periods of agitation, aggression, depression and insomnia. Sleep disorders have also been reported.Abnormal facial features – Individuals with Mulvihill-Smith syndrome can have various abnormal facial features. The majority of diagnosed patients (10/11) showed reduced levels of the layer of fatty tissue directly beneath the skin of the face (facial subcutaneous fat). In 4 patients, abnormally large distance between the eyes (hypertelorism) was reported. In addition, affected individuals may have an abnormally small face, a severely underdeveloped jaw (micrognathia), a small, pointed chin; and/or absence of one or more teeth (hypodontia). Taken together, these changes in facial features lead to a narrower face and several scientific papers described patients as having a “bird-like” facial appearance. The abnormal structures in the face may be the reason these patients often have a high pitched voice (reported in 9 cases). Sensory issues – Deafness has been reported in 91% of individuals diagnosed with Mulvihill-Smith syndrome. Clouding of lens in the eye that can impair vision (cataracts) have been reported in three individuals with Mulvihill-Smith syndrome. Shortness in height and other anatomic abnormalities – Short stature is a central characteristic of Mulvihill-Smith syndrome, as it has been reported in 91% of individuals. In addition, some afflicted individuals may have physical characteristics such as abnormally bent or curved fingers (clinodactyly) and shortened fingers and toes (brachydactyly). Some affected children may have an abnormal sideways curvature of the spine involving the chest (thoracic scoliosis) and/or impaired joint mobility. Some affected males may have genital abnormalities such as abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), causing the penis to point downward (chordee). Low birth weight has been reported as a common trait in patients diagnosed with Mulvihill-Smith syndrome.Impaired immune system (immunodeficiency) – The ability of the body’s immune system to fight invading organisms seems to be impaired in individuals with Mulvihill-Smith syndrome. In several patients, analysis of blood revealed reduced levels of key cells of the immune system (T- and B-cells). In addition, reoccurring infection occured in 91% of individuals diagnosed with Mulvihill-Smith syndrome. Impaired immune function is often associated with increased risk of cancer, and 4 patients had various tumors (gastric, tongue, pancreas, and melanoma). These cancers occurred in individuals aged 16-28 years old. An impaired immune system is seen as a hallmark characteristic of Mulvihill-Smith syndrome, and often used to distinguish it from other premature aging diseases such as Cockayne syndrome.Multiple non-cancerous moles (pigmented nevi) – 100% of patients with Mulvihill-Smith syndrome have been reported to have excessive moles on the face. These pigmented nevi may be present at birth (congenital) or shortly after birth. A high number of moles is a symptom seen in several other diseases associated with a compromised immune system. Some infants and children with Mulvihill-Smith syndrome also have numerous freckles or dark pigmented lesions (pigmented spitz nevus) on the skin of the face, neck, hands, trunk and/or other parts of the body.Premature aging (progeroid syndrome) – Individuals with Mulvihill-Smith syndrome have been described as looking older in their physical appearance, particularly the face. This advanced aging appearance along with the fact that affected individuals develop conditions more often seen in older populations such as cataracts, cancer and vulnerability to infections has led to this condition being described as a progeroid syndrome. Some patients with Mulvihill-Smith syndrome have been reported to have elevated levels of cholesterol (hypercholesterolemia), another condition usually observed in older populations. Mulvihill-Smith syndrome is one of about 30 diseases associated with premature aging.
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Symptoms of Mulvihill-Smith Syndrome. Mulvihill-Smith syndrome is diagnosed based on a series of symptoms described in the scientific literature. There can be some variation of symptoms between affected individuals. The core symptoms include the following:Abnormally small head (microcephaly) – Microcephaly is a rare condition in which a child’s head size is significantly smaller compared to children of the same age and sex. Microcephaly is usually caused by abnormal brain development in the womb or failure of the brain to grow after birth. This characteristic has been reported in a 100% of individuals diagnosed with Mulvihill-Smith syndrome. Intellectual disabilities – Children with microcephaly tend to have intellectual disabilities that range from mild to severe. 82% of individuals diagnosed with Mulvihill-Smith syndrome had some type of intellectual disabilities. In most patients, intellectual disabilities result from slower brain development during childhood, but in a few patients, some cognitive deterioration in adulthood has also been reported. Psychological symptoms – Individuals diagnosed with Mulvihill-Smith syndrome have been reported to have various psychological symptoms such as major mood swings, periods of agitation, aggression, depression and insomnia. Sleep disorders have also been reported.Abnormal facial features – Individuals with Mulvihill-Smith syndrome can have various abnormal facial features. The majority of diagnosed patients (10/11) showed reduced levels of the layer of fatty tissue directly beneath the skin of the face (facial subcutaneous fat). In 4 patients, abnormally large distance between the eyes (hypertelorism) was reported. In addition, affected individuals may have an abnormally small face, a severely underdeveloped jaw (micrognathia), a small, pointed chin; and/or absence of one or more teeth (hypodontia). Taken together, these changes in facial features lead to a narrower face and several scientific papers described patients as having a “bird-like” facial appearance. The abnormal structures in the face may be the reason these patients often have a high pitched voice (reported in 9 cases). Sensory issues – Deafness has been reported in 91% of individuals diagnosed with Mulvihill-Smith syndrome. Clouding of lens in the eye that can impair vision (cataracts) have been reported in three individuals with Mulvihill-Smith syndrome. Shortness in height and other anatomic abnormalities – Short stature is a central characteristic of Mulvihill-Smith syndrome, as it has been reported in 91% of individuals. In addition, some afflicted individuals may have physical characteristics such as abnormally bent or curved fingers (clinodactyly) and shortened fingers and toes (brachydactyly). Some affected children may have an abnormal sideways curvature of the spine involving the chest (thoracic scoliosis) and/or impaired joint mobility. Some affected males may have genital abnormalities such as abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), causing the penis to point downward (chordee). Low birth weight has been reported as a common trait in patients diagnosed with Mulvihill-Smith syndrome.Impaired immune system (immunodeficiency) – The ability of the body’s immune system to fight invading organisms seems to be impaired in individuals with Mulvihill-Smith syndrome. In several patients, analysis of blood revealed reduced levels of key cells of the immune system (T- and B-cells). In addition, reoccurring infection occured in 91% of individuals diagnosed with Mulvihill-Smith syndrome. Impaired immune function is often associated with increased risk of cancer, and 4 patients had various tumors (gastric, tongue, pancreas, and melanoma). These cancers occurred in individuals aged 16-28 years old. An impaired immune system is seen as a hallmark characteristic of Mulvihill-Smith syndrome, and often used to distinguish it from other premature aging diseases such as Cockayne syndrome.Multiple non-cancerous moles (pigmented nevi) – 100% of patients with Mulvihill-Smith syndrome have been reported to have excessive moles on the face. These pigmented nevi may be present at birth (congenital) or shortly after birth. A high number of moles is a symptom seen in several other diseases associated with a compromised immune system. Some infants and children with Mulvihill-Smith syndrome also have numerous freckles or dark pigmented lesions (pigmented spitz nevus) on the skin of the face, neck, hands, trunk and/or other parts of the body.Premature aging (progeroid syndrome) – Individuals with Mulvihill-Smith syndrome have been described as looking older in their physical appearance, particularly the face. This advanced aging appearance along with the fact that affected individuals develop conditions more often seen in older populations such as cataracts, cancer and vulnerability to infections has led to this condition being described as a progeroid syndrome. Some patients with Mulvihill-Smith syndrome have been reported to have elevated levels of cholesterol (hypercholesterolemia), another condition usually observed in older populations. Mulvihill-Smith syndrome is one of about 30 diseases associated with premature aging.
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Mulvihill-Smith Syndrome
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Causes of Mulvihill-Smith Syndrome
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The cause of Mulvihill-Smith syndrome is not presently known. All reported affected individuals have been isolated and independent cases. This makes it likely that the disease results from a new spontaneous mutation in a gene or gene(s) or caused by other genetic defects (chromosome abnormalities). The possibility that the disease may be inherited (autosomal recessive inheritance) has been suggested in one scientific paper. Autosomal recessive diseases occur when the affected individual inherits two abnormal copies of the gene, one from each parent. It is also possible that the disease is both autosomal recessive and spontaneous, with one mutation inherited from one parent and the other mutation arising spontaneously. No specific genes associated with Mulvihill-Smith syndrome have been identified, so this condition cannot be identified through genetic testing. Mulvihill-Smith syndrome is diagnosed by the symptoms that have been described above.
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Causes of Mulvihill-Smith Syndrome. The cause of Mulvihill-Smith syndrome is not presently known. All reported affected individuals have been isolated and independent cases. This makes it likely that the disease results from a new spontaneous mutation in a gene or gene(s) or caused by other genetic defects (chromosome abnormalities). The possibility that the disease may be inherited (autosomal recessive inheritance) has been suggested in one scientific paper. Autosomal recessive diseases occur when the affected individual inherits two abnormal copies of the gene, one from each parent. It is also possible that the disease is both autosomal recessive and spontaneous, with one mutation inherited from one parent and the other mutation arising spontaneously. No specific genes associated with Mulvihill-Smith syndrome have been identified, so this condition cannot be identified through genetic testing. Mulvihill-Smith syndrome is diagnosed by the symptoms that have been described above.
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Mulvihill-Smith Syndrome
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Affects of Mulvihill-Smith Syndrome
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Mulvihill-Smith syndrome is an extremely rare disorder (11 reported cases) that, in theory, affects males and females in equal numbers. Most of the reported affected individuals, however, have been males (7 males, 4 females).
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Affects of Mulvihill-Smith Syndrome. Mulvihill-Smith syndrome is an extremely rare disorder (11 reported cases) that, in theory, affects males and females in equal numbers. Most of the reported affected individuals, however, have been males (7 males, 4 females).
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Mulvihill-Smith Syndrome
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Related disorders of Mulvihill-Smith Syndrome
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Symptoms of the following disorders may be similar to those of Mulvihill-Smith syndrome. Comparisons may be useful for a differential diagnosis: Cerebro-oculo-facio-skeletal (COFS) syndrome is a genetic degenerative disorder of the brain and spinal cord that begins before birth. It is characterized by craniofacial and skeletal abnormalities, severely reduced muscle tone and impairment of reflexes. Symptoms may include large, low-set ears, small eyes, microcephaly, micrognathia clenched fists, wide-set nipples, vision impairment, involuntary eye movements and intellectual disability, which can be moderate or severe. Respiratory infections are frequent. COFS syndrome is inherited in an autosomal recessive pattern. COFS is now considered to be part of the spectrum of disorders within Cockayne syndrome.Cockayne syndrome and Mulvihill-Smith syndrome are premature aging diseases that share many similar features or symptoms. For example, persons affected by either syndrome will present with short stature, “bird-like face” with pointed chin and nose (precociously senile appearance), intellectual disability and a number of other of multisystem diseases. However, Cockayne syndrome is not associated with an impaired immune system observed in Mulvihill-Smith syndrome. Cockayne syndrome is an autosomal recessive genetic disorder caused by a malfunction of the cell’s normal process of repairing damaged DNA (DNA excision and repair).Noonan syndrome with multiple lentigines (NSML of LEOPARD syndrome) is a rare genetic disorder characterized by abnormalities of the skin, structure and function of the heart, inner ear, head and facial (craniofacial) area and/or the genitals. The range and severity of symptoms and physical characteristics may vary from person to person. LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some affected individuals may also exhibit mild intellectual disability, speech difficulties and/or, in some patients, additional physical abnormalities. NSML is an autosomal dominant genetic disorder. NSML and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes. (For more information on this disorder, choose “NMSL” as your search term in the Rare Disease Database.)Nucleotide excision repair disorders result from a breakdown of the process that repairs damaged DNA in the cell. A person’s genetic material is protected by several repair systems. Environmental factors, e.g. ultraviolet light and exposure to radiation, as well spontaneous mutations can cause damage (lesions) to the strands of DNA. Nucleotide excision repair is one of the more important and useful DNA repair systems. DNA repair disorders occur when this process does not work properly. Examples of DNA repair disorders include xeroderma pigmentosum (XP) and Cockayne syndrome (CS), and PIBIDS, a recently recognized disorder involving a photosensitive form of the brittle hair disorder trichothiodystrophy.Progeria or Hutchinson-Gilford progeria syndrome is perhaps the most known of the premature aging diseases. Characteristic features of this condition include gray hair or baldness; wrinkled skin; loss of fat, resulting in thin limbs and sagging skin; short stature; and/or internal abnormalities such as thickening of artery walls, resulting in impaired blood flow (atherosclerosis). (For more information on this disorder, choose “Hutchinson Gilford progeria” as your search terms in the Rare Disease Database.)
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Related disorders of Mulvihill-Smith Syndrome. Symptoms of the following disorders may be similar to those of Mulvihill-Smith syndrome. Comparisons may be useful for a differential diagnosis: Cerebro-oculo-facio-skeletal (COFS) syndrome is a genetic degenerative disorder of the brain and spinal cord that begins before birth. It is characterized by craniofacial and skeletal abnormalities, severely reduced muscle tone and impairment of reflexes. Symptoms may include large, low-set ears, small eyes, microcephaly, micrognathia clenched fists, wide-set nipples, vision impairment, involuntary eye movements and intellectual disability, which can be moderate or severe. Respiratory infections are frequent. COFS syndrome is inherited in an autosomal recessive pattern. COFS is now considered to be part of the spectrum of disorders within Cockayne syndrome.Cockayne syndrome and Mulvihill-Smith syndrome are premature aging diseases that share many similar features or symptoms. For example, persons affected by either syndrome will present with short stature, “bird-like face” with pointed chin and nose (precociously senile appearance), intellectual disability and a number of other of multisystem diseases. However, Cockayne syndrome is not associated with an impaired immune system observed in Mulvihill-Smith syndrome. Cockayne syndrome is an autosomal recessive genetic disorder caused by a malfunction of the cell’s normal process of repairing damaged DNA (DNA excision and repair).Noonan syndrome with multiple lentigines (NSML of LEOPARD syndrome) is a rare genetic disorder characterized by abnormalities of the skin, structure and function of the heart, inner ear, head and facial (craniofacial) area and/or the genitals. The range and severity of symptoms and physical characteristics may vary from person to person. LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some affected individuals may also exhibit mild intellectual disability, speech difficulties and/or, in some patients, additional physical abnormalities. NSML is an autosomal dominant genetic disorder. NSML and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes. (For more information on this disorder, choose “NMSL” as your search term in the Rare Disease Database.)Nucleotide excision repair disorders result from a breakdown of the process that repairs damaged DNA in the cell. A person’s genetic material is protected by several repair systems. Environmental factors, e.g. ultraviolet light and exposure to radiation, as well spontaneous mutations can cause damage (lesions) to the strands of DNA. Nucleotide excision repair is one of the more important and useful DNA repair systems. DNA repair disorders occur when this process does not work properly. Examples of DNA repair disorders include xeroderma pigmentosum (XP) and Cockayne syndrome (CS), and PIBIDS, a recently recognized disorder involving a photosensitive form of the brittle hair disorder trichothiodystrophy.Progeria or Hutchinson-Gilford progeria syndrome is perhaps the most known of the premature aging diseases. Characteristic features of this condition include gray hair or baldness; wrinkled skin; loss of fat, resulting in thin limbs and sagging skin; short stature; and/or internal abnormalities such as thickening of artery walls, resulting in impaired blood flow (atherosclerosis). (For more information on this disorder, choose “Hutchinson Gilford progeria” as your search terms in the Rare Disease Database.)
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Mulvihill-Smith Syndrome
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Diagnosis of Mulvihill-Smith Syndrome
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The diagnosis of Mulvihill-Smith syndrome may be suspected upon the identification of characteristic described in the Signs and Symptoms section above. A diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. For example, hearing tests may be performed to determine the range and severity of hearing impairment, blood tests may be performed to analyze levels of immune cells and a detailed physical exam would look at many physical traits such as skin conditions. The clinical diagnosis by a physician is based on whether the individual meets enough of the core criteria of Mulvihill-Smith syndrome and following the exclusion of all other diseases or disorders that share some similar symptoms.
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Diagnosis of Mulvihill-Smith Syndrome. The diagnosis of Mulvihill-Smith syndrome may be suspected upon the identification of characteristic described in the Signs and Symptoms section above. A diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. For example, hearing tests may be performed to determine the range and severity of hearing impairment, blood tests may be performed to analyze levels of immune cells and a detailed physical exam would look at many physical traits such as skin conditions. The clinical diagnosis by a physician is based on whether the individual meets enough of the core criteria of Mulvihill-Smith syndrome and following the exclusion of all other diseases or disorders that share some similar symptoms.
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Mulvihill-Smith Syndrome
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Therapies of Mulvihill-Smith Syndrome
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Treatment
Because the cause of the disease is unknown, there is no direct or specific treatment available for Mulvihill-Smith syndrome. Therapies are focused on managing the specific symptoms that are apparent in each individual. Because of the complex nature of the disease, treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the skin (dermatologists), speech pathologists, specialists who assess and treat hearing problems (audiologists), specialists who diagnose and treat skeletal abnormalities and other health care professionals may need to systematically and comprehensively plan an manage an afflicted person’s symptoms. Overall, therapies for the treatment of Mulvihill-Smith syndrome are symptomatic and supportive.
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Therapies of Mulvihill-Smith Syndrome. Treatment
Because the cause of the disease is unknown, there is no direct or specific treatment available for Mulvihill-Smith syndrome. Therapies are focused on managing the specific symptoms that are apparent in each individual. Because of the complex nature of the disease, treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the skin (dermatologists), speech pathologists, specialists who assess and treat hearing problems (audiologists), specialists who diagnose and treat skeletal abnormalities and other health care professionals may need to systematically and comprehensively plan an manage an afflicted person’s symptoms. Overall, therapies for the treatment of Mulvihill-Smith syndrome are symptomatic and supportive.
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Mulvihill-Smith Syndrome
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Overview of Mumps
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Mumps is an acute viral illness that causes a painful inflammation and swelling of the saliva glands. These glands include the parotid, submaxillary, sublingual and buccal salivary glands. Mumps used to be a common infectious disease of childhood until a vaccine was developed in 1967 to immunize children against the virus that causes the disorder. However, recent outbreaks of mumps among adolescents and young adults have raised questions about lifetime immunity from the vaccine.
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Overview of Mumps. Mumps is an acute viral illness that causes a painful inflammation and swelling of the saliva glands. These glands include the parotid, submaxillary, sublingual and buccal salivary glands. Mumps used to be a common infectious disease of childhood until a vaccine was developed in 1967 to immunize children against the virus that causes the disorder. However, recent outbreaks of mumps among adolescents and young adults have raised questions about lifetime immunity from the vaccine.
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Mumps
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Symptoms of Mumps
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Mumps is a very contagious viral illness that has an incubation period of about 14-24 days after exposure. The onset of this illness is characterized by headache, loss of appetite, a general feeling of ill-health (malaise), and a low to moderate fever. Within 24 hours the temperature may suddenly rise to about 104 degrees Fahrenheit and be associated with a painful swelling of the parotid glands in front of the ears and under the jaw. In most cases, the salivary glands on both sides of the jaw are affected. The submaxillary and sublingual glands (principally in the floor of the mouth) and the buccal glands (that are scattered beneath the mucous membranes of the cheeks) may also be swollen and tender. The skin over the affected area may be stretched, opening the mouth can be difficult, and there may be a sensitivity to pressure on the jaw. Chewing and swallowing is painful and foods that are sour or acidic should be avoided. The disease lasts between 5 to 6 days and usually results in a lifelong immunity to the virus.Mumps can involve other organs especially in those people past puberty. Males who contract mumps can develop a painful inflammation of the testes. This inflammation can damage the testes and may cause sterility. Females with mumps can develop inflammation of the ovaries (oophoritis).
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Symptoms of Mumps. Mumps is a very contagious viral illness that has an incubation period of about 14-24 days after exposure. The onset of this illness is characterized by headache, loss of appetite, a general feeling of ill-health (malaise), and a low to moderate fever. Within 24 hours the temperature may suddenly rise to about 104 degrees Fahrenheit and be associated with a painful swelling of the parotid glands in front of the ears and under the jaw. In most cases, the salivary glands on both sides of the jaw are affected. The submaxillary and sublingual glands (principally in the floor of the mouth) and the buccal glands (that are scattered beneath the mucous membranes of the cheeks) may also be swollen and tender. The skin over the affected area may be stretched, opening the mouth can be difficult, and there may be a sensitivity to pressure on the jaw. Chewing and swallowing is painful and foods that are sour or acidic should be avoided. The disease lasts between 5 to 6 days and usually results in a lifelong immunity to the virus.Mumps can involve other organs especially in those people past puberty. Males who contract mumps can develop a painful inflammation of the testes. This inflammation can damage the testes and may cause sterility. Females with mumps can develop inflammation of the ovaries (oophoritis).
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Mumps
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Causes of Mumps
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Mumps is a contagious viral disease that is transmitted through saliva by direct contact, or in the form of airborne droplets from the nose, throat or mouth. The virus enters the body through the upper respiratory tract.
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Causes of Mumps. Mumps is a contagious viral disease that is transmitted through saliva by direct contact, or in the form of airborne droplets from the nose, throat or mouth. The virus enters the body through the upper respiratory tract.
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Affects of Mumps
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Since 1967 when an effective and safe vaccine was developed, mumps has become uncommon. It affects males and females in equal numbers. Among those not immunized, the disease strikes most often in children between the ages of five and fifteen, but adults can also be affected. In recent years outbreaks of mumps on college campuses in the United States have raised question about long-term immunity from the mumps vaccine. The Centers for Disease Control (CDC) is trying to determine whether people during specific years should be re-vaccinated.
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Affects of Mumps. Since 1967 when an effective and safe vaccine was developed, mumps has become uncommon. It affects males and females in equal numbers. Among those not immunized, the disease strikes most often in children between the ages of five and fifteen, but adults can also be affected. In recent years outbreaks of mumps on college campuses in the United States have raised question about long-term immunity from the mumps vaccine. The Centers for Disease Control (CDC) is trying to determine whether people during specific years should be re-vaccinated.
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Related disorders of Mumps
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Mumps may give rise to the following complications:Infectious Arthritis focused on the inflammation of one or more joints may occur as a complication of mumps. The affected joint or joints often become painful, swollen, slightly red, and stiff within hours or days. (For more information on this disorder, choose “Arthritis, Infectious” as your search term in the Rare Disease Database.)Meningioencephalitis characterized by inflammation of the membranes (meninges) around the brain or spinal cord or the brain tissue can present as a dangerous complication of mumps. It can begin suddenly (acute) or develop gradually (subacute). (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.)Orchitis causes very painful swelling of the testes, headache, nausea and vomiting. This infection can cause damage to the testes which may include wasting (atrophy) and sterility.Oophoritis is a painful inflammation of the ovaries. It is characterized by lower abdominal pain, vaginal discharge or irregular bleeding. Excessive menstrual bleeding may also be symptomatic of this disorder.Pancreatitis, inflammation of the pancreas, can be the result of one or more of many different conditions or infections, including mumps.
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Related disorders of Mumps. Mumps may give rise to the following complications:Infectious Arthritis focused on the inflammation of one or more joints may occur as a complication of mumps. The affected joint or joints often become painful, swollen, slightly red, and stiff within hours or days. (For more information on this disorder, choose “Arthritis, Infectious” as your search term in the Rare Disease Database.)Meningioencephalitis characterized by inflammation of the membranes (meninges) around the brain or spinal cord or the brain tissue can present as a dangerous complication of mumps. It can begin suddenly (acute) or develop gradually (subacute). (For more information on this disorder, choose “Meningitis” as your search term in the Rare Disease Database.)Orchitis causes very painful swelling of the testes, headache, nausea and vomiting. This infection can cause damage to the testes which may include wasting (atrophy) and sterility.Oophoritis is a painful inflammation of the ovaries. It is characterized by lower abdominal pain, vaginal discharge or irregular bleeding. Excessive menstrual bleeding may also be symptomatic of this disorder.Pancreatitis, inflammation of the pancreas, can be the result of one or more of many different conditions or infections, including mumps.
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Mumps
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Diagnosis of Mumps
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Diagnosis of Mumps.
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Mumps
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Therapies of Mumps
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Mumps is a self-limiting disease that requires little or no treatment. A soft, bland diet may help the pain caused by chewing. Acetominophen (e.g.,Tylenol), given every 4 hours, will help reduce the fever and pain. Aspirin should NOT be given to children with Mumps because it can cause Reye's Syndrome. (For more information on this disorder, choose "Reye Syndrome" as your search term in the Rare Disease Database.)Cases of the Mumps have been greatly reduced with the introduction of the live attenuated mumps virus vaccine in 1967. All children should be immunized with this vaccine. It can be given singularly or together with the measles and rubella vaccine (MMR), around 15 months of age.Because of recent outbreaks of measles, mumps, and rubella in those persons previously immunized, lifetime immunity with only one vaccination is in question. It may be advisable to ask a pediatrician whether a second immunization be given before entering school. Adults who have been exposed to mumps or question their immunity to the mumps virus, should consider being immunized as a precaution.
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Therapies of Mumps. Mumps is a self-limiting disease that requires little or no treatment. A soft, bland diet may help the pain caused by chewing. Acetominophen (e.g.,Tylenol), given every 4 hours, will help reduce the fever and pain. Aspirin should NOT be given to children with Mumps because it can cause Reye's Syndrome. (For more information on this disorder, choose "Reye Syndrome" as your search term in the Rare Disease Database.)Cases of the Mumps have been greatly reduced with the introduction of the live attenuated mumps virus vaccine in 1967. All children should be immunized with this vaccine. It can be given singularly or together with the measles and rubella vaccine (MMR), around 15 months of age.Because of recent outbreaks of measles, mumps, and rubella in those persons previously immunized, lifetime immunity with only one vaccination is in question. It may be advisable to ask a pediatrician whether a second immunization be given before entering school. Adults who have been exposed to mumps or question their immunity to the mumps virus, should consider being immunized as a precaution.
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Overview of Muscular Dystrophy, Becker
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Becker muscular dystrophy is in the category of inherited muscle wasting diseases caused by a gene abnormality (mutation) that results in deficient or abnormal production of the dystrophin protein (dystrophinopathies). The abnormal gene is called DMD and is located on the X chromosome. Becker muscular dystrophy follows x-linked recessive inheritance so it mostly affects males, but some females are affected. Becker muscular dystrophy usually begins in the teens or early twenties and symptoms vary greatly between affected individuals. Muscle deterioration progresses slowly but usually results in the need for a wheel chair. Muscles of the heart deteriorate (cardiomyopathy) in some affected individuals, and this process can become life-threatening. Learning disabilities involving visual abilities may be present.
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Overview of Muscular Dystrophy, Becker. Becker muscular dystrophy is in the category of inherited muscle wasting diseases caused by a gene abnormality (mutation) that results in deficient or abnormal production of the dystrophin protein (dystrophinopathies). The abnormal gene is called DMD and is located on the X chromosome. Becker muscular dystrophy follows x-linked recessive inheritance so it mostly affects males, but some females are affected. Becker muscular dystrophy usually begins in the teens or early twenties and symptoms vary greatly between affected individuals. Muscle deterioration progresses slowly but usually results in the need for a wheel chair. Muscles of the heart deteriorate (cardiomyopathy) in some affected individuals, and this process can become life-threatening. Learning disabilities involving visual abilities may be present.
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Muscular Dystrophy, Becker
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Symptoms of Muscular Dystrophy, Becker
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Symptoms of Becker muscular dystrophy usually begin in the teens or late twenties. Initial symptoms may include cramping during exercise and reduced stamina during exercise. Muscle gradually deteriorates in the hips, pelvis, thighs and shoulders that can lead to walking on toes with the stomach forward. Shortening of muscle fibers can result in the inability to move certain muscles (contractures). The progression of BMD is slower and more variable than Duchenne muscular dystrophy but usually results in the need for a wheel chair. The heart muscle is also affected and can result in feeling breathless, fluid accumulation in the lungs and swelling in the feet and lower legs. Dilated cardiomyopathy is the most common cause of death in individuals with BMD, and most affected individuals die in their mid 40's. Approximately 5-10% of female DMD gene carriers have some symptoms of muscle weakness that progress slowly or not at all. Muscle weakness is frequently more severe on one side of the body (asymmetric).
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Symptoms of Muscular Dystrophy, Becker. Symptoms of Becker muscular dystrophy usually begin in the teens or late twenties. Initial symptoms may include cramping during exercise and reduced stamina during exercise. Muscle gradually deteriorates in the hips, pelvis, thighs and shoulders that can lead to walking on toes with the stomach forward. Shortening of muscle fibers can result in the inability to move certain muscles (contractures). The progression of BMD is slower and more variable than Duchenne muscular dystrophy but usually results in the need for a wheel chair. The heart muscle is also affected and can result in feeling breathless, fluid accumulation in the lungs and swelling in the feet and lower legs. Dilated cardiomyopathy is the most common cause of death in individuals with BMD, and most affected individuals die in their mid 40's. Approximately 5-10% of female DMD gene carriers have some symptoms of muscle weakness that progress slowly or not at all. Muscle weakness is frequently more severe on one side of the body (asymmetric).
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Muscular Dystrophy, Becker
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Causes of Muscular Dystrophy, Becker
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Becker muscular dystrophy is caused by abnormalities (mutations) in the DMD gene that is responsible for the production of the dystrophin protein. Dystrophin is necessary for the stability and protection of muscle. The gene mutation causes the dystrophin protein to be shorter than normal and not function normally. The DMD gene is located on the X chromosome and Becker muscular dystrophy follows x-linked recessive inheritance. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. 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.
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Causes of Muscular Dystrophy, Becker. Becker muscular dystrophy is caused by abnormalities (mutations) in the DMD gene that is responsible for the production of the dystrophin protein. Dystrophin is necessary for the stability and protection of muscle. The gene mutation causes the dystrophin protein to be shorter than normal and not function normally. The DMD gene is located on the X chromosome and Becker muscular dystrophy follows x-linked recessive inheritance. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. 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.
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Muscular Dystrophy, Becker
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Affects of Muscular Dystrophy, Becker
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Becker muscular dystrophy occurs in approximately 1 in 30,000 male births.
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Affects of Muscular Dystrophy, Becker. Becker muscular dystrophy occurs in approximately 1 in 30,000 male births.
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Muscular Dystrophy, Becker
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Related disorders of Muscular Dystrophy, Becker
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Symptoms of the following disorders can be similar to those of Becker muscular dystrophy (BMD). Comparisons may be useful for a differential diagnosis:Duchenne muscular dystrophy is an x-linked recessive genetic disease that is also caused by mutations in the DMD gene. The DMD gene mutations that cause Duchenne muscular dystrophy result in little or no dystrophin protein to be made. Symptoms usually begin in early childhood and progress rapidly. The disease is initially characterized by delays in sitting and standing and difficulty climbing. Children often need a wheel chair by the age of twelve. A disease affecting the heart muscle (cardiomyopathy) occurs in the teenage years and can be life threatening. (For more information about this condition, choose “Duchenne” as your search term in the Rare Disease Database.) Limb-girdle muscular dystrophy is a group of inherited, progressive disorders that are characterized by weakness and of muscles of the hip and shoulder areas. Several different forms of the disorder have been identified that are caused by mutations in certain genes. Some of these disease subtypes follow autosomal recessive inheritance and some follow autosomal dominant inheritance. In most individuals with limb-girdle muscular dystrophy, symptoms begin during childhood, but they may also begin during adolescence or adulthood. Muscle weakness may spread from the lower limbs to the upper limbs or vice versa. Although the disorder typically progresses slowly, some affected individuals experience rapid disease progression. (For more information about this condition, choose “limb girdle” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy is a rare, often slowly progressive form of muscular dystrophy affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of weakness and degeneration of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in the upper legs and arms and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. Emery-Dreifuss muscular dystrophy is inherited as an x-linked, autosomal dominant or autosomal recessive trait. (For more information about this condition, choose “Emery Dreifuss” as your search term in the Rare Disease Database.)Spinal muscular atrophy is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting. Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. Spinal muscular atrophy is inherited as an autosomal recessive trait and is caused by mutations in the SMN (survival motor neuron) gene. (For more information about this condition, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.)
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Related disorders of Muscular Dystrophy, Becker. Symptoms of the following disorders can be similar to those of Becker muscular dystrophy (BMD). Comparisons may be useful for a differential diagnosis:Duchenne muscular dystrophy is an x-linked recessive genetic disease that is also caused by mutations in the DMD gene. The DMD gene mutations that cause Duchenne muscular dystrophy result in little or no dystrophin protein to be made. Symptoms usually begin in early childhood and progress rapidly. The disease is initially characterized by delays in sitting and standing and difficulty climbing. Children often need a wheel chair by the age of twelve. A disease affecting the heart muscle (cardiomyopathy) occurs in the teenage years and can be life threatening. (For more information about this condition, choose “Duchenne” as your search term in the Rare Disease Database.) Limb-girdle muscular dystrophy is a group of inherited, progressive disorders that are characterized by weakness and of muscles of the hip and shoulder areas. Several different forms of the disorder have been identified that are caused by mutations in certain genes. Some of these disease subtypes follow autosomal recessive inheritance and some follow autosomal dominant inheritance. In most individuals with limb-girdle muscular dystrophy, symptoms begin during childhood, but they may also begin during adolescence or adulthood. Muscle weakness may spread from the lower limbs to the upper limbs or vice versa. Although the disorder typically progresses slowly, some affected individuals experience rapid disease progression. (For more information about this condition, choose “limb girdle” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy is a rare, often slowly progressive form of muscular dystrophy affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of weakness and degeneration of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in the upper legs and arms and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. Emery-Dreifuss muscular dystrophy is inherited as an x-linked, autosomal dominant or autosomal recessive trait. (For more information about this condition, choose “Emery Dreifuss” as your search term in the Rare Disease Database.)Spinal muscular atrophy is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting. Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. Spinal muscular atrophy is inherited as an autosomal recessive trait and is caused by mutations in the SMN (survival motor neuron) gene. (For more information about this condition, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.)
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Muscular Dystrophy, Becker
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Diagnosis of Muscular Dystrophy, Becker
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The diagnosis of Becker muscular dystrophy is based on physical symptoms, family history, an elevated concentration of creatine kinase (CK) in the blood indicating destruction of muscle, and molecular genetic testing. DMD is the only gene that has been associated with Becker muscular dystrophy and many different types of DMD gene mutations have been identified in individuals with this condition. Identification of a DMD gene mutation from molecular genetic testing confirms the diagnosis. If molecular genetic testing is performed and a DMD gene mutation is not found, a skeletal muscle biopsy is recommended to examine the appearance of the dystrophin protein.
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Diagnosis of Muscular Dystrophy, Becker. The diagnosis of Becker muscular dystrophy is based on physical symptoms, family history, an elevated concentration of creatine kinase (CK) in the blood indicating destruction of muscle, and molecular genetic testing. DMD is the only gene that has been associated with Becker muscular dystrophy and many different types of DMD gene mutations have been identified in individuals with this condition. Identification of a DMD gene mutation from molecular genetic testing confirms the diagnosis. If molecular genetic testing is performed and a DMD gene mutation is not found, a skeletal muscle biopsy is recommended to examine the appearance of the dystrophin protein.
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Muscular Dystrophy, Becker
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Therapies of Muscular Dystrophy, Becker
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TreatmentNo specific treatment is available for Becker muscular dystrophy but quality of life and lifespan can be improved with appropriate care. Physical and occupational therapy can reduce or delay joint contractures. Surgery is sometimes recommended to treat contractures or scoliosis. Weight control can help to reduce stress on the heart and muscles. Corticosteroids are often prescribed to help slow down the loss of muscle function. Routine monitoring by a cardiologist is recommended.
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Therapies of Muscular Dystrophy, Becker. TreatmentNo specific treatment is available for Becker muscular dystrophy but quality of life and lifespan can be improved with appropriate care. Physical and occupational therapy can reduce or delay joint contractures. Surgery is sometimes recommended to treat contractures or scoliosis. Weight control can help to reduce stress on the heart and muscles. Corticosteroids are often prescribed to help slow down the loss of muscle function. Routine monitoring by a cardiologist is recommended.
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Muscular Dystrophy, Becker
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Overview of Mutism, Selective
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Selective mutism is a rare psychiatric condition primarily occurring during childhood. It is characterized by the failure to speak in certain social situations. The ability to speak and understand spoken language is not impaired, and may be exhibited in more familiar environments. Symptoms include excessive shyness and social anxiety.
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Overview of Mutism, Selective. Selective mutism is a rare psychiatric condition primarily occurring during childhood. It is characterized by the failure to speak in certain social situations. The ability to speak and understand spoken language is not impaired, and may be exhibited in more familiar environments. Symptoms include excessive shyness and social anxiety.
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Mutism, Selective
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Symptoms of Mutism, Selective
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Selective mutism is a rare psychiatric disorder characterized by persistent failure to speakin specific social situations (e.g., school, with playmates, or when strangers are present) where speaking is expected. Affected individuals may communicate by gesturing, nodding their heads, uttering sounds or one-syllable words, or whispering. However, individuals with selective mutism usually talk normally at home and appear to have typical language skills – although they may have subtle language difficulties in areas such as grammar when compared to other children their age. Symptoms may also include fear of social embarrassment, clinginess and anxiety. Individuals with selective mutism are also more likely to have anxiety disorders such as social phobia.Individuals with selective mutism may be excessively shy, socially isolated, and withdrawn. In some cases, selective mutism lasts only a few weeks or months. However, some cases have been reported to continue for several years.Symptoms of selective mutism usually become noticeable between the ages of two and four years. However, the diagnosis may not be apparent until the child has entered school or other social situations. Functioning in school and social situations may be impaired. Individuals with selective mutism are commonly compliant, reticent, and almost “frozen” around strangers.
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Symptoms of Mutism, Selective. Selective mutism is a rare psychiatric disorder characterized by persistent failure to speakin specific social situations (e.g., school, with playmates, or when strangers are present) where speaking is expected. Affected individuals may communicate by gesturing, nodding their heads, uttering sounds or one-syllable words, or whispering. However, individuals with selective mutism usually talk normally at home and appear to have typical language skills – although they may have subtle language difficulties in areas such as grammar when compared to other children their age. Symptoms may also include fear of social embarrassment, clinginess and anxiety. Individuals with selective mutism are also more likely to have anxiety disorders such as social phobia.Individuals with selective mutism may be excessively shy, socially isolated, and withdrawn. In some cases, selective mutism lasts only a few weeks or months. However, some cases have been reported to continue for several years.Symptoms of selective mutism usually become noticeable between the ages of two and four years. However, the diagnosis may not be apparent until the child has entered school or other social situations. Functioning in school and social situations may be impaired. Individuals with selective mutism are commonly compliant, reticent, and almost “frozen” around strangers.
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Mutism, Selective
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Causes of Mutism, Selective
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The exact cause of selective mutism is unknown. Some research suggests a geneticinfluence or “vulnerability” to selective mutism that interplays with environmental factors. Particular personal and family characteristics may contribute to the appearance of selective mutism. Individuals with selective mutism may come from families in which there is a history of anxiety disorders and/or shyness. The term “selective” means that these children fail to speak in some social settings. The cause is not due to an underlying physical abnormality.
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Causes of Mutism, Selective. The exact cause of selective mutism is unknown. Some research suggests a geneticinfluence or “vulnerability” to selective mutism that interplays with environmental factors. Particular personal and family characteristics may contribute to the appearance of selective mutism. Individuals with selective mutism may come from families in which there is a history of anxiety disorders and/or shyness. The term “selective” means that these children fail to speak in some social settings. The cause is not due to an underlying physical abnormality.
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Mutism, Selective
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Affects of Mutism, Selective
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Selective mutism is recorded to affect less than one percent of children in the United States. This disorder appears slightly more common in females than in males. The percent of affected population is unknown due to undiagnosis and misdiagnosis.
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Affects of Mutism, Selective. Selective mutism is recorded to affect less than one percent of children in the United States. This disorder appears slightly more common in females than in males. The percent of affected population is unknown due to undiagnosis and misdiagnosis.
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Mutism, Selective
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Related disorders of Mutism, Selective
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Symptoms of the following disorders can be similar to those of selective mutism.Comparisons may be useful for a differential diagnosis:Delayed speech and language development can be signs of a system abnormality, athinking/learning (cognitive) difficulty, or a hearing problem. This delayed development can also be a sign of emotional, social, family, or behavioral problems. The possibility of abnormalities of tracheal (windpipe) and laryngeal (voice box) function or oral-motordevelopment should be investigated by a physician.Aphasia is a defect or loss of language function. Comprehension or expression of wordsis impaired as a result of injury to the language centers in the brain. The most common form of aphasia occurs in people who have had a stroke or head injury. However, it can also occur in children as a congenital disorder. The severity of the brain injury determines the extent of impairment. Severe damage may cause the patient not to understand any information related to language. Smaller injuries may cause selective language impairment.Pervasive developmental disorders comprise a group of neuro-psychiatric disorderscharacterized by impairment in social skills, in the development of verbal and nonverbalcommunication skills, and by the presence of repetitive behaviors/narrow restrictedinterests. There may be delays in developing intellectual skills and language and speech,as well as epilepsy. The severity and type of these impairments vary greatly from child tochild. The most well-known pervasive developmental disorder is autism.Autism is a lifelong neurological disorder characterized by onset before 36 months of age, retarded development of communication and language, lack of normal response to people, and extreme sensitivity to changes in their environment. About two-thirds of autistic children have lower than normal IQs. Occasionally, a child shows distinct and unusual skills in music, mathematics, or using spatial concepts. Children with autism may have mild, moderate, or severe symptoms. Boys are affected four times more frequently than girls. (For more information on this disorder, choose “Autism” as your search term in the Rare Disease Database.)Developmental expressive language disorder is an uncommon disorder characterized byimpairment in the development of expressive language. Language development is slowwith speech beginning late and progressing slowly. Severe forms usually occur beforeage three. Less severe forms may not be evident until early adolescence.
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Related disorders of Mutism, Selective. Symptoms of the following disorders can be similar to those of selective mutism.Comparisons may be useful for a differential diagnosis:Delayed speech and language development can be signs of a system abnormality, athinking/learning (cognitive) difficulty, or a hearing problem. This delayed development can also be a sign of emotional, social, family, or behavioral problems. The possibility of abnormalities of tracheal (windpipe) and laryngeal (voice box) function or oral-motordevelopment should be investigated by a physician.Aphasia is a defect or loss of language function. Comprehension or expression of wordsis impaired as a result of injury to the language centers in the brain. The most common form of aphasia occurs in people who have had a stroke or head injury. However, it can also occur in children as a congenital disorder. The severity of the brain injury determines the extent of impairment. Severe damage may cause the patient not to understand any information related to language. Smaller injuries may cause selective language impairment.Pervasive developmental disorders comprise a group of neuro-psychiatric disorderscharacterized by impairment in social skills, in the development of verbal and nonverbalcommunication skills, and by the presence of repetitive behaviors/narrow restrictedinterests. There may be delays in developing intellectual skills and language and speech,as well as epilepsy. The severity and type of these impairments vary greatly from child tochild. The most well-known pervasive developmental disorder is autism.Autism is a lifelong neurological disorder characterized by onset before 36 months of age, retarded development of communication and language, lack of normal response to people, and extreme sensitivity to changes in their environment. About two-thirds of autistic children have lower than normal IQs. Occasionally, a child shows distinct and unusual skills in music, mathematics, or using spatial concepts. Children with autism may have mild, moderate, or severe symptoms. Boys are affected four times more frequently than girls. (For more information on this disorder, choose “Autism” as your search term in the Rare Disease Database.)Developmental expressive language disorder is an uncommon disorder characterized byimpairment in the development of expressive language. Language development is slowwith speech beginning late and progressing slowly. Severe forms usually occur beforeage three. Less severe forms may not be evident until early adolescence.
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Mutism, Selective
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Diagnosis of Mutism, Selective
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The diagnosis of selective mutism may be confirmed by an extensive medical evaluationto rule out other possible causes. The evaluation should include hearing tests to assur. that the child is not hearing impaired. A child with selective mutism has the ability tounderstand and speak spoken language but will not speak in some social situations. The Selective Mutism Questionnaire for parent or teacher may aid in diagnostic screening.
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Diagnosis of Mutism, Selective. The diagnosis of selective mutism may be confirmed by an extensive medical evaluationto rule out other possible causes. The evaluation should include hearing tests to assur. that the child is not hearing impaired. A child with selective mutism has the ability tounderstand and speak spoken language but will not speak in some social situations. The Selective Mutism Questionnaire for parent or teacher may aid in diagnostic screening.
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Mutism, Selective
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nord_847_6
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Therapies of Mutism, Selective
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TreatmentTreatment of selective mutism consists of behaviour management and psychotherapy (such as cognitive behavioural therapy and family therapy). A multi-modal approach is often recommended. The therapies that may be effective in treating selective mutism are counter-conditioning, modeling, shaping (successive approximations), and contingency management. Counter-conditioning involves developing new behaviors that are not compatible with the undesirable behaviors. Modeling includes demonstration of the appropriate behaviour and can also effectively include self-modeling. Self-modeling may involve repeatedly watching digitally edited video/audio recordings of the child exhibiting the desired behaviour, i.e. talking in social situations. Shaping is a method for developing complex behaviors by progressively reinforcing simple behaviors that will eventually lead to the desired complex behavior. Bribery and consequences should be avoided to meet this end. Contingency management consists of providing positive reinforcement to the child when something has been done correctly and consequences when an inappropriate behaviour has occurred.
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Therapies of Mutism, Selective. TreatmentTreatment of selective mutism consists of behaviour management and psychotherapy (such as cognitive behavioural therapy and family therapy). A multi-modal approach is often recommended. The therapies that may be effective in treating selective mutism are counter-conditioning, modeling, shaping (successive approximations), and contingency management. Counter-conditioning involves developing new behaviors that are not compatible with the undesirable behaviors. Modeling includes demonstration of the appropriate behaviour and can also effectively include self-modeling. Self-modeling may involve repeatedly watching digitally edited video/audio recordings of the child exhibiting the desired behaviour, i.e. talking in social situations. Shaping is a method for developing complex behaviors by progressively reinforcing simple behaviors that will eventually lead to the desired complex behavior. Bribery and consequences should be avoided to meet this end. Contingency management consists of providing positive reinforcement to the child when something has been done correctly and consequences when an inappropriate behaviour has occurred.
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Mutism, Selective
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nord_848_0
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Overview of Myasthenia Gravis
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Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10 percent of patients, affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body's natural immune defenses (i.e., antibodies) inappropriately attack and gradually injure certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response).
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Overview of Myasthenia Gravis. Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10 percent of patients, affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body's natural immune defenses (i.e., antibodies) inappropriately attack and gradually injure certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response).
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Myasthenia Gravis
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nord_848_1
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Symptoms of Myasthenia Gravis
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Symptoms may be variable, with disease involvement potentially localized to certain muscles or affecting multiple muscles. In some affected individuals, the disease process may be limited to certain eye muscles, which is often described as “ocular myasthenia.” In those with more generalized disease or “generalized myasthenia gravis,” affected muscles may include those of the eyes, face, jaw, and throat region; arm and leg (limb) muscles; and muscles involved in breathing (respiratory muscles).The disorder often begins with weakness of muscles controlling the eyes, resulting in drooping of the upper eyelids (ptosis), double vision (diplopia), or both. Individuals may also develop weakness of muscles of the face, jaw, and throat. In such cases, associated symptoms may include difficulties speaking (dysarthria), causing the voice to sound weak, hoarse, or “nasally,” and increasing chewing and swallowing difficulties (dysphagia) during the course of meals, leading to choking, coughing, or inhalation (aspiration) of food or liquids. Some individuals may also develop limb weakness and easy fatigability of arm and leg muscles. In approximately 10 percent of patients, myasthenic crisis or sudden severe weakness of the jaw and throat (oropharyngeal) or respiratory muscles occurs, requiring respiratory assistance. Sudden worsening of weakness may be triggered by infections, severe stress, surgery, or a reduction or sudden increase of prednisone. Patients with antibodies to MuSK may develop muscle atrophy, in particular of facial and tongue muscles.The course of the myasthenia gravis is highly variable. For example, the degree of muscle weakness may vary over hours, from day to day, or over weeks and months, tending to increase with repeated muscle use and to improve with rest. In addition, particularly during the first years after disease onset, some affected individuals may experience alternating periods in which symptoms temporarily subside or worsen (remissions and exacerbations). A short-term aggravation of symptoms may be triggered by a variety of factors, including infection, excessive physical activity, menstruation, and after delivery of a child.Infants of mothers who have myasthenia gravis may develop a temporary (transient) form of the disorder beginning within approximately 48 hours after birth. Known as transient neonatal myasthenia gravis, the condition may be characterized by generalized muscle weakness and low muscle tone (hypotonia); impaired sucking or swallowing; a weak cry; respiratory insufficiency; and/or little spontaneous movement. Such abnormalities may be present for days to weeks, after which affected infants have normal muscle strength.Congenital myasthenia is caused by genetic defects of muscle and nerve communication (neuromuscular transmission), and not an abnormal immune system. Congenital myasthenia usually occurs in infants but may become evident in adulthood. Other features may vary in severity among patients. Such abnormalities may include feeding difficulties, sudden episodes of reduced breathing (apnea), failure to grow and gain weight at an expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and other abnormalities.
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Symptoms of Myasthenia Gravis. Symptoms may be variable, with disease involvement potentially localized to certain muscles or affecting multiple muscles. In some affected individuals, the disease process may be limited to certain eye muscles, which is often described as “ocular myasthenia.” In those with more generalized disease or “generalized myasthenia gravis,” affected muscles may include those of the eyes, face, jaw, and throat region; arm and leg (limb) muscles; and muscles involved in breathing (respiratory muscles).The disorder often begins with weakness of muscles controlling the eyes, resulting in drooping of the upper eyelids (ptosis), double vision (diplopia), or both. Individuals may also develop weakness of muscles of the face, jaw, and throat. In such cases, associated symptoms may include difficulties speaking (dysarthria), causing the voice to sound weak, hoarse, or “nasally,” and increasing chewing and swallowing difficulties (dysphagia) during the course of meals, leading to choking, coughing, or inhalation (aspiration) of food or liquids. Some individuals may also develop limb weakness and easy fatigability of arm and leg muscles. In approximately 10 percent of patients, myasthenic crisis or sudden severe weakness of the jaw and throat (oropharyngeal) or respiratory muscles occurs, requiring respiratory assistance. Sudden worsening of weakness may be triggered by infections, severe stress, surgery, or a reduction or sudden increase of prednisone. Patients with antibodies to MuSK may develop muscle atrophy, in particular of facial and tongue muscles.The course of the myasthenia gravis is highly variable. For example, the degree of muscle weakness may vary over hours, from day to day, or over weeks and months, tending to increase with repeated muscle use and to improve with rest. In addition, particularly during the first years after disease onset, some affected individuals may experience alternating periods in which symptoms temporarily subside or worsen (remissions and exacerbations). A short-term aggravation of symptoms may be triggered by a variety of factors, including infection, excessive physical activity, menstruation, and after delivery of a child.Infants of mothers who have myasthenia gravis may develop a temporary (transient) form of the disorder beginning within approximately 48 hours after birth. Known as transient neonatal myasthenia gravis, the condition may be characterized by generalized muscle weakness and low muscle tone (hypotonia); impaired sucking or swallowing; a weak cry; respiratory insufficiency; and/or little spontaneous movement. Such abnormalities may be present for days to weeks, after which affected infants have normal muscle strength.Congenital myasthenia is caused by genetic defects of muscle and nerve communication (neuromuscular transmission), and not an abnormal immune system. Congenital myasthenia usually occurs in infants but may become evident in adulthood. Other features may vary in severity among patients. Such abnormalities may include feeding difficulties, sudden episodes of reduced breathing (apnea), failure to grow and gain weight at an expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and other abnormalities.
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Myasthenia Gravis
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nord_848_2
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Causes of Myasthenia Gravis
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Most individuals with myasthenia gravis (MG) have no family history of MG and the disorder appears to occur spontaneously (sporadically) for unknown reasons. However, upwards of 5 percent of patients may have family members with MG or other autoimmune disorders. Individuals with MG have an increased frequency of certain genetically determined “human leukocyte antigens” (HLAs), suggesting that genetic predisposition may play some role. (HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of transplantation and appear to affect an individual’s predisposition to certain diseases.) Other autoimmune diseases also appear to occur with increased frequency in individuals with MG, including thyroid disorders and systemic lupus erythematosus. These observations suggest that there is some genetic predisposition to MG which requires a trigger from the environment to cause the disease.Myasthenia gravis is caused by an abnormal immune reaction (antibody-mediated autoimmune response) in which the body’s immune defenses (i.e., antibodies) inappropriately attack certain proteins in muscles that receive nerve impulses. The areas of contact between nerve endings and skeletal muscle fibers are known as neuromuscular junctions. Nerve endings release a chemical (the neurotransmitter acetylcholine) that transmits impulses to muscle fibers, ultimately resulting in their contraction. However, in individuals with myasthenia gravis, antibodies are inappropriately directed against sites (receptors) on the surface of certain muscle cells that bind with the neurotransmitter acetylcholine (acetylcholine receptors). (These antibodies are known as “anti-acetylcholine receptor antibodies [anti-AChR].) The abnormal autoimmune response results in a decreased number of acetylcholine receptors, causing failed nerve transmission at certain neuromuscular junctions and associated deficiency or weakness of muscle contractions. Some patients with anti-AChR have antibodies that attack another protein called the muscle specific kinase protein (MuSK). These anti-MuSK antibodies also lead to a decrease in the number of acetylcholine receptors. Recently, antibodies to LRP-4 (lipoprotein receptor protein 4) were identified in patients without antibodies to MuSK or AChR. In five to eight percent of patients an antibody in the blood cannot be identified but patients have other tests consistent with myasthenia gravis.The specific cause of abnormal autoimmune responses in patients with myasthenia gravis is unknown. However, researchers suggest that the thymus has some role in this process. According to reports in the medical literature, up to approximately 75 percent of individuals with myasthenia gravis have distinctive abnormalities of the thymus. In most cases, there are increased numbers of cells in the thymus (hyperplasia). In addition, in about 10 percent of affected individuals, the thymus contains a tumor (thymoma) that is typically noncancerous (benign). However, some thymomas may be malignant. Researchers suggest that the thymus of MG patients does not appropriately eliminate cells that produce antibodies that attack body tissues. In the case of MG antibodies are produced that react against acetylcholine receptors, triggering the abnormal autoimmune response within the thymus. (A lymphoid tissue organ located behind the breastbone, the thymus plays an important role in the immune system beginning during early fetal development until puberty. It is important in the maturation of certain specialized white blood cells [T lymphocytes] that have several functions, including assisting in the recognition of certain foreign proteins [antigens] or binding to cells invaded by microorganisms and destroying them.) The abnormalities that lead to production of anti-MuSK antibodies is poorly understood and appears not to involve the thymus.Some infants born to mothers with myasthenia gravis may develop temporary muscle weakness and associated findings (i.e., transient neonatal myasthenia gravis). This condition results from the passage of anti-acetylcholine receptor antibodies through the placenta to the unborn child during pregnancy.
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Causes of Myasthenia Gravis. Most individuals with myasthenia gravis (MG) have no family history of MG and the disorder appears to occur spontaneously (sporadically) for unknown reasons. However, upwards of 5 percent of patients may have family members with MG or other autoimmune disorders. Individuals with MG have an increased frequency of certain genetically determined “human leukocyte antigens” (HLAs), suggesting that genetic predisposition may play some role. (HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of transplantation and appear to affect an individual’s predisposition to certain diseases.) Other autoimmune diseases also appear to occur with increased frequency in individuals with MG, including thyroid disorders and systemic lupus erythematosus. These observations suggest that there is some genetic predisposition to MG which requires a trigger from the environment to cause the disease.Myasthenia gravis is caused by an abnormal immune reaction (antibody-mediated autoimmune response) in which the body’s immune defenses (i.e., antibodies) inappropriately attack certain proteins in muscles that receive nerve impulses. The areas of contact between nerve endings and skeletal muscle fibers are known as neuromuscular junctions. Nerve endings release a chemical (the neurotransmitter acetylcholine) that transmits impulses to muscle fibers, ultimately resulting in their contraction. However, in individuals with myasthenia gravis, antibodies are inappropriately directed against sites (receptors) on the surface of certain muscle cells that bind with the neurotransmitter acetylcholine (acetylcholine receptors). (These antibodies are known as “anti-acetylcholine receptor antibodies [anti-AChR].) The abnormal autoimmune response results in a decreased number of acetylcholine receptors, causing failed nerve transmission at certain neuromuscular junctions and associated deficiency or weakness of muscle contractions. Some patients with anti-AChR have antibodies that attack another protein called the muscle specific kinase protein (MuSK). These anti-MuSK antibodies also lead to a decrease in the number of acetylcholine receptors. Recently, antibodies to LRP-4 (lipoprotein receptor protein 4) were identified in patients without antibodies to MuSK or AChR. In five to eight percent of patients an antibody in the blood cannot be identified but patients have other tests consistent with myasthenia gravis.The specific cause of abnormal autoimmune responses in patients with myasthenia gravis is unknown. However, researchers suggest that the thymus has some role in this process. According to reports in the medical literature, up to approximately 75 percent of individuals with myasthenia gravis have distinctive abnormalities of the thymus. In most cases, there are increased numbers of cells in the thymus (hyperplasia). In addition, in about 10 percent of affected individuals, the thymus contains a tumor (thymoma) that is typically noncancerous (benign). However, some thymomas may be malignant. Researchers suggest that the thymus of MG patients does not appropriately eliminate cells that produce antibodies that attack body tissues. In the case of MG antibodies are produced that react against acetylcholine receptors, triggering the abnormal autoimmune response within the thymus. (A lymphoid tissue organ located behind the breastbone, the thymus plays an important role in the immune system beginning during early fetal development until puberty. It is important in the maturation of certain specialized white blood cells [T lymphocytes] that have several functions, including assisting in the recognition of certain foreign proteins [antigens] or binding to cells invaded by microorganisms and destroying them.) The abnormalities that lead to production of anti-MuSK antibodies is poorly understood and appears not to involve the thymus.Some infants born to mothers with myasthenia gravis may develop temporary muscle weakness and associated findings (i.e., transient neonatal myasthenia gravis). This condition results from the passage of anti-acetylcholine receptor antibodies through the placenta to the unborn child during pregnancy.
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Myasthenia Gravis
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Affects of Myasthenia Gravis
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Autoimmune myasthenia gravis has a prevalence of approximately 14-40 per 100,000 individuals in the United States. Reports indicate that the frequency of the disorder has appeared to increase over the last several decades. This may be because of better identification of patients, but also autoimmune disorders in general are increasing in frequency across the world.Autoimmune myasthenia gravis more frequently affects women than men. Associated symptoms may become apparent at any age; however, symptom onset most commonly peaks in women during their 20s or 30s and in men in their 50s or 60s.
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Affects of Myasthenia Gravis. Autoimmune myasthenia gravis has a prevalence of approximately 14-40 per 100,000 individuals in the United States. Reports indicate that the frequency of the disorder has appeared to increase over the last several decades. This may be because of better identification of patients, but also autoimmune disorders in general are increasing in frequency across the world.Autoimmune myasthenia gravis more frequently affects women than men. Associated symptoms may become apparent at any age; however, symptom onset most commonly peaks in women during their 20s or 30s and in men in their 50s or 60s.
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Myasthenia Gravis
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nord_848_4
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Related disorders of Myasthenia Gravis
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Symptoms of the following disorders may be similar to those of myasthenia gravis (MG). Comparisons may be useful for a differential diagnosis:Lambert-Eaton (myasthenic) syndrome is also known as Eaton-Lambert syndrome. It is a rare autoimmune disorder of adulthood in which antibodies abnormally attack certain proteins on the surface of nerve endings that regulate calcium levels (calcium channels), resulting in inadequate release of acetylcholine. It is characterized by muscle weakness and fatigue, particularly of the hip and thigh muscles. Additional symptoms and findings may include absence of certain reduced reflex responses and dysfunction of particular involuntary functions (autonomic symptoms), such as dryness of the mouth, constipation, impotence, and/or other abnormalities. Cancer, particularly certain types of lung cancer, is frequently associated with the disease. (For more information, choose “Lambert-Eaton” as your search term in the Rare Disease Database.)Patients with ocular myasthenia may be confused with having a stroke in the brainstem or within nerves that control eye movements. Patients with Graves’ disease that involves the muscles that move the eyes may also be misdiagnosed with MG. However, MG and Graves’ disease may occur simultaneously in a patient.Congenital myasthenia is not an autoimmune disease and therefore anti-acetylcholine receptor or anti-MuSK antibodies are not present. This group of disorders may result from various changes (mutations) in genes involved in nerve-muscle communication, with some involving abnormalities of the acetylcholine receptor.Additional disorders may also be characterized by certain symptoms and findings similar to those associated with the different forms of myasthenia gravis. Such disorders are typically associated with characteristic features that may help to differentiate them from MG. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Myasthenia Gravis. Symptoms of the following disorders may be similar to those of myasthenia gravis (MG). Comparisons may be useful for a differential diagnosis:Lambert-Eaton (myasthenic) syndrome is also known as Eaton-Lambert syndrome. It is a rare autoimmune disorder of adulthood in which antibodies abnormally attack certain proteins on the surface of nerve endings that regulate calcium levels (calcium channels), resulting in inadequate release of acetylcholine. It is characterized by muscle weakness and fatigue, particularly of the hip and thigh muscles. Additional symptoms and findings may include absence of certain reduced reflex responses and dysfunction of particular involuntary functions (autonomic symptoms), such as dryness of the mouth, constipation, impotence, and/or other abnormalities. Cancer, particularly certain types of lung cancer, is frequently associated with the disease. (For more information, choose “Lambert-Eaton” as your search term in the Rare Disease Database.)Patients with ocular myasthenia may be confused with having a stroke in the brainstem or within nerves that control eye movements. Patients with Graves’ disease that involves the muscles that move the eyes may also be misdiagnosed with MG. However, MG and Graves’ disease may occur simultaneously in a patient.Congenital myasthenia is not an autoimmune disease and therefore anti-acetylcholine receptor or anti-MuSK antibodies are not present. This group of disorders may result from various changes (mutations) in genes involved in nerve-muscle communication, with some involving abnormalities of the acetylcholine receptor.Additional disorders may also be characterized by certain symptoms and findings similar to those associated with the different forms of myasthenia gravis. Such disorders are typically associated with characteristic features that may help to differentiate them from MG. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Myasthenia Gravis
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nord_848_5
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Diagnosis of Myasthenia Gravis
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Myasthenia gravis is diagnosed based upon a thorough clinical evaluation, detection of characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. The diagnosis is suspected based on a characteristic distribution of muscle weakness and fatigue, without impairment other of neurologic function. Diagnostic studies include the intravenous injection of a drug that rapidly inhibits the action of an enzyme involved in breaking down acetylcholine, allowing the neurotransmitter to repeatedly interact with available acetylcholine receptors (edrophonium or Tensilon test). In those with the disorder, anticholinesterase testing of weak muscle groups temporarily restores muscle strength. The drugs edrophonium or neostigmine may be used during such testing. The ice pack test involves placing a cold pack across the eyes for 10 minutes and then determining if eye lid droop has significantly improved. The rest test involves a patient closing their eyelids for 30 minutes and again assessment for improved lid position or eye movement is made. For all these tests there can be “false negatives” in which a patient with disease does not show improvement with the testing.Specialized blood studies are also conducted to detect the presence of antibodies to the acetylcholine receptor or muscle specific kinase. Acetylcholine receptor antibodies may be detected in up to 90 percent of affected individuals with generalized disease and up to 50 percent of those with the ocular form. Muscle specific kinase antibodies are found in about 3-6 percent of patients and LRP-4 antibodies even more rarely.Additional diagnostic studies may include electromyography (EMG), a test that records electrical activity in skeletal muscles. A specialized test usually performed only at academic medical centers called a single fiber exam is highly sensitive for detecting the abnormalities of MG. In addition, advanced imaging techniques may be conducted to help detect tumors of the thymus. Such studies may include computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the mediastinum, which is the space between the lungs that contains the thymus and several other bodily structures. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues.
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Diagnosis of Myasthenia Gravis. Myasthenia gravis is diagnosed based upon a thorough clinical evaluation, detection of characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. The diagnosis is suspected based on a characteristic distribution of muscle weakness and fatigue, without impairment other of neurologic function. Diagnostic studies include the intravenous injection of a drug that rapidly inhibits the action of an enzyme involved in breaking down acetylcholine, allowing the neurotransmitter to repeatedly interact with available acetylcholine receptors (edrophonium or Tensilon test). In those with the disorder, anticholinesterase testing of weak muscle groups temporarily restores muscle strength. The drugs edrophonium or neostigmine may be used during such testing. The ice pack test involves placing a cold pack across the eyes for 10 minutes and then determining if eye lid droop has significantly improved. The rest test involves a patient closing their eyelids for 30 minutes and again assessment for improved lid position or eye movement is made. For all these tests there can be “false negatives” in which a patient with disease does not show improvement with the testing.Specialized blood studies are also conducted to detect the presence of antibodies to the acetylcholine receptor or muscle specific kinase. Acetylcholine receptor antibodies may be detected in up to 90 percent of affected individuals with generalized disease and up to 50 percent of those with the ocular form. Muscle specific kinase antibodies are found in about 3-6 percent of patients and LRP-4 antibodies even more rarely.Additional diagnostic studies may include electromyography (EMG), a test that records electrical activity in skeletal muscles. A specialized test usually performed only at academic medical centers called a single fiber exam is highly sensitive for detecting the abnormalities of MG. In addition, advanced imaging techniques may be conducted to help detect tumors of the thymus. Such studies may include computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the mediastinum, which is the space between the lungs that contains the thymus and several other bodily structures. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues.
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Myasthenia Gravis
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nord_848_6
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Therapies of Myasthenia Gravis
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TreatmentDecisions about specific treatment are based on specifics of each patient’s case. Recommended treatments for myasthenia gravis may include various measures that may alleviate symptoms, including anticholinesterase drugs (cholinesterase inhibitors) or alter the disease course, such as immunosuppressive drugs or surgery (thymectomy).Initial treatment commonly includes the use of cholinesterase inhibitors, which increase muscle strength by preventing the normal breakdown of the neurotransmitter acetylcholine. Pyridostigmine by mouth (orally) is primarily used.For infants with transient neonatal myasthenia gravis, therapy with cholinesterase inhibitors may be required for only a few days or weeks. In addition, in some cases, physicians may recommend therapy with cholinesterase inhibitors for infants with certain forms of congenital myasthenia.In many individuals with autoimmune MG, therapy with medications that reduce activity of the immune system (immunosuppressive therapy) also results in improvement. Such agents, which may be combined with cholinesterase inhibitors, may include corticosteroids (e.g., prednisone) or certain other immunosuppressive drugs, particularly azathioprine, mycophenolate mofetil, tacrolimus, and cyclosporine. Generally, corticosteroids result in rapid improvement in the first 2 months of therapy while the other immunosuppressive drugs requiring many months to over a year to be effective. Patients receiving long-term therapy with such medications require ongoing monitoring to help prevent or appropriately treat adverse side effects.Based on a randomized clinical trial of thymectomy plus prednisone plus prednisone alone, it is generally recommended that thymectomy should be considered for individuals with generalized disease between the ages of eighteen to 65 and have acetylcholine receptor antibodies. Decisions must be individualized for those who have localized involvement of eye muscles, are older than 65 years, or are children (i.e., with autoimmune myasthenia gravis). Thymectomy usually is not recommended for those with ocular myasthenia gravis unless thymoma is detected. In those with autoimmune myasthenia gravis associated with thymoma, recommended treatment is surgical removal of the tumor and the remaining thymus (thymectomy). Many physicians may recommend that thymectomy should be considered in appropriate cases for affected children with autoimmune myasthenia gravis. However, it is important to note that thymectomy is not effective in cases of congenital myasthenia (which does not involve autoimmune abnormalities).Myasthenic crisis is a medical emergency that requires management in an intensive care unit. Treatment may include emergency respiratory assistance (assisted ventilation); temporary cessation of anticholinesterase therapy to exclude excessive dosage as a possible cause; immediate treatment of possible causative infection with appropriate antibiotic medication or other therapy including plasmapheresis; intravenous immunoglobulin, high dose prednisone, and possibly other therapies.Plasmapheresis may alleviate symptoms in individuals with autoimmune myasthenia gravis. During this procedure, which is also known as plasma exchange, damaging antibodies are filtered from the blood. By providing a short-term reduction in the levels of anti-ACh receptor antibodies, plasmapheresis may be effective as a temporary therapy in those with severe symptoms or to help treat myasthenic crisis. In addition, plasmapheresis may be recommended to help improve an affected individual’s condition before undergoing surgical removal of the thymus.Infusion of antibodies (immunoglobulins) obtained from thousands of blood donors and by purification of the fluid portion of the blood (intravenous immunoglobulin IVIG) may also be provided as a temporary therapy before surgical removal of the thymus or for those who experience periods of severe muscle weakness.Soliris (eculizumab) is for the treatment of generalized myasthenia gravis in patients who are anti-acetylcholine receptor (AchR) antibody-positive. Soliris is extremely expensive and requires intravenous infusion. It is generally limited for treatment of patients who failed other therapies. Medications, such as particular antibiotics or antiarrhythmic agents, may also aggravate symptoms in individuals with myasthenia gravis and therefore should be avoided or used with caution. . Exacerbation of weakness may occur with various antibiotics, including aminoglycosides, macrolides, and some fluoroquinolones. Patients needing antibiotics should discuss this with their physicians. A complete list of medications to use with caution may be found at myasthenia.org Individuals with myasthenia gravis may have increased sensitivity to the use of certain medications, such as particular anesthetics or muscle relaxants (e.g., succinylcholine, pancuronium). Therefore, this risk must be taken into consideration by surgeons, anesthesiologists, or other health care workers when making decisions concerning potential surgery and use of anesthetics. Physical therapy may also be recommended to help patients maintain muscle strength and range of motion, but must be performed in a manner to limit any over-exertion Additional treatment for the different forms of myasthenia gravis is symptomatic and supportive.In 2021, Vyvgart (efgartigimod) was approved to treat adult patients with generalized myasthenia gravis who test positive for the anti-acetylcholine receptor antibody.
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Therapies of Myasthenia Gravis. TreatmentDecisions about specific treatment are based on specifics of each patient’s case. Recommended treatments for myasthenia gravis may include various measures that may alleviate symptoms, including anticholinesterase drugs (cholinesterase inhibitors) or alter the disease course, such as immunosuppressive drugs or surgery (thymectomy).Initial treatment commonly includes the use of cholinesterase inhibitors, which increase muscle strength by preventing the normal breakdown of the neurotransmitter acetylcholine. Pyridostigmine by mouth (orally) is primarily used.For infants with transient neonatal myasthenia gravis, therapy with cholinesterase inhibitors may be required for only a few days or weeks. In addition, in some cases, physicians may recommend therapy with cholinesterase inhibitors for infants with certain forms of congenital myasthenia.In many individuals with autoimmune MG, therapy with medications that reduce activity of the immune system (immunosuppressive therapy) also results in improvement. Such agents, which may be combined with cholinesterase inhibitors, may include corticosteroids (e.g., prednisone) or certain other immunosuppressive drugs, particularly azathioprine, mycophenolate mofetil, tacrolimus, and cyclosporine. Generally, corticosteroids result in rapid improvement in the first 2 months of therapy while the other immunosuppressive drugs requiring many months to over a year to be effective. Patients receiving long-term therapy with such medications require ongoing monitoring to help prevent or appropriately treat adverse side effects.Based on a randomized clinical trial of thymectomy plus prednisone plus prednisone alone, it is generally recommended that thymectomy should be considered for individuals with generalized disease between the ages of eighteen to 65 and have acetylcholine receptor antibodies. Decisions must be individualized for those who have localized involvement of eye muscles, are older than 65 years, or are children (i.e., with autoimmune myasthenia gravis). Thymectomy usually is not recommended for those with ocular myasthenia gravis unless thymoma is detected. In those with autoimmune myasthenia gravis associated with thymoma, recommended treatment is surgical removal of the tumor and the remaining thymus (thymectomy). Many physicians may recommend that thymectomy should be considered in appropriate cases for affected children with autoimmune myasthenia gravis. However, it is important to note that thymectomy is not effective in cases of congenital myasthenia (which does not involve autoimmune abnormalities).Myasthenic crisis is a medical emergency that requires management in an intensive care unit. Treatment may include emergency respiratory assistance (assisted ventilation); temporary cessation of anticholinesterase therapy to exclude excessive dosage as a possible cause; immediate treatment of possible causative infection with appropriate antibiotic medication or other therapy including plasmapheresis; intravenous immunoglobulin, high dose prednisone, and possibly other therapies.Plasmapheresis may alleviate symptoms in individuals with autoimmune myasthenia gravis. During this procedure, which is also known as plasma exchange, damaging antibodies are filtered from the blood. By providing a short-term reduction in the levels of anti-ACh receptor antibodies, plasmapheresis may be effective as a temporary therapy in those with severe symptoms or to help treat myasthenic crisis. In addition, plasmapheresis may be recommended to help improve an affected individual’s condition before undergoing surgical removal of the thymus.Infusion of antibodies (immunoglobulins) obtained from thousands of blood donors and by purification of the fluid portion of the blood (intravenous immunoglobulin IVIG) may also be provided as a temporary therapy before surgical removal of the thymus or for those who experience periods of severe muscle weakness.Soliris (eculizumab) is for the treatment of generalized myasthenia gravis in patients who are anti-acetylcholine receptor (AchR) antibody-positive. Soliris is extremely expensive and requires intravenous infusion. It is generally limited for treatment of patients who failed other therapies. Medications, such as particular antibiotics or antiarrhythmic agents, may also aggravate symptoms in individuals with myasthenia gravis and therefore should be avoided or used with caution. . Exacerbation of weakness may occur with various antibiotics, including aminoglycosides, macrolides, and some fluoroquinolones. Patients needing antibiotics should discuss this with their physicians. A complete list of medications to use with caution may be found at myasthenia.org Individuals with myasthenia gravis may have increased sensitivity to the use of certain medications, such as particular anesthetics or muscle relaxants (e.g., succinylcholine, pancuronium). Therefore, this risk must be taken into consideration by surgeons, anesthesiologists, or other health care workers when making decisions concerning potential surgery and use of anesthetics. Physical therapy may also be recommended to help patients maintain muscle strength and range of motion, but must be performed in a manner to limit any over-exertion Additional treatment for the different forms of myasthenia gravis is symptomatic and supportive.In 2021, Vyvgart (efgartigimod) was approved to treat adult patients with generalized myasthenia gravis who test positive for the anti-acetylcholine receptor antibody.
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Myasthenia Gravis
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Overview of Mycosis Fungoides
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Mycosis fungoides is a rare form of T-cell lymphoma of the skin (cutaneous); the disease is typically slowly progressive and chronic. In individuals with mycosis fungoides, the skin becomes infiltrated with plaques and nodules that are composed of lymphocytes. In advanced cases, ulcerated tumors and infiltration of lymph nodes by diseased cells may occur. The disorder may spread to other parts of the body including the gastrointestinal system, liver, spleen, or brain.
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Overview of Mycosis Fungoides. Mycosis fungoides is a rare form of T-cell lymphoma of the skin (cutaneous); the disease is typically slowly progressive and chronic. In individuals with mycosis fungoides, the skin becomes infiltrated with plaques and nodules that are composed of lymphocytes. In advanced cases, ulcerated tumors and infiltration of lymph nodes by diseased cells may occur. The disorder may spread to other parts of the body including the gastrointestinal system, liver, spleen, or brain.
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Symptoms of Mycosis Fungoides
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STAGE I: The first sign of mycosis fungoides is usually generalized itching (pruritus), and pain in the affected area of the skin. Sleeplessness (insomnia) may also occur. Red (erythematous) patches scattered over the skin of the trunk and the extremities appear. These lesions may resemble other skin disorders such as psoriasis, parapsoriasis, lichen planus, or eczema. STAGE II: The second stage is called the plaque or “infiltrating stage.” Bluish red circular or oval plaques develop on affected areas. The buttocks may be the first area to be affected. Initially, these plaques are typically small and elevated. The plaques may slowly enlarge and run together (coalesce), covering approximately 10 percent of the body. At this point, the lesions may resemble a skin disorder known as exfoliative dermatitis. Another condition of the lymph nodes may also develop known as lipomelanotic reticulosis. This condition is characterized by abnormal development of certain cells called macrophages and the presence of dark colored fatty tissue. Additionally, inflammation of the lymph nodes (lymphadenitis) may also develop. STAGE III: The third stage of the disease is the fungoid or tumor stage. Tumors appear that resemble mushrooms; they may appear rounded or lobulated. These ulcerated lesions are typically 1 to 15 cm (1/2 to 6 inches) in diameter and bluish or red-brown in color. Skin layers may become thick and atypical bands of lymphoid cells may infiltrate the upper skin layer. These cells may also infiltrate the clear spaces in the lower skin layers causing skin cell death (necrosis). In the tumuer d'emblee form of the disease, affected individuals may develop large nodules without previous formation of plaque. STAGE IV: During this stage, the disorder may spread throughout the body. Symptoms may include a general feeling of ill health (malaise) and weakness, elevated temperatures, weight loss, and anemia. There may be gastrointestinal involvement with or without ulceration of the intestines. The liver and spleen may also become enlarged. In addition, coughing and difficulty swallowing (dysphagia) may occur. In some cases, the heart muscle may also be affected. If the brain is involved, eye pain and loss of clear vision may occur.
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Symptoms of Mycosis Fungoides. STAGE I: The first sign of mycosis fungoides is usually generalized itching (pruritus), and pain in the affected area of the skin. Sleeplessness (insomnia) may also occur. Red (erythematous) patches scattered over the skin of the trunk and the extremities appear. These lesions may resemble other skin disorders such as psoriasis, parapsoriasis, lichen planus, or eczema. STAGE II: The second stage is called the plaque or “infiltrating stage.” Bluish red circular or oval plaques develop on affected areas. The buttocks may be the first area to be affected. Initially, these plaques are typically small and elevated. The plaques may slowly enlarge and run together (coalesce), covering approximately 10 percent of the body. At this point, the lesions may resemble a skin disorder known as exfoliative dermatitis. Another condition of the lymph nodes may also develop known as lipomelanotic reticulosis. This condition is characterized by abnormal development of certain cells called macrophages and the presence of dark colored fatty tissue. Additionally, inflammation of the lymph nodes (lymphadenitis) may also develop. STAGE III: The third stage of the disease is the fungoid or tumor stage. Tumors appear that resemble mushrooms; they may appear rounded or lobulated. These ulcerated lesions are typically 1 to 15 cm (1/2 to 6 inches) in diameter and bluish or red-brown in color. Skin layers may become thick and atypical bands of lymphoid cells may infiltrate the upper skin layer. These cells may also infiltrate the clear spaces in the lower skin layers causing skin cell death (necrosis). In the tumuer d'emblee form of the disease, affected individuals may develop large nodules without previous formation of plaque. STAGE IV: During this stage, the disorder may spread throughout the body. Symptoms may include a general feeling of ill health (malaise) and weakness, elevated temperatures, weight loss, and anemia. There may be gastrointestinal involvement with or without ulceration of the intestines. The liver and spleen may also become enlarged. In addition, coughing and difficulty swallowing (dysphagia) may occur. In some cases, the heart muscle may also be affected. If the brain is involved, eye pain and loss of clear vision may occur.
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Mycosis Fungoides
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Causes of Mycosis Fungoides
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The exact cause of mycosis fungoides is not known. Current theories include antigen persistence, retroviruses (e.g., HTLV-1, etc.), and exposure to cancer-causing (carcinogenic) substances.
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Causes of Mycosis Fungoides. The exact cause of mycosis fungoides is not known. Current theories include antigen persistence, retroviruses (e.g., HTLV-1, etc.), and exposure to cancer-causing (carcinogenic) substances.
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Affects of Mycosis Fungoides
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Mycosis fungoides rarely occurs before age 40 years. It affects males twice as often as females.
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Affects of Mycosis Fungoides. Mycosis fungoides rarely occurs before age 40 years. It affects males twice as often as females.
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Related disorders of Mycosis Fungoides
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Symptoms of the following skin disorders may resemble those of mycosis fungoides. Comparisons may be useful for a differential diagnosis: Discoid lupus erythematosus is a chronic and recurrent autoimmune disorder primarily affecting the skin. It is characterized by sharply circumscribed red spots (erythematous macules) and plaques, plugging of follicles, scales, vascular lesions (telangiectasia), and loss of skin tissue (atrophy). There are two varieties: one with lesions above the chin, the other with or without facial involvement but causing skin lesions on the rest of the body. (For more information on this disorder, choose “lupus” as your search term in the Rare Disease Database.) Eczema (dermatitis) is a common superficial inflammation of the skin, characterized by extremely dry and cracked skin with blisters (when acute), redness, swelling, oozing, crusting, and scaling. It is usually itchy and commonly associated with allergies. Leprosy (Hansen's disease) is a chronic infectious disorder caused by bacteria (Mycobacterium leprae). It tends to occur in tropical and subtropical areas of the world. Skin, mucous membranes, eyes and peripheral nerves may be involved. Nerve damage can result in loss of sensation and movement in the face, hands and feet. This in turn can lead to crippling and disfigurement. Blindness may result from eye complications. (For more information on this disorder, choose “leprosy” as your search term in the Rare Disease Database.) Lichen planus is a recurrent, itchy, inflammatory eruption of the skin which is characterized by small separate, angular spots that may flow together into rough scaly patches. It is often accompanied by lesions in the mouth. Women are most commonly affected by the disorder. (For more information on this disorder, choose “lichen planus” as your search term in the Rare Disease Database.) Lymphocytic infiltrate of Jessner (benign lymphocytic infiltrate of the skin) is a skin disorder characterized by benign accumulations of lymph cells in the skin, whereas Mycosis fungoides is a malignant infiltration of lymph cells. These small lesions are solid, pink or red, and appear on itchy and reddened areas of the face, neck and/or back. Lesions may remain unchanged and then spontaneously resolve after several years, leaving no scars. (For more information on this disorder, choose “lymphocytic infiltrate of Jessner” as your search term in the Rare Disease Database.) Chronic lymphocytic leukemia is characterized by an abnormal accumulation of lymph cells from the lymph nodes and tissues. These cells infiltrate the bone marrow and replace the normal blood forming elements. The disorder, almost three times more common in males than in females, occurs chiefly between the ages of 50 to 70, but may occur at any age. (For more information on this disorder, choose “chronic lymphocytic leukemia” as your search term in the Rare Disease Database.) Parapsoriasis lichenoides chronica (parapsoriasis varioliformis chronica) is a relatively benign, chronic, scaly skin disorder characterized by elevated spots (papules). It may occur at any age and is not easily treatable. (For more information, choose “psoriasis” as your search term in the Rare Disease Database.) Sezary syndrome (Sezary reticulosis syndrome; Sezary erythroderma) is a generalized redness of the skin (erythroderma) in which areas of the skin fall off in scales. It is caused by infiltration of the skin by young blood (reticular) cells. The disorder is associated with intense itching, loss of hair, swelling, and overdevelopment of the horn layer of the skin (hyperkeratosis). Changes in skin pigment, fingernails, and toe nails may occur. Bone marrow and lymph nodes are normal in patients with this disorder but abnormal young red blood cells may often be found.
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Related disorders of Mycosis Fungoides. Symptoms of the following skin disorders may resemble those of mycosis fungoides. Comparisons may be useful for a differential diagnosis: Discoid lupus erythematosus is a chronic and recurrent autoimmune disorder primarily affecting the skin. It is characterized by sharply circumscribed red spots (erythematous macules) and plaques, plugging of follicles, scales, vascular lesions (telangiectasia), and loss of skin tissue (atrophy). There are two varieties: one with lesions above the chin, the other with or without facial involvement but causing skin lesions on the rest of the body. (For more information on this disorder, choose “lupus” as your search term in the Rare Disease Database.) Eczema (dermatitis) is a common superficial inflammation of the skin, characterized by extremely dry and cracked skin with blisters (when acute), redness, swelling, oozing, crusting, and scaling. It is usually itchy and commonly associated with allergies. Leprosy (Hansen's disease) is a chronic infectious disorder caused by bacteria (Mycobacterium leprae). It tends to occur in tropical and subtropical areas of the world. Skin, mucous membranes, eyes and peripheral nerves may be involved. Nerve damage can result in loss of sensation and movement in the face, hands and feet. This in turn can lead to crippling and disfigurement. Blindness may result from eye complications. (For more information on this disorder, choose “leprosy” as your search term in the Rare Disease Database.) Lichen planus is a recurrent, itchy, inflammatory eruption of the skin which is characterized by small separate, angular spots that may flow together into rough scaly patches. It is often accompanied by lesions in the mouth. Women are most commonly affected by the disorder. (For more information on this disorder, choose “lichen planus” as your search term in the Rare Disease Database.) Lymphocytic infiltrate of Jessner (benign lymphocytic infiltrate of the skin) is a skin disorder characterized by benign accumulations of lymph cells in the skin, whereas Mycosis fungoides is a malignant infiltration of lymph cells. These small lesions are solid, pink or red, and appear on itchy and reddened areas of the face, neck and/or back. Lesions may remain unchanged and then spontaneously resolve after several years, leaving no scars. (For more information on this disorder, choose “lymphocytic infiltrate of Jessner” as your search term in the Rare Disease Database.) Chronic lymphocytic leukemia is characterized by an abnormal accumulation of lymph cells from the lymph nodes and tissues. These cells infiltrate the bone marrow and replace the normal blood forming elements. The disorder, almost three times more common in males than in females, occurs chiefly between the ages of 50 to 70, but may occur at any age. (For more information on this disorder, choose “chronic lymphocytic leukemia” as your search term in the Rare Disease Database.) Parapsoriasis lichenoides chronica (parapsoriasis varioliformis chronica) is a relatively benign, chronic, scaly skin disorder characterized by elevated spots (papules). It may occur at any age and is not easily treatable. (For more information, choose “psoriasis” as your search term in the Rare Disease Database.) Sezary syndrome (Sezary reticulosis syndrome; Sezary erythroderma) is a generalized redness of the skin (erythroderma) in which areas of the skin fall off in scales. It is caused by infiltration of the skin by young blood (reticular) cells. The disorder is associated with intense itching, loss of hair, swelling, and overdevelopment of the horn layer of the skin (hyperkeratosis). Changes in skin pigment, fingernails, and toe nails may occur. Bone marrow and lymph nodes are normal in patients with this disorder but abnormal young red blood cells may often be found.
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Mycosis Fungoides
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Diagnosis of Mycosis Fungoides
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A diagnosis of mycosis fungoides may be made by a thorough clinical evaluation and a variety of specialized techniques and tests including DNA cytophotometry, nuclear contour analysis, and analysis of T-cell receptor gene rearrangement.
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Diagnosis of Mycosis Fungoides. A diagnosis of mycosis fungoides may be made by a thorough clinical evaluation and a variety of specialized techniques and tests including DNA cytophotometry, nuclear contour analysis, and analysis of T-cell receptor gene rearrangement.
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Mycosis Fungoides
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Therapies of Mycosis Fungoides
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Treatment
Treatment methods for mycosis fungoides include photochemotherapy (PUVA), topical steroids, short courses of UVB (during winter months), a drug known as topical nitrogen mustard (mechlorethamine), interferons, oral retinoid therapy, and/or photopheresis. In later stages of the disorder, electron beam therapy may prove beneficial.The FDA has approved mechlorethamine gel for the topical treatment of stage IA-IB mycosis fungoides-type cutaneous T-cell lymphoma. The mechlorethamine gel is applied once per day on the affected skin.In 2018, Poteligeo (mogamulizumab-kpkc) injection was approved for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF Poteligeo is manufactured by Kyowa Kirin, Inc.Other treatment for mycosis fungoides is symptomatic and supportive.
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Therapies of Mycosis Fungoides. Treatment
Treatment methods for mycosis fungoides include photochemotherapy (PUVA), topical steroids, short courses of UVB (during winter months), a drug known as topical nitrogen mustard (mechlorethamine), interferons, oral retinoid therapy, and/or photopheresis. In later stages of the disorder, electron beam therapy may prove beneficial.The FDA has approved mechlorethamine gel for the topical treatment of stage IA-IB mycosis fungoides-type cutaneous T-cell lymphoma. The mechlorethamine gel is applied once per day on the affected skin.In 2018, Poteligeo (mogamulizumab-kpkc) injection was approved for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF Poteligeo is manufactured by Kyowa Kirin, Inc.Other treatment for mycosis fungoides is symptomatic and supportive.
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Mycosis Fungoides
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Overview of Myelodysplastic Syndromes
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SummaryMyelodysplastic syndromes (MDS) are a rare group of blood disorders that occur as a result of disordered development of blood cells within the bone marrow. The three main types of blood elements (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. In MDS, dysfunctional blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS generally have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some affected individuals, MDS may progress to life-threatening failure of the bone marrow or develop into acute leukemia. The exact cause of MDS is unknown but genetics and certain chemotherapeutic drugs or toxic exposures in the environment may play a part.IntroductionMyelodysplastic syndromes were first noted in the medical literature in 1950s where they were described as pre-leukemic conditions. Myelodysplastic syndromes were not regarded as separate, distinct disorders until 1982. In the past, these disorders have also been known by a variety of names including refractory anemia, oligoblastic anemia, myelodysplastic anemia, pre-leukemia, and smoldering leukemia.
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Overview of Myelodysplastic Syndromes. SummaryMyelodysplastic syndromes (MDS) are a rare group of blood disorders that occur as a result of disordered development of blood cells within the bone marrow. The three main types of blood elements (i.e., red blood cells, white blood cells and platelets) are affected. Red blood cells deliver oxygen to the body, white blood cells help fight infections, and platelets assist in clotting to stop blood loss. In MDS, dysfunctional blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS generally have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some affected individuals, MDS may progress to life-threatening failure of the bone marrow or develop into acute leukemia. The exact cause of MDS is unknown but genetics and certain chemotherapeutic drugs or toxic exposures in the environment may play a part.IntroductionMyelodysplastic syndromes were first noted in the medical literature in 1950s where they were described as pre-leukemic conditions. Myelodysplastic syndromes were not regarded as separate, distinct disorders until 1982. In the past, these disorders have also been known by a variety of names including refractory anemia, oligoblastic anemia, myelodysplastic anemia, pre-leukemia, and smoldering leukemia.
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Myelodysplastic Syndromes
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Symptoms of Myelodysplastic Syndromes
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The symptoms of MDS occur because the bone marrow fails to produce enough functioning blood cells. The specific symptoms and progression of the disorder vary greatly from person to person. Some individuals may have mild symptoms that remain stable for many years; others may rapidly develop serious symptoms that can progress to life-threatening complications.The bone marrow, occupies the spongy center of large bones of the body. Blood cells, produced in the red marrow, are released into the bloodstream to travel throughout the body performing their specific functions. In individuals with MDS, the bone marrow develops immature or defective versions of red cells white cells and platelets, some of which are destroyed within the bone marrow. In the process, healthy marrow cells are progressively eliminated. The consequence is a lack of healthy blood cells in the bloodstream and a reduced supply of MDS blood cells, causing symptoms associated with MDS.The most common symptom in individuals with MDS is fatigue due to low levels of circulating red blood cells. Anemia causes tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, palpitations, headaches, and pale skin color. Low levels of white blood cells (neutropenia) increase the risk of contracting bacterial and fungal infections. Low levels of platelets (thrombocytopenia) makes the individual more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the gums and nose. Women may develop increased menstrual blood loss. Bleeding may also occur in the digestive tube causing blood loss in the stools. Sometimes the bleeding occurs as a scattered red rash chiefly on the limbs–so-called petechial hemorrhages.MDS has a tendency to get worse with time as the normal bone marrow function dwindles. The pace of progression varies. In some individuals the condition worsens within a few months of diagnosis, while others have relatively little problem for several decades. In about 50 percent of cases, MDS deteriorates into a form of cancer known as acute myeloid leukemia (AML). The transition to leukemia is accompanied by worsening marrow function and the accumulation, first in the marrow and subsequently in the blood, of undeveloped immature cells called blasts which have no useful function and suppress any remaining marrow cell production. As a consequence, the complications from anemia, bleeding, and infection become life-threatening. Because some cases of MDS may progress into leukemia, myelodysplastic syndromes have also been known as pre-leukemia and smoldering leukemia. Patients who do not progress to leukemia may experience a gradual fall-off in marrow function leading to worsening anemia bleeding and infection which despite transfusions of red cells and platelets and antibiotics to treat infection can ultimately be fatal.MDS is sub-classified according to the type and number of blasts in the bone marrow. A group of French, American and British hematologists created the so-called FAB classification. This classification describes five MDS subtypes: refractory anemia; refractory anemia with sideroblasts; refractory anemia with excess blasts; refractory anemia with excess blasts in transformation; and chronic myelomonocytic leukemia. The first two types are the most common forms of myelodysplastic syndromes and are also the most stable.The World Health Organization (WHO) released its own classification system for MDS that modifies the FAB classification system, using different terms for the MDS subtypes. The new system has been universally accepted. For more information on the WHO system, contact the World Health Organization listed in the Resources section below.
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Symptoms of Myelodysplastic Syndromes. The symptoms of MDS occur because the bone marrow fails to produce enough functioning blood cells. The specific symptoms and progression of the disorder vary greatly from person to person. Some individuals may have mild symptoms that remain stable for many years; others may rapidly develop serious symptoms that can progress to life-threatening complications.The bone marrow, occupies the spongy center of large bones of the body. Blood cells, produced in the red marrow, are released into the bloodstream to travel throughout the body performing their specific functions. In individuals with MDS, the bone marrow develops immature or defective versions of red cells white cells and platelets, some of which are destroyed within the bone marrow. In the process, healthy marrow cells are progressively eliminated. The consequence is a lack of healthy blood cells in the bloodstream and a reduced supply of MDS blood cells, causing symptoms associated with MDS.The most common symptom in individuals with MDS is fatigue due to low levels of circulating red blood cells. Anemia causes tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, palpitations, headaches, and pale skin color. Low levels of white blood cells (neutropenia) increase the risk of contracting bacterial and fungal infections. Low levels of platelets (thrombocytopenia) makes the individual more susceptible to excessive bruising following minimal injury and spontaneous bleeding from the gums and nose. Women may develop increased menstrual blood loss. Bleeding may also occur in the digestive tube causing blood loss in the stools. Sometimes the bleeding occurs as a scattered red rash chiefly on the limbs–so-called petechial hemorrhages.MDS has a tendency to get worse with time as the normal bone marrow function dwindles. The pace of progression varies. In some individuals the condition worsens within a few months of diagnosis, while others have relatively little problem for several decades. In about 50 percent of cases, MDS deteriorates into a form of cancer known as acute myeloid leukemia (AML). The transition to leukemia is accompanied by worsening marrow function and the accumulation, first in the marrow and subsequently in the blood, of undeveloped immature cells called blasts which have no useful function and suppress any remaining marrow cell production. As a consequence, the complications from anemia, bleeding, and infection become life-threatening. Because some cases of MDS may progress into leukemia, myelodysplastic syndromes have also been known as pre-leukemia and smoldering leukemia. Patients who do not progress to leukemia may experience a gradual fall-off in marrow function leading to worsening anemia bleeding and infection which despite transfusions of red cells and platelets and antibiotics to treat infection can ultimately be fatal.MDS is sub-classified according to the type and number of blasts in the bone marrow. A group of French, American and British hematologists created the so-called FAB classification. This classification describes five MDS subtypes: refractory anemia; refractory anemia with sideroblasts; refractory anemia with excess blasts; refractory anemia with excess blasts in transformation; and chronic myelomonocytic leukemia. The first two types are the most common forms of myelodysplastic syndromes and are also the most stable.The World Health Organization (WHO) released its own classification system for MDS that modifies the FAB classification system, using different terms for the MDS subtypes. The new system has been universally accepted. For more information on the WHO system, contact the World Health Organization listed in the Resources section below.
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Myelodysplastic Syndromes
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Causes of Myelodysplastic Syndromes
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When the cause of MDS is unknown it is called idiopathic MDS. A so-called secondary MDS can develop after chemotherapy and radiation treatment for cancer or autoimmune diseases. It is possible that some chemicals (pesticides and benzene), cigarette smoking, and possibly viral infections can predispose to MDS. However, these links are circumstantial and in the majority of individuals developing MDS no obvious connection with environmental hazards can be found. MDS sometimes runs in families, suggesting a genetic link with the disease, particularly in younger patients with this disease.
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Causes of Myelodysplastic Syndromes. When the cause of MDS is unknown it is called idiopathic MDS. A so-called secondary MDS can develop after chemotherapy and radiation treatment for cancer or autoimmune diseases. It is possible that some chemicals (pesticides and benzene), cigarette smoking, and possibly viral infections can predispose to MDS. However, these links are circumstantial and in the majority of individuals developing MDS no obvious connection with environmental hazards can be found. MDS sometimes runs in families, suggesting a genetic link with the disease, particularly in younger patients with this disease.
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Myelodysplastic Syndromes
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Affects of Myelodysplastic Syndromes
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Myelodysplastic syndromes affect males slightly more often than females. The disorder occurs in any age group, but is far more common in older adults, occurring most often in individuals over 60 years of age. According to one estimate, 22 to 45 per 100,000 people over the age of 70 years have MDS. Approximately 20,000 new patients are diagnosed each year in the United States. The number of new cases diagnosed each year is increasing, possibly due to better recognition of the disorder combined with an increasing proportion of elderly adults in the general population. Determining the exact frequency of MDS in the general population is difficult because of lack of reporting of patients with mild cytopenias.
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Affects of Myelodysplastic Syndromes. Myelodysplastic syndromes affect males slightly more often than females. The disorder occurs in any age group, but is far more common in older adults, occurring most often in individuals over 60 years of age. According to one estimate, 22 to 45 per 100,000 people over the age of 70 years have MDS. Approximately 20,000 new patients are diagnosed each year in the United States. The number of new cases diagnosed each year is increasing, possibly due to better recognition of the disorder combined with an increasing proportion of elderly adults in the general population. Determining the exact frequency of MDS in the general population is difficult because of lack of reporting of patients with mild cytopenias.
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Related disorders of Myelodysplastic Syndromes
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MDS shares features with other blood disorders which need to be considered before reaching the correct diagnosis.Many diseases present with anemia and it is important to remember that iron and vitamin deficiency, and chronic blood loss, are by far the most common causes of anemia. MDS is diagnosed by bone marrow examination, indicated when more easily treated forms of anemia have been excluded.Several less common bone marrow conditions present with low neutrophil, platelet and red cell counts. The precise diagnosis will require examination of the blood and bone marrow: In aplastic anemia there is almost complete failure of bone marrow to make blood cells with symptoms of marrow failure identical to those described above. Aplastic anemia only rarely develops into leukemia. Sometimes, when very few cells are present in the marrow biopsy it is difficult to decide whether the diagnosis is aplastic anemia or MDS. In the absence of clear signs of MDS, such individuals are treated as though they have aplastic anemia. In fact, about 10 percent of people with aplastic anemia eventually develop MDS. The main difference between the two disorders is that in aplastic anemia the major problem is almost complete absence of any blood-producing cells in the marrow while in MDS the marrow contains cells but they are defective and abnormal. Both processes result in failure of the marrow to deliver working blood cells into the bloodstream. The exact cause of aplastic anemia is unknown. (For more information on this disorder, choose “aplastic anemia” as your search term in the Rare Disease Database.)Acute leukemia: Approximately 30% of patients with MDS can develop into acute myeloid leukemia. This potential is based on their initial prognostic classification, related to the marrow morphology, chromosomal abnormalities and depth of cytopenias. Some patients can present with bone marrow failure symptoms and low blood counts but on examination of the bone marrow large numbers of blast cells are found, confirming a diagnosis of acute leukemia. Other disorders that can be confused with MDS because they produce low blood counts are the bone marrow disease myelofibrosis, and, rarely, some cancers. Again, bone marrow examination is the main way to sort out the precise diagnosis.
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Related disorders of Myelodysplastic Syndromes. MDS shares features with other blood disorders which need to be considered before reaching the correct diagnosis.Many diseases present with anemia and it is important to remember that iron and vitamin deficiency, and chronic blood loss, are by far the most common causes of anemia. MDS is diagnosed by bone marrow examination, indicated when more easily treated forms of anemia have been excluded.Several less common bone marrow conditions present with low neutrophil, platelet and red cell counts. The precise diagnosis will require examination of the blood and bone marrow: In aplastic anemia there is almost complete failure of bone marrow to make blood cells with symptoms of marrow failure identical to those described above. Aplastic anemia only rarely develops into leukemia. Sometimes, when very few cells are present in the marrow biopsy it is difficult to decide whether the diagnosis is aplastic anemia or MDS. In the absence of clear signs of MDS, such individuals are treated as though they have aplastic anemia. In fact, about 10 percent of people with aplastic anemia eventually develop MDS. The main difference between the two disorders is that in aplastic anemia the major problem is almost complete absence of any blood-producing cells in the marrow while in MDS the marrow contains cells but they are defective and abnormal. Both processes result in failure of the marrow to deliver working blood cells into the bloodstream. The exact cause of aplastic anemia is unknown. (For more information on this disorder, choose “aplastic anemia” as your search term in the Rare Disease Database.)Acute leukemia: Approximately 30% of patients with MDS can develop into acute myeloid leukemia. This potential is based on their initial prognostic classification, related to the marrow morphology, chromosomal abnormalities and depth of cytopenias. Some patients can present with bone marrow failure symptoms and low blood counts but on examination of the bone marrow large numbers of blast cells are found, confirming a diagnosis of acute leukemia. Other disorders that can be confused with MDS because they produce low blood counts are the bone marrow disease myelofibrosis, and, rarely, some cancers. Again, bone marrow examination is the main way to sort out the precise diagnosis.
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Diagnosis of Myelodysplastic Syndromes
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A diagnosis of myelodysplastic syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests including complete blood counts, examination of the blood smear and bone marrow aspiration and biopsy. A complete blood count measures the number of red and white blood cells and platelets in the body. The blood smear and the small sample of bone marrow removed via a needle (the aspirate) is examined under a microscope to evaluate for the characteristic features of MDS. Chromosome analysis is helpful for diagnostic and prognostic purposes as is a blood test determining the presence of certain mutations (changes) within the blood cells.
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Diagnosis of Myelodysplastic Syndromes. A diagnosis of myelodysplastic syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests including complete blood counts, examination of the blood smear and bone marrow aspiration and biopsy. A complete blood count measures the number of red and white blood cells and platelets in the body. The blood smear and the small sample of bone marrow removed via a needle (the aspirate) is examined under a microscope to evaluate for the characteristic features of MDS. Chromosome analysis is helpful for diagnostic and prognostic purposes as is a blood test determining the presence of certain mutations (changes) within the blood cells.
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Therapies of Myelodysplastic Syndromes
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Treatment
Treatment varies, depending upon the individual’s age, general health, prognostic risk status, specific cytopenia (low blood count) and subtype of MDS. The first aim of treatment is supportive care – giving red cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding, and antibiotics to treat or prevent infections. A consequence of multiple red cell transfusions of red cells is the accumulation of iron derived from red cell hemoglobin being broken down in the body. Too much build-up of iron can lead to complications which can be avoided by treatment with drugs that bind the iron and eliminate it from the body. In 2005, the drug Exjade (desferasirox) given in tablet form was approved by the U.S. Food and Drug Administration (FDA) for marketing for the treatment of some MDS individuals who have been transfused for many years and have dangerous build-up of iron in the body. Further treatment aims, where possible, to correct the bone marrow failure. The marrow failure in some patients responds to immunosuppressive treatment with an agent called antithymocyte globulin (ATG). This can sometimes restore the blood count to normal indefinitely and can be repeated if relapses occur. The same treatment is used with success to treat aplastic anemia. Younger patients with the refractory anemia MDS subtype respond best to ATG. Growth factors are substances normally found in the body that control production of blood cells. They include Neupogen (filgrastim granulocyte-colony stimulating factor [G-CFS]) and Procrit or Epogen (erythropoietin). These growth factors stimulate the production of red white cells and red cells (but not platelets) in MDS. Given by daily to weekly injection, according to blood count severity, these marrow stimulators can be very helpful in some patients. Replacement of the MDS bone marrow with that of a healthy donor is the only curative treatment for MDS. Patients who are relatively fit even into their 70s may be suitable for a bone marrow stem cell transplant (SCT) from a healthy related donor or an unrelated volunteer. Although SCT can cure MDS this success is offset by the mortality from the transplant. SCT is therefore only performed in selected patients and in specialized centers. Many centers throughout the United States perform marrow stem cell transplants for MDS. For more information, contact the International Bone Marrow Transplant Registry (IBMTR) in Milwaukee (see Resources section). In the bone marrow, immature cells known as stem cells and myeloblasts develop through cell divisions into the mature healthy cells that populate the bloodstream, a process known as differentiation. In MDS the marrow cells fail to differentiate normally. Certain drugs including Vidaza (5-azacytidine) and Dacogen (decitabine) may correct the problem and improve blood cell production in MDS. Clinical studies have demonstrated the effectiveness of these agents. These drugs were approved in 2004 by the FDA for treatment of MDS. These drugs can delay progression of MDS and prolong survival, but may cause a temporary drop in blood counts during the treatment period requiring dose adjustments. In 2005, the FDA approved the drug Revlimid (lenalidomide) for the treatment of patients with a subtype of myelodysplastic syndrome. The subtype is MDS patients with deletion 5q cytogenetic abnormality. Revlimid is structurally similar to thalidomide, a drug known to cause severe birth defects. Additional studies are ongoing in animals to address whether there is a risk that Revlimid will also cause birth defects when taken during pregnancy. While these studies are underway, Revlimid is being marketed under a risk management plan called RevAssist, designed to prevent fetal exposure. Under RevAssist, only pharmacists and prescribers registered with the program will prescribe and dispense Revlimid. Most recently, in 2020, FDA approved Inqovi (decitabine and cedazuridine) to treat adult patients with MDS. Inqovi is the first therapy for MDS patients that does not require them to go into a treatment facility to receive intravenous (IV) treatment.
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Therapies of Myelodysplastic Syndromes. Treatment
Treatment varies, depending upon the individual’s age, general health, prognostic risk status, specific cytopenia (low blood count) and subtype of MDS. The first aim of treatment is supportive care – giving red cell transfusions to correct anemia, platelet transfusions to treat or prevent serious bleeding, and antibiotics to treat or prevent infections. A consequence of multiple red cell transfusions of red cells is the accumulation of iron derived from red cell hemoglobin being broken down in the body. Too much build-up of iron can lead to complications which can be avoided by treatment with drugs that bind the iron and eliminate it from the body. In 2005, the drug Exjade (desferasirox) given in tablet form was approved by the U.S. Food and Drug Administration (FDA) for marketing for the treatment of some MDS individuals who have been transfused for many years and have dangerous build-up of iron in the body. Further treatment aims, where possible, to correct the bone marrow failure. The marrow failure in some patients responds to immunosuppressive treatment with an agent called antithymocyte globulin (ATG). This can sometimes restore the blood count to normal indefinitely and can be repeated if relapses occur. The same treatment is used with success to treat aplastic anemia. Younger patients with the refractory anemia MDS subtype respond best to ATG. Growth factors are substances normally found in the body that control production of blood cells. They include Neupogen (filgrastim granulocyte-colony stimulating factor [G-CFS]) and Procrit or Epogen (erythropoietin). These growth factors stimulate the production of red white cells and red cells (but not platelets) in MDS. Given by daily to weekly injection, according to blood count severity, these marrow stimulators can be very helpful in some patients. Replacement of the MDS bone marrow with that of a healthy donor is the only curative treatment for MDS. Patients who are relatively fit even into their 70s may be suitable for a bone marrow stem cell transplant (SCT) from a healthy related donor or an unrelated volunteer. Although SCT can cure MDS this success is offset by the mortality from the transplant. SCT is therefore only performed in selected patients and in specialized centers. Many centers throughout the United States perform marrow stem cell transplants for MDS. For more information, contact the International Bone Marrow Transplant Registry (IBMTR) in Milwaukee (see Resources section). In the bone marrow, immature cells known as stem cells and myeloblasts develop through cell divisions into the mature healthy cells that populate the bloodstream, a process known as differentiation. In MDS the marrow cells fail to differentiate normally. Certain drugs including Vidaza (5-azacytidine) and Dacogen (decitabine) may correct the problem and improve blood cell production in MDS. Clinical studies have demonstrated the effectiveness of these agents. These drugs were approved in 2004 by the FDA for treatment of MDS. These drugs can delay progression of MDS and prolong survival, but may cause a temporary drop in blood counts during the treatment period requiring dose adjustments. In 2005, the FDA approved the drug Revlimid (lenalidomide) for the treatment of patients with a subtype of myelodysplastic syndrome. The subtype is MDS patients with deletion 5q cytogenetic abnormality. Revlimid is structurally similar to thalidomide, a drug known to cause severe birth defects. Additional studies are ongoing in animals to address whether there is a risk that Revlimid will also cause birth defects when taken during pregnancy. While these studies are underway, Revlimid is being marketed under a risk management plan called RevAssist, designed to prevent fetal exposure. Under RevAssist, only pharmacists and prescribers registered with the program will prescribe and dispense Revlimid. Most recently, in 2020, FDA approved Inqovi (decitabine and cedazuridine) to treat adult patients with MDS. Inqovi is the first therapy for MDS patients that does not require them to go into a treatment facility to receive intravenous (IV) treatment.
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Overview of Myhre Syndrome
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SummaryMyhre syndrome is a rare, but increasingly diagnosed genetic disorder characterized by short stature, characteristic facial features, distinctive heart and aorta problems, mild to moderate intellectual disability, autism/autistic-like behavior, and various bone and joint abnormalities. The familiar facial features are often mild in very young children, but present in almost all individuals. These include a small narrow eye opening (blepharophimosis, short palpebral fissure), flat facial profile (maxillary hypoplasia), and a relatively prominent nose. The chin is small in young children, but over time, there is often a prominent jaw (prognathism). Other findings include hearing impairment, short fingers and toes (brachydactyly), muscles that appear abnormally large (muscular pseudohypertrophy), joint stiffness, and narrowing (stenosis) of the voice box (larynx) and windpipe (trachea). Abnormalities of the heart structure (congenital heart defects), heart muscle (cardiomyopathy) and pericardium are common and distinctive. A risk for certain types of cancer is recognized. Myhre syndrome is caused by mutations (pathologic variants) in the SMAD4 gene. It was thought that all molecularly proven cases were due to a de novo mutation (a new gene change that arises around the time of conception, not carried by the parents). However, it has been reported that Myhre syndrome can be transmitted from parent to child. A person with Myhre syndrome would have a 50-50 chance of transmitting this to each child.IntroductionMyhre syndrome was first described in two unrelated males in 1981 by Drs. Myhre, Ruvalcaba and Graham. In 1998, the first of a series of papers reported on a similar condition consisting of (L)aryngotracheal stenosis (A)rthropathy, (P)rognathism, (S)hort stature syndrome (LAPS), that was recognized to be the same as Myhre syndrome (Hopkins et al., 1998; Lindor et al., 2002, 2009 and 2012). It was proven that both disorders had the same mutation in the same gene (SMAD4). This was viewed as different expression (variants) of the same disorder. Part of the variable expression of Myhre syndrome is related to the age of diagnosis. Of the four variants in SMAD4, it is not yet known whether there are correlations between the specific variant and clinical features.
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Overview of Myhre Syndrome. SummaryMyhre syndrome is a rare, but increasingly diagnosed genetic disorder characterized by short stature, characteristic facial features, distinctive heart and aorta problems, mild to moderate intellectual disability, autism/autistic-like behavior, and various bone and joint abnormalities. The familiar facial features are often mild in very young children, but present in almost all individuals. These include a small narrow eye opening (blepharophimosis, short palpebral fissure), flat facial profile (maxillary hypoplasia), and a relatively prominent nose. The chin is small in young children, but over time, there is often a prominent jaw (prognathism). Other findings include hearing impairment, short fingers and toes (brachydactyly), muscles that appear abnormally large (muscular pseudohypertrophy), joint stiffness, and narrowing (stenosis) of the voice box (larynx) and windpipe (trachea). Abnormalities of the heart structure (congenital heart defects), heart muscle (cardiomyopathy) and pericardium are common and distinctive. A risk for certain types of cancer is recognized. Myhre syndrome is caused by mutations (pathologic variants) in the SMAD4 gene. It was thought that all molecularly proven cases were due to a de novo mutation (a new gene change that arises around the time of conception, not carried by the parents). However, it has been reported that Myhre syndrome can be transmitted from parent to child. A person with Myhre syndrome would have a 50-50 chance of transmitting this to each child.IntroductionMyhre syndrome was first described in two unrelated males in 1981 by Drs. Myhre, Ruvalcaba and Graham. In 1998, the first of a series of papers reported on a similar condition consisting of (L)aryngotracheal stenosis (A)rthropathy, (P)rognathism, (S)hort stature syndrome (LAPS), that was recognized to be the same as Myhre syndrome (Hopkins et al., 1998; Lindor et al., 2002, 2009 and 2012). It was proven that both disorders had the same mutation in the same gene (SMAD4). This was viewed as different expression (variants) of the same disorder. Part of the variable expression of Myhre syndrome is related to the age of diagnosis. Of the four variants in SMAD4, it is not yet known whether there are correlations between the specific variant and clinical features.
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Symptoms of Myhre Syndrome
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Although researchers have been able to describe a recognizable syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients and the lack of large clinical studies prevent physicians from developing a complete picture of associated symptoms and prognosis. No other genes have been identified to cause Myhre syndrome. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every patient is unique. Parents of affected children and adults with Myhre syndrome should talk to their primary care physician and medical team about their specific case, associated symptoms and overall prognosis.Growth deficiency is a common finding and usually occurs before birth (prenatally), often resulting in low birth weight. Growth deficiencies continue after birth and most children are shorter than would be expected for age (short stature). Puberty has occurred early in some patients, while in others it has been delayed. Affected females may experience absence of menstruation (amenorrhea), irregular menstruation, or early-onset heavy menstruation. Affected males may experience failure of the testes to descend into the scrotum (cryptorchidism). Some have premature puberty.Most affected infants and children have distinctive facial features including eyes which are small and narrow (blepharophimosis, short palpebral fissure), underdeveloped midfacial structures (maxillary hypoplasia), and prominent nose. The jaw can be small in childhood, but is usually prominent later in life and occasionally pointed (prognathism). Affected individuals may also have a shorter than normal groove in the upper lip (philtrum), thin lips, an unusually narrow mouth, and small ears.The airway can be affected at various levels such as narrowing or blockage of the nasal airway by tissue (choanal atresia). Further down, there can be progressive narrowing of the larynx and trachea, a condition known as laryngotracheal stenosis. This results in noisy breathing (stridor), a loud cough (croup) and respiratory insufficiency sometimes requiring oxygen or breathing tubes (tracheostomy). Without treatment, laryngotracheal stenosis can cause life-threatening complications; the condition can recur after treatment. The risk for this condition appears to increase with age and it usually presents in adolescence or young adulthood.In a few affected individuals, the trachea itself and the branches can be narrowed because of the accumulation of tissue. The lungs may be unable to take in enough air for the affected person to breathe properly (bronchopulmonary insufficiency). This condition may result from obstructive or restrictive disorders of the respiratory system or due to narrowing (stenosis) of the pulmonary arteries. Bronchopulmonary insufficiency can potentially cause life-threatening breathing difficulties. In addition, the rib cage is often stiff which limits breathing.Most individuals with Myhre syndrome develop hearing loss. In some, it is due to the accumulation of wax-like material or from recurrent ear infections. This prevents sound waves from being conducted through the middle ear (conductive hearing loss). Other individuals may have hearing loss due to an impaired ability of the auditory nerves to transmit sensory input from the ears to the brain (sensorineural hearing loss). A few patients have abnormal inner ear structures (dysplasia). Hearing loss can also be mixed, which means individuals have a combination of conductive and sensorineural hearing loss. Most patients have either conductive or mixed. Hearing loss usually affects both ears (bilateral), although the degree of severity varies from one person to another. Narrowing of the tear ducts can occur, but may not be diagnosed as such. Instead there may be persistent tearing or puffiness of the eyes.Developmental delays occur in all people with Myhre syndrome. Mild to moderate intellectual disability occurs in most people. Behavioral abnormalities including difficulties with social interactions, poor communication skills, hyperactivity, stubbornness, and/or repetitive behaviors are common. Many patients are considered to be on the autism spectrum. Several skeletal abnormalities have been described in individuals with Myhre syndrome. Bones of the skull (calvaria) may be abnormally thick, but this does not harm a person. The ribs may be abnormally broad and wide, and the upper portions of the hip bone may be underdeveloped (hypoplastic iliac wings). The long bones of the body (i.e., those in the arms and legs) may be unusually narrow, round (tubular) and short. The fingers and toes may be short (brachydactyly). Webbing (syndactyly) of the hands and feet, fifth fingers that are curved inward (clinodactyly), and fingers which are stiff and contracted (camptodactyly) are also common findings. Joint involvement is also common and affected individuals may experience stiff joints eventually resulting in limited mobility of small or large joints that may increase with age.In early childhood, certain muscles may look abnormally large (muscular pseudohypertrophy), especially those of the arms and legs, giving affected individuals a muscular appearance. Progressive stiffening or thickening of the skin may also be noticeable and is quite common. Scars may thicken.
Affected individuals may have an increased susceptibility to infections, particularly of the ears and lungs. Narrowing of the airways and the anatomy of the ear may predispose individuals to respiratory and ear infections.Most people with Myhre syndrome have at least one problem involving the heart or aorta. These can be very mild or occasionally severe. Congenital heart defects are structural problems that are usually present at birth. Later in life there can be pericarditis which involves tightening, or inflammation of the sac around the heart. Pericarditis can be recurrent and progress to cause life-threatening complications and may be associated with pleural effusion (fluid buildup in the chest cavity outside of the lungs). The aorta can have areas of narrowing (stenosis, coarctation). High blood pressure (hypertension) can be present.Less common signs and symptoms include cleft palate, cleft lip, and drooping of the upper eyelids (ptosis). Intestinal problems include chronic constipation, which can lead to inability to be toilet trained. There can be obstruction of the duodenum and pylorus. Renal abnormalities include absence (agenesis) of a kidney or obstruction (hydronephrosis). Eye (ophthalmologic) abnormalities are common and include refraction abnormalities such as an inability to focus on objects which are close (hypermetropia or farsightedness) or an imperfection in the curvature of the eye leading to blurred vision (astigmatism); less often, there can be crossing of the eyes (strabismus) or cataracts at a young age. Rarely, the optic nerves at the back of the eye can appear enlarged (pseudopapilledema).
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Symptoms of Myhre Syndrome. Although researchers have been able to describe a recognizable syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients and the lack of large clinical studies prevent physicians from developing a complete picture of associated symptoms and prognosis. No other genes have been identified to cause Myhre syndrome. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that every patient is unique. Parents of affected children and adults with Myhre syndrome should talk to their primary care physician and medical team about their specific case, associated symptoms and overall prognosis.Growth deficiency is a common finding and usually occurs before birth (prenatally), often resulting in low birth weight. Growth deficiencies continue after birth and most children are shorter than would be expected for age (short stature). Puberty has occurred early in some patients, while in others it has been delayed. Affected females may experience absence of menstruation (amenorrhea), irregular menstruation, or early-onset heavy menstruation. Affected males may experience failure of the testes to descend into the scrotum (cryptorchidism). Some have premature puberty.Most affected infants and children have distinctive facial features including eyes which are small and narrow (blepharophimosis, short palpebral fissure), underdeveloped midfacial structures (maxillary hypoplasia), and prominent nose. The jaw can be small in childhood, but is usually prominent later in life and occasionally pointed (prognathism). Affected individuals may also have a shorter than normal groove in the upper lip (philtrum), thin lips, an unusually narrow mouth, and small ears.The airway can be affected at various levels such as narrowing or blockage of the nasal airway by tissue (choanal atresia). Further down, there can be progressive narrowing of the larynx and trachea, a condition known as laryngotracheal stenosis. This results in noisy breathing (stridor), a loud cough (croup) and respiratory insufficiency sometimes requiring oxygen or breathing tubes (tracheostomy). Without treatment, laryngotracheal stenosis can cause life-threatening complications; the condition can recur after treatment. The risk for this condition appears to increase with age and it usually presents in adolescence or young adulthood.In a few affected individuals, the trachea itself and the branches can be narrowed because of the accumulation of tissue. The lungs may be unable to take in enough air for the affected person to breathe properly (bronchopulmonary insufficiency). This condition may result from obstructive or restrictive disorders of the respiratory system or due to narrowing (stenosis) of the pulmonary arteries. Bronchopulmonary insufficiency can potentially cause life-threatening breathing difficulties. In addition, the rib cage is often stiff which limits breathing.Most individuals with Myhre syndrome develop hearing loss. In some, it is due to the accumulation of wax-like material or from recurrent ear infections. This prevents sound waves from being conducted through the middle ear (conductive hearing loss). Other individuals may have hearing loss due to an impaired ability of the auditory nerves to transmit sensory input from the ears to the brain (sensorineural hearing loss). A few patients have abnormal inner ear structures (dysplasia). Hearing loss can also be mixed, which means individuals have a combination of conductive and sensorineural hearing loss. Most patients have either conductive or mixed. Hearing loss usually affects both ears (bilateral), although the degree of severity varies from one person to another. Narrowing of the tear ducts can occur, but may not be diagnosed as such. Instead there may be persistent tearing or puffiness of the eyes.Developmental delays occur in all people with Myhre syndrome. Mild to moderate intellectual disability occurs in most people. Behavioral abnormalities including difficulties with social interactions, poor communication skills, hyperactivity, stubbornness, and/or repetitive behaviors are common. Many patients are considered to be on the autism spectrum. Several skeletal abnormalities have been described in individuals with Myhre syndrome. Bones of the skull (calvaria) may be abnormally thick, but this does not harm a person. The ribs may be abnormally broad and wide, and the upper portions of the hip bone may be underdeveloped (hypoplastic iliac wings). The long bones of the body (i.e., those in the arms and legs) may be unusually narrow, round (tubular) and short. The fingers and toes may be short (brachydactyly). Webbing (syndactyly) of the hands and feet, fifth fingers that are curved inward (clinodactyly), and fingers which are stiff and contracted (camptodactyly) are also common findings. Joint involvement is also common and affected individuals may experience stiff joints eventually resulting in limited mobility of small or large joints that may increase with age.In early childhood, certain muscles may look abnormally large (muscular pseudohypertrophy), especially those of the arms and legs, giving affected individuals a muscular appearance. Progressive stiffening or thickening of the skin may also be noticeable and is quite common. Scars may thicken.
Affected individuals may have an increased susceptibility to infections, particularly of the ears and lungs. Narrowing of the airways and the anatomy of the ear may predispose individuals to respiratory and ear infections.Most people with Myhre syndrome have at least one problem involving the heart or aorta. These can be very mild or occasionally severe. Congenital heart defects are structural problems that are usually present at birth. Later in life there can be pericarditis which involves tightening, or inflammation of the sac around the heart. Pericarditis can be recurrent and progress to cause life-threatening complications and may be associated with pleural effusion (fluid buildup in the chest cavity outside of the lungs). The aorta can have areas of narrowing (stenosis, coarctation). High blood pressure (hypertension) can be present.Less common signs and symptoms include cleft palate, cleft lip, and drooping of the upper eyelids (ptosis). Intestinal problems include chronic constipation, which can lead to inability to be toilet trained. There can be obstruction of the duodenum and pylorus. Renal abnormalities include absence (agenesis) of a kidney or obstruction (hydronephrosis). Eye (ophthalmologic) abnormalities are common and include refraction abnormalities such as an inability to focus on objects which are close (hypermetropia or farsightedness) or an imperfection in the curvature of the eye leading to blurred vision (astigmatism); less often, there can be crossing of the eyes (strabismus) or cataracts at a young age. Rarely, the optic nerves at the back of the eye can appear enlarged (pseudopapilledema).
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Causes of Myhre Syndrome
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Myhre syndrome is caused by a gain-of-function mutation (pathogenic variant) in the SMAD4 gene. It is the only gene known to cause the disorder. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a mutation occurs, the protein product of the gene may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The SMAD4 gene contains instructions for creating (encoding) a protein that is expressed throughout the developing fetus and in most adult tissue and cell types. Mutations in the SMAD4 gene lead to insufficient levels of working (functional/normal) copies of the protein. Because this protein is expressed throughout the body (ubiquitously), this accounts for the widespread and varied symptoms that are potentially associated with Myhre syndrome.Until recently, all reported mutations have occurred as new (sporadic or de novo) mutations, which means that in these patients, the gene mutation occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. However, a family with an affected mother and two affected children was reported in Belgium (Meerschaut et al., 2019). We know now that an affected individual (at least with the variant in the reported family) could potentially pass on the gene that causes Myhre syndrome in an autosomal dominant manner.Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual (as described above). The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Myhre Syndrome. Myhre syndrome is caused by a gain-of-function mutation (pathogenic variant) in the SMAD4 gene. It is the only gene known to cause the disorder. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a mutation occurs, the protein product of the gene may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The SMAD4 gene contains instructions for creating (encoding) a protein that is expressed throughout the developing fetus and in most adult tissue and cell types. Mutations in the SMAD4 gene lead to insufficient levels of working (functional/normal) copies of the protein. Because this protein is expressed throughout the body (ubiquitously), this accounts for the widespread and varied symptoms that are potentially associated with Myhre syndrome.Until recently, all reported mutations have occurred as new (sporadic or de novo) mutations, which means that in these patients, the gene mutation occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. However, a family with an affected mother and two affected children was reported in Belgium (Meerschaut et al., 2019). We know now that an affected individual (at least with the variant in the reported family) could potentially pass on the gene that causes Myhre syndrome in an autosomal dominant manner.Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual (as described above). The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of Myhre Syndrome
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Myhre syndrome is an extremely rare inherited disorder that, in theory, affects males and females in equal numbers. Fewer than 100 patients have been reported in the medical literature, but cases are being steadily published. Because some cases of Myhre syndrome most likely go undiagnosed or misdiagnosed, determining the true frequency of the disorder in the general population is difficult.
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Affects of Myhre Syndrome. Myhre syndrome is an extremely rare inherited disorder that, in theory, affects males and females in equal numbers. Fewer than 100 patients have been reported in the medical literature, but cases are being steadily published. Because some cases of Myhre syndrome most likely go undiagnosed or misdiagnosed, determining the true frequency of the disorder in the general population is difficult.
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Related disorders of Myhre Syndrome
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Symptoms of the following disorders can be similar to those of Myhre syndrome. Comparisons may be useful for a differential diagnosis:There are other congenital disorders that may be characterized by intellectual disability and growth deficiency occurring in association with facial abnormalities, skeletal malformations, and/or other physical abnormalities similar to those associated with Myhre syndrome. Such disorders include, but are not limited to, GOMBO syndrome, acromicric dysplasia, geleophysic dysplasia, Weil-Marchesani syndrome, and acromesomelic dysplasia. However, none of these syndromes is identical to Myhre syndrome. The thickened skin associated with Myhre syndrome may resemble the stiffened skin seen in stiff skin syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Myhre Syndrome. Symptoms of the following disorders can be similar to those of Myhre syndrome. Comparisons may be useful for a differential diagnosis:There are other congenital disorders that may be characterized by intellectual disability and growth deficiency occurring in association with facial abnormalities, skeletal malformations, and/or other physical abnormalities similar to those associated with Myhre syndrome. Such disorders include, but are not limited to, GOMBO syndrome, acromicric dysplasia, geleophysic dysplasia, Weil-Marchesani syndrome, and acromesomelic dysplasia. However, none of these syndromes is identical to Myhre syndrome. The thickened skin associated with Myhre syndrome may resemble the stiffened skin seen in stiff skin syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Myhre Syndrome
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Diagnosis of Myhre Syndrome
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A provisional clinical diagnosis of Myhre syndrome is usually confirmed on the basis of a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient history, and/or specialized tests (particularly advanced imaging techniques). All patients must have molecular genetic testing which is rarely done as a targeted gene analysis (for SMAD4). Currently, testing is performed as either whole exome sequencing (WES) analysis or using a panel of genes related to intellectual disability and autism.Developmental delays which typically present in some form in infancy and into the toddler years persist. Intellectual disability may not be detected until the child is in school and old enough to participate in clinical testing. Clinical evaluation, ideally a neuropsychologic evaluation, should be conducted early in development and on a continuing basis to help determine the presence and extent of certain findings such as intellectual disability and behavioral issues which are on the autism spectrum. Such evaluations can help ensure that appropriate steps are taken to help affected individuals reach their potential. It is important to emphasize that the vast majority of people living with Myhre syndrome are active and engaged in social activities. They can make progress living with their challenges. A small number of adults have married, others have jobs.Characteristic facial features, and/or heart defects may also be present at birth. X-ray testing (skeletal survey) may be used to identify skeletal malformations which are usually mild. A baseline echocardiogram and complete cardiology consultation is essential for all patients at time of diagnosis and may help to determine the exact nature of heart defects. This should be repeated on a regular basis (every 1-2 years) since some features can progress, but the exact schedule is determined by the cardiologist.Growth delay, abnormally stiff joints, and hearing impairment may not become obvious until late infancy or early childhood. Periodic testing of an infant’s or child’s hearing is essential to detect any loss in hearing capability.
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Diagnosis of Myhre Syndrome. A provisional clinical diagnosis of Myhre syndrome is usually confirmed on the basis of a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient history, and/or specialized tests (particularly advanced imaging techniques). All patients must have molecular genetic testing which is rarely done as a targeted gene analysis (for SMAD4). Currently, testing is performed as either whole exome sequencing (WES) analysis or using a panel of genes related to intellectual disability and autism.Developmental delays which typically present in some form in infancy and into the toddler years persist. Intellectual disability may not be detected until the child is in school and old enough to participate in clinical testing. Clinical evaluation, ideally a neuropsychologic evaluation, should be conducted early in development and on a continuing basis to help determine the presence and extent of certain findings such as intellectual disability and behavioral issues which are on the autism spectrum. Such evaluations can help ensure that appropriate steps are taken to help affected individuals reach their potential. It is important to emphasize that the vast majority of people living with Myhre syndrome are active and engaged in social activities. They can make progress living with their challenges. A small number of adults have married, others have jobs.Characteristic facial features, and/or heart defects may also be present at birth. X-ray testing (skeletal survey) may be used to identify skeletal malformations which are usually mild. A baseline echocardiogram and complete cardiology consultation is essential for all patients at time of diagnosis and may help to determine the exact nature of heart defects. This should be repeated on a regular basis (every 1-2 years) since some features can progress, but the exact schedule is determined by the cardiologist.Growth delay, abnormally stiff joints, and hearing impairment may not become obvious until late infancy or early childhood. Periodic testing of an infant’s or child’s hearing is essential to detect any loss in hearing capability.
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Myhre Syndrome
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Therapies of Myhre Syndrome
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Treatment
The treatment of Myhre syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment requires the coordinated efforts of a team of specialists. Pediatricians are key to providing standard health maintenance (including vaccinations). Primary care providers need the insights of specialists. These include orthopedic specialists and rheumatologists who treat skeletal and joint problems, cardiologists who diagnose and treat disorders of the heart, otolaryngologists and pulmonologists who assess and treat ear, nose, airway and lung disorders, audiologists who assess and treat hearing problems, ophthalmologists who assess and treat eye disorders. Other specialists may be needed for skin problems (dermatologists), puberty issues (endocrinologists), kidney problems (nephrologists). To evaluate and treat problems related to development, behavior and school, neuropsychologists, speech pathologists, physical therapists 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. There should be a care coordinator to assist the primary care physician, a role which is often performed by the medical geneticist. As it appears that individuals with Myhre syndrome are susceptible to development of excessive scar tissue (fibrosis) related to tissue injury which might be related to surgery. Efforts should be made to avoid anything but the most necessary of invasive interventions, including endoscopic procedures. As needed, anesthesiologists should use the smallest sized endotracheal tube.There are no standardized treatment protocols or evidence-based guidelines for affected individuals. The recommendations in GeneReviews (Starr, Lindor and Lin) provide pragmatic guidance. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Myhre syndrome.Certain abnormalities (e.g., small mouth with narrow palate, syndactyly, congenital heart defects, cleft palate or lip, duodenal atresia, pyloric stenosis, and/or cryptorchidism) may require surgical intervention. Affected infants should be evaluated for choanal atresia which can be fixed by surgery and has led to improved feeding. Other conditions that can be treated surgically include scoliosis, congenital cataracts and hypospadias.Laryngotracheal stenosis may require surgical treatment; however, the condition may recur after successful treatment. In affected individuals who require a tube to be inserted into the windpipe to assist breathing (as might be needed when undergoing anesthesia), special care must be taken because of the risk of developing laryngotracheal stenosis. Ultimately, affected individuals may require a tracheostomy in which a tube is surgically implanted through a cut in the throat to allow direct access to the windpipe.Some individuals with Myhre syndrome may have difficulty swallowing and/or feeding. In some patients, this may necessitate placing a tube through a small insertion in the abdominal wall and directly into the stomach (gastrostomy tube). It is not known if there is an immune deficiency in Myhre syndrome. As indicated, appropriate immunologic tests should be conducted with consultation from an immunologist. Early intervention is important to ensure that children with Myhre syndrome reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services. Long-term follow up and regular clinical evaluation of affected individuals is required to detect specific symptoms or complications potentially associated with Myhre syndrome. Applied Behavioral Analysis (ABA) has been reported by providers and families to be of great help, although this has not been formally studied. When possible, it should be included. Females who have early onset puberty and menstruation, and those who had heavy, painful periods, should be evaluated by a gynecologist. Although endometrial cancer and some forms of brain tumor have been reported, cancer remains a rare event and surveillance has not been addressed. Affected females have specific requirements for follow up because of abnormalities involving the beginning of puberty and possible early development of menopause.
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Therapies of Myhre Syndrome. Treatment
The treatment of Myhre syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment requires the coordinated efforts of a team of specialists. Pediatricians are key to providing standard health maintenance (including vaccinations). Primary care providers need the insights of specialists. These include orthopedic specialists and rheumatologists who treat skeletal and joint problems, cardiologists who diagnose and treat disorders of the heart, otolaryngologists and pulmonologists who assess and treat ear, nose, airway and lung disorders, audiologists who assess and treat hearing problems, ophthalmologists who assess and treat eye disorders. Other specialists may be needed for skin problems (dermatologists), puberty issues (endocrinologists), kidney problems (nephrologists). To evaluate and treat problems related to development, behavior and school, neuropsychologists, speech pathologists, physical therapists 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. There should be a care coordinator to assist the primary care physician, a role which is often performed by the medical geneticist. As it appears that individuals with Myhre syndrome are susceptible to development of excessive scar tissue (fibrosis) related to tissue injury which might be related to surgery. Efforts should be made to avoid anything but the most necessary of invasive interventions, including endoscopic procedures. As needed, anesthesiologists should use the smallest sized endotracheal tube.There are no standardized treatment protocols or evidence-based guidelines for affected individuals. The recommendations in GeneReviews (Starr, Lindor and Lin) provide pragmatic guidance. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Myhre syndrome.Certain abnormalities (e.g., small mouth with narrow palate, syndactyly, congenital heart defects, cleft palate or lip, duodenal atresia, pyloric stenosis, and/or cryptorchidism) may require surgical intervention. Affected infants should be evaluated for choanal atresia which can be fixed by surgery and has led to improved feeding. Other conditions that can be treated surgically include scoliosis, congenital cataracts and hypospadias.Laryngotracheal stenosis may require surgical treatment; however, the condition may recur after successful treatment. In affected individuals who require a tube to be inserted into the windpipe to assist breathing (as might be needed when undergoing anesthesia), special care must be taken because of the risk of developing laryngotracheal stenosis. Ultimately, affected individuals may require a tracheostomy in which a tube is surgically implanted through a cut in the throat to allow direct access to the windpipe.Some individuals with Myhre syndrome may have difficulty swallowing and/or feeding. In some patients, this may necessitate placing a tube through a small insertion in the abdominal wall and directly into the stomach (gastrostomy tube). It is not known if there is an immune deficiency in Myhre syndrome. As indicated, appropriate immunologic tests should be conducted with consultation from an immunologist. Early intervention is important to ensure that children with Myhre syndrome reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services. Long-term follow up and regular clinical evaluation of affected individuals is required to detect specific symptoms or complications potentially associated with Myhre syndrome. Applied Behavioral Analysis (ABA) has been reported by providers and families to be of great help, although this has not been formally studied. When possible, it should be included. Females who have early onset puberty and menstruation, and those who had heavy, painful periods, should be evaluated by a gynecologist. Although endometrial cancer and some forms of brain tumor have been reported, cancer remains a rare event and surveillance has not been addressed. Affected females have specific requirements for follow up because of abnormalities involving the beginning of puberty and possible early development of menopause.
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Overview of Myocarditis
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Myocarditis is a rare cause of cardiovascular disease primarily manifest as sudden death, chest pain or heart failure. The symptoms of heart failure from myocarditis include shortness of breath, fatigue and ankle swelling. The cause is an inflammation of the heart muscle, most often following a viral infection. Between 0.5 and 3.5 percent of heart failure hospitalizations are due to myocarditis. Most cases of myocarditis are identified in young adults with males affected more often than females. The diagnosis should be considered in any young adult with unexplained cardiac causes of shortness of breath or loss of consciousness. Many authorities recommend the diagnosis be made by heart biopsy, but imaging with magnetic resonance is growing as an accepted diagnostic method. Specific causes of myocarditis vary by world region, which mandates region-specific diagnostic and management strategies.
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Overview of Myocarditis. Myocarditis is a rare cause of cardiovascular disease primarily manifest as sudden death, chest pain or heart failure. The symptoms of heart failure from myocarditis include shortness of breath, fatigue and ankle swelling. The cause is an inflammation of the heart muscle, most often following a viral infection. Between 0.5 and 3.5 percent of heart failure hospitalizations are due to myocarditis. Most cases of myocarditis are identified in young adults with males affected more often than females. The diagnosis should be considered in any young adult with unexplained cardiac causes of shortness of breath or loss of consciousness. Many authorities recommend the diagnosis be made by heart biopsy, but imaging with magnetic resonance is growing as an accepted diagnostic method. Specific causes of myocarditis vary by world region, which mandates region-specific diagnostic and management strategies.
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Myocarditis
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Symptoms of Myocarditis
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The symptoms of myocarditis are not specific to the disease and are similar to symptoms of more common heart disorders. A sensation of tightness or squeezing in the chest that is present with rest and with exertion is common. Not infrequently chest pain is improved with leaning forward and worse with lying back when the inflammation affects the outer lining of the heart or pericardium as well as the heart muscle. If the heart pacing or conduction tissues become inflamed, a slow heart rate may cause fatigue or lightheadedness. Inflammation can also cause extra beats that feel like a flutter in the chest. Sustained runs of extra beats in quick succession may lead to lightheadedness or even loss of consciousness. Sudden death resulting from a myocarditis-related arrhythmia is an important cause of death in children and young athletes.In a majority of cases, the symptoms of myocarditis are preceded a few days to weeks by a flu-like illness. Specific viruses and even multiple virus infections may be seen in immunocompromised patients such as persons infected with HIV. Rarely myocarditis may result from an adverse drug reaction. In this setting, a temporal association between a new medication and myocarditis symptoms can suggest the cause.Most cases of myocarditis are mild and improve with standard medical therapy directed at improving heart function or correcting abnormal heart rhythms. In a minority of cases the symptoms do not improve or become recurrent. In these circumstances referral to a medical center with expertise in myocarditis management is useful. The evaluation and management of chronic or recurrent myocarditis is not standardized.
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Symptoms of Myocarditis. The symptoms of myocarditis are not specific to the disease and are similar to symptoms of more common heart disorders. A sensation of tightness or squeezing in the chest that is present with rest and with exertion is common. Not infrequently chest pain is improved with leaning forward and worse with lying back when the inflammation affects the outer lining of the heart or pericardium as well as the heart muscle. If the heart pacing or conduction tissues become inflamed, a slow heart rate may cause fatigue or lightheadedness. Inflammation can also cause extra beats that feel like a flutter in the chest. Sustained runs of extra beats in quick succession may lead to lightheadedness or even loss of consciousness. Sudden death resulting from a myocarditis-related arrhythmia is an important cause of death in children and young athletes.In a majority of cases, the symptoms of myocarditis are preceded a few days to weeks by a flu-like illness. Specific viruses and even multiple virus infections may be seen in immunocompromised patients such as persons infected with HIV. Rarely myocarditis may result from an adverse drug reaction. In this setting, a temporal association between a new medication and myocarditis symptoms can suggest the cause.Most cases of myocarditis are mild and improve with standard medical therapy directed at improving heart function or correcting abnormal heart rhythms. In a minority of cases the symptoms do not improve or become recurrent. In these circumstances referral to a medical center with expertise in myocarditis management is useful. The evaluation and management of chronic or recurrent myocarditis is not standardized.
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Causes of Myocarditis
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Most cases of myocarditis are of unknown cause (idiopathic). When a cause is identified, it is usually the result of an infection. In North America and Western Europe, viral infections are the most common identified causes of myocarditis. In specific world regions, other important causes include myocarditis following a streptococcal bacterial infection and HIV related infections. In specific Eurasian groups bacteria such as diphtheria, rubella, and even scorpion bite have been reported.The heart injury may result directly from a toxic effect such as a toxin or a virus. More commonly myocarditis is a result of the body’s immune reaction to the initial heart damage. Most immune reactions are helpful and serve to clear infections, but sometimes the scar tissue resulting from the inflammation can lead to long term decline in heart function or chronic abnormalities in heart rhythm. Sometimes the immune reaction fails to clear an infection which can lead to chronic viral myocarditis. Myocarditis can also accompany systemic inflammatory disorders such as lupus or Kawasaki disease.Myocarditis is not inherited. There are no known genes associated with human myocarditis. When multiple family members are affected, the cause is usually due to common infection or environmental exposure. For example, experimental studies suggest that low blood levels of selenium and high levels of mercury may worsen viral myocarditis.
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Causes of Myocarditis. Most cases of myocarditis are of unknown cause (idiopathic). When a cause is identified, it is usually the result of an infection. In North America and Western Europe, viral infections are the most common identified causes of myocarditis. In specific world regions, other important causes include myocarditis following a streptococcal bacterial infection and HIV related infections. In specific Eurasian groups bacteria such as diphtheria, rubella, and even scorpion bite have been reported.The heart injury may result directly from a toxic effect such as a toxin or a virus. More commonly myocarditis is a result of the body’s immune reaction to the initial heart damage. Most immune reactions are helpful and serve to clear infections, but sometimes the scar tissue resulting from the inflammation can lead to long term decline in heart function or chronic abnormalities in heart rhythm. Sometimes the immune reaction fails to clear an infection which can lead to chronic viral myocarditis. Myocarditis can also accompany systemic inflammatory disorders such as lupus or Kawasaki disease.Myocarditis is not inherited. There are no known genes associated with human myocarditis. When multiple family members are affected, the cause is usually due to common infection or environmental exposure. For example, experimental studies suggest that low blood levels of selenium and high levels of mercury may worsen viral myocarditis.
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Affects of Myocarditis
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Myocarditis is most frequently diagnosed in younger adults between the ages of 20 and 40 years. Children seem to have a more severe presentation than adults with a greater proportion requiring temporary mechanical circulatory support. Men are generally more frequently affected than women, possibly due to effects of testosterone on the immune reaction to infection. The relative frequency of more common age related cardiovascular diseases such as coronary artery disease may lead to under diagnosis in the elderly. Certain forms of myocarditis, such as cardiac sarcoidosis, are more common in black than white persons in the US. However, most forms of myocarditis have no known ethnic predisposition.The incidence and prevalence of myocarditis are not known from population-based studies because there is no widely available test that can be applied at a population level. The global burden of myocarditis has been estimated from population-based studies of heart muscle disease (heart disease not related to blocked arteries or abnormal heart valves). In 2010, approximately 400,000 people died of heart muscle disease (cardiomyopathy that includes myocarditis) world wide, including 160,000 women and 240,000 men. Expert consensus opinion extrapolating from regional clinical registries and treatment trials estimates that up to 40% of dilated cardiomyopathy results from myocarditis.
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Affects of Myocarditis. Myocarditis is most frequently diagnosed in younger adults between the ages of 20 and 40 years. Children seem to have a more severe presentation than adults with a greater proportion requiring temporary mechanical circulatory support. Men are generally more frequently affected than women, possibly due to effects of testosterone on the immune reaction to infection. The relative frequency of more common age related cardiovascular diseases such as coronary artery disease may lead to under diagnosis in the elderly. Certain forms of myocarditis, such as cardiac sarcoidosis, are more common in black than white persons in the US. However, most forms of myocarditis have no known ethnic predisposition.The incidence and prevalence of myocarditis are not known from population-based studies because there is no widely available test that can be applied at a population level. The global burden of myocarditis has been estimated from population-based studies of heart muscle disease (heart disease not related to blocked arteries or abnormal heart valves). In 2010, approximately 400,000 people died of heart muscle disease (cardiomyopathy that includes myocarditis) world wide, including 160,000 women and 240,000 men. Expert consensus opinion extrapolating from regional clinical registries and treatment trials estimates that up to 40% of dilated cardiomyopathy results from myocarditis.
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Myocarditis
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Related disorders of Myocarditis
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Myocarditis is a rare cause of many common clinical symptoms. For example chest pain and shortness of breath with activity can result from many forms of heart disease and non-cardiac causes. Because the diagnostic tests for cardiac inflammation, magnetic resonance imaging or heart biopsy, are not widely available, the diagnosis is often overlooked. In people who have autoimmune disorders, myocarditis may result from an autoimmune reaction against heart tissues and not a viral infection. In this setting, myocarditis is a part of a more widespread process that may require treatment with medication to suppress the immune system. Myocarditis can also exacerbate the cardiac damage from other rare heart diseases such as amyloidosis.
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Related disorders of Myocarditis. Myocarditis is a rare cause of many common clinical symptoms. For example chest pain and shortness of breath with activity can result from many forms of heart disease and non-cardiac causes. Because the diagnostic tests for cardiac inflammation, magnetic resonance imaging or heart biopsy, are not widely available, the diagnosis is often overlooked. In people who have autoimmune disorders, myocarditis may result from an autoimmune reaction against heart tissues and not a viral infection. In this setting, myocarditis is a part of a more widespread process that may require treatment with medication to suppress the immune system. Myocarditis can also exacerbate the cardiac damage from other rare heart diseases such as amyloidosis.
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Diagnosis of Myocarditis
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Myocarditis should be suspected in people who have recent onset cardiac symptoms, such as chest pains or trouble breathing, and who have no evidence of more common disorders such as coronary artery disease, heart valve damage or severe high blood pressure. In mild cases characteristic features on cardiac magnetic resonance imaging (MRI) strongly support the diagnosis and heart biopsy is not usually required. In more severe cases or if patients fail to respond to standard medical care, a heart biopsy may be needed to confirm the diagnosis and guide therapy. There are no specific blood tests to confirm the diagnosis of myocarditis; however, an otherwise unexplained elevation in troponin (a blood test that indicates heart muscle damage) and/or electrocardiographic features of cardiac injury are supportive. Similarly new heart wall motion abnormalities or a fluid around the heart seen on echocardiography are not specific but support the diagnosis once other more common disorders have been excluded.In mild cases of myocarditis, particularly with normal heart pump function and evidence of inflammation of the adjacent pericardium, cardiac MRI is a reasonable confirmatory test. The diagnostic MRI features of acute myocarditis are often transient and evolve from a focal to a more diffuse pattern of injury. Over months these diagnostic features may resolve.In more severe cases of myocarditis a heart biopsy should be performed when the information will uniquely impact prognosis or guide treatment. Heart biopsy should be done at centers with expertise in the technique so as to minimize risk of procedure-related complications. Centers performing heart biopsy should have access to cardiac pathologists to examine the heart tissue. In general the diagnostic strategy to confirm myocarditis should balance probable clinical impact with safety.Persons diagnosed with myocarditis often require follow up physician visits and cardiac testing to ensure the disease is responding to treatment. The specific tests and the intervals and duration of follow up depend on the presentation and severity of the initial illness.
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Diagnosis of Myocarditis. Myocarditis should be suspected in people who have recent onset cardiac symptoms, such as chest pains or trouble breathing, and who have no evidence of more common disorders such as coronary artery disease, heart valve damage or severe high blood pressure. In mild cases characteristic features on cardiac magnetic resonance imaging (MRI) strongly support the diagnosis and heart biopsy is not usually required. In more severe cases or if patients fail to respond to standard medical care, a heart biopsy may be needed to confirm the diagnosis and guide therapy. There are no specific blood tests to confirm the diagnosis of myocarditis; however, an otherwise unexplained elevation in troponin (a blood test that indicates heart muscle damage) and/or electrocardiographic features of cardiac injury are supportive. Similarly new heart wall motion abnormalities or a fluid around the heart seen on echocardiography are not specific but support the diagnosis once other more common disorders have been excluded.In mild cases of myocarditis, particularly with normal heart pump function and evidence of inflammation of the adjacent pericardium, cardiac MRI is a reasonable confirmatory test. The diagnostic MRI features of acute myocarditis are often transient and evolve from a focal to a more diffuse pattern of injury. Over months these diagnostic features may resolve.In more severe cases of myocarditis a heart biopsy should be performed when the information will uniquely impact prognosis or guide treatment. Heart biopsy should be done at centers with expertise in the technique so as to minimize risk of procedure-related complications. Centers performing heart biopsy should have access to cardiac pathologists to examine the heart tissue. In general the diagnostic strategy to confirm myocarditis should balance probable clinical impact with safety.Persons diagnosed with myocarditis often require follow up physician visits and cardiac testing to ensure the disease is responding to treatment. The specific tests and the intervals and duration of follow up depend on the presentation and severity of the initial illness.
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Myocarditis
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Therapies of Myocarditis
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TreatmentMyocarditis that presents with heart failure symptoms and decreased heart pump function should be treated according to the current national society guidelines for “systolic” heart failure. Drugs that block the immune system are generally not indicated for the management of the most common forms of myocarditis in adults. However, in specific forms of myocarditis such as giant cell myocarditis, cardiac sarcoidosis or eosinophilic myocarditis, medications that modify the immune response should be considered. These specific forms of myocarditis are diagnosed by heart biopsy. Sports participation during acute viral myocarditis may cause sudden death. Thus high levels of physical activity following the diagnosis of myocarditis should be avoided for at least 3 to 6 months. Non-steroidal anti-inflammatory drugs such as ibuprofen should be avoided due to a risk of increased inflammation. Some patients with severe myocarditis develop low blood pressure despite optimal medical care. These patients may require a temporary heart pump (a kind of mechanical circulatory support device) to survive the acute injury. Some of these patients with myocarditis can be bridged to recovery and have the pump removed. The survival after heart transplantation for adult patients with myocarditis is similar to that for other causes of cardiac failure. Patients with severe myocarditis should be seen by cardiologists with expertise in heart failure and heart rhythm disorder management.
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Therapies of Myocarditis. TreatmentMyocarditis that presents with heart failure symptoms and decreased heart pump function should be treated according to the current national society guidelines for “systolic” heart failure. Drugs that block the immune system are generally not indicated for the management of the most common forms of myocarditis in adults. However, in specific forms of myocarditis such as giant cell myocarditis, cardiac sarcoidosis or eosinophilic myocarditis, medications that modify the immune response should be considered. These specific forms of myocarditis are diagnosed by heart biopsy. Sports participation during acute viral myocarditis may cause sudden death. Thus high levels of physical activity following the diagnosis of myocarditis should be avoided for at least 3 to 6 months. Non-steroidal anti-inflammatory drugs such as ibuprofen should be avoided due to a risk of increased inflammation. Some patients with severe myocarditis develop low blood pressure despite optimal medical care. These patients may require a temporary heart pump (a kind of mechanical circulatory support device) to survive the acute injury. Some of these patients with myocarditis can be bridged to recovery and have the pump removed. The survival after heart transplantation for adult patients with myocarditis is similar to that for other causes of cardiac failure. Patients with severe myocarditis should be seen by cardiologists with expertise in heart failure and heart rhythm disorder management.
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Overview of Myofibrillar Myopathy
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Myofibrillar myopathies are a group of rare genetic neuromuscular disorders that may be diagnosed in childhood but most often appear after 40 years of age. These conditions are highly variable but are characterized by a slowly progressive muscle weakness that can involve skeletal muscle (muscles that function to move bones) and smooth muscle (muscle often associated with organs, such as the digestive tract). Skeletal muscle weakness can be present in the limb muscles close to the center of the body (proximal) as well as the muscle farther from the center of the body (distal). A weakening of the heart muscle (cardiomyopathy) is common and may result in an irregular heartbeat (arrhythmia or conduction defects) or congestive heart failure.
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Overview of Myofibrillar Myopathy. Myofibrillar myopathies are a group of rare genetic neuromuscular disorders that may be diagnosed in childhood but most often appear after 40 years of age. These conditions are highly variable but are characterized by a slowly progressive muscle weakness that can involve skeletal muscle (muscles that function to move bones) and smooth muscle (muscle often associated with organs, such as the digestive tract). Skeletal muscle weakness can be present in the limb muscles close to the center of the body (proximal) as well as the muscle farther from the center of the body (distal). A weakening of the heart muscle (cardiomyopathy) is common and may result in an irregular heartbeat (arrhythmia or conduction defects) or congestive heart failure.
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Symptoms of Myofibrillar Myopathy
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Specific signs and symptoms of myofibrillar myopathies vary by subtype, which are defined by the causative gene (see below). However, all involve progressive muscle weakness and characteristic abnormalities in muscle cells (myofibrillar disorganization and protein accumulation). Some people with myofibrillar myopathy have muscle stiffness, aching, cramps or decreased muscle mass (atrophy). Cardiomyopathy is sometimes the first symptom and may present as arrhythmia, conduction defects or congestive heart failure.Most individuals with myofibrillar myopathy due to desmin mutations (desminopathies) present with slowly progressive muscle weakness. Distal muscle weakness is more common than proximal muscle weakness but symptoms may vary between people in the same family. Difficulty breathing may occur and children with desminopathies may present with cardiomyopathy.For those with alpha-b crystallinopathy, which is myofibrillar myopathy caused due to mutations in the CRYAB gene, symptoms usually occur in adulthood, and include limb muscle weakness that is more severe in the distal muscles than the proximal muscles as well as cardiomyopathy, difficulty breathing and cataracts. If alpha-b crystallinopathy begins in infancy, it can be associated with muscle stiffness and weakness and respiratory failure. For people with the myotilinopathy subtype, which is caused by mutations in the MYOT gene, symptoms mostly begin in middle or late adulthood. The main symptoms are limb weakness, cardiopathy and difficulty breathing. A small portion of patients have a form that begins in early or middle adulthood. This form involves limb weakness and can result in arrhythmia.The ZASPopathy subtype, caused by mutations in the ZASP gene, usually presents in middle or late adulthood with the features of limb weakness (proximal more affected than distal) and difficulty breathing. Cardiopathy and neuropathy can occur in a small portion of this group. Most individuals with the filaminopathy subtype, caused by mutations in the FLNC gene, usually experience symptoms in middle adulthood, with features of muscle weakness that is more severe in the proximal limbs than the distal limbs and difficulty breathing. Cardiopathy may occur in a subset of people, and pain, loss of sensation and inability to control muscles may also occur. Children with BAG3-related myofibrillar myopathies may present before the age of 20 with proximal weakness, respiratory failure and restrictive cardiomyopathy. This condition is frequently rapidly progressive and fatal.
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Symptoms of Myofibrillar Myopathy. Specific signs and symptoms of myofibrillar myopathies vary by subtype, which are defined by the causative gene (see below). However, all involve progressive muscle weakness and characteristic abnormalities in muscle cells (myofibrillar disorganization and protein accumulation). Some people with myofibrillar myopathy have muscle stiffness, aching, cramps or decreased muscle mass (atrophy). Cardiomyopathy is sometimes the first symptom and may present as arrhythmia, conduction defects or congestive heart failure.Most individuals with myofibrillar myopathy due to desmin mutations (desminopathies) present with slowly progressive muscle weakness. Distal muscle weakness is more common than proximal muscle weakness but symptoms may vary between people in the same family. Difficulty breathing may occur and children with desminopathies may present with cardiomyopathy.For those with alpha-b crystallinopathy, which is myofibrillar myopathy caused due to mutations in the CRYAB gene, symptoms usually occur in adulthood, and include limb muscle weakness that is more severe in the distal muscles than the proximal muscles as well as cardiomyopathy, difficulty breathing and cataracts. If alpha-b crystallinopathy begins in infancy, it can be associated with muscle stiffness and weakness and respiratory failure. For people with the myotilinopathy subtype, which is caused by mutations in the MYOT gene, symptoms mostly begin in middle or late adulthood. The main symptoms are limb weakness, cardiopathy and difficulty breathing. A small portion of patients have a form that begins in early or middle adulthood. This form involves limb weakness and can result in arrhythmia.The ZASPopathy subtype, caused by mutations in the ZASP gene, usually presents in middle or late adulthood with the features of limb weakness (proximal more affected than distal) and difficulty breathing. Cardiopathy and neuropathy can occur in a small portion of this group. Most individuals with the filaminopathy subtype, caused by mutations in the FLNC gene, usually experience symptoms in middle adulthood, with features of muscle weakness that is more severe in the proximal limbs than the distal limbs and difficulty breathing. Cardiopathy may occur in a subset of people, and pain, loss of sensation and inability to control muscles may also occur. Children with BAG3-related myofibrillar myopathies may present before the age of 20 with proximal weakness, respiratory failure and restrictive cardiomyopathy. This condition is frequently rapidly progressive and fatal.
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Causes of Myofibrillar Myopathy
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Myofibrillar myopathies may be caused by disease-causing mutations in a single gene or by many changes in multiple genes in combination with environmental factors. Genes function as the instructions for the creation of proteins, and the disease-causing mutations result in excess amounts of a particular protein in muscle. The genes responsible for myofibrillar myopathies are identified in approximately 20% of affected individuals. These disorders have been categorized by the gene involved. Desminopathy—(onset age 20-30) DES gene/desmin proteinAlpha-B crystallinopathy—(onset age 20-40 years) CRYAB gene/a-B crystallin proteinMyotilinopathy—(onset age 27-77) titin immunoglobulin domain protein MYOT gene/myotilin proteinFilaminopathy—(onset age 37-57) FLNC gene/filamin C proteinBAG3-related myofibrillar myopathy—(onset childhood) BAG3 gene/BCL2-associated athanogene 3 protein ZASPopathy—(onset age 44-73 years) ZASP gene/LIM domain-binding protein 3HSPB8 myopathy—(onset early/middle adulthood) HSPB8 gene/ HSPB8 proteinIn some patients, genes that cause other types of neuromuscular conditions have disease-causing mutations that cause features of myofibrillar myopathy. These conditions include reducing body myopathy (FHL1 gene), hereditary myopathy with early respiratory failure (HMERF gene), epidermolysis bullosa simplex with muscular dystrophy (PLEC gene), MFM-actinopathy (ACTA1 gene) and limb girdle muscular dystrophy type 1D (DNAJB6 gene). Myofibrillar myopathies are usually inherited in an autosomal dominant pattern. Everyone has two copies of the genes that cause myofibrillar myopathy. Autosomal dominant genetic disorders occur when one copy of the gene has a disease-causing change in it. A disease-causing change in a gene is sometimes called a mutation. The gene copy with the mutation can be inherited from either parent or it can be the result of a new mutation in the affected individual. Approximately 25% of affected individuals inherited the disease-causing mutation from an affected parent. In autosomal dominant myofibrillar myopathies, the risk of it passing from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. It is possible for children to have autosomal recessive desminopathy, meaning that disease-causing mutation(s) must be present in both copies of the Desmin (DES) gene in order for a person to develop disease. In this case, onset can be in early childhood. It is not always possible to know if a person is affected with autosomal dominant or autosomal recessive myofibrillar myopathy. While clues can be found in the family history, some people within the same family with the same disease-causing mutations may remain undiagnosed or be diagnosed later in life.
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Causes of Myofibrillar Myopathy. Myofibrillar myopathies may be caused by disease-causing mutations in a single gene or by many changes in multiple genes in combination with environmental factors. Genes function as the instructions for the creation of proteins, and the disease-causing mutations result in excess amounts of a particular protein in muscle. The genes responsible for myofibrillar myopathies are identified in approximately 20% of affected individuals. These disorders have been categorized by the gene involved. Desminopathy—(onset age 20-30) DES gene/desmin proteinAlpha-B crystallinopathy—(onset age 20-40 years) CRYAB gene/a-B crystallin proteinMyotilinopathy—(onset age 27-77) titin immunoglobulin domain protein MYOT gene/myotilin proteinFilaminopathy—(onset age 37-57) FLNC gene/filamin C proteinBAG3-related myofibrillar myopathy—(onset childhood) BAG3 gene/BCL2-associated athanogene 3 protein ZASPopathy—(onset age 44-73 years) ZASP gene/LIM domain-binding protein 3HSPB8 myopathy—(onset early/middle adulthood) HSPB8 gene/ HSPB8 proteinIn some patients, genes that cause other types of neuromuscular conditions have disease-causing mutations that cause features of myofibrillar myopathy. These conditions include reducing body myopathy (FHL1 gene), hereditary myopathy with early respiratory failure (HMERF gene), epidermolysis bullosa simplex with muscular dystrophy (PLEC gene), MFM-actinopathy (ACTA1 gene) and limb girdle muscular dystrophy type 1D (DNAJB6 gene). Myofibrillar myopathies are usually inherited in an autosomal dominant pattern. Everyone has two copies of the genes that cause myofibrillar myopathy. Autosomal dominant genetic disorders occur when one copy of the gene has a disease-causing change in it. A disease-causing change in a gene is sometimes called a mutation. The gene copy with the mutation can be inherited from either parent or it can be the result of a new mutation in the affected individual. Approximately 25% of affected individuals inherited the disease-causing mutation from an affected parent. In autosomal dominant myofibrillar myopathies, the risk of it passing from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. It is possible for children to have autosomal recessive desminopathy, meaning that disease-causing mutation(s) must be present in both copies of the Desmin (DES) gene in order for a person to develop disease. In this case, onset can be in early childhood. It is not always possible to know if a person is affected with autosomal dominant or autosomal recessive myofibrillar myopathy. While clues can be found in the family history, some people within the same family with the same disease-causing mutations may remain undiagnosed or be diagnosed later in life.
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Affects of Myofibrillar Myopathy
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The frequency of myofibrillar myopathies is not well understood. It is likely that these conditions are unrecognized and underdiagnosed.
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Affects of Myofibrillar Myopathy. The frequency of myofibrillar myopathies is not well understood. It is likely that these conditions are unrecognized and underdiagnosed.
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Related disorders of Myofibrillar Myopathy
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Signs and symptoms of the following muscle disorders may be similar to those of myofibrillar myopathies. Comparisons may be useful for a differential diagnosis:Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multi-system disorder that affects both smooth and skeletal muscles and may affect the central nervous system, heart, eyes and/or endocrine systems. Classic DM1 is characterized by muscle weakness and atrophy, cataracts, myotonia (impaired muscle relaxation) and abnormalities in the heart’s conduction of electrical impulses. Myotonic dystrophy type 2 (DM2), is an autosomal dominant disorder with symptoms that are similar to DM1, but tend to be milder and more variable than DM1. (For more information on this disorder, choose “myotonic dystrophy” as your search term in the Rare Disease Database.)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.. (For more information on this disorder, choose “sporadic inclusion body myositis” as your search term in the Rare Disease Database.)GNE myopathy, also known as HIBM, Nonaka myopathy, IBM2 and distal myopathy with rimmed vacuoles, is a genetic disorder that affects primarily the skeletal muscles (muscles that the body uses to perform daily physical activity). First signs of the disease appear between 20 and 40 years of age and affect males and females at the same rate. This condition is characterized by progressive muscle weakness which typically worsens over time, decreased grip strength and frequent loss of balance. GNE myopathy is caused by changes (mutations) in the GNE gene and follows autosomal recessive inheritance. (For more information on this disorder, choose “GNE myopathy” as your search term in the Rare Disease Database.)
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Related disorders of Myofibrillar Myopathy. Signs and symptoms of the following muscle disorders may be similar to those of myofibrillar myopathies. Comparisons may be useful for a differential diagnosis:Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multi-system disorder that affects both smooth and skeletal muscles and may affect the central nervous system, heart, eyes and/or endocrine systems. Classic DM1 is characterized by muscle weakness and atrophy, cataracts, myotonia (impaired muscle relaxation) and abnormalities in the heart’s conduction of electrical impulses. Myotonic dystrophy type 2 (DM2), is an autosomal dominant disorder with symptoms that are similar to DM1, but tend to be milder and more variable than DM1. (For more information on this disorder, choose “myotonic dystrophy” as your search term in the Rare Disease Database.)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.. (For more information on this disorder, choose “sporadic inclusion body myositis” as your search term in the Rare Disease Database.)GNE myopathy, also known as HIBM, Nonaka myopathy, IBM2 and distal myopathy with rimmed vacuoles, is a genetic disorder that affects primarily the skeletal muscles (muscles that the body uses to perform daily physical activity). First signs of the disease appear between 20 and 40 years of age and affect males and females at the same rate. This condition is characterized by progressive muscle weakness which typically worsens over time, decreased grip strength and frequent loss of balance. GNE myopathy is caused by changes (mutations) in the GNE gene and follows autosomal recessive inheritance. (For more information on this disorder, choose “GNE myopathy” as your search term in the Rare Disease Database.)
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Diagnosis of Myofibrillar Myopathy
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A diagnosis of myofibrillar myopathy is made based on clinical evaluation of the patient’s symptoms as well as tests such as electromyography (EMG), nerve conduction studies (NCV) and muscle biopsy. Molecular genetic testing for mutations in the DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, PLEC, ACTA1, HSPB8, and DNAJB6 genes may confirm the diagnosis.
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Diagnosis of Myofibrillar Myopathy. A diagnosis of myofibrillar myopathy is made based on clinical evaluation of the patient’s symptoms as well as tests such as electromyography (EMG), nerve conduction studies (NCV) and muscle biopsy. Molecular genetic testing for mutations in the DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, PLEC, ACTA1, HSPB8, and DNAJB6 genes may confirm the diagnosis.
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Therapies of Myofibrillar Myopathy
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TreatmentThere are currently no curative treatments for myofibrillar myopathies. Treatment is directed toward each symptom that a person develops, and should be directed by a specialist. Individuals affected with cardiomyopathy may consider implantation of a mechanical device to regulate heartbeat (pacemaker) and cardioverter defibrillator (ICD). Heart transplantation may be considered if the cardiomyopathy is progressive or life threatening. Respiratory therapy and physical therapy may be helpful for those with advanced muscle weakness. Orthotics may be helpful if foot drop develops.Cardiac screening including electrocardiography, echocardiography, and 24-hour Holter monitoring is recommended once per year in individuals with myofibrillar myopathy, and a cardiac MRI when available. Respiratory function should also be monitored.
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Therapies of Myofibrillar Myopathy. TreatmentThere are currently no curative treatments for myofibrillar myopathies. Treatment is directed toward each symptom that a person develops, and should be directed by a specialist. Individuals affected with cardiomyopathy may consider implantation of a mechanical device to regulate heartbeat (pacemaker) and cardioverter defibrillator (ICD). Heart transplantation may be considered if the cardiomyopathy is progressive or life threatening. Respiratory therapy and physical therapy may be helpful for those with advanced muscle weakness. Orthotics may be helpful if foot drop develops.Cardiac screening including electrocardiography, echocardiography, and 24-hour Holter monitoring is recommended once per year in individuals with myofibrillar myopathy, and a cardiac MRI when available. Respiratory function should also be monitored.
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Myofibrillar Myopathy
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Overview of Myopathy, Scapuloperoneal
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Scapuloperoneal myopathy is a rare genetic disorder characterized by weakness and wasting of certain muscles. Symptoms are usually limited to the shoulder blade area (scapula) and the smaller of the two leg muscle groups below the knee (peroneal). Facial muscles may be affected in a few cases. The leg symptoms often appear before the shoulder muscles become weakened. The rate of progression of the disorder varies from case to case. This condition can also occur in combination with other disorders. Scapuloperoneal myopathy is inherited as an autosomal dominant trait.
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Overview of Myopathy, Scapuloperoneal. Scapuloperoneal myopathy is a rare genetic disorder characterized by weakness and wasting of certain muscles. Symptoms are usually limited to the shoulder blade area (scapula) and the smaller of the two leg muscle groups below the knee (peroneal). Facial muscles may be affected in a few cases. The leg symptoms often appear before the shoulder muscles become weakened. The rate of progression of the disorder varies from case to case. This condition can also occur in combination with other disorders. Scapuloperoneal myopathy is inherited as an autosomal dominant trait.
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Symptoms of Myopathy, Scapuloperoneal
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Symptoms of scapuloperoneal myopathy primarily include muscle weakness and wasting usually limited to muscles in the shoulder blade and girdle area and the legs below the knees. This disorder can begin in childhood or adulthood. The progression rate and severity may vary greatly, with some cases progressing more quickly than others. In most cases, the progression is slow. The shoulder muscles are affected first, in most cases. In some cases, shoulder involvement may precede lower leg involvement by years or decades. In some cases, lower leg involvement may precede shoulder involvement. In rare cases, some facial muscles may be mildly affected.
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Symptoms of Myopathy, Scapuloperoneal. Symptoms of scapuloperoneal myopathy primarily include muscle weakness and wasting usually limited to muscles in the shoulder blade and girdle area and the legs below the knees. This disorder can begin in childhood or adulthood. The progression rate and severity may vary greatly, with some cases progressing more quickly than others. In most cases, the progression is slow. The shoulder muscles are affected first, in most cases. In some cases, shoulder involvement may precede lower leg involvement by years or decades. In some cases, lower leg involvement may precede shoulder involvement. In rare cases, some facial muscles may be mildly affected.
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Causes of Myopathy, Scapuloperoneal
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Scapuloperoneal myopathy is inherited as an autosomal dominant trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. In some cases, scapuloperoneal myopathy may be due to new genetic changes (mutations) that appear to occur spontaneously for unknown reasons (sporadically).Investigators have determined that some cases of scapuloperoneal myopathy may be caused by disruption or changes (mutations) of a gene located on the long arm (q) of chromosome 12 (12q13.3-q15). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 12q13.3-q15” refers to bands 13.3-15 on the long arm of chromosome 12.
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Causes of Myopathy, Scapuloperoneal. Scapuloperoneal myopathy is inherited as an autosomal dominant trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. In some cases, scapuloperoneal myopathy may be due to new genetic changes (mutations) that appear to occur spontaneously for unknown reasons (sporadically).Investigators have determined that some cases of scapuloperoneal myopathy may be caused by disruption or changes (mutations) of a gene located on the long arm (q) of chromosome 12 (12q13.3-q15). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 12q13.3-q15” refers to bands 13.3-15 on the long arm of chromosome 12.
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Affects of Myopathy, Scapuloperoneal
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Scapuloperoneal myopathy affects males and females in equal numbers. Symptoms may begin in childhood or during adulthood. Scapuloperoneal myopathy is a rare disorder; the exact prevalence of this disorder in the general population is unknown.
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Affects of Myopathy, Scapuloperoneal. Scapuloperoneal myopathy affects males and females in equal numbers. Symptoms may begin in childhood or during adulthood. Scapuloperoneal myopathy is a rare disorder; the exact prevalence of this disorder in the general population is unknown.
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Related disorders of Myopathy, Scapuloperoneal
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Symptoms of the following disorders can be similar to those of scapuloperoneal myopathy. Comparisons may be useful for a differential diagnosis:Scapuloperoneal amyotrophy (also known as Kaeser syndrome or scapuloperoneal syndrome, neurogenic type) is characterized by muscle weakness and wasting (atrophy) below the knees accompanied by foot abnormalities and an unusual walk. Eventually, the shoulder muscles may also become involved. Nerve impulses may become measurably slowed, which does not occur in scapuloperoneal myopathy. Pain, unusual sensations in the legs, heart problems, and muscle contractures may also occur. Scapuloperoneal amyotrophy is inherited as an autosomal dominant trait.Facioscapulohumeral dystrophy (FSHD) is a rare disorder that belongs to a group of disorders known as the muscular dystrophies. FSHD is characterized by weakness of facial muscles as well as weakness and wasting (atrophy) of muscles of the shoulders and arms. The disorder usually progresses slowly over many years and decades, although there may be periods of rapid deterioration. Associated abnormalities may include an impaired ability to completely close the eyes, limited movements of the lips, and difficulties raising the arms over the head. Affected individuals may also eventually develop weakness and associated wasting (atrophy) of muscles of the hips and thighs and/or involvement of lower leg muscles, potentially leading to an impaired ability to flex the foot upward (footdrop). In those with FSHD, the disease course may be variable, with relatively slow, moderate, or rapid progression or, in other instances, nonprogressive involvement of certain muscles. However, FSHD is most typically characterized by relatively slow disease progression. In some cases, the disorder is inherited as an autosomal dominant trait. (For more information on this disorder, choose Facioscapulohumeral Muscular Dystrophy as your search term in the Rare Disease Database.)
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Related disorders of Myopathy, Scapuloperoneal. Symptoms of the following disorders can be similar to those of scapuloperoneal myopathy. Comparisons may be useful for a differential diagnosis:Scapuloperoneal amyotrophy (also known as Kaeser syndrome or scapuloperoneal syndrome, neurogenic type) is characterized by muscle weakness and wasting (atrophy) below the knees accompanied by foot abnormalities and an unusual walk. Eventually, the shoulder muscles may also become involved. Nerve impulses may become measurably slowed, which does not occur in scapuloperoneal myopathy. Pain, unusual sensations in the legs, heart problems, and muscle contractures may also occur. Scapuloperoneal amyotrophy is inherited as an autosomal dominant trait.Facioscapulohumeral dystrophy (FSHD) is a rare disorder that belongs to a group of disorders known as the muscular dystrophies. FSHD is characterized by weakness of facial muscles as well as weakness and wasting (atrophy) of muscles of the shoulders and arms. The disorder usually progresses slowly over many years and decades, although there may be periods of rapid deterioration. Associated abnormalities may include an impaired ability to completely close the eyes, limited movements of the lips, and difficulties raising the arms over the head. Affected individuals may also eventually develop weakness and associated wasting (atrophy) of muscles of the hips and thighs and/or involvement of lower leg muscles, potentially leading to an impaired ability to flex the foot upward (footdrop). In those with FSHD, the disease course may be variable, with relatively slow, moderate, or rapid progression or, in other instances, nonprogressive involvement of certain muscles. However, FSHD is most typically characterized by relatively slow disease progression. In some cases, the disorder is inherited as an autosomal dominant trait. (For more information on this disorder, choose Facioscapulohumeral Muscular Dystrophy as your search term in the Rare Disease Database.)
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Diagnosis of Myopathy, Scapuloperoneal
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Diagnosis of Myopathy, Scapuloperoneal.
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Therapies of Myopathy, Scapuloperoneal
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There is no specific treatment for individuals with scapuloperoneal myopathy. Treatment may include specified amounts of therapeutic exercise and physical therapy alternating with periods of rest.Genetic counseling may benefit affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Myopathy, Scapuloperoneal. There is no specific treatment for individuals with scapuloperoneal myopathy. Treatment may include specified amounts of therapeutic exercise and physical therapy alternating with periods of rest.Genetic counseling may benefit affected individuals and their families. Other treatment is symptomatic and supportive.
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Myopathy, Scapuloperoneal
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Overview of Myotonia Congenita
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Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals have difficulty relaxing certain muscles after contracting them (myotonia), muscle stiffness (rigidity), and associated symptoms. Such symptoms tend to occur when attempting to move certain muscles after rest. In many cases, individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a “herculean” or “body-builder like” appearance.Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. In individuals with Thomsen disease, symptoms and findings such as myotonia, associated muscle rigidity, and abnormal muscle enlargement may become apparent from infancy to approximately two to three years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. Thomsen disease is transmitted as an autosomal dominant trait.In those with Becker disease, symptoms most commonly become apparent between the ages of four and 12 years. As in Thomsen type myotonia congenita, affected individuals develop myotonia, associated muscle rigidity, and abnormal muscle enlargement (hypertrophy). The symptoms tend to remain constant, with little progression. Becker disease is inherited as an autosomal recessive trait.
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Overview of Myotonia Congenita. Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals have difficulty relaxing certain muscles after contracting them (myotonia), muscle stiffness (rigidity), and associated symptoms. Such symptoms tend to occur when attempting to move certain muscles after rest. In many cases, individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a “herculean” or “body-builder like” appearance.Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. In individuals with Thomsen disease, symptoms and findings such as myotonia, associated muscle rigidity, and abnormal muscle enlargement may become apparent from infancy to approximately two to three years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. Thomsen disease is transmitted as an autosomal dominant trait.In those with Becker disease, symptoms most commonly become apparent between the ages of four and 12 years. As in Thomsen type myotonia congenita, affected individuals develop myotonia, associated muscle rigidity, and abnormal muscle enlargement (hypertrophy). The symptoms tend to remain constant, with little progression. Becker disease is inherited as an autosomal recessive trait.
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Symptoms of Myotonia Congenita
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Myotonia congenita is a disorder of voluntary (skeletal) muscle characterized by an exaggerated response to stimulation of certain muscle fibers (hyperexcitability). As a result, there is painless spasm (tonic spasm) of affected muscle after forceful voluntary contraction, abnormal muscle stiffness, and difficulty relaxing muscle (myotonia). Such symptoms tend to occur when affected individuals attempt to move certain muscles following a period of inactivity or when affected muscles are mechanically stimulated. Characteristic symptoms may include difficulties relaxing hand grip; completely opening the eyes after forcibly closing them (e.g., following crying or sneezing); arising from a chair; starting to walk or run; climbing stairs; and/or arising from bed at night. As noted above, the myotonia is characteristically most pronounced following a period of rest. In addition, it typically improves by gradually increasing the force or intensity of movements through “warming up.” Most individuals with myotonia congenita also develop abnormal enlargement of voluntary muscles (hypertrophy), resulting in an athletic appearance.As noted above, two major forms of myotonia congenita have been described: Thomsen disease (autosomal dominant type) and Becker disease (autosomal recessive type). (For more information on mode of inheritance, please see the “Causes” section of this report below.) In Thomsen type myotonia congenita, symptoms may become evident from infancy to approximately two to three years of age and are typically nonprogressive. However, the severity of the myotonia may vary greatly among members of the same family, with males typically more severely affected. According to some reports, exposure to cold temperatures may aggravate symptoms in some cases. In many individuals with Thomsen disease, muscles of the legs, hands, and/or eyelids are most affected, particularly those of the legs. Characteristic symptoms may include those mentioned above (e.g., difficulties starting to walk or run, arising from a bed or chair, relaxing the hand grip, etc.). In addition, some may experience spasms of other muscles, including certain muscles of the face, trunk, or other regions. For example, involvement of muscles that control movements of the eyeballs (extraocular muscles) may lead to temporary episodes of double vision or abnormal deviation of one eye in relation to the other (strabismus). In addition, in some cases, if myotonia affects muscles of the throat, affected individuals may have difficulties with chewing, swallowing, and/or attempting to talk after a long period of silence.As mentioned above, individuals with Thomsen disease may develop abnormal enlargement (hypertrophy) of the muscles. Affected individuals typically have normal muscle strength or only minimal muscle weakness.In individuals with Becker type myotonia congenita, symptoms tend to become apparent between the ages of four to 12 years. However, in some rare cases, onset may occur as late as approximately 18 years of age. Associated symptoms are similar to those of Thomsen disease; however, they tend to progress over many years and to be more severe. In most cases of Becker disease, the myotonia is initially apparent in muscles of the legs. With disease progression, muscles of the arms, trunk, and face are eventually affected. Enhancement of symptoms by cold exposure appears to be less common than seen with Thomsen disease.Abnormal muscle enlargement (hypertrophy) is typically present in individuals with Becker disease and may be particularly striking, resulting in an even more pronounced “body-builder like” appearance. In addition, in contrast to Thomsen type myotonia congenita, muscle weakness and muscle wasting (atrophy) may also be present. According to the medical literature, two sisters with Becker type myotonia congenita demonstrated susceptibility to malignant hyperthermia (MH). MH is a potentially life-threatening condition that may be triggered due to exposure to certain general anesthetics (e.g., halothane) or skeletal muscle relaxants (e.g., succinylcholine) that may be administered during surgical procedures. Such a reaction may be characterized by a dangerous, sudden rise in body temperature (hyperthermia); stiffness of skeletal muscles; low blood pressure (hypotension); an irregular heartbeat (arrhythmias); and/or other complications, requiring immediate emergency intervention. In the two sisters described, exposure to succinylcholine resulted in generalized muscle rigidity without a rise in body temperature. According to researchers, it is unclear whether this was an incidental finding or whether MH or an MH-like condition may be associated with Becker disease in some cases. Therefore, the implications of this finding are not yet fully understood.
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Symptoms of Myotonia Congenita. Myotonia congenita is a disorder of voluntary (skeletal) muscle characterized by an exaggerated response to stimulation of certain muscle fibers (hyperexcitability). As a result, there is painless spasm (tonic spasm) of affected muscle after forceful voluntary contraction, abnormal muscle stiffness, and difficulty relaxing muscle (myotonia). Such symptoms tend to occur when affected individuals attempt to move certain muscles following a period of inactivity or when affected muscles are mechanically stimulated. Characteristic symptoms may include difficulties relaxing hand grip; completely opening the eyes after forcibly closing them (e.g., following crying or sneezing); arising from a chair; starting to walk or run; climbing stairs; and/or arising from bed at night. As noted above, the myotonia is characteristically most pronounced following a period of rest. In addition, it typically improves by gradually increasing the force or intensity of movements through “warming up.” Most individuals with myotonia congenita also develop abnormal enlargement of voluntary muscles (hypertrophy), resulting in an athletic appearance.As noted above, two major forms of myotonia congenita have been described: Thomsen disease (autosomal dominant type) and Becker disease (autosomal recessive type). (For more information on mode of inheritance, please see the “Causes” section of this report below.) In Thomsen type myotonia congenita, symptoms may become evident from infancy to approximately two to three years of age and are typically nonprogressive. However, the severity of the myotonia may vary greatly among members of the same family, with males typically more severely affected. According to some reports, exposure to cold temperatures may aggravate symptoms in some cases. In many individuals with Thomsen disease, muscles of the legs, hands, and/or eyelids are most affected, particularly those of the legs. Characteristic symptoms may include those mentioned above (e.g., difficulties starting to walk or run, arising from a bed or chair, relaxing the hand grip, etc.). In addition, some may experience spasms of other muscles, including certain muscles of the face, trunk, or other regions. For example, involvement of muscles that control movements of the eyeballs (extraocular muscles) may lead to temporary episodes of double vision or abnormal deviation of one eye in relation to the other (strabismus). In addition, in some cases, if myotonia affects muscles of the throat, affected individuals may have difficulties with chewing, swallowing, and/or attempting to talk after a long period of silence.As mentioned above, individuals with Thomsen disease may develop abnormal enlargement (hypertrophy) of the muscles. Affected individuals typically have normal muscle strength or only minimal muscle weakness.In individuals with Becker type myotonia congenita, symptoms tend to become apparent between the ages of four to 12 years. However, in some rare cases, onset may occur as late as approximately 18 years of age. Associated symptoms are similar to those of Thomsen disease; however, they tend to progress over many years and to be more severe. In most cases of Becker disease, the myotonia is initially apparent in muscles of the legs. With disease progression, muscles of the arms, trunk, and face are eventually affected. Enhancement of symptoms by cold exposure appears to be less common than seen with Thomsen disease.Abnormal muscle enlargement (hypertrophy) is typically present in individuals with Becker disease and may be particularly striking, resulting in an even more pronounced “body-builder like” appearance. In addition, in contrast to Thomsen type myotonia congenita, muscle weakness and muscle wasting (atrophy) may also be present. According to the medical literature, two sisters with Becker type myotonia congenita demonstrated susceptibility to malignant hyperthermia (MH). MH is a potentially life-threatening condition that may be triggered due to exposure to certain general anesthetics (e.g., halothane) or skeletal muscle relaxants (e.g., succinylcholine) that may be administered during surgical procedures. Such a reaction may be characterized by a dangerous, sudden rise in body temperature (hyperthermia); stiffness of skeletal muscles; low blood pressure (hypotension); an irregular heartbeat (arrhythmias); and/or other complications, requiring immediate emergency intervention. In the two sisters described, exposure to succinylcholine resulted in generalized muscle rigidity without a rise in body temperature. According to researchers, it is unclear whether this was an incidental finding or whether MH or an MH-like condition may be associated with Becker disease in some cases. Therefore, the implications of this finding are not yet fully understood.
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Causes of Myotonia Congenita
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Thomsen type myotonia congenita is transmitted as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Becker type myotonia congenita is inherited as an autosomal recessive trait. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% 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%. According to reports in the medical literature, parents of several individuals with Becker disease have been closely related by blood (consanguineous). With closely related parents, there may be an increased likelihood that both carry the same recessive disease gene, increasing the risk that their children may inherit the two genes necessary for the development of the disease.Some cases have also been reported in which myotonia congenita has appeared to occur randomly for unknown reasons (sporadically) in the apparent absence of a family history.Numerous mutations in the same gene have been identified in individuals with Thomsen and Becker types myotonia congenita. The gene, known as “CLCN1”, has been mapped to the long arm (q) of chromosome 7 (7q35). (For more on the CLCN1 gene, see below.) Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. Therefore, “7q35” refers to band 35 on the long arm of chromosome 7.Thomsen and Becker types myotonia congenita are considered “ion channel diseases” or “channelopathies”, meaning that they result from abnormalities in the flow of certain ions across muscle cell membranes. Ions are particles that carry a positive or negative electrical charge. For example, positively charged ions (cations) include sodium and calcium; ions carrying a negative charge (anions) include chloride and phosphate. As mentioned above, both Thomsen and Becker types myotonia congenita appear to be linked to “CLCN1” and therefore are more specifically classified as “chloride channel diseases”. CLCN1 is a gene that is responsible for the normal functioning of certain chloride channels in voluntary (skeletal) muscle cell membranes. Ion channels, including chloride channels, are specialized proteins that regulate the flow or exchange of ions across certain cellular membranes. Chloride channels play an important role in regulating the skeletal muscle membranes' electric response to stimuli (i.e., electric excitability). Researchers suspect that certain mutations of the CLCN1 gene result in reduced numbers or insufficient functioning of chloride channels (i.e., abnormally reduced chloride conductance), causing an impaired ability to maintain normal muscle excitability (electrical instability), associated myotonia, and other findings seen in myotonia congenita. Evidence also suggests that abnormal sodium channel activation may play some role in the hyperexcitability associated with the disease.
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Causes of Myotonia Congenita. Thomsen type myotonia congenita is transmitted as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Becker type myotonia congenita is inherited as an autosomal recessive trait. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% 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%. According to reports in the medical literature, parents of several individuals with Becker disease have been closely related by blood (consanguineous). With closely related parents, there may be an increased likelihood that both carry the same recessive disease gene, increasing the risk that their children may inherit the two genes necessary for the development of the disease.Some cases have also been reported in which myotonia congenita has appeared to occur randomly for unknown reasons (sporadically) in the apparent absence of a family history.Numerous mutations in the same gene have been identified in individuals with Thomsen and Becker types myotonia congenita. The gene, known as “CLCN1”, has been mapped to the long arm (q) of chromosome 7 (7q35). (For more on the CLCN1 gene, see below.) Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. Therefore, “7q35” refers to band 35 on the long arm of chromosome 7.Thomsen and Becker types myotonia congenita are considered “ion channel diseases” or “channelopathies”, meaning that they result from abnormalities in the flow of certain ions across muscle cell membranes. Ions are particles that carry a positive or negative electrical charge. For example, positively charged ions (cations) include sodium and calcium; ions carrying a negative charge (anions) include chloride and phosphate. As mentioned above, both Thomsen and Becker types myotonia congenita appear to be linked to “CLCN1” and therefore are more specifically classified as “chloride channel diseases”. CLCN1 is a gene that is responsible for the normal functioning of certain chloride channels in voluntary (skeletal) muscle cell membranes. Ion channels, including chloride channels, are specialized proteins that regulate the flow or exchange of ions across certain cellular membranes. Chloride channels play an important role in regulating the skeletal muscle membranes' electric response to stimuli (i.e., electric excitability). Researchers suspect that certain mutations of the CLCN1 gene result in reduced numbers or insufficient functioning of chloride channels (i.e., abnormally reduced chloride conductance), causing an impaired ability to maintain normal muscle excitability (electrical instability), associated myotonia, and other findings seen in myotonia congenita. Evidence also suggests that abnormal sodium channel activation may play some role in the hyperexcitability associated with the disease.
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Affects of Myotonia Congenita
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Thomsen and Becker types myotonia congenita are thought to affect males and females in relatively equal numbers. Reported cases have included multiple affected members in multigenerational families (kindreds) as well as apparently sporadic cases. The reported incidence of these disorders is between .3 and .6 per 100,000 people in the general population. Thomsen type myotonia congenita was initially described in 1876 by a Danish physician (Thomsen J). The disease affected the physician himself as well as multiple family members in several generations (approximately 64 family members in seven consecutive generations). The autosomal recessive form, designated Becker type myotonia congenita, was later described by another investigator (Becker PE).According to reports in the medical literature, Thomsen disease tends to occur over multiple generations, usually without skipping generations. However, some rare exceptions have been noted in which skipped generations have been shown. As mentioned earlier, in individuals with Thomsen disease, the severity of associated symptoms may vary greatly among family members, with males typically more affected than females.Becker type myotonia congenita has been reported in multiple siblings of unaffected parents. As noted above, in some of these cases, parents of children with Becker disease have been closely related by blood (consanguineous).
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Affects of Myotonia Congenita. Thomsen and Becker types myotonia congenita are thought to affect males and females in relatively equal numbers. Reported cases have included multiple affected members in multigenerational families (kindreds) as well as apparently sporadic cases. The reported incidence of these disorders is between .3 and .6 per 100,000 people in the general population. Thomsen type myotonia congenita was initially described in 1876 by a Danish physician (Thomsen J). The disease affected the physician himself as well as multiple family members in several generations (approximately 64 family members in seven consecutive generations). The autosomal recessive form, designated Becker type myotonia congenita, was later described by another investigator (Becker PE).According to reports in the medical literature, Thomsen disease tends to occur over multiple generations, usually without skipping generations. However, some rare exceptions have been noted in which skipped generations have been shown. As mentioned earlier, in individuals with Thomsen disease, the severity of associated symptoms may vary greatly among family members, with males typically more affected than females.Becker type myotonia congenita has been reported in multiple siblings of unaffected parents. As noted above, in some of these cases, parents of children with Becker disease have been closely related by blood (consanguineous).
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Related disorders of Myotonia Congenita
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Symptoms of the following disorders may be similar to those of myotonia congenita. Comparisons may be useful for a differential diagnosis: Paramyotonia congenita is a rare genetic nonprogressive disorder that usually becomes apparent during infancy. The disorder is often characterized by myotonia triggered or aggravated by exposure to cold and alleviated by warm temperatures; in addition, the myotonia is sometimes described as “paradoxic,” since it tends to become more severe rather than to improve with exercise. Some with the disorder may also be affected by episodes of weakness or partial paralysis (paresis) that do not necessarily coincide with exposure to cold temperatures or myotonia. In addition, in some cases, periods of weakness may be induced by the administration of potassium. The disorder is not associated with muscle wasting or hypertrophy. Paramyotonia congenita is a sodium channel disease (sodium channelopathy). It results from mutations of a gene (called SCN4A) that has also been linked to hyperkalemic periodic paralysis (see below). The disease gene has been mapped to the long arm (q) of chromosome 17. Paramyotonia congenita is transmitted as an autosomal dominant trait. (For more information on this disorder, choose “paramyotonia congenita” as your search term in the Rare Disease Database.) Hyperkalemic periodic paralysis is a rare genetic disorder that usually becomes apparent during infancy or childhood. The disorder is characterized by periodic episodes of muscle weakness that tend to occur during the daytime. In some cases, such episodes may also be characterized by myotonia. In addition, potassium levels may be abnormally increased in the blood (hyperkalemia) during episodes, potentially due to leakage of potassium from muscle. Reports suggest that such attacks may be triggered by exposure to cold temperatures (paramyotonia), rest, hunger, or administration of potassium. Hyperkalemic periodic paralysis is transmitted as an autosomal dominant trait and is due to mutations in the sodium channel gene SCN4A on chromosome 17. In addition, a number of additional neuromuscular disorders have been linked to defects of the SCN4A gene.Rippling muscle disease is a rare genetic disorder in which mechanically triggered contractions of skeletal muscle spread to adjacent muscle fibers, potentially causing visible “rippling” moving over the muscle. Affected individuals may experience myotonia, abnormal stiffness, cramping, and/or pain within certain affected muscles, particularly with exercise, and abnormal muscle enlargement (hypertrophy). The disorder is transmitted as an autosomal dominant trait. There are also a number of rare disease variants, including atypical painful myotonia, that have been described in the medical literature. Their possible relationship with Thomsen and Becker types myotonia congenita remains uncertain, pending further genetic studies. In addition, there are a number of other disorders (e.g., Schwartz Jampel syndrome, myotonic dystrophy) that may be characterized by myotonia, muscle stiffness and/or weakness, abnormal muscle enlargement (hypertrophy), and/or other symptoms similar to those that may occur in association with myotonia congenita. However, such disorders typically have other characteristic features that may differentiate them from Thomsen or Becker disease. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Myotonia Congenita. Symptoms of the following disorders may be similar to those of myotonia congenita. Comparisons may be useful for a differential diagnosis: Paramyotonia congenita is a rare genetic nonprogressive disorder that usually becomes apparent during infancy. The disorder is often characterized by myotonia triggered or aggravated by exposure to cold and alleviated by warm temperatures; in addition, the myotonia is sometimes described as “paradoxic,” since it tends to become more severe rather than to improve with exercise. Some with the disorder may also be affected by episodes of weakness or partial paralysis (paresis) that do not necessarily coincide with exposure to cold temperatures or myotonia. In addition, in some cases, periods of weakness may be induced by the administration of potassium. The disorder is not associated with muscle wasting or hypertrophy. Paramyotonia congenita is a sodium channel disease (sodium channelopathy). It results from mutations of a gene (called SCN4A) that has also been linked to hyperkalemic periodic paralysis (see below). The disease gene has been mapped to the long arm (q) of chromosome 17. Paramyotonia congenita is transmitted as an autosomal dominant trait. (For more information on this disorder, choose “paramyotonia congenita” as your search term in the Rare Disease Database.) Hyperkalemic periodic paralysis is a rare genetic disorder that usually becomes apparent during infancy or childhood. The disorder is characterized by periodic episodes of muscle weakness that tend to occur during the daytime. In some cases, such episodes may also be characterized by myotonia. In addition, potassium levels may be abnormally increased in the blood (hyperkalemia) during episodes, potentially due to leakage of potassium from muscle. Reports suggest that such attacks may be triggered by exposure to cold temperatures (paramyotonia), rest, hunger, or administration of potassium. Hyperkalemic periodic paralysis is transmitted as an autosomal dominant trait and is due to mutations in the sodium channel gene SCN4A on chromosome 17. In addition, a number of additional neuromuscular disorders have been linked to defects of the SCN4A gene.Rippling muscle disease is a rare genetic disorder in which mechanically triggered contractions of skeletal muscle spread to adjacent muscle fibers, potentially causing visible “rippling” moving over the muscle. Affected individuals may experience myotonia, abnormal stiffness, cramping, and/or pain within certain affected muscles, particularly with exercise, and abnormal muscle enlargement (hypertrophy). The disorder is transmitted as an autosomal dominant trait. There are also a number of rare disease variants, including atypical painful myotonia, that have been described in the medical literature. Their possible relationship with Thomsen and Becker types myotonia congenita remains uncertain, pending further genetic studies. In addition, there are a number of other disorders (e.g., Schwartz Jampel syndrome, myotonic dystrophy) that may be characterized by myotonia, muscle stiffness and/or weakness, abnormal muscle enlargement (hypertrophy), and/or other symptoms similar to those that may occur in association with myotonia congenita. However, such disorders typically have other characteristic features that may differentiate them from Thomsen or Becker disease. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Myotonia Congenita
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Myotonia congenita may be diagnosed from infancy or early childhood to adulthood, based upon a thorough clinical evaluation, a detailed patient and family history, various specialized tests, and genetic analysis, if available.In patients with myotonia congenita, clinical examination may reveal an inability to quickly release the hand grip, sustained muscle contraction after direct muscle percussion (percussion myotonia), and other characteristic findings. (During direct muscle percussion, the examining physician may lightly tap the contractile part of muscles with a small, hammerlike instrument [percussor].. In addition, specialized testing that records electrical activity in skeletal muscle at rest and during muscle contraction (electromyography [EMG]) typically demonstrates a repetitive discharge of electrical impulses (action potentials) after forceful contraction (myotonic discharges). According to reports in the medical literature, although people who carry one mutated gene for Becker disease typically do not have symptoms (asymptomatic heterozygous carriers), EMG testing may reveal myotonic discharges in some (particularly male) carriers (subclinical myotonia).In some individuals, recommended diagnostic evaluation may include muscle biopsies. During a muscle biopsy, small samples of muscle tissue are removed and examined microscopically with the use of special stains (histochemistry). However, in those with myotonia congenita, such evaluation typically reveals only minimal abnormal changes (e.g., muscle fiber enlargement in hypertrophied muscle).In some cases of suspected myotonia congenita, additional diagnostic studies may be recommended to help eliminate other diseases with similar symptoms and to confirm the diagnosis.In rare cases, it is possible that laboratory studies in which skeletal muscle tissue is exposed to the anesthetic halothane (halothane contracture testing in vitro) may demonstrate findings consistent with a susceptibility to a malignant hyperthermia-like response.
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Diagnosis of Myotonia Congenita. Myotonia congenita may be diagnosed from infancy or early childhood to adulthood, based upon a thorough clinical evaluation, a detailed patient and family history, various specialized tests, and genetic analysis, if available.In patients with myotonia congenita, clinical examination may reveal an inability to quickly release the hand grip, sustained muscle contraction after direct muscle percussion (percussion myotonia), and other characteristic findings. (During direct muscle percussion, the examining physician may lightly tap the contractile part of muscles with a small, hammerlike instrument [percussor].. In addition, specialized testing that records electrical activity in skeletal muscle at rest and during muscle contraction (electromyography [EMG]) typically demonstrates a repetitive discharge of electrical impulses (action potentials) after forceful contraction (myotonic discharges). According to reports in the medical literature, although people who carry one mutated gene for Becker disease typically do not have symptoms (asymptomatic heterozygous carriers), EMG testing may reveal myotonic discharges in some (particularly male) carriers (subclinical myotonia).In some individuals, recommended diagnostic evaluation may include muscle biopsies. During a muscle biopsy, small samples of muscle tissue are removed and examined microscopically with the use of special stains (histochemistry). However, in those with myotonia congenita, such evaluation typically reveals only minimal abnormal changes (e.g., muscle fiber enlargement in hypertrophied muscle).In some cases of suspected myotonia congenita, additional diagnostic studies may be recommended to help eliminate other diseases with similar symptoms and to confirm the diagnosis.In rare cases, it is possible that laboratory studies in which skeletal muscle tissue is exposed to the anesthetic halothane (halothane contracture testing in vitro) may demonstrate findings consistent with a susceptibility to a malignant hyperthermia-like response.
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Therapies of Myotonia Congenita
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TreatmentThe treatment of Thomsen and Becker types myotonia congenita is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; specialists who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physical therapists; and/or other health care professionals.Specific therapies for the treatment of Thomsen and Becker diseases are symptomatic and supportive. In some cases, certain medications may be prescribed to help diminish muscle stiffness and other symptoms resulting from myotonia. (For more information, see the "Investigational Therapies" section below.) In addition, special exercises may be advised to help alleviate myotonic symptoms, since associated muscle rigidity may improve with proper movement and exercise of involved muscle groups.As discussed earlier, two sisters with Becker type myotonia congenita demonstrated susceptibility to a malignant hyperthermia-like response. Although the implications of this finding are not fully understood, this potential risk must be taken into consideration by surgeons, anesthesiologists, dentists, and other health care workers when making decisions concerning surgery, the use of particular anesthetics, and the administration of certain medications.Early intervention is important to ensure that affected children reach their potential. Special services that may be beneficial include special social support, physical therapy, and/or other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Therapies of Myotonia Congenita. TreatmentThe treatment of Thomsen and Becker types myotonia congenita is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; specialists who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); physical therapists; and/or other health care professionals.Specific therapies for the treatment of Thomsen and Becker diseases are symptomatic and supportive. In some cases, certain medications may be prescribed to help diminish muscle stiffness and other symptoms resulting from myotonia. (For more information, see the "Investigational Therapies" section below.) In addition, special exercises may be advised to help alleviate myotonic symptoms, since associated muscle rigidity may improve with proper movement and exercise of involved muscle groups.As discussed earlier, two sisters with Becker type myotonia congenita demonstrated susceptibility to a malignant hyperthermia-like response. Although the implications of this finding are not fully understood, this potential risk must be taken into consideration by surgeons, anesthesiologists, dentists, and other health care workers when making decisions concerning surgery, the use of particular anesthetics, and the administration of certain medications.Early intervention is important to ensure that affected children reach their potential. Special services that may be beneficial include special social support, physical therapy, and/or other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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Overview of Myotonic Dystrophy
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SummaryMyotonic dystrophy refers to two rare genetic disorders of muscle that actually affect multiple systems of the body. The disorder is abbreviated DM, which is for dystrophia myotonia. This is the Latin name for the disorder. There are two main types DM. DM type 1 (DM1) can be further classified as mild DM1, classic DM1 and congenital DM1. Mild DM1 is characterized by clouding of the lenses of the eyes (cataracts) and sustained muscle contractions (myotonia), in which the muscles do not relax after use. Classic DM1 is characterized by muscle weakness and wasting (atrophy), myotonia, early-onset cataracts (i.e. before the age of 50), and abnormalities in the heart’s conduction of electrical impulses. Congenital DM1 is characterized by muscle weakness (hypotonia), difficulty breathing, intellectual disability and early death. DM type 2 (DM2) causes similar symptoms to DM1, but is generally a less severe disorder and does not cause congenital disease. DM1 is caused by an alteration in the DMPK gene. DM2 is caused by an alteration in the CNBP gene. These alterations are inherited in an autosomal dominant manner.IntroductionDM is a type of muscular dystrophy. The muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. Each disorder is characterized by specific abnormalities (e.g. variation of muscle fiber size, muscle fiber necrosis, scar tissue formation and inflammation) in muscle biopsy from patients. DM1 is also known as Steinert disease, named after Dr. Steinert who, along with colleagues, first described the classic form in the medical literature in 1909. DM2 is also known as Ricker syndrome or proximal myotonic dystrophy or PROMM.
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Overview of Myotonic Dystrophy. SummaryMyotonic dystrophy refers to two rare genetic disorders of muscle that actually affect multiple systems of the body. The disorder is abbreviated DM, which is for dystrophia myotonia. This is the Latin name for the disorder. There are two main types DM. DM type 1 (DM1) can be further classified as mild DM1, classic DM1 and congenital DM1. Mild DM1 is characterized by clouding of the lenses of the eyes (cataracts) and sustained muscle contractions (myotonia), in which the muscles do not relax after use. Classic DM1 is characterized by muscle weakness and wasting (atrophy), myotonia, early-onset cataracts (i.e. before the age of 50), and abnormalities in the heart’s conduction of electrical impulses. Congenital DM1 is characterized by muscle weakness (hypotonia), difficulty breathing, intellectual disability and early death. DM type 2 (DM2) causes similar symptoms to DM1, but is generally a less severe disorder and does not cause congenital disease. DM1 is caused by an alteration in the DMPK gene. DM2 is caused by an alteration in the CNBP gene. These alterations are inherited in an autosomal dominant manner.IntroductionDM is a type of muscular dystrophy. The muscular dystrophies are characterized by weakness and degeneration of various voluntary muscles of the body. Each disorder is characterized by specific abnormalities (e.g. variation of muscle fiber size, muscle fiber necrosis, scar tissue formation and inflammation) in muscle biopsy from patients. DM1 is also known as Steinert disease, named after Dr. Steinert who, along with colleagues, first described the classic form in the medical literature in 1909. DM2 is also known as Ricker syndrome or proximal myotonic dystrophy or PROMM.
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Symptoms of Myotonic Dystrophy
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The signs and symptoms of DM1 or DM2 can vary greatly among affected individuals. This is true even among members of the same family. Many people will not develop all of the symptoms discussed below. Every person is unique and how these disorders affect a person can be very different. In addition, DM1 and DM2 have many symptoms that overlap, but there are also symptoms unique to each disorder, clearly marking them distinct disorders. DM1 can develop at birth (congenital form), during childhood (juvenile form) and during adulthood (adult form). The adult form is the most common form and usually begins in a person’s 30s. Generally, the signs and symptoms of these disorders progress slowly.ADULT-ONSET DM1
This is the most common form of myotonic dystrophy. People may have mild disease or severe complications. Mild DM1 may be associated with cataract, mild myotonia and sometimes diabetes. Men with the mild form have an increased likelihood of going bald. Affected individuals may have fully active lives with little impact on the lifespan or quality of life. Individuals with a more severe form of DM1 (commonly referred to as the classic form) have muscle weakness that most often affects certain muscles including a muscle that elevates the upper eyelid, a muscle that helps people to chew (masticate), a muscle that helps to move the neck, the muscles of the forearm closest to the hands, certain muscles in the hands, and muscles of the lower legs that help to move the ankles. Less often, muscles around the eyes (extraocular), a group of muscles located on the front of the thighs (quadriceps) and various muscles of the respiratory tract are affected. Muscle weakness and wasting is progressive. Muscle pain and fatigue are common.For some people, it may take longer for their muscles to relax after using them (myotonia). This is often described as the muscles stiffening. Myotonia is usually mild or moderate in severity. Two common examples of myotonia are being unable to release a doorknob after opening or shutting a door, or taking a moment to be able to release a person’s hand after shaking hands. Because of weakness of facial muscles, affected individuals may not have facial expressions or have a mask-like facial appearance. Because of weakness of the muscle that elevates the upper eyelids, the eyelids may droop and hang partially in front of the eyes (ptosis). Some individuals may have slurred speech because of weakness of muscles required to speak. Many people with DM1 have conduction defects of the heart. This means that there are problems with the transfer of electrical impulses (conduction) that regulate the normal, rhythmic pumping action of the heart. The normal heart has four chambers. The two upper chambers are the atria and the two lower chambers are the ventricles. Within the right atrium of a normal heart is a natural pacemaker that initiates and controls the heartbeat. The electrical stimulus travels from the pacemaker (sinoatrial or SA node) to the ventricles along a very specific path consisting of conducting tissue and known as the AV (atrioventricular) node. If the electrical impulse is transmitted normally, the heart behaves normally. If the transmission of the signal is impeded, the blocked transmission is known as a heart block or an AV block. People with DM1 may have irregular heartbeats (arrhythmias), disease of the heart muscle (cardiomyopathy), overgrowth of the left ventricle (ventricular hypertrophy). The various heart abnormalities potentially associated with DM1 can lead to life-threatening complications. Weakness of muscles necessary for breathing can occur and can lead to hypoventilation, which is the insufficient exchange of carbon dioxide and oxygen in the lungs. People with hypoventilation breathe at a slower rate and there is an increased about of carbon dioxide in the blood. It is possible for respiratory failure to occur, particularly late in life. Individuals with DM1 can develop problems in the gastrointestinal system. This involves the smooth muscle of the stomach and intestines. Affected individuals may have abdominal pain, gallstones, constipation, diarrhea, loss of bladder control (incontinence), and pseudo-obstruction, which is caused by abnormalities in the involuntary, coordinated muscle contractions (peristalsis) of the gastrointestinal tract. Peristalsis propels food and other material through the digestive system. Because of weakened muscles, peristalsis becomes altered and inefficient. Symptoms of pseudo-obstruction resemble those caused by mechanical obstruction of the small bowel. Mechanical obstruction refers to something (such as a tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. With pseudo-obstruction, no such physical obstruction is present. Common symptoms include nausea, vomiting, abdominal pain, abdominal swelling (distention) and constipation.Some individuals with DM1 have difficulty swallowing (dysphagia). Dysphagia may result in aspiration pneumonia, an infection that develops when food, saliva and bacteria are inhaled into the lungs. This can potentially be a life-threatening complication. Men who have DM1 have changes in hormones that cause balding. Some men are unable to father a child (infertility) due to underdevelopment of the testes (hypogonadism). People with the classic or adult form of DM are also at a greater risk of developing diabetes. Some individuals have problems with their sleep including sleep apnea, and episodes of drowsiness, tiredness and lack of energy during the day (excessive daytime sleepiness). Some individuals have small, benign growths called pilomatrixomas and epitheliomas, particularly on the scalp. Behavioral issues including obsessive-compulsive disorder and passive-aggressive personality have been reported. JUVENILE DM1
Some medical sources classify certain individuals with DM1 as having juvenile DM1. Onset is often before the age of 12. They may or may not have signs of muscle weakness or myotonia. Affected individuals usually have some intellectual and behavioral issues such as learning disabilities and difficulties with socialization at school. Difficulty with speech (dysarthria), hearing problems, and problems with coordination may also occur. Heart issues including heart rhythm disturbances and irregular heartbeats (arrhythmias) have been reported. Heart issues have occurred in adolescents who did not have any other symptoms. CONGENITAL DM1
This is the most severe form of DM. Infants show signs and symptoms of the disorder at birth (congenital) including severe muscle weakness and hypotonia. Hypotonia is when an infant lacks muscles tone; such infants are described as ‘floppy’. Some infants have muscle weakness affecting both sides of the face (facial diplegia). Clubfoot (talipes equinovarus), in which the foot appears to be turned in toward the body, is also common at birth. Some infants have a low clarity of vision (visual acuity), farsightedness (hyperopia), and an abnormal curving of the lenses of the eye (astigmatism), which can contribute to poor or blurred vision. Mild to moderate intellectual disability can also occur in infants and children with congenital DM1. Learning and behavioral disabilities may become apparent as children grow older. Poor feeding is common in affected infants and they often fail to grow and gain weight as expected (failure to thrive). Some infants have gastroparesis, a condition in which there is sluggish emptying of solid food (and more rarely, liquid nutrients) from the stomach. This can result in persistent digestive symptoms, especially nausea.Infants and children with congenital DM1 may have breathing difficulties due to muscle weakness. Breathing difficulties are often severe and can lead to respiratory failure, which is a common cause of mortality in congenital DM1. Infants and children with congenital DM1 who survive early, severe complications will go on and develop symptoms of adult onset DM1 including heart (cardiac) abnormalities. Cardiac issues can begin as early as the second decade of life. In rare instances, severely affected infants can have cardiac abnormalities in the newborn (neonatal) period. MYOTONIC DYSTROPHY TYPE 2 (DM2)
The onset of DM2 is typically in the third decade, but anywhere between the second and sixth decade of life is common. The signs and symptoms are highly variable. The most common symptoms are muscle weakness and pain, myotonia, and cataracts. However, some people will not develop these symptoms. Sometimes, the severity of these symptoms change in a person. For example, myotonia may worsen or improve. Symptoms do not appear in the congenital or juvenile ages.The muscles of the neck and fingers are often the first muscles affected in DM2. Muscle weakness slowly affects other muscles including muscles of the elbows and hips. About one-third of affected individuals develop muscle weakness in the hips after the age of 50. Less commonly affected are facial muscles and muscles of the ankles. The muscles of the thighs are commonly affected and some people may have stiffness and weakness of these muscles when running up stairs. Muscle pain may come and go and can fluctuate in severity. Sometimes, muscle pain can be debilitating. Fatigue is common.In addition to muscle weakness and pain, it may also take longer for the muscles to relax after using them (myotonia). This is often described as the muscles stiffening. Although uncommon, myotonia has been reported to occur as early as the first decade of life. Some individuals with DM2 will not develop myotonia. Cataracts are common and can develop as early as the second decade of life. Affected individuals are at a greater risk than the general population of developing diabetes. Some affected men may be unable to father a child (infertility). Excessive sweating and difficulty swallowing (dysphagia) are also common in DM2. Some people may have problems with concentration, organization and finding the right word when writing or speaking (word finding). Heart (cardiac) abnormalities are less severe in DM2 than in DM1, and they occur with less frequency as well. Conduction defects, irregular heartbeats (arrhythmias), and disease of the heart muscle (cardiomyopathy) are potential complications. Sudden death because of heart abnormalities is possible in some people, but is a rare occurrence.
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Symptoms of Myotonic Dystrophy. The signs and symptoms of DM1 or DM2 can vary greatly among affected individuals. This is true even among members of the same family. Many people will not develop all of the symptoms discussed below. Every person is unique and how these disorders affect a person can be very different. In addition, DM1 and DM2 have many symptoms that overlap, but there are also symptoms unique to each disorder, clearly marking them distinct disorders. DM1 can develop at birth (congenital form), during childhood (juvenile form) and during adulthood (adult form). The adult form is the most common form and usually begins in a person’s 30s. Generally, the signs and symptoms of these disorders progress slowly.ADULT-ONSET DM1
This is the most common form of myotonic dystrophy. People may have mild disease or severe complications. Mild DM1 may be associated with cataract, mild myotonia and sometimes diabetes. Men with the mild form have an increased likelihood of going bald. Affected individuals may have fully active lives with little impact on the lifespan or quality of life. Individuals with a more severe form of DM1 (commonly referred to as the classic form) have muscle weakness that most often affects certain muscles including a muscle that elevates the upper eyelid, a muscle that helps people to chew (masticate), a muscle that helps to move the neck, the muscles of the forearm closest to the hands, certain muscles in the hands, and muscles of the lower legs that help to move the ankles. Less often, muscles around the eyes (extraocular), a group of muscles located on the front of the thighs (quadriceps) and various muscles of the respiratory tract are affected. Muscle weakness and wasting is progressive. Muscle pain and fatigue are common.For some people, it may take longer for their muscles to relax after using them (myotonia). This is often described as the muscles stiffening. Myotonia is usually mild or moderate in severity. Two common examples of myotonia are being unable to release a doorknob after opening or shutting a door, or taking a moment to be able to release a person’s hand after shaking hands. Because of weakness of facial muscles, affected individuals may not have facial expressions or have a mask-like facial appearance. Because of weakness of the muscle that elevates the upper eyelids, the eyelids may droop and hang partially in front of the eyes (ptosis). Some individuals may have slurred speech because of weakness of muscles required to speak. Many people with DM1 have conduction defects of the heart. This means that there are problems with the transfer of electrical impulses (conduction) that regulate the normal, rhythmic pumping action of the heart. The normal heart has four chambers. The two upper chambers are the atria and the two lower chambers are the ventricles. Within the right atrium of a normal heart is a natural pacemaker that initiates and controls the heartbeat. The electrical stimulus travels from the pacemaker (sinoatrial or SA node) to the ventricles along a very specific path consisting of conducting tissue and known as the AV (atrioventricular) node. If the electrical impulse is transmitted normally, the heart behaves normally. If the transmission of the signal is impeded, the blocked transmission is known as a heart block or an AV block. People with DM1 may have irregular heartbeats (arrhythmias), disease of the heart muscle (cardiomyopathy), overgrowth of the left ventricle (ventricular hypertrophy). The various heart abnormalities potentially associated with DM1 can lead to life-threatening complications. Weakness of muscles necessary for breathing can occur and can lead to hypoventilation, which is the insufficient exchange of carbon dioxide and oxygen in the lungs. People with hypoventilation breathe at a slower rate and there is an increased about of carbon dioxide in the blood. It is possible for respiratory failure to occur, particularly late in life. Individuals with DM1 can develop problems in the gastrointestinal system. This involves the smooth muscle of the stomach and intestines. Affected individuals may have abdominal pain, gallstones, constipation, diarrhea, loss of bladder control (incontinence), and pseudo-obstruction, which is caused by abnormalities in the involuntary, coordinated muscle contractions (peristalsis) of the gastrointestinal tract. Peristalsis propels food and other material through the digestive system. Because of weakened muscles, peristalsis becomes altered and inefficient. Symptoms of pseudo-obstruction resemble those caused by mechanical obstruction of the small bowel. Mechanical obstruction refers to something (such as a tumor, scar tissue, etc.) physically blocking the passage of food and other material through the GI tract. With pseudo-obstruction, no such physical obstruction is present. Common symptoms include nausea, vomiting, abdominal pain, abdominal swelling (distention) and constipation.Some individuals with DM1 have difficulty swallowing (dysphagia). Dysphagia may result in aspiration pneumonia, an infection that develops when food, saliva and bacteria are inhaled into the lungs. This can potentially be a life-threatening complication. Men who have DM1 have changes in hormones that cause balding. Some men are unable to father a child (infertility) due to underdevelopment of the testes (hypogonadism). People with the classic or adult form of DM are also at a greater risk of developing diabetes. Some individuals have problems with their sleep including sleep apnea, and episodes of drowsiness, tiredness and lack of energy during the day (excessive daytime sleepiness). Some individuals have small, benign growths called pilomatrixomas and epitheliomas, particularly on the scalp. Behavioral issues including obsessive-compulsive disorder and passive-aggressive personality have been reported. JUVENILE DM1
Some medical sources classify certain individuals with DM1 as having juvenile DM1. Onset is often before the age of 12. They may or may not have signs of muscle weakness or myotonia. Affected individuals usually have some intellectual and behavioral issues such as learning disabilities and difficulties with socialization at school. Difficulty with speech (dysarthria), hearing problems, and problems with coordination may also occur. Heart issues including heart rhythm disturbances and irregular heartbeats (arrhythmias) have been reported. Heart issues have occurred in adolescents who did not have any other symptoms. CONGENITAL DM1
This is the most severe form of DM. Infants show signs and symptoms of the disorder at birth (congenital) including severe muscle weakness and hypotonia. Hypotonia is when an infant lacks muscles tone; such infants are described as ‘floppy’. Some infants have muscle weakness affecting both sides of the face (facial diplegia). Clubfoot (talipes equinovarus), in which the foot appears to be turned in toward the body, is also common at birth. Some infants have a low clarity of vision (visual acuity), farsightedness (hyperopia), and an abnormal curving of the lenses of the eye (astigmatism), which can contribute to poor or blurred vision. Mild to moderate intellectual disability can also occur in infants and children with congenital DM1. Learning and behavioral disabilities may become apparent as children grow older. Poor feeding is common in affected infants and they often fail to grow and gain weight as expected (failure to thrive). Some infants have gastroparesis, a condition in which there is sluggish emptying of solid food (and more rarely, liquid nutrients) from the stomach. This can result in persistent digestive symptoms, especially nausea.Infants and children with congenital DM1 may have breathing difficulties due to muscle weakness. Breathing difficulties are often severe and can lead to respiratory failure, which is a common cause of mortality in congenital DM1. Infants and children with congenital DM1 who survive early, severe complications will go on and develop symptoms of adult onset DM1 including heart (cardiac) abnormalities. Cardiac issues can begin as early as the second decade of life. In rare instances, severely affected infants can have cardiac abnormalities in the newborn (neonatal) period. MYOTONIC DYSTROPHY TYPE 2 (DM2)
The onset of DM2 is typically in the third decade, but anywhere between the second and sixth decade of life is common. The signs and symptoms are highly variable. The most common symptoms are muscle weakness and pain, myotonia, and cataracts. However, some people will not develop these symptoms. Sometimes, the severity of these symptoms change in a person. For example, myotonia may worsen or improve. Symptoms do not appear in the congenital or juvenile ages.The muscles of the neck and fingers are often the first muscles affected in DM2. Muscle weakness slowly affects other muscles including muscles of the elbows and hips. About one-third of affected individuals develop muscle weakness in the hips after the age of 50. Less commonly affected are facial muscles and muscles of the ankles. The muscles of the thighs are commonly affected and some people may have stiffness and weakness of these muscles when running up stairs. Muscle pain may come and go and can fluctuate in severity. Sometimes, muscle pain can be debilitating. Fatigue is common.In addition to muscle weakness and pain, it may also take longer for the muscles to relax after using them (myotonia). This is often described as the muscles stiffening. Although uncommon, myotonia has been reported to occur as early as the first decade of life. Some individuals with DM2 will not develop myotonia. Cataracts are common and can develop as early as the second decade of life. Affected individuals are at a greater risk than the general population of developing diabetes. Some affected men may be unable to father a child (infertility). Excessive sweating and difficulty swallowing (dysphagia) are also common in DM2. Some people may have problems with concentration, organization and finding the right word when writing or speaking (word finding). Heart (cardiac) abnormalities are less severe in DM2 than in DM1, and they occur with less frequency as well. Conduction defects, irregular heartbeats (arrhythmias), and disease of the heart muscle (cardiomyopathy) are potential complications. Sudden death because of heart abnormalities is possible in some people, but is a rare occurrence.
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Myotonic Dystrophy
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Causes of Myotonic Dystrophy
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DM1 is caused by a change or alteration in the myotonic dystrophy protein kinase (DMPK) gene. DM2 is caused by a change or alteration in the nucleic acid-binding protein (CNBP) gene; this gene is also called the ZNF9 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, including the brain.The change or alteration that affects these genes is called a repeat expansion. This means that a segment of DNA in the gene is repeated many times. In DM1, the segment that is repeated contains three building blocks of DNA (nucleotides). This segment is written as CTG and in most people is repeated anywhere from 5 to 34 or 37 times. If this segment is repeated more than 34 times, that is considered abnormal. If a person has between 38-49 CTG repeats, they will usually not develop symptoms, but their children will be at risk of developing myotonic dystrophy. In general, the more repeats there are, the more severe the symptoms will be. For example, people with the mild form of DM1 have fewer repeats than people with classic or congenital forms. People with the congenital form have the most. In DM2, the segment that is repeated contains four building blocks of DNA and is written as CCTG. The number of repeats can range from about 75 to more than 11,000. The mean is approximately 5,000. In DM2 there is no correlation between severity of symptoms and size of the repeat expansion.The DNA repeat expansions seen in DM1 and DM2 do not actually affect the genes they are connected with. Instead they work through a genetic mechanism called “RNA gain of function” in which they interfere with the coding of several other more distant genes such as a muscle chloride channel, an insulin receptor and a cardiac muscle protein gene. This explains the systemic effects of the disease on skeletal muscle, risk for diabetes and heart problems.In addition, DM1 is associated with a phenomenon called “anticipation.” In genetics, anticipation refers to the finding that children of parents with a disorder have symptom onset at a significantly early age and more severe symptoms. This may be partly because the expanded CTG and CCTG repeats are unstable and likely to expand further over time and with successive generations. Researchers have also noted that women with DM are more likely to have a child with congenital DM (the most severe form). The reason for this is not fully understood. There are no reports of anticipation in DM2.DM1 and DM2 are inherited in an autosomal dominant fashion. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Myotonic Dystrophy. DM1 is caused by a change or alteration in the myotonic dystrophy protein kinase (DMPK) gene. DM2 is caused by a change or alteration in the nucleic acid-binding protein (CNBP) gene; this gene is also called the ZNF9 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, including the brain.The change or alteration that affects these genes is called a repeat expansion. This means that a segment of DNA in the gene is repeated many times. In DM1, the segment that is repeated contains three building blocks of DNA (nucleotides). This segment is written as CTG and in most people is repeated anywhere from 5 to 34 or 37 times. If this segment is repeated more than 34 times, that is considered abnormal. If a person has between 38-49 CTG repeats, they will usually not develop symptoms, but their children will be at risk of developing myotonic dystrophy. In general, the more repeats there are, the more severe the symptoms will be. For example, people with the mild form of DM1 have fewer repeats than people with classic or congenital forms. People with the congenital form have the most. In DM2, the segment that is repeated contains four building blocks of DNA and is written as CCTG. The number of repeats can range from about 75 to more than 11,000. The mean is approximately 5,000. In DM2 there is no correlation between severity of symptoms and size of the repeat expansion.The DNA repeat expansions seen in DM1 and DM2 do not actually affect the genes they are connected with. Instead they work through a genetic mechanism called “RNA gain of function” in which they interfere with the coding of several other more distant genes such as a muscle chloride channel, an insulin receptor and a cardiac muscle protein gene. This explains the systemic effects of the disease on skeletal muscle, risk for diabetes and heart problems.In addition, DM1 is associated with a phenomenon called “anticipation.” In genetics, anticipation refers to the finding that children of parents with a disorder have symptom onset at a significantly early age and more severe symptoms. This may be partly because the expanded CTG and CCTG repeats are unstable and likely to expand further over time and with successive generations. Researchers have also noted that women with DM are more likely to have a child with congenital DM (the most severe form). The reason for this is not fully understood. There are no reports of anticipation in DM2.DM1 and DM2 are inherited in an autosomal dominant fashion. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Myotonic Dystrophy
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Affects of Myotonic Dystrophy
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DM1 is estimated to affect about 1 in 8,000-20,000 people in the general population. However, the prevalence of DM1 and DM2 vary greatly among different countries and different ethnic groups. The incidence of DM2 is higher in Germany and Finland. Because some people with DM may go unrecognized or undiagnosed, determining the true frequency of these disorders in the general population is difficult. Researchers have determined that DM is the most common form of adult onset muscular dystrophy.
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Affects of Myotonic Dystrophy. DM1 is estimated to affect about 1 in 8,000-20,000 people in the general population. However, the prevalence of DM1 and DM2 vary greatly among different countries and different ethnic groups. The incidence of DM2 is higher in Germany and Finland. Because some people with DM may go unrecognized or undiagnosed, determining the true frequency of these disorders in the general population is difficult. Researchers have determined that DM is the most common form of adult onset muscular dystrophy.
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Myotonic Dystrophy
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Related disorders of Myotonic Dystrophy
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Symptoms of the following disorders can be similar to those of myotonic dystrophy. Comparisons may be useful for a differential diagnosis.Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals complain of muscle stiffness due to difficulty relaxing certain muscles after contracting them (myotonia) Such symptoms tend to occur when attempting to move certain muscles after rest and the myotonia improves with repeat use of the muscle. In many cases, individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a “herculean” or “body-builder like” appearance. Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. Individuals with Thomsen disease may have myotonia, associated muscle rigidity, and abnormal muscle enlargement that becomes apparent from infancy to approximately two to three years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. Thomsen disease is an autosomal dominant condition. People with Becker disease develop symptoms most commonly between the ages of four and 12 years. As in Thomsen type myotonia congenita, affected individuals develop myotonia, associated muscle rigidity, and abnormal muscle enlargement (hypertrophy). The symptoms tend to remain constant, with little progression. Becker disease is inherited as an autosomal recessive condition. This should not be confused with the mild so-called “Becker type” of Duchenne muscular dystrophy, a completely different disease. (For more information on this disorder, choose “Myotonia Congenita” as your search term in the Rare Disease Database.) Paramyotonia congenita (PMC) is a rare non-progressive genetic disorder that affects the skeletal muscles. The disorder typically begins in infancy or early childhood. Affected individuals experience spells of muscle stiffness or when the muscles do not relax after contracting (myotonia). Symptoms can be triggered by exposure to the cold or after physical activity. The stiffness most commonly affects the muscles in the neck, face, arms and hands, however it can occur in the lower back and the muscles used for breathing. The stiffness of the muscles can get worse with repeated movements. There are also intermittent periods of a type of muscle weakness in which there is no muscle tone (flaccid paresis). This condition does not necessarily coincide with exposure to cold temperatures or myotonia. There is generally no wasting (atrophy) of muscles; however, there is often increase in bulk (hypertrophy) of muscles with this disorder. There is no cure to PMC; however, with the proper management of diet, lifestyle and medication, patients can lead normal lives. PMC is an autosomal dominant genetic condition caused by a mutation in the muscle sodium channel gene SCN4A. (For more information on this disorder, choose “Paramyotonia Congenita” as your search term in the Rare Disease Database.)Hypokalemic periodic paralysis is an autosomal dominant genetic condition typically detected in the first decade of life. The major symptom in hypokalemic periodic paralysis is periodic muscle weakness without muscle stiffness. Patients may have attacks once a week or once a day. Typically, the periods of muscle weakness last from hours to a couple days. This weakness may affect muscles of the arms and legs but typically not the speech and swallow or breathing muscles. Periods of muscle weakness are associated with low blood potassium levels and usually follow rest after exercise, large carbohydrate meals, infection, and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.Several other disorders need to be differentiated from myotonic dystrophy. These disorders include GNE-related myopathy, myofibrillar myopathy, limb-girdle muscular dystrophies, spinal muscular atrophy, Andersen-Tawil syndrome, and cerebral palsy. (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 Myotonic Dystrophy. Symptoms of the following disorders can be similar to those of myotonic dystrophy. Comparisons may be useful for a differential diagnosis.Myotonia congenita is a rare genetic disorder in which an abnormality of voluntary (skeletal) muscle fiber membranes causes an unusually exaggerated response to stimulation (hyperexcitability). As a result, affected individuals complain of muscle stiffness due to difficulty relaxing certain muscles after contracting them (myotonia) Such symptoms tend to occur when attempting to move certain muscles after rest and the myotonia improves with repeat use of the muscle. In many cases, individuals with myotonia congenita also have abnormal enlargement of the muscles (hypertrophy), resulting in a “herculean” or “body-builder like” appearance. Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. Individuals with Thomsen disease may have myotonia, associated muscle rigidity, and abnormal muscle enlargement that becomes apparent from infancy to approximately two to three years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. Thomsen disease is an autosomal dominant condition. People with Becker disease develop symptoms most commonly between the ages of four and 12 years. As in Thomsen type myotonia congenita, affected individuals develop myotonia, associated muscle rigidity, and abnormal muscle enlargement (hypertrophy). The symptoms tend to remain constant, with little progression. Becker disease is inherited as an autosomal recessive condition. This should not be confused with the mild so-called “Becker type” of Duchenne muscular dystrophy, a completely different disease. (For more information on this disorder, choose “Myotonia Congenita” as your search term in the Rare Disease Database.) Paramyotonia congenita (PMC) is a rare non-progressive genetic disorder that affects the skeletal muscles. The disorder typically begins in infancy or early childhood. Affected individuals experience spells of muscle stiffness or when the muscles do not relax after contracting (myotonia). Symptoms can be triggered by exposure to the cold or after physical activity. The stiffness most commonly affects the muscles in the neck, face, arms and hands, however it can occur in the lower back and the muscles used for breathing. The stiffness of the muscles can get worse with repeated movements. There are also intermittent periods of a type of muscle weakness in which there is no muscle tone (flaccid paresis). This condition does not necessarily coincide with exposure to cold temperatures or myotonia. There is generally no wasting (atrophy) of muscles; however, there is often increase in bulk (hypertrophy) of muscles with this disorder. There is no cure to PMC; however, with the proper management of diet, lifestyle and medication, patients can lead normal lives. PMC is an autosomal dominant genetic condition caused by a mutation in the muscle sodium channel gene SCN4A. (For more information on this disorder, choose “Paramyotonia Congenita” as your search term in the Rare Disease Database.)Hypokalemic periodic paralysis is an autosomal dominant genetic condition typically detected in the first decade of life. The major symptom in hypokalemic periodic paralysis is periodic muscle weakness without muscle stiffness. Patients may have attacks once a week or once a day. Typically, the periods of muscle weakness last from hours to a couple days. This weakness may affect muscles of the arms and legs but typically not the speech and swallow or breathing muscles. Periods of muscle weakness are associated with low blood potassium levels and usually follow rest after exercise, large carbohydrate meals, infection, and/or emotional stress. Permanent weakness and wasting of muscles may develop later on.Several other disorders need to be differentiated from myotonic dystrophy. These disorders include GNE-related myopathy, myofibrillar myopathy, limb-girdle muscular dystrophies, spinal muscular atrophy, Andersen-Tawil syndrome, and cerebral palsy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Myotonic Dystrophy
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Diagnosis of Myotonic Dystrophy
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A diagnosis of myotonic dystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient and family history, and identification of characteristic physical findings. A family history of muscle weakness and myotonia is a strong indicator of a diagnosis for DM. Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis of DM1 or DM2. Molecular genetic testing looks for changes or alterations in the DMPK gene known to cause DM1, or in the CNBP gene for DM2. However, this testing is available only as a diagnostic service at specialized laboratories.An electromyography (EMG) is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. An EMG can demonstrate characteristic changes that indicate the presence of myotonia or myopathy. This was a common test for DM before molecular genetic testing was developed. The EMG changes are not specific for DM1 or DM2.Individuals with DM may have mildly or moderately elevated levels of a muscle enzyme called creatine kinase or CK in their blood serum. Some individuals have low levels of immunoglobulin G. Immunoglobulins are specialized proteins produced by certain white blood cells. They play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells.A specialized imaging technique called magnetic resonance imaging or MRI can be used to create images of the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In DM, this can show characteristic changes in the brain including degeneration (atrophy) of the cerebellum, the area of the brain that controls movement and balance. Liver function tests may show elevated levels of liver enzymes in some people. The cause of this elevation is unknown. The liver function test abnormalities in DM1 and DM2 may be misinterpreted as a sign of hepatitis or other liver disease.
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Diagnosis of Myotonic Dystrophy. A diagnosis of myotonic dystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient and family history, and identification of characteristic physical findings. A family history of muscle weakness and myotonia is a strong indicator of a diagnosis for DM. Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis of DM1 or DM2. Molecular genetic testing looks for changes or alterations in the DMPK gene known to cause DM1, or in the CNBP gene for DM2. However, this testing is available only as a diagnostic service at specialized laboratories.An electromyography (EMG) is a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. An EMG can demonstrate characteristic changes that indicate the presence of myotonia or myopathy. This was a common test for DM before molecular genetic testing was developed. The EMG changes are not specific for DM1 or DM2.Individuals with DM may have mildly or moderately elevated levels of a muscle enzyme called creatine kinase or CK in their blood serum. Some individuals have low levels of immunoglobulin G. Immunoglobulins are specialized proteins produced by certain white blood cells. They play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells.A specialized imaging technique called magnetic resonance imaging or MRI can be used to create images of the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In DM, this can show characteristic changes in the brain including degeneration (atrophy) of the cerebellum, the area of the brain that controls movement and balance. Liver function tests may show elevated levels of liver enzymes in some people. The cause of this elevation is unknown. The liver function test abnormalities in DM1 and DM2 may be misinterpreted as a sign of hepatitis or other liver disease.
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Myotonic Dystrophy
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nord_856_6
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Therapies of Myotonic Dystrophy
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There is no cure yet for myotonic dystrophy, but researchers are studying ways to help people with these disorders. Current 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 who assess and treat problems of the skeleton and associated muscles and joints (orthopedists), specialists who assess and treat problems of the brain and central nervous system (neurologists), specialists who assess and treat problems of the heart (cardiologists), specialists who assess and treat problems of the lungs (pulmonologists), specialists who asses and treat eye problems (ophthalmologists), speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is of benefit for affected individuals and their families. There is no specific treatment for muscle weakness. Physical and occupational therapy can be of benefit. Some individuals may need braces, ankles supports, or walkers. In severe instances, a wheelchair may become necessary. Children with skeletal malformations may require orthopedic surgery. These interventions are commonly needed in DM1 than DM2. Myotonia is usually not severe enough to require treatment. However, certain medications have been reported in the medical literature as being effective. The most commonly used is mexiletine which has been shown to be moderately effective. (See Investigational Therapies below) Pain medications are sometimes recommended. A variety of medications have been used including nonsteroidal anti-inflammatories (NSAIDs), gabapentin, tricyclic antidepressants, mexiletine, and low-doses of glucocorticoids such as prednisone. Cataracts can be removed surgically if they affect vision. However, there have been reports that cataracts can recur after removal. Drooping of the upper eyelid (ptosis) can be treated by an eyelid crutch, which is a small device added onto to existing glasses to prop the eyelid up. Sometimes blepharoplasty is required. This surgery involves removing excess muscle, fat and other tissue. Some people with breathing problems during sleep may require non-invasive ventilation, which involves breathing support with a mask or similar device. Some individuals have a pacemaker or implantable cardioverter defibrillator (ICD). A pacemaker sends pulses to speed up a heart when there is an abnormally slow heartbeat or rhythm. An ICD sends a shock to the heart if it is beating irregularly in order to return the heartbeat to normal. Some infants with congenital DM1 require ongoing breathing support with a machine. Some infants require a gastronomy tube, which is a thin tube that is inserted directly into the stomach through a small surgical opening. This ensures that infants receive the required nutrients, but avoid the risk of aspiration. Some affected individuals may develop hypothyroidism, a condition characterized by underactivity of the thyroid gland. This means that the thyroid produces low levels of thyroid hormone. Hypothyroidism has been shown to worsen myotonic dystrophy. Hypothyroidism is treated by medications that replace the activity of the underproduced hormones. Men who experience hypogonadism are treated with hormone replacement therapy. People with DM1 are at risk for complications involving the use of anesthesia. Close consultation among the medical team and the anesthesiologist should be recommended before a person with DM1 undergoes any procedure that requires anesthesia. An anesthesiologist experienced with treating individuals with muscle disorders like DM1 is recommended.
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Therapies of Myotonic Dystrophy. There is no cure yet for myotonic dystrophy, but researchers are studying ways to help people with these disorders. Current 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 who assess and treat problems of the skeleton and associated muscles and joints (orthopedists), specialists who assess and treat problems of the brain and central nervous system (neurologists), specialists who assess and treat problems of the heart (cardiologists), specialists who assess and treat problems of the lungs (pulmonologists), specialists who asses and treat eye problems (ophthalmologists), speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is of benefit for affected individuals and their families. There is no specific treatment for muscle weakness. Physical and occupational therapy can be of benefit. Some individuals may need braces, ankles supports, or walkers. In severe instances, a wheelchair may become necessary. Children with skeletal malformations may require orthopedic surgery. These interventions are commonly needed in DM1 than DM2. Myotonia is usually not severe enough to require treatment. However, certain medications have been reported in the medical literature as being effective. The most commonly used is mexiletine which has been shown to be moderately effective. (See Investigational Therapies below) Pain medications are sometimes recommended. A variety of medications have been used including nonsteroidal anti-inflammatories (NSAIDs), gabapentin, tricyclic antidepressants, mexiletine, and low-doses of glucocorticoids such as prednisone. Cataracts can be removed surgically if they affect vision. However, there have been reports that cataracts can recur after removal. Drooping of the upper eyelid (ptosis) can be treated by an eyelid crutch, which is a small device added onto to existing glasses to prop the eyelid up. Sometimes blepharoplasty is required. This surgery involves removing excess muscle, fat and other tissue. Some people with breathing problems during sleep may require non-invasive ventilation, which involves breathing support with a mask or similar device. Some individuals have a pacemaker or implantable cardioverter defibrillator (ICD). A pacemaker sends pulses to speed up a heart when there is an abnormally slow heartbeat or rhythm. An ICD sends a shock to the heart if it is beating irregularly in order to return the heartbeat to normal. Some infants with congenital DM1 require ongoing breathing support with a machine. Some infants require a gastronomy tube, which is a thin tube that is inserted directly into the stomach through a small surgical opening. This ensures that infants receive the required nutrients, but avoid the risk of aspiration. Some affected individuals may develop hypothyroidism, a condition characterized by underactivity of the thyroid gland. This means that the thyroid produces low levels of thyroid hormone. Hypothyroidism has been shown to worsen myotonic dystrophy. Hypothyroidism is treated by medications that replace the activity of the underproduced hormones. Men who experience hypogonadism are treated with hormone replacement therapy. People with DM1 are at risk for complications involving the use of anesthesia. Close consultation among the medical team and the anesthesiologist should be recommended before a person with DM1 undergoes any procedure that requires anesthesia. An anesthesiologist experienced with treating individuals with muscle disorders like DM1 is recommended.
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Myotonic Dystrophy
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nord_857_0
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Overview of N-Acetylglutamate Synthetase Deficiency
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SummaryIntroductionThe urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.
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Overview of N-Acetylglutamate Synthetase Deficiency. SummaryIntroductionThe urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.
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N-Acetylglutamate Synthetase Deficiency
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