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nord_300_0 | Overview of Congenital Central Hypoventilation Syndrome | SummaryCongenital central hypoventilation syndrome (CCHS) is a rare lifelong and life-threatening disorder. CCHS affects the central and autonomic nervous system which controls many of the automatic functions in the body such as heart rate, blood pressure, sensing of oxygen and carbon dioxide levels in the blood, temperature, bowel and bladder control, and more. The most recognized symptom of CCHS is the inability to control breathing that varies in severity, resulting in the need for life-long ventilatory support during sleep in some patients or all the time in others. There are estimated to be 1000 – 1200 cases of CCHS world-wide. CCHS affects males and females equally. Currently, there is no cure for CCHS.IntroductionThe underlying cause of CCHS is mutation in the PHOX2B gene. Most children with CCHS have mutations of the PHOX2B gene called poly-alanine repeat expansion mutations (PARMs). Some children with CCHS have different mutations in the PHOX2B gene not related to PARMs called non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein. See the Causes section for more information. | Overview of Congenital Central Hypoventilation Syndrome. SummaryCongenital central hypoventilation syndrome (CCHS) is a rare lifelong and life-threatening disorder. CCHS affects the central and autonomic nervous system which controls many of the automatic functions in the body such as heart rate, blood pressure, sensing of oxygen and carbon dioxide levels in the blood, temperature, bowel and bladder control, and more. The most recognized symptom of CCHS is the inability to control breathing that varies in severity, resulting in the need for life-long ventilatory support during sleep in some patients or all the time in others. There are estimated to be 1000 – 1200 cases of CCHS world-wide. CCHS affects males and females equally. Currently, there is no cure for CCHS.IntroductionThe underlying cause of CCHS is mutation in the PHOX2B gene. Most children with CCHS have mutations of the PHOX2B gene called poly-alanine repeat expansion mutations (PARMs). Some children with CCHS have different mutations in the PHOX2B gene not related to PARMs called non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein. See the Causes section for more information. | 300 | Congenital Central Hypoventilation Syndrome |
nord_300_1 | Symptoms of Congenital Central Hypoventilation Syndrome | Respiratory system
The hallmark of CCHS is reduced or shallow breathing due to dysregulation of the respiratory drive. In general, reduced and shallow breathing is most apparent in non–REM sleep, but breathing is also abnormal during REM sleep and wakefulness, although usually to a milder degree. Individuals with CCHS also cannot sense oxygen or carbon dioxide levels in their body, which results in discoloration of their skin and lips, indicating that oxygen levels in the body are low. Low oxygen levels can cause increased risk for organ damage, especially to the brain. Thus, it is important to optimize oxygenation and ventilation in these patients. Depending on the severity of CCHS, the degree of life-long ventilatory support can vary from sleep only to constant support.Adequate ventilation is essential to ensure optimal growth and development of CCHS patients. Ventilation can be managed with a mechanical ventilator via tracheostomy or masks, or using phrenic pacemakers. Monitoring both oxygen saturations and CO2 using end-tidal capnography at home helps ensure adequate ventilation in all conditions (sleep, awake, during illness and growth spurts). The support of experienced at-home nursing care will help families continue functioning at home. Ventilatory needs vary greatly across mutations, and sometimes within the same mutation. Appropriate ventilation for each child is essential to ensure optimal developmental outcomes. Because of the CCHS patient’s inability to sense changes in CO2, as well as O2, supplemental oxygen alone is not adequate for treating the individual with CCHS, and can mask elevated CO2 levels when both are not monitored.Cardiovascular system
Cardiac asystoles (heart stops beating) have been noted in several PARM mutations, and should be monitored extensively and actively throughout CCHS patients’ lives. This can include, but not be limited to regular extended Holter monitoring, implantable loop recorders, etc. CCHS patients do not sense cardiac pauses and are often asymptomatic until a life-threatening event occurs (loss of consciousness, sudden death). Within the CCHS community, children across many PARM mutations have demonstrated need for cardiac pacemaker implantation, even at a young age.Additional cardiovascular symptoms of CCHS include altered temperature regulation, altered heart rate variability, altered blood pressure regulation, and poor circulation that may only be apparent under stressors such as illness or surgery.Digestive system
Both PARM and NPARM CCHS patients can present with alterations in their digestive system. Mild symptoms can be reflux and poor upper GI motility. Other patients can present with Hirschsprung’s disease (HD). HD is more often present in NPARMs or higher PARM expansions. Reflux is often treated via medication, while poor upper GI motility may often be managed with therapy and altered diets. Surgical treatment is required for HD.Ophthalmology
Some children with CCHS have been identified with ophthalmological problems associated with CCHS. These include, strabismus, abnormal pupil dilation, the need to wear corrective lenses, as well as Marcus Gunn jaw-winking syndrome and absent or reduced depth perception. Management can range from corrective lenses, wearing sunglasses when outside to surgical procedures.Endocrine system
The endocrine system can be affected by mutations in the PHOX2B gene. The most commonly noted are growth hormone deficiency and congenital hyperinsulinemia.Cancer
Patients with CCHS can develop tumors of neural crest origin, such as ganglioneuromas, ganglioneurblastomas, and neuroblastomas. Treatment for these tumors involves surgery followed by chemotherapy, if needed.The 2010 ATS Statement recommends that CCHS children with 20/29-20/33 PARM mutations as well as those with NPARMs should be screened at diagnosis of CCHS and with advancing age for neural crest tumors. | Symptoms of Congenital Central Hypoventilation Syndrome. Respiratory system
The hallmark of CCHS is reduced or shallow breathing due to dysregulation of the respiratory drive. In general, reduced and shallow breathing is most apparent in non–REM sleep, but breathing is also abnormal during REM sleep and wakefulness, although usually to a milder degree. Individuals with CCHS also cannot sense oxygen or carbon dioxide levels in their body, which results in discoloration of their skin and lips, indicating that oxygen levels in the body are low. Low oxygen levels can cause increased risk for organ damage, especially to the brain. Thus, it is important to optimize oxygenation and ventilation in these patients. Depending on the severity of CCHS, the degree of life-long ventilatory support can vary from sleep only to constant support.Adequate ventilation is essential to ensure optimal growth and development of CCHS patients. Ventilation can be managed with a mechanical ventilator via tracheostomy or masks, or using phrenic pacemakers. Monitoring both oxygen saturations and CO2 using end-tidal capnography at home helps ensure adequate ventilation in all conditions (sleep, awake, during illness and growth spurts). The support of experienced at-home nursing care will help families continue functioning at home. Ventilatory needs vary greatly across mutations, and sometimes within the same mutation. Appropriate ventilation for each child is essential to ensure optimal developmental outcomes. Because of the CCHS patient’s inability to sense changes in CO2, as well as O2, supplemental oxygen alone is not adequate for treating the individual with CCHS, and can mask elevated CO2 levels when both are not monitored.Cardiovascular system
Cardiac asystoles (heart stops beating) have been noted in several PARM mutations, and should be monitored extensively and actively throughout CCHS patients’ lives. This can include, but not be limited to regular extended Holter monitoring, implantable loop recorders, etc. CCHS patients do not sense cardiac pauses and are often asymptomatic until a life-threatening event occurs (loss of consciousness, sudden death). Within the CCHS community, children across many PARM mutations have demonstrated need for cardiac pacemaker implantation, even at a young age.Additional cardiovascular symptoms of CCHS include altered temperature regulation, altered heart rate variability, altered blood pressure regulation, and poor circulation that may only be apparent under stressors such as illness or surgery.Digestive system
Both PARM and NPARM CCHS patients can present with alterations in their digestive system. Mild symptoms can be reflux and poor upper GI motility. Other patients can present with Hirschsprung’s disease (HD). HD is more often present in NPARMs or higher PARM expansions. Reflux is often treated via medication, while poor upper GI motility may often be managed with therapy and altered diets. Surgical treatment is required for HD.Ophthalmology
Some children with CCHS have been identified with ophthalmological problems associated with CCHS. These include, strabismus, abnormal pupil dilation, the need to wear corrective lenses, as well as Marcus Gunn jaw-winking syndrome and absent or reduced depth perception. Management can range from corrective lenses, wearing sunglasses when outside to surgical procedures.Endocrine system
The endocrine system can be affected by mutations in the PHOX2B gene. The most commonly noted are growth hormone deficiency and congenital hyperinsulinemia.Cancer
Patients with CCHS can develop tumors of neural crest origin, such as ganglioneuromas, ganglioneurblastomas, and neuroblastomas. Treatment for these tumors involves surgery followed by chemotherapy, if needed.The 2010 ATS Statement recommends that CCHS children with 20/29-20/33 PARM mutations as well as those with NPARMs should be screened at diagnosis of CCHS and with advancing age for neural crest tumors. | 300 | Congenital Central Hypoventilation Syndrome |
nord_300_2 | Causes of Congenital Central Hypoventilation Syndrome | The underlying cause of CCHS is a change (mutation) in the PHOX2B gene, a key player in the prenatal development of the nervous system. The majority of individuals with CCHS (~90%) have mutations in exon 3 of the PHOX2B gene that normally has a repeat of 20 alanines. These mutations cause an increase in the number of these alanine repeats from the normal 20 alanines to a range of 24 to 33 alanines and are called poly-alanine repeat expansion mutations (PARMs). The remaining individuals with CCHS have different mutations in the PHOX2B gene not related to PARMs including missense, nonsense, frameshift, or stop codon mutations. These are non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein, and the variations in these mutations result in the broad range of symptoms and differing degrees of severity encountered among individuals with CCHS.CCHS is a dominant genetic condition, meaning only one PHOX2B gene needs to contain a mutation to result in the phenotypic presentation of CCHS. Although most genetic diseases are inherited from parents, the majority of CCHS cases are spontaneous in nature. The rate of inheritance of CCHS from a parent who has CCHS is believed to be 50%. Mosaic parents have been identified within the CCHS population, but this is still extremely rare. Parents who wish to have additional children after having a child with CCHS are encouraged to seek genetic counseling. PHOX2B mutations are stable in transmission from one generation to the next, but penetrance and phenotype can still vary significantly. | Causes of Congenital Central Hypoventilation Syndrome. The underlying cause of CCHS is a change (mutation) in the PHOX2B gene, a key player in the prenatal development of the nervous system. The majority of individuals with CCHS (~90%) have mutations in exon 3 of the PHOX2B gene that normally has a repeat of 20 alanines. These mutations cause an increase in the number of these alanine repeats from the normal 20 alanines to a range of 24 to 33 alanines and are called poly-alanine repeat expansion mutations (PARMs). The remaining individuals with CCHS have different mutations in the PHOX2B gene not related to PARMs including missense, nonsense, frameshift, or stop codon mutations. These are non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein, and the variations in these mutations result in the broad range of symptoms and differing degrees of severity encountered among individuals with CCHS.CCHS is a dominant genetic condition, meaning only one PHOX2B gene needs to contain a mutation to result in the phenotypic presentation of CCHS. Although most genetic diseases are inherited from parents, the majority of CCHS cases are spontaneous in nature. The rate of inheritance of CCHS from a parent who has CCHS is believed to be 50%. Mosaic parents have been identified within the CCHS population, but this is still extremely rare. Parents who wish to have additional children after having a child with CCHS are encouraged to seek genetic counseling. PHOX2B mutations are stable in transmission from one generation to the next, but penetrance and phenotype can still vary significantly. | 300 | Congenital Central Hypoventilation Syndrome |
nord_300_3 | Affects of Congenital Central Hypoventilation Syndrome | CCHS is a rare disorder that affects females and males in equal numbers. Though the mutation is already present before birth, in milder cases the diagnosis may be missed until after the newborn period. Some affected individuals will not be identified until after receiving sedation, anesthesia, or anti-seizure medications, making it especially important to educate health care personnel about CCHS and to have a high index of suspicion for considering a diagnosis of CCHS. As of 2013, more than 1,000 cases are known worldwide. The birth prevalence of CCHS has been extrapolated from incidence figures and general birth rates, but the true prevalence is unknown as culturally diverse large population based studies have not been reported. Because the milder cases of CCHS may go unrecognized or misdiagnosed, it is difficult to estimate the true frequency of CCHS in the general population, though the anticipation is far greater than the current estimate. | Affects of Congenital Central Hypoventilation Syndrome. CCHS is a rare disorder that affects females and males in equal numbers. Though the mutation is already present before birth, in milder cases the diagnosis may be missed until after the newborn period. Some affected individuals will not be identified until after receiving sedation, anesthesia, or anti-seizure medications, making it especially important to educate health care personnel about CCHS and to have a high index of suspicion for considering a diagnosis of CCHS. As of 2013, more than 1,000 cases are known worldwide. The birth prevalence of CCHS has been extrapolated from incidence figures and general birth rates, but the true prevalence is unknown as culturally diverse large population based studies have not been reported. Because the milder cases of CCHS may go unrecognized or misdiagnosed, it is difficult to estimate the true frequency of CCHS in the general population, though the anticipation is far greater than the current estimate. | 300 | Congenital Central Hypoventilation Syndrome |
nord_300_4 | Related disorders of Congenital Central Hypoventilation Syndrome | The following disorders might be considered in the differential diagnosis of CCHS:Before the opportunity for genetic testing to confirm CCHS, and the description of the characteristic facies in CCHS, the diagnosis was essentially one of exclusion. CCHS was diagnosed in the absence of primary lung, cardiac, neuromuscular, or causative brainstem abnormalities. Even those diagnoses listed below do not have the anticipated phenotype of CCHS including symptoms of autonomic dysregulation and a PHOX2B gene mutation.Congenital myopathy is a term for any muscle disorder present at birth. By this definition the congenital myopathies could include hundreds of distinct neuromuscular syndromes and disorders. In general, congenital myopathies cause loss of muscle tone and muscle weakness in infancy and delayed motor milestones, such as walking, later in childhood. Three distinct disorders are definitively classified as congenital myopathies: central core disease, nemaline rod myopathy, and centronuclear (myotubular) myopathy.Congenital myasthenia usually occurs in infants but may become evident in adulthood. Associated features may vary in severity from person to person. Such abnormalities may include feeding difficulties, periods with absence of spontaneous breathing (apnea), failure to grow and gain weight at the expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and/or other abnormalities.Moebius syndrome is a rare developmental disorder that may have a number of different causes and is characterized by facial paralysis present at birth (congenital). Facial nerve development is absent or diminished causing abnormalities of the facial muscles and jaw. Additional symptoms may include numerous abnormalities of the mouth and face (orofacial region) and potentially malformations of limbs. Intellectual disability occurs in approximately 10 percent of patients. (For more information on this disorder, choose “Moebius” as your search term in the Rare Disease Database.)When CCHS occurs in adults it may be confused with other more common respiratory diseases such as obstructive sleep apnea unresponsive to traditional management. Notably individuals with CCHS, regardless of age at presentation/diagnosis, will not have shortness of breath as they do not perceive low oxygen or elevated carbon dioxide. After the airway obstruction has been treated, the hypoventilation becomes more apparent. Among adults in whom a diagnosis of CCHS is considered, a careful family tree asking about offspring with CCHS should be obtained.Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a related but separate disorder. Children with ROHHAD typically present between the ages of 1.5 and 7 years of age with a rapid weight gain of 20 or more pounds over a 6 month period. They are then noted to have symptoms of hypothalamic dysfunction such as water imbalance, growth insufficiency, hypothyroidism, cortisol abnormalities, and more. A subset of the cases of ROHHAD will experience a respiratory arrest early in their course but subsequent to another illness. Many of the children with ROHHAD will have obstructive sleep apnea and once this is treated, the children will be noted to have hypoventilation, even among those who did not endure a cardiorespiratory arrest. Children with ROHHAD do not have CCHS-related mutations in the PHOX2B gene. The genetic basis for ROHHAD is not yet known. (For more information on this disorder, choose “ROHHAD” as your search term in the Rare Disease Database.) | Related disorders of Congenital Central Hypoventilation Syndrome. The following disorders might be considered in the differential diagnosis of CCHS:Before the opportunity for genetic testing to confirm CCHS, and the description of the characteristic facies in CCHS, the diagnosis was essentially one of exclusion. CCHS was diagnosed in the absence of primary lung, cardiac, neuromuscular, or causative brainstem abnormalities. Even those diagnoses listed below do not have the anticipated phenotype of CCHS including symptoms of autonomic dysregulation and a PHOX2B gene mutation.Congenital myopathy is a term for any muscle disorder present at birth. By this definition the congenital myopathies could include hundreds of distinct neuromuscular syndromes and disorders. In general, congenital myopathies cause loss of muscle tone and muscle weakness in infancy and delayed motor milestones, such as walking, later in childhood. Three distinct disorders are definitively classified as congenital myopathies: central core disease, nemaline rod myopathy, and centronuclear (myotubular) myopathy.Congenital myasthenia usually occurs in infants but may become evident in adulthood. Associated features may vary in severity from person to person. Such abnormalities may include feeding difficulties, periods with absence of spontaneous breathing (apnea), failure to grow and gain weight at the expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and/or other abnormalities.Moebius syndrome is a rare developmental disorder that may have a number of different causes and is characterized by facial paralysis present at birth (congenital). Facial nerve development is absent or diminished causing abnormalities of the facial muscles and jaw. Additional symptoms may include numerous abnormalities of the mouth and face (orofacial region) and potentially malformations of limbs. Intellectual disability occurs in approximately 10 percent of patients. (For more information on this disorder, choose “Moebius” as your search term in the Rare Disease Database.)When CCHS occurs in adults it may be confused with other more common respiratory diseases such as obstructive sleep apnea unresponsive to traditional management. Notably individuals with CCHS, regardless of age at presentation/diagnosis, will not have shortness of breath as they do not perceive low oxygen or elevated carbon dioxide. After the airway obstruction has been treated, the hypoventilation becomes more apparent. Among adults in whom a diagnosis of CCHS is considered, a careful family tree asking about offspring with CCHS should be obtained.Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a related but separate disorder. Children with ROHHAD typically present between the ages of 1.5 and 7 years of age with a rapid weight gain of 20 or more pounds over a 6 month period. They are then noted to have symptoms of hypothalamic dysfunction such as water imbalance, growth insufficiency, hypothyroidism, cortisol abnormalities, and more. A subset of the cases of ROHHAD will experience a respiratory arrest early in their course but subsequent to another illness. Many of the children with ROHHAD will have obstructive sleep apnea and once this is treated, the children will be noted to have hypoventilation, even among those who did not endure a cardiorespiratory arrest. Children with ROHHAD do not have CCHS-related mutations in the PHOX2B gene. The genetic basis for ROHHAD is not yet known. (For more information on this disorder, choose “ROHHAD” as your search term in the Rare Disease Database.) | 300 | Congenital Central Hypoventilation Syndrome |
nord_300_5 | Diagnosis of Congenital Central Hypoventilation Syndrome | Along with early recognition of the clinical features of CCHS, the gold standard test to diagnose CCHS is genetic testing to identify mutations in the PHOX2B gene, including PARMs, NPARMs, or deletions and duplications.
PHOX2B gene testing is appropriate for:Please contact the CCHS Family Network for additional information about genetic testing:
http://www.cchsnetwork.org/ | Diagnosis of Congenital Central Hypoventilation Syndrome. Along with early recognition of the clinical features of CCHS, the gold standard test to diagnose CCHS is genetic testing to identify mutations in the PHOX2B gene, including PARMs, NPARMs, or deletions and duplications.
PHOX2B gene testing is appropriate for:Please contact the CCHS Family Network for additional information about genetic testing:
http://www.cchsnetwork.org/ | 300 | Congenital Central Hypoventilation Syndrome |
nord_300_6 | Therapies of Congenital Central Hypoventilation Syndrome | A multidisciplinary team approach to the management of CCHS is essential to ensuring proper ventilation and development of children with CCHS. Local children’s hospitals may be sufficient in the management of CCHS. In complex cases, CCHS specialists (listed below) can be found throughout the world and can be consulted, or seen for management of CCHS. Primary team members who play an active role in patient management should include: the primary caregivers (parents or family members), pulmonologists, cardiologists, ENT physicians, gastroenterologists, endocrinologists, neurologists, ophthalmologists, social workers, and speech/language pathologists (SLPs).Early detection and management of CCHS with adequate ventilation and appropriate therapies have helped CCHS patients live fulfilling lives. Proper management has allowed CCHS patients to seek higher education, enter the work force and have families of their ownPlease refer to the Signs and Symptoms section for additional information.Clinical Testing and Work-Up
The 2010 American Thoracic Society (ATS) statement on CCHS recommends that CCHS patients undergo annual assessment of spontaneous breathing awake, as well as during sleep in a pediatric respiratory physiology laboratory. At minimum, a 72-hour Holter study should also be performed annually to evaluate for cardiac pauses, pauses greater than 3.0 seconds should be assessed for cardiac pacemaker implantation by a cardiologist. An echocardiogram, hematocrits, and reticulocyte counts may also be needed to evaluate for signs of heart problems (cor pulmonale) that occur as a consequence of inadequate ventilation. Consultation with a gastroenterologist (and possibly rectal biopsy) may be needed for patients with constipation to evaluate for Hirschsprung’s disease. In patients with PARM mutations 20/29 and higher, and patients with NPARM mutations, routine serial chest and abdominal imaging is crucial for detecting emergence of a neural crest tumor, specifically neuroblastoma (NPARMs) and ganglioneuroblastoma/ganglioneuroma (PARMs). Ophthalmologic testing may also need to be done in some patients to assess for ophthalmologic dysfunction. | Therapies of Congenital Central Hypoventilation Syndrome. A multidisciplinary team approach to the management of CCHS is essential to ensuring proper ventilation and development of children with CCHS. Local children’s hospitals may be sufficient in the management of CCHS. In complex cases, CCHS specialists (listed below) can be found throughout the world and can be consulted, or seen for management of CCHS. Primary team members who play an active role in patient management should include: the primary caregivers (parents or family members), pulmonologists, cardiologists, ENT physicians, gastroenterologists, endocrinologists, neurologists, ophthalmologists, social workers, and speech/language pathologists (SLPs).Early detection and management of CCHS with adequate ventilation and appropriate therapies have helped CCHS patients live fulfilling lives. Proper management has allowed CCHS patients to seek higher education, enter the work force and have families of their ownPlease refer to the Signs and Symptoms section for additional information.Clinical Testing and Work-Up
The 2010 American Thoracic Society (ATS) statement on CCHS recommends that CCHS patients undergo annual assessment of spontaneous breathing awake, as well as during sleep in a pediatric respiratory physiology laboratory. At minimum, a 72-hour Holter study should also be performed annually to evaluate for cardiac pauses, pauses greater than 3.0 seconds should be assessed for cardiac pacemaker implantation by a cardiologist. An echocardiogram, hematocrits, and reticulocyte counts may also be needed to evaluate for signs of heart problems (cor pulmonale) that occur as a consequence of inadequate ventilation. Consultation with a gastroenterologist (and possibly rectal biopsy) may be needed for patients with constipation to evaluate for Hirschsprung’s disease. In patients with PARM mutations 20/29 and higher, and patients with NPARM mutations, routine serial chest and abdominal imaging is crucial for detecting emergence of a neural crest tumor, specifically neuroblastoma (NPARMs) and ganglioneuroblastoma/ganglioneuroma (PARMs). Ophthalmologic testing may also need to be done in some patients to assess for ophthalmologic dysfunction. | 300 | Congenital Central Hypoventilation Syndrome |
nord_301_0 | Overview of Congenital Contractural Arachnodactyly | Congenital contractural arachnodactyly (CCA) is an extremely rare genetic disorder characterized by a Marfan-like body habitus (tall, slender), the permanent fixation of certain joints (e.g., fingers, elbows, knees, and hips) in a flexed position (contractures); abnormally long, slender fingers and toes (arachnodactyly); permanently flexed fingers (camptodactyly); and/or differently shaped ears resulting in a “crumpled” appearance. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are differently positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); a short neck. Rarely, affected individuals may have a slight deformity of the valve on the left side of the heart (mitral valve prolapse). CCA is inherited in an autosomal dominant pattern. | Overview of Congenital Contractural Arachnodactyly. Congenital contractural arachnodactyly (CCA) is an extremely rare genetic disorder characterized by a Marfan-like body habitus (tall, slender), the permanent fixation of certain joints (e.g., fingers, elbows, knees, and hips) in a flexed position (contractures); abnormally long, slender fingers and toes (arachnodactyly); permanently flexed fingers (camptodactyly); and/or differently shaped ears resulting in a “crumpled” appearance. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are differently positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); a short neck. Rarely, affected individuals may have a slight deformity of the valve on the left side of the heart (mitral valve prolapse). CCA is inherited in an autosomal dominant pattern. | 301 | Congenital Contractural Arachnodactyly |
nord_301_1 | Symptoms of Congenital Contractural Arachnodactyly | CCA encompasses a broad range of symptoms. The specific symptoms that develop in each individual case and the severity of symptoms often vary. Most individuals have permanent fixation of certain joints in a flexed position (contractures) that is present a birth (congenital). The joints of the fingers, elbows, knees and hips are most often affected. In most cases, contractures improve with age.Some affected infants have differently shaped ears giving them a “crumpled” appearance. Additional common symptoms include long, slender fingers and toes (arachnodactyly), permanently flexed fingers (camptodactyly), underdevelopment of certain muscles (muscular hypoplasia), and front-to-back and side-to-side curvature of the spine (kyphoscoliosis). Kyphoscoliosis is usually progressive and severe, often necessitating surgery.Some children have a specific heart defect known as mitral valve prolapse (MVP). The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle) of the heart. MVP occurs when one or both flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction (systole). In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation). In some patients, no associated symptoms are apparent (asymptomatic). However, in other people, MVP can result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, dizziness and/or other symptoms and signs.Less common symptoms may occur in some children. Additional differences of the head and face (craniofacial) region include a small jaw (micrognathia), a prominent forehead (frontal bossing), a highly arched palate, a long narrow head (dolichocephaly or scaphocephaly), or a wide head (brachycephaly). Nearsightedness (myopia) affecting the eyes may also occur.Some individuals may have a short neck. Some affected individuals have a clubbed foot, inwardly clasped (adducted thumbs) and bowed long bones of the arms and leg.Rarely, individuals with CCA may develop a severe form of the disorder associated with life-threatening complications. This severe form of CCA is associated with various heart and intestinal abnormalities including atrial and ventricular septal defects; improper development of the aorta resulting in blockage of blood flow (interrupted aortic arch); a single umbilical artery; a condition in which the tube (esophagus) that normally carries food from the mouth to the stomach narrows to a thin cord or ends in a pouch rather than providing passage to the stomach (esophageal atresia); abnormal closure or blockage of the first part of the small intestine (duodenal atresia); and obstruction of the intestines due to malformation of part of the intestines (intestinal malrotation).Rarer still, CCA may be associated with aortic root dilatation, a condition characterized by widening (dilatation) of the opening where the aorta and the heart chamber connect (aortic root). | Symptoms of Congenital Contractural Arachnodactyly. CCA encompasses a broad range of symptoms. The specific symptoms that develop in each individual case and the severity of symptoms often vary. Most individuals have permanent fixation of certain joints in a flexed position (contractures) that is present a birth (congenital). The joints of the fingers, elbows, knees and hips are most often affected. In most cases, contractures improve with age.Some affected infants have differently shaped ears giving them a “crumpled” appearance. Additional common symptoms include long, slender fingers and toes (arachnodactyly), permanently flexed fingers (camptodactyly), underdevelopment of certain muscles (muscular hypoplasia), and front-to-back and side-to-side curvature of the spine (kyphoscoliosis). Kyphoscoliosis is usually progressive and severe, often necessitating surgery.Some children have a specific heart defect known as mitral valve prolapse (MVP). The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle) of the heart. MVP occurs when one or both flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left atrium during ventricular contraction (systole). In some cases, this may allow leakage or the backward flow of blood from the left ventricle back into the left atrium (mitral regurgitation). In some patients, no associated symptoms are apparent (asymptomatic). However, in other people, MVP can result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, dizziness and/or other symptoms and signs.Less common symptoms may occur in some children. Additional differences of the head and face (craniofacial) region include a small jaw (micrognathia), a prominent forehead (frontal bossing), a highly arched palate, a long narrow head (dolichocephaly or scaphocephaly), or a wide head (brachycephaly). Nearsightedness (myopia) affecting the eyes may also occur.Some individuals may have a short neck. Some affected individuals have a clubbed foot, inwardly clasped (adducted thumbs) and bowed long bones of the arms and leg.Rarely, individuals with CCA may develop a severe form of the disorder associated with life-threatening complications. This severe form of CCA is associated with various heart and intestinal abnormalities including atrial and ventricular septal defects; improper development of the aorta resulting in blockage of blood flow (interrupted aortic arch); a single umbilical artery; a condition in which the tube (esophagus) that normally carries food from the mouth to the stomach narrows to a thin cord or ends in a pouch rather than providing passage to the stomach (esophageal atresia); abnormal closure or blockage of the first part of the small intestine (duodenal atresia); and obstruction of the intestines due to malformation of part of the intestines (intestinal malrotation).Rarer still, CCA may be associated with aortic root dilatation, a condition characterized by widening (dilatation) of the opening where the aorta and the heart chamber connect (aortic root). | 301 | Congenital Contractural Arachnodactyly |
nord_301_2 | Causes of Congenital Contractural Arachnodactyly | CCA occurs due to changes (variants or mutations) to the fibrillin-2 (FBN2) gene.CCA is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of gene variant is necessary to cause a particular disease. The gene variant can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the gene variant from an affected parent to children is 50% for each pregnancy. The risk is the same for males and females.Interestingly, studies of a largely Ashkenazi Jewish population have shown that deletions of exons 1-8 in the FBN2 gene are not associated with any pathology and is considered a benign variant. | Causes of Congenital Contractural Arachnodactyly. CCA occurs due to changes (variants or mutations) to the fibrillin-2 (FBN2) gene.CCA is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of gene variant is necessary to cause a particular disease. The gene variant can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the gene variant from an affected parent to children is 50% for each pregnancy. The risk is the same for males and females.Interestingly, studies of a largely Ashkenazi Jewish population have shown that deletions of exons 1-8 in the FBN2 gene are not associated with any pathology and is considered a benign variant. | 301 | Congenital Contractural Arachnodactyly |
nord_301_3 | Affects of Congenital Contractural Arachnodactyly | CCA affects males and females in equal numbers. The prevalence of CCA is unknown. For years, researchers speculated that the Marfan syndrome (another rare connective tissue disorder) and CCA may be the same disorder because of the overlap of clinical symptoms. However, investigators have determined these disorders are caused by variants in different genes confirming that CCA is a distinct disorder.Because of the similarities with the more recognized Marfan syndrome, it is difficult to determine the true incidence of CCA in the general population. However, molecular genetic testing can confirm a diagnosis of CCA and should allow researchers to obtain a more accurate idea of its incidence in the future.The recent identification of another condition with overlapping symptoms, Loeys-Dietz syndrome has led to additional misdiagnosis (see below). | Affects of Congenital Contractural Arachnodactyly. CCA affects males and females in equal numbers. The prevalence of CCA is unknown. For years, researchers speculated that the Marfan syndrome (another rare connective tissue disorder) and CCA may be the same disorder because of the overlap of clinical symptoms. However, investigators have determined these disorders are caused by variants in different genes confirming that CCA is a distinct disorder.Because of the similarities with the more recognized Marfan syndrome, it is difficult to determine the true incidence of CCA in the general population. However, molecular genetic testing can confirm a diagnosis of CCA and should allow researchers to obtain a more accurate idea of its incidence in the future.The recent identification of another condition with overlapping symptoms, Loeys-Dietz syndrome has led to additional misdiagnosis (see below). | 301 | Congenital Contractural Arachnodactyly |
nord_301_4 | Related disorders of Congenital Contractural Arachnodactyly | Symptoms of the following disorders can be similar to those of CCA. Comparisons may be useful for a differential diagnosis:Arthrogryposis multiplex congenita is a rare congenital disease characterized by reduced mobility of multiple joints at birth due to proliferation of fibrous tissue. Symptoms of this disorder may be a fixed range of motion of joints; shoulders that are bent inward and internally rotated; wrists and fingers that are bent and muscles that are underdeveloped. (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.)Marfan syndrome is an inherited disorder of the connective tissue. It is characterized by unusually thin, long, limbs, feet and fingers, an unusual limberness of the joints, a relaxation of the muscles, a progressive curvature of the spine, a protruding or indented breastbone and flat feet. Enlargement and degeneration of the aorta, mitral valve prolapse and the possibility of an aortic aneurysm are serious consequences of Marfan syndrome. (For more information on this disorder, choose “Marfan syndrome” as your search term in the Rare Disease Database.)Gordon syndrome is an extremely rare disorder that belongs to a group of genetic disorders known as the distal arthrogryposes. These disorders typically involve stiffness and impaired mobility of certain joints of the lower arms and legs (distal extremities) including the knees, elbows, wrists and/or ankles. These joints tend to be permanently fixed in a bent or flexed position (contractures). Gordon syndrome is characterized by the permanent fixation of several fingers in a flexed position (camptodactyly), bending inward of the foot (clubfoot or talipes), and, less frequently, incomplete closure of the roof of the mouth (cleft palate). In some patients, additional abnormalities may also be present. The range and severity of symptoms may vary from person to person. Gordon syndrome is inherited in an autosomal dominant pattern (For more information on this disorder, choose “Gordon” as your search term in the Rare Disease Database.)Homocystinuria is a rare metabolic condition characterized by an excess of the compound homocysteine in the urine. The condition may result from deficiency of any of several enzymes involved in the conversion of the essential amino acid methionine to another amino acid (cysteine)–or, less commonly, impaired conversion of the compound homocysteine to methionine. Enzymes are proteins that accelerate the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most patients, homocystinuria is caused by reduced activity of an enzyme known as cystathionine beta-synthase (CBS). Due to deficiency of the CBS enzyme, affected infants fail to grow and gain weight at the expected rate (failure to thrive) and have developmental delays. By approximately age three, additional, more specific symptoms and findings may become apparent. These may include partial dislocation (subluxation) of the lens of the eyes (ectopia lentis), associated “quivering” (iridodonesis) of the colored region of the eyes (iris), severe nearsightedness (myopia) and other eye (ocular) abnormalities. Intelligence is normal in some affected people, but many children have progressive intellectual disability. In addition, some may develop psychiatric disturbances and/or episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals also tend to be thin with unusually tall stature; long, slender fingers and toes (arachnodactyly); and elongated arms and legs (“marfanoid” features). Additional skeletal abnormalities may include progressive sideways curvature of the spine (scoliosis), protrusion or depression of the breastbone (pectus carinatum or excavatum), and generalized loss of bone density (osteoporosis). In addition, in those with the disorder, blood clots may tend to develop or become lodged within certain large and small blood vessels (thromboembolisms), potentially leading to life-threatening complications. (For more information on this disorder, choose “homocystinuria” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body’s organ systems such as the eye, skeleton, inner ear and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor) and the ends of the bones that make up the joints of the body (epiphysis). (For more information on this disorder, choose “Stickler” as your search term in the Rare Disease Database.)Loeys-Dietz Syndrome, first delineated in 2005, is characterized by aneurysms in cerebral, thoracic and abdominal arteries. Skeletal anomalies are similar to those seen in CCA and the Marfan syndrome and include chest wall deformities, arachnodactyly, club feet, and craniofacial features including bifid uvula, cleft palate and hypertelorism. Variants in the TGFBR1 and TGFBR2 genes are known to cause Loeys-Dietz syndrome. (For more information on this disorder, choose “Loeys-Dietz Syndrome” as your search term in the Rare Disease Database.)The following disorders may occur along with CCA:Keratoconus is a slowly progressive enlargement of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea). The resulting conical shape of the cornea causes blurred vision and other vision problems. Inherited forms of this disorder usually begin after puberty. Keratoconus can also occur in conjunction with a variety of other disorders.Mitral valve prolapse syndrome is a heart disorder. The exact cause is unknown. It can be a symptom of other disorders such as connective tissue diseases or muscular dystrophy, or it may occur by itself. Major symptoms include chest pain and/or palpitations, accompanied by a heart murmur. Shortness of breath, fatigue, lightheadedness and dizzy spells, and in some people, this progresses to an inability to breathe except when sitting in an upright position. There is a characteristic click heard through a stethoscope upon physical examination. Blood may flow back through the heart valve (mitral regurgitation) causing other complications. | Related disorders of Congenital Contractural Arachnodactyly. Symptoms of the following disorders can be similar to those of CCA. Comparisons may be useful for a differential diagnosis:Arthrogryposis multiplex congenita is a rare congenital disease characterized by reduced mobility of multiple joints at birth due to proliferation of fibrous tissue. Symptoms of this disorder may be a fixed range of motion of joints; shoulders that are bent inward and internally rotated; wrists and fingers that are bent and muscles that are underdeveloped. (For more information on this disorder, choose “arthrogryposis multiplex congenita” as your search term in the Rare Disease Database.)Marfan syndrome is an inherited disorder of the connective tissue. It is characterized by unusually thin, long, limbs, feet and fingers, an unusual limberness of the joints, a relaxation of the muscles, a progressive curvature of the spine, a protruding or indented breastbone and flat feet. Enlargement and degeneration of the aorta, mitral valve prolapse and the possibility of an aortic aneurysm are serious consequences of Marfan syndrome. (For more information on this disorder, choose “Marfan syndrome” as your search term in the Rare Disease Database.)Gordon syndrome is an extremely rare disorder that belongs to a group of genetic disorders known as the distal arthrogryposes. These disorders typically involve stiffness and impaired mobility of certain joints of the lower arms and legs (distal extremities) including the knees, elbows, wrists and/or ankles. These joints tend to be permanently fixed in a bent or flexed position (contractures). Gordon syndrome is characterized by the permanent fixation of several fingers in a flexed position (camptodactyly), bending inward of the foot (clubfoot or talipes), and, less frequently, incomplete closure of the roof of the mouth (cleft palate). In some patients, additional abnormalities may also be present. The range and severity of symptoms may vary from person to person. Gordon syndrome is inherited in an autosomal dominant pattern (For more information on this disorder, choose “Gordon” as your search term in the Rare Disease Database.)Homocystinuria is a rare metabolic condition characterized by an excess of the compound homocysteine in the urine. The condition may result from deficiency of any of several enzymes involved in the conversion of the essential amino acid methionine to another amino acid (cysteine)–or, less commonly, impaired conversion of the compound homocysteine to methionine. Enzymes are proteins that accelerate the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most patients, homocystinuria is caused by reduced activity of an enzyme known as cystathionine beta-synthase (CBS). Due to deficiency of the CBS enzyme, affected infants fail to grow and gain weight at the expected rate (failure to thrive) and have developmental delays. By approximately age three, additional, more specific symptoms and findings may become apparent. These may include partial dislocation (subluxation) of the lens of the eyes (ectopia lentis), associated “quivering” (iridodonesis) of the colored region of the eyes (iris), severe nearsightedness (myopia) and other eye (ocular) abnormalities. Intelligence is normal in some affected people, but many children have progressive intellectual disability. In addition, some may develop psychiatric disturbances and/or episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals also tend to be thin with unusually tall stature; long, slender fingers and toes (arachnodactyly); and elongated arms and legs (“marfanoid” features). Additional skeletal abnormalities may include progressive sideways curvature of the spine (scoliosis), protrusion or depression of the breastbone (pectus carinatum or excavatum), and generalized loss of bone density (osteoporosis). In addition, in those with the disorder, blood clots may tend to develop or become lodged within certain large and small blood vessels (thromboembolisms), potentially leading to life-threatening complications. (For more information on this disorder, choose “homocystinuria” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body’s organ systems such as the eye, skeleton, inner ear and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor) and the ends of the bones that make up the joints of the body (epiphysis). (For more information on this disorder, choose “Stickler” as your search term in the Rare Disease Database.)Loeys-Dietz Syndrome, first delineated in 2005, is characterized by aneurysms in cerebral, thoracic and abdominal arteries. Skeletal anomalies are similar to those seen in CCA and the Marfan syndrome and include chest wall deformities, arachnodactyly, club feet, and craniofacial features including bifid uvula, cleft palate and hypertelorism. Variants in the TGFBR1 and TGFBR2 genes are known to cause Loeys-Dietz syndrome. (For more information on this disorder, choose “Loeys-Dietz Syndrome” as your search term in the Rare Disease Database.)The following disorders may occur along with CCA:Keratoconus is a slowly progressive enlargement of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea). The resulting conical shape of the cornea causes blurred vision and other vision problems. Inherited forms of this disorder usually begin after puberty. Keratoconus can also occur in conjunction with a variety of other disorders.Mitral valve prolapse syndrome is a heart disorder. The exact cause is unknown. It can be a symptom of other disorders such as connective tissue diseases or muscular dystrophy, or it may occur by itself. Major symptoms include chest pain and/or palpitations, accompanied by a heart murmur. Shortness of breath, fatigue, lightheadedness and dizzy spells, and in some people, this progresses to an inability to breathe except when sitting in an upright position. There is a characteristic click heard through a stethoscope upon physical examination. Blood may flow back through the heart valve (mitral regurgitation) causing other complications. | 301 | Congenital Contractural Arachnodactyly |
nord_301_5 | Diagnosis of Congenital Contractural Arachnodactyly | A diagnosis of CCA is suspected based upon a thorough clinical evaluation and identification of characteristic findings. A diagnosis may be confirmed by molecular genetic testing which detects an FBN-2 gene variant in approximately 75 percent of patients.Recently, Meerschaut et al. have proposed a scoring system for CCA to help support a diagnosis. They suggest this as a quantitative tool for research purposes and as clinical guidance in diagnosis. | Diagnosis of Congenital Contractural Arachnodactyly. A diagnosis of CCA is suspected based upon a thorough clinical evaluation and identification of characteristic findings. A diagnosis may be confirmed by molecular genetic testing which detects an FBN-2 gene variant in approximately 75 percent of patients.Recently, Meerschaut et al. have proposed a scoring system for CCA to help support a diagnosis. They suggest this as a quantitative tool for research purposes and as clinical guidance in diagnosis. | 301 | Congenital Contractural Arachnodactyly |
nord_301_6 | Therapies of Congenital Contractural Arachnodactyly | Treatment
The treatment of CCA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, orthopedists, and other health care professionals may need to plan an affect child’s treatment systematically and comprehensively.Physical therapy, often started during childhood, may be used to treat joint contractures. Physical therapy can improve joint mobility and lessen the effects of muscular hypoplasia. In many people, joint contractures improve without treatment (spontaneously) as individuals grow older. However, for some people, surgery may be necessary to treat contractures. Kyphoscoliosis is often progressive and severe and may necessitate treatment with braces or surgery.Many physicians recommend that individuals with CCA receive an echocardiogram to distinguish the disorder from Marfan syndrome and detect any heart defects that may potentially be associated with the disorder. During an echocardiogram, high-frequency sound waves are used to create a structural image of the heart and nearby tissue.A thorough eye (ophthalmologic) examination is recommended to detect any potential eye abnormalities that are sometimes associated with CCA.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Congenital Contractural Arachnodactyly. Treatment
The treatment of CCA is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, orthopedists, and other health care professionals may need to plan an affect child’s treatment systematically and comprehensively.Physical therapy, often started during childhood, may be used to treat joint contractures. Physical therapy can improve joint mobility and lessen the effects of muscular hypoplasia. In many people, joint contractures improve without treatment (spontaneously) as individuals grow older. However, for some people, surgery may be necessary to treat contractures. Kyphoscoliosis is often progressive and severe and may necessitate treatment with braces or surgery.Many physicians recommend that individuals with CCA receive an echocardiogram to distinguish the disorder from Marfan syndrome and detect any heart defects that may potentially be associated with the disorder. During an echocardiogram, high-frequency sound waves are used to create a structural image of the heart and nearby tissue.A thorough eye (ophthalmologic) examination is recommended to detect any potential eye abnormalities that are sometimes associated with CCA.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 301 | Congenital Contractural Arachnodactyly |
nord_302_0 | Overview of Congenital Disorders of Glycosylation | SummaryCongenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of over 130 rare genetic, metabolic disorders due to defects in a complex chemical process known as glycosylation. Glycosylation is the process by which sugar ‘trees’ (glycans) are created, altered and attached to 1000’s of proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems. CDG can affect any part of the body and there is nearly always an important neurological component. CDG can be associated with a broad variety of symptoms and can vary in severity from mild to severe, disabling or life-threatening. CDG are usually apparent from infancy. Individual CDG are caused by changes (mutations) in a specific gene. Most CDG are inherited as autosomal recessive conditions, but some are X-linked or dominant. Others may arise spontaneously (de novo). IntroductionCDG were first reported in the medical literature in 1980 by Dr. Jaak Jaeken and colleagues. More than 130 different forms of CDG have been identified in the ensuing years. Recently, Jaeken and colleagues proposed a classification system that names each type by the official abbreviation of the abnormal gene followed by a dash and CDG. For example, congenital disorder of glycosylation type 1a is now known as PMM2-CDG because a mutation in the PMM2 gene causes this type of CDG. Major categories of CDG are based on the glycosylation pathway or molecule that is affected. For instance, disorders of protein glycosylation are broken down into two groups known as disorders of N-glycosylation and disorders of O-glycosylation. Other types of CDG include disorders of glycosphingolipid and GPI-anchor glycosylation, and disorders of multiple glycosylation and other pathways. These four categories of CDG are described below.Disorders of protein N-glycosylationMost types of CDG are classified as disorders of N-glycosylation, which involve carbohydrates called N-linked oligosaccharides (glycans). Disorders of N-glycosylation are due to an enzyme deficiency or other malfunction somewhere along the N-glycosylation pathway. This category of CDG can be further divided into two subtypes: defects of oligosaccharide assembly and transfer (type 1) and defects in oligosaccharide trimming and processing that occur after they are bound to proteins (type 2). Disorders of protein N-glycosylation notably include PMM2-CDG, the most common type of CDG. (For more information on this disorder, choose “PMM2-CDG” as your search term in the Rare Disease Database.)Disorders of protein O-glycosylationDisorders of O-glycosylation are due to an enzyme deficiency or other malfunction somewhere along the O-glycosylation pathway. Some of these disorders are better known than the N-linked forms and many have more traditional names. In some cases, they have also been classified as subtypes of other umbrella groups. For instance, some disorders of O-linked glycosylation are also classified as forms of muscular dystrophy. These disorders are collectively termed the dystroglycanopathies. The NORD database has individual reports on Walker-Warburg syndrome and Fukuyama muscular dystrophy, as well as general overviews on congenital muscular dystrophy and limb-girdle muscular dystrophy. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database. Other disorders involve defects in the synthesis of large molecules called glycosaminoglycans (GAGs) which are the sugar components of proteoglycans.Disorders of glycosphingolipid and GPI-anchor glycosylationAs their name indicates, these disorders involve defects in the glycosylation of two types of lipid-containing molecules: glycosphingolipids (GSL) and glycosylphosphatidylinositol (GPI) anchors. These glycolipids have a wide range of functions in the body. Disorders associated with a defect in their production can therefore have a wide range of manifestations, as it is the case for disorders of protein glycosylation. There are over 20 types of GPI anchor disorders, but just a couple in GSL synthesis. Defects of multiple glycosylation and other pathwaysSome CDG occur due to defects that impact and alter multiple glycosylation pathways. For example, some individuals may have defects affecting both the N-linked and O-linked glycosylation pathways. These can also include defects in the organization, delivery, or trafficking of proteins within cells. These disorders usually have manifestations similar to other categories of congenital disorders of glycosylation. | Overview of Congenital Disorders of Glycosylation. SummaryCongenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of over 130 rare genetic, metabolic disorders due to defects in a complex chemical process known as glycosylation. Glycosylation is the process by which sugar ‘trees’ (glycans) are created, altered and attached to 1000’s of proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems. CDG can affect any part of the body and there is nearly always an important neurological component. CDG can be associated with a broad variety of symptoms and can vary in severity from mild to severe, disabling or life-threatening. CDG are usually apparent from infancy. Individual CDG are caused by changes (mutations) in a specific gene. Most CDG are inherited as autosomal recessive conditions, but some are X-linked or dominant. Others may arise spontaneously (de novo). IntroductionCDG were first reported in the medical literature in 1980 by Dr. Jaak Jaeken and colleagues. More than 130 different forms of CDG have been identified in the ensuing years. Recently, Jaeken and colleagues proposed a classification system that names each type by the official abbreviation of the abnormal gene followed by a dash and CDG. For example, congenital disorder of glycosylation type 1a is now known as PMM2-CDG because a mutation in the PMM2 gene causes this type of CDG. Major categories of CDG are based on the glycosylation pathway or molecule that is affected. For instance, disorders of protein glycosylation are broken down into two groups known as disorders of N-glycosylation and disorders of O-glycosylation. Other types of CDG include disorders of glycosphingolipid and GPI-anchor glycosylation, and disorders of multiple glycosylation and other pathways. These four categories of CDG are described below.Disorders of protein N-glycosylationMost types of CDG are classified as disorders of N-glycosylation, which involve carbohydrates called N-linked oligosaccharides (glycans). Disorders of N-glycosylation are due to an enzyme deficiency or other malfunction somewhere along the N-glycosylation pathway. This category of CDG can be further divided into two subtypes: defects of oligosaccharide assembly and transfer (type 1) and defects in oligosaccharide trimming and processing that occur after they are bound to proteins (type 2). Disorders of protein N-glycosylation notably include PMM2-CDG, the most common type of CDG. (For more information on this disorder, choose “PMM2-CDG” as your search term in the Rare Disease Database.)Disorders of protein O-glycosylationDisorders of O-glycosylation are due to an enzyme deficiency or other malfunction somewhere along the O-glycosylation pathway. Some of these disorders are better known than the N-linked forms and many have more traditional names. In some cases, they have also been classified as subtypes of other umbrella groups. For instance, some disorders of O-linked glycosylation are also classified as forms of muscular dystrophy. These disorders are collectively termed the dystroglycanopathies. The NORD database has individual reports on Walker-Warburg syndrome and Fukuyama muscular dystrophy, as well as general overviews on congenital muscular dystrophy and limb-girdle muscular dystrophy. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database. Other disorders involve defects in the synthesis of large molecules called glycosaminoglycans (GAGs) which are the sugar components of proteoglycans.Disorders of glycosphingolipid and GPI-anchor glycosylationAs their name indicates, these disorders involve defects in the glycosylation of two types of lipid-containing molecules: glycosphingolipids (GSL) and glycosylphosphatidylinositol (GPI) anchors. These glycolipids have a wide range of functions in the body. Disorders associated with a defect in their production can therefore have a wide range of manifestations, as it is the case for disorders of protein glycosylation. There are over 20 types of GPI anchor disorders, but just a couple in GSL synthesis. Defects of multiple glycosylation and other pathwaysSome CDG occur due to defects that impact and alter multiple glycosylation pathways. For example, some individuals may have defects affecting both the N-linked and O-linked glycosylation pathways. These can also include defects in the organization, delivery, or trafficking of proteins within cells. These disorders usually have manifestations similar to other categories of congenital disorders of glycosylation. | 302 | Congenital Disorders of Glycosylation |
nord_302_1 | Symptoms of Congenital Disorders of Glycosylation | CDG encompass a wide variety of disorders and symptoms. Their severity and prognosis vary greatly depending upon the specific type of CDG, even among individuals with the same type or from the same family. In addition, most types of CDG have only been reported in a handful of individuals, which makes it difficult for physicians to have an accurate picture of associated symptoms and prognosis. In most cases, these disorders become apparent in infancy. It is important to note that affected individuals will not always have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Despite the wide variety in presentation, many types of CDG have a significant neurological component involving the brain and/or spine (central nervous system). Common neurological symptoms include diminished muscle tone (hypotonia), seizures, deficits in attaining developmental milestones (developmental disability), varying degrees of cognitive impairment and underdevelopment of the cerebellum (cerebellar hypoplasia) which can cause problems with balance and coordination. Additional common symptoms include abnormal fat distribution, defects in blood clotting that can cause abnormal bleeding or clotting (coagulation defects), gastrointestinal symptoms such as vomiting and diarrhea, eye abnormalities such as crossed eyes (strabismus) and retinal degeneration, and abnormal or distinctive facial features (facial dysmorphism). Although facial dysmorphism can occur in any type of CDG, it is most often associated with disorders of O-glycosylation. Feeding difficulties leading to failure to thrive are also common. Failure to thrive is defined as the failure to grow and gain weight as would be expected based upon age and gender. Another factor that can contribute to failure to thrive is excessive loss of proteins from the gastrointestinal tract (protein-losing enteropathy) which can also cause swelling due to fluid retention (edema). Fluid accumulation around the lungs or heart (pleural or pericardial effusions) has also been reported. Additional symptoms include various abnormalities of the kidneys, liver and heart; skeletal abnormalities including bony overgrowth or deformities; abnormalities of muscle fibers that can cause pain and weakness (myopathy); skin changes such as scaly skin or rashes; stroke-like episodes; and deficiencies of the immune system (immunodeficiency). As mentioned, the manifestations of CDG vary greatly between affected individuals. However, certain patterns of features are more frequently seen in certain types. For instance, patients with PGM1-CDG (a type 1 disorder of N-glycosylation) frequently have hypoglycemia, hormonal dysregulations, growth delay, seizures, cleft lip and/or palate, a uvula that is split in two (bifid uvula), myopathy and bleeding. | Symptoms of Congenital Disorders of Glycosylation. CDG encompass a wide variety of disorders and symptoms. Their severity and prognosis vary greatly depending upon the specific type of CDG, even among individuals with the same type or from the same family. In addition, most types of CDG have only been reported in a handful of individuals, which makes it difficult for physicians to have an accurate picture of associated symptoms and prognosis. In most cases, these disorders become apparent in infancy. It is important to note that affected individuals will not always have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.Despite the wide variety in presentation, many types of CDG have a significant neurological component involving the brain and/or spine (central nervous system). Common neurological symptoms include diminished muscle tone (hypotonia), seizures, deficits in attaining developmental milestones (developmental disability), varying degrees of cognitive impairment and underdevelopment of the cerebellum (cerebellar hypoplasia) which can cause problems with balance and coordination. Additional common symptoms include abnormal fat distribution, defects in blood clotting that can cause abnormal bleeding or clotting (coagulation defects), gastrointestinal symptoms such as vomiting and diarrhea, eye abnormalities such as crossed eyes (strabismus) and retinal degeneration, and abnormal or distinctive facial features (facial dysmorphism). Although facial dysmorphism can occur in any type of CDG, it is most often associated with disorders of O-glycosylation. Feeding difficulties leading to failure to thrive are also common. Failure to thrive is defined as the failure to grow and gain weight as would be expected based upon age and gender. Another factor that can contribute to failure to thrive is excessive loss of proteins from the gastrointestinal tract (protein-losing enteropathy) which can also cause swelling due to fluid retention (edema). Fluid accumulation around the lungs or heart (pleural or pericardial effusions) has also been reported. Additional symptoms include various abnormalities of the kidneys, liver and heart; skeletal abnormalities including bony overgrowth or deformities; abnormalities of muscle fibers that can cause pain and weakness (myopathy); skin changes such as scaly skin or rashes; stroke-like episodes; and deficiencies of the immune system (immunodeficiency). As mentioned, the manifestations of CDG vary greatly between affected individuals. However, certain patterns of features are more frequently seen in certain types. For instance, patients with PGM1-CDG (a type 1 disorder of N-glycosylation) frequently have hypoglycemia, hormonal dysregulations, growth delay, seizures, cleft lip and/or palate, a uvula that is split in two (bifid uvula), myopathy and bleeding. | 302 | Congenital Disorders of Glycosylation |
nord_302_2 | Causes of Congenital Disorders of Glycosylation | As discussed above, CDG are caused by a deficiency or lack of specific enzymes or other proteins involved in the formation of sugar trees (glycans) and their binding to other proteins or lipids (glycosylation). Glycosylation is an extensive and complex process that modifies 1000’s of proteins. Hundreds of different genes and unique enzymes are involved in glycosylation. These genes contain instructions for creating (encoding) these enzymes. An individual with a CDG lacks functional levels of one of these enzymes because of a mutation in the corresponding gene. Due to lack of or diminished levels of these enzymes, glycosylation is impaired. Improper glycosylation is the underlying problem in individuals with CDG. The specific organs affected and the various symptoms that develop depend, in part, upon the specific gene and protein product involved. Not all CDG types are caused by mutations in enzymes. Sometimes they result from mutations in proteins that transport, organize or direct other molecules within cells.Most forms of CDG are inherited in an autosomal recessive pattern. 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 abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Certain forms of CDG are inherited in an autosomal dominant pattern. 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 in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. However, if an affected child has a new mutation that is not carried by either parent, other children of the same parents are much less likely to develop the disease. | Causes of Congenital Disorders of Glycosylation. As discussed above, CDG are caused by a deficiency or lack of specific enzymes or other proteins involved in the formation of sugar trees (glycans) and their binding to other proteins or lipids (glycosylation). Glycosylation is an extensive and complex process that modifies 1000’s of proteins. Hundreds of different genes and unique enzymes are involved in glycosylation. These genes contain instructions for creating (encoding) these enzymes. An individual with a CDG lacks functional levels of one of these enzymes because of a mutation in the corresponding gene. Due to lack of or diminished levels of these enzymes, glycosylation is impaired. Improper glycosylation is the underlying problem in individuals with CDG. The specific organs affected and the various symptoms that develop depend, in part, upon the specific gene and protein product involved. Not all CDG types are caused by mutations in enzymes. Sometimes they result from mutations in proteins that transport, organize or direct other molecules within cells.Most forms of CDG are inherited in an autosomal recessive pattern. 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 abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Certain forms of CDG are inherited in an autosomal dominant pattern. 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 in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. However, if an affected child has a new mutation that is not carried by either parent, other children of the same parents are much less likely to develop the disease. | 302 | Congenital Disorders of Glycosylation |
nord_302_3 | Affects of Congenital Disorders of Glycosylation | Congenital disorders of glycosylation affect males and females in equal numbers. The exact incidence or prevalence of these disorders is the general population is unknown. Researchers believe that many cases go unrecognized or misdiagnosed, making it difficult to determine their true frequency. As these disorders become better known and more types are identified, more cases should be recognized. The most common type (PMM2-CDG) has been reported in more than 1,000 individuals, but the real frequency is probably much higher. | Affects of Congenital Disorders of Glycosylation. Congenital disorders of glycosylation affect males and females in equal numbers. The exact incidence or prevalence of these disorders is the general population is unknown. Researchers believe that many cases go unrecognized or misdiagnosed, making it difficult to determine their true frequency. As these disorders become better known and more types are identified, more cases should be recognized. The most common type (PMM2-CDG) has been reported in more than 1,000 individuals, but the real frequency is probably much higher. | 302 | Congenital Disorders of Glycosylation |
nord_302_4 | Related disorders of Congenital Disorders of Glycosylation | Numerous different metabolic disorders share similar signs and symptoms to CDG, and comparisons may be useful for a differential diagnosis. Such disorders include congenital muscle disorders (myopathies), urea cycle disorders, inborn errors of bile metabolism, fatty acid oxidation disorders, organic acidurias, peroxisome biogenesis disorders and sphingolipidoses. Additional disorders that have similar signs and symptoms include cerebral palsy, Prader-Willi syndrome, congenital coagulation disorders, ataxia-telangiectasia and other hereditary ataxias. (For more information on these disorders, choose the specific disorder or umbrella group name as your search term in the Rare Disease Database.) | Related disorders of Congenital Disorders of Glycosylation. Numerous different metabolic disorders share similar signs and symptoms to CDG, and comparisons may be useful for a differential diagnosis. Such disorders include congenital muscle disorders (myopathies), urea cycle disorders, inborn errors of bile metabolism, fatty acid oxidation disorders, organic acidurias, peroxisome biogenesis disorders and sphingolipidoses. Additional disorders that have similar signs and symptoms include cerebral palsy, Prader-Willi syndrome, congenital coagulation disorders, ataxia-telangiectasia and other hereditary ataxias. (For more information on these disorders, choose the specific disorder or umbrella group name as your search term in the Rare Disease Database.) | 302 | Congenital Disorders of Glycosylation |
nord_302_5 | Diagnosis of Congenital Disorders of Glycosylation | A diagnosis of a CDG may be suspected based upon the identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests may be necessary to confirm a diagnosis of CDG and/or to determine the specific subtype. CDG should be considered and ruled out in any unexplained syndrome.Sequencing an individual’s DNA is rapidly becoming an early test when physicians suspect a genetic abnormality. The speed and accuracy of the test can save a lot of time and expense and provides a provisional diagnosis. This sequencing approach can spot an abnormality in the DNA, but not every variant is harmful (pathogenic). In fact, most are not, so it is important to find an independent way to assess the impact. For CDG due to N-glycosylation defects, a simple blood test to analyze the glycosylation status of transferrin can help diagnose or confirm many (not all) types. Transferrin is a glycoprotein found in the blood plasma that is essential for the proper transport of iron within the body. Abnormal transferrin patterns can be detected through a test known as isoelectric focusing (IEF). IEF allows separation molecules such as proteins or enzymes based upon their electrical charge. This allows detection of abnormal serum transferrin. IEF is the standard test for diagnosing CDG due to a defect of N-glycosylation. Another test known as mass spectrometry may be used to detect abnormal transferrin. It is much more sensitive than IEF and can sometimes narrow down or confirm suspected defects. Further testing may include measuring the activity of a specific type of enzyme or using other methods. However, for most types no enzyme assay has been developed. Molecular genetic testing is needed to identify mutations that can cause CDG and therefore confirm the genetic diagnosis. | Diagnosis of Congenital Disorders of Glycosylation. A diagnosis of a CDG may be suspected based upon the identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests may be necessary to confirm a diagnosis of CDG and/or to determine the specific subtype. CDG should be considered and ruled out in any unexplained syndrome.Sequencing an individual’s DNA is rapidly becoming an early test when physicians suspect a genetic abnormality. The speed and accuracy of the test can save a lot of time and expense and provides a provisional diagnosis. This sequencing approach can spot an abnormality in the DNA, but not every variant is harmful (pathogenic). In fact, most are not, so it is important to find an independent way to assess the impact. For CDG due to N-glycosylation defects, a simple blood test to analyze the glycosylation status of transferrin can help diagnose or confirm many (not all) types. Transferrin is a glycoprotein found in the blood plasma that is essential for the proper transport of iron within the body. Abnormal transferrin patterns can be detected through a test known as isoelectric focusing (IEF). IEF allows separation molecules such as proteins or enzymes based upon their electrical charge. This allows detection of abnormal serum transferrin. IEF is the standard test for diagnosing CDG due to a defect of N-glycosylation. Another test known as mass spectrometry may be used to detect abnormal transferrin. It is much more sensitive than IEF and can sometimes narrow down or confirm suspected defects. Further testing may include measuring the activity of a specific type of enzyme or using other methods. However, for most types no enzyme assay has been developed. Molecular genetic testing is needed to identify mutations that can cause CDG and therefore confirm the genetic diagnosis. | 302 | Congenital Disorders of Glycosylation |
nord_302_6 | Therapies of Congenital Disorders of Glycosylation | TreatmentThe treatment of most forms of CDG is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, surgeons, cardiologists, speech pathologists, ophthalmologists, gastroenterologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. The specific therapeutic procedures and interventions for individuals with a CDG will vary depending upon numerous factors including the specific symptoms, severity of the disorder, an individual’s age and overall health and tolerance to certain medications or procedures. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of their case; a thorough discussion of the potential benefits and risks including possible side effects and long-term effects; patient preference; and other appropriate factors.Although there is no specific therapy for most forms of CDG, certain disorders have an existing therapy and others are in development. Some examples are provided below: Individuals with PMM2-CDG treated with acetazolamide showed improvement on standardized evaluation tests. It was clearly effective for improving motor cerebellar functions. Larger trials are underway. Acetazolamide has been used since the 1950’s and is approved for use in multiple disorders including glaucoma and epilepsy. Trials are also planned for another drug, epalrestat, which is approved in Japan to treat diabetic neuropathies. Some reports claim that mannose can improve PMM2-CDG transferrin and clinical features, however, this not accurate. While mannose is unlikely to be harmful, its use is discouraged because it offers false hope. On the other hand, individuals with MPI-CDG are treated with oral mannose. This therapy bypasses the underlying genetic defect in glycosylation that causes the disorder. Some individuals have experienced a near complete resolution of most symptoms following mannose therapy. This therapy is life-saving, but close monitoring of affected individuals is required because few individuals have been diagnosed (and thus treated) for MPI-CDG. In some individuals, liver disease did not improve when given mannose.A few individuals with SLC35C1-CDG have been treated with fucose. This therapy depends upon the nature of the underlying mutation of the SLC35C1 gene. Fucose therapy can be beneficial in treating recurrent infections associated with this form of CDG and improving health. However, fucose therapy does not help with other symptoms of this disorder. Some individuals with PIGM-CDG have been treated with butyrate, which increases the production of protein from the PIGM gene and is able to help manage seizures associated with this form of CDG.Individuals with PGM1-CDG can be treated with D-galactose supplementation, which is usually well tolerated and associated with decreased bleeding, improvement of laboratory markers and increased quality of life in some patients. Larger trials are underway. Other disorders, such as SLC35A2-CDG may respond to D-galactose supplementation, but these results are at very preliminary. CAD-CDG is caused by mutations that limit the body’s ability to make uridine, an important molecule for many cellular functions. Symptoms include developmental delay and seizures among other issues. Providing uridine supplements (triacetyl uridine) shows remarkable improvement within days of starting therapy and prolonged treatment gives further improvements. Symptomatic therapies are common for infants and children with CDG including nutritional supplements to ensure maximum caloric intake. In addition, some children may require the insertion of a tube through a small surgical opening in the stomach (gastrostomy) or a tube through the nose, down the esophagus and into the stomach (nasogastric tube). Many children with a CDG develop persistent vomiting and dysfunction of oral motor skills, which involve the muscles of the face and throat. A variety of therapies may be necessary to ensure proper feeding including agents to thicken food, antacids and maintaining an upright position when eating. Maintaining proper nutrition and caloric intake is critical for infants with chronic disorders and often a particular challenge for infants and children with CDG. Additional therapies for CDG depend upon the specific abnormalities present and generally follow standard guidelines. For example, anti-seizure medications (anti-convulsants) may be used to treat seizures, thyroid hormone may be used to treat hypothyroidism and surgery may be used to treat certain skeletal malformations. Blood clotting abnormalities (coagulopathies) require special attention if affected individuals need surgery, but rarely pose problems during normal daily activities. Early developmental intervention is also important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Additional medical, social, and/or vocational services including special remedial education may also be beneficial. Ongoing counseling and support for parents is beneficial as well. Genetic counseling is also important for affected individuals and their families. | Therapies of Congenital Disorders of Glycosylation. TreatmentThe treatment of most forms of CDG is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, surgeons, cardiologists, speech pathologists, ophthalmologists, gastroenterologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. The specific therapeutic procedures and interventions for individuals with a CDG will vary depending upon numerous factors including the specific symptoms, severity of the disorder, an individual’s age and overall health and tolerance to certain medications or procedures. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of their case; a thorough discussion of the potential benefits and risks including possible side effects and long-term effects; patient preference; and other appropriate factors.Although there is no specific therapy for most forms of CDG, certain disorders have an existing therapy and others are in development. Some examples are provided below: Individuals with PMM2-CDG treated with acetazolamide showed improvement on standardized evaluation tests. It was clearly effective for improving motor cerebellar functions. Larger trials are underway. Acetazolamide has been used since the 1950’s and is approved for use in multiple disorders including glaucoma and epilepsy. Trials are also planned for another drug, epalrestat, which is approved in Japan to treat diabetic neuropathies. Some reports claim that mannose can improve PMM2-CDG transferrin and clinical features, however, this not accurate. While mannose is unlikely to be harmful, its use is discouraged because it offers false hope. On the other hand, individuals with MPI-CDG are treated with oral mannose. This therapy bypasses the underlying genetic defect in glycosylation that causes the disorder. Some individuals have experienced a near complete resolution of most symptoms following mannose therapy. This therapy is life-saving, but close monitoring of affected individuals is required because few individuals have been diagnosed (and thus treated) for MPI-CDG. In some individuals, liver disease did not improve when given mannose.A few individuals with SLC35C1-CDG have been treated with fucose. This therapy depends upon the nature of the underlying mutation of the SLC35C1 gene. Fucose therapy can be beneficial in treating recurrent infections associated with this form of CDG and improving health. However, fucose therapy does not help with other symptoms of this disorder. Some individuals with PIGM-CDG have been treated with butyrate, which increases the production of protein from the PIGM gene and is able to help manage seizures associated with this form of CDG.Individuals with PGM1-CDG can be treated with D-galactose supplementation, which is usually well tolerated and associated with decreased bleeding, improvement of laboratory markers and increased quality of life in some patients. Larger trials are underway. Other disorders, such as SLC35A2-CDG may respond to D-galactose supplementation, but these results are at very preliminary. CAD-CDG is caused by mutations that limit the body’s ability to make uridine, an important molecule for many cellular functions. Symptoms include developmental delay and seizures among other issues. Providing uridine supplements (triacetyl uridine) shows remarkable improvement within days of starting therapy and prolonged treatment gives further improvements. Symptomatic therapies are common for infants and children with CDG including nutritional supplements to ensure maximum caloric intake. In addition, some children may require the insertion of a tube through a small surgical opening in the stomach (gastrostomy) or a tube through the nose, down the esophagus and into the stomach (nasogastric tube). Many children with a CDG develop persistent vomiting and dysfunction of oral motor skills, which involve the muscles of the face and throat. A variety of therapies may be necessary to ensure proper feeding including agents to thicken food, antacids and maintaining an upright position when eating. Maintaining proper nutrition and caloric intake is critical for infants with chronic disorders and often a particular challenge for infants and children with CDG. Additional therapies for CDG depend upon the specific abnormalities present and generally follow standard guidelines. For example, anti-seizure medications (anti-convulsants) may be used to treat seizures, thyroid hormone may be used to treat hypothyroidism and surgery may be used to treat certain skeletal malformations. Blood clotting abnormalities (coagulopathies) require special attention if affected individuals need surgery, but rarely pose problems during normal daily activities. Early developmental intervention is also important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Additional medical, social, and/or vocational services including special remedial education may also be beneficial. Ongoing counseling and support for parents is beneficial as well. Genetic counseling is also important for affected individuals and their families. | 302 | Congenital Disorders of Glycosylation |
nord_303_0 | Overview of Congenital Erythropoietic Porphyria | Congenital erythropoietic porphyria (CEP) is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in the skin cause bullae (blistering) and the fluid-filled sacs rupture, and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. CEP is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Neither parent has symptoms of CEP, but each carries a defective gene that they can pass to their children. Affected offspring have two copies of the defective gene, one inherited from each parent.CEP is one of a group of disorders known as the porphyrias. Each porphyria is characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes in the step-wise synthesis of heme, the essential component of hemoglobin and various hemo-proteins. The porphyrias can be classified as cutaneous or acute, depending on their respective manifestations (See www.porphyriafoundation.com). There are eight major porphyrias. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. People who have one type of porphyria do not develop the other types, although very rarely, patients may have two different porphyrias. | Overview of Congenital Erythropoietic Porphyria. Congenital erythropoietic porphyria (CEP) is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in the skin cause bullae (blistering) and the fluid-filled sacs rupture, and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. CEP is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Neither parent has symptoms of CEP, but each carries a defective gene that they can pass to their children. Affected offspring have two copies of the defective gene, one inherited from each parent.CEP is one of a group of disorders known as the porphyrias. Each porphyria is characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes in the step-wise synthesis of heme, the essential component of hemoglobin and various hemo-proteins. The porphyrias can be classified as cutaneous or acute, depending on their respective manifestations (See www.porphyriafoundation.com). There are eight major porphyrias. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. People who have one type of porphyria do not develop the other types, although very rarely, patients may have two different porphyrias. | 303 | Congenital Erythropoietic Porphyria |
nord_303_1 | Symptoms of Congenital Erythropoietic Porphyria | The most common symptom of CEP is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with blistering of the skin occurring after exposure. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). Affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also have loss of nails and end digits of the fingers due to infection of the underlying bone. Loss of sun exposed facial features such as lips, parts of the ears, and nose can also occur. The severity and degree of photosensitivity differ depending on the severity of the patient’s gene lesions which correlate with the deficient enzyme activity. Photosensitivity is seen from birth; however, in some cases, it may not occur until childhood, adolescence or adulthood. Patients also often have brownish discolored teeth (erythrodontia) which fluoresce under ultraviolet light as well as increased hair growth (hypertrichosis).In more severe cases, other symptoms can include a low level of red blood cells (anemia) and enlargement of the spleen. The anemia can be severe and such patients require periodic blood transfusions to maintain sufficient numbers of red blood cells. In severely affected patients, anemia may be present in the fetus. Ocular problems also can occur including corneal scarring, eye inflammation, and infections.Symptoms usually start in infancy or childhood and the diagnosis in most patients is suggested by the reddish color of the urine which stains the diapers. The diagnosis is made by finding increased levels of specific porphyrins in the urine. Diagnostic confirmation is made by measuring the specific (UROS) enzyme activity and/or by identifying the specific lesion(s) in the UROS gene which is/are responsible for the impaired enzyme. | Symptoms of Congenital Erythropoietic Porphyria. The most common symptom of CEP is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with blistering of the skin occurring after exposure. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). Affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also have loss of nails and end digits of the fingers due to infection of the underlying bone. Loss of sun exposed facial features such as lips, parts of the ears, and nose can also occur. The severity and degree of photosensitivity differ depending on the severity of the patient’s gene lesions which correlate with the deficient enzyme activity. Photosensitivity is seen from birth; however, in some cases, it may not occur until childhood, adolescence or adulthood. Patients also often have brownish discolored teeth (erythrodontia) which fluoresce under ultraviolet light as well as increased hair growth (hypertrichosis).In more severe cases, other symptoms can include a low level of red blood cells (anemia) and enlargement of the spleen. The anemia can be severe and such patients require periodic blood transfusions to maintain sufficient numbers of red blood cells. In severely affected patients, anemia may be present in the fetus. Ocular problems also can occur including corneal scarring, eye inflammation, and infections.Symptoms usually start in infancy or childhood and the diagnosis in most patients is suggested by the reddish color of the urine which stains the diapers. The diagnosis is made by finding increased levels of specific porphyrins in the urine. Diagnostic confirmation is made by measuring the specific (UROS) enzyme activity and/or by identifying the specific lesion(s) in the UROS gene which is/are responsible for the impaired enzyme. | 303 | Congenital Erythropoietic Porphyria |
nord_303_2 | Causes of Congenital Erythropoietic Porphyria | Congenital erythropoietic porphyria is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Mutations in the UROS gene cause CEP. The symptoms of CEP develop due to excessive levels of the specific porphyrins that accumulate in tissues of the body as a result of the markedly impaired function of the UROS enzyme. One female patient with very severe CEP symptoms was found to have two lesions in the UROS gene and in addition, she also had a genetic variant in a gene called ALAS2, which is usually associated with another form of cutaneous porphyria (X-linked protoporphyria). It is assumed that this additional gene variant in the ALAS2 gene is the reason why her CEP symptoms were more severe than expected.In very rare cases, one particular mutation in another gene called GATA1 has been found to cause CEP. So far, three CEP patients have been reported with the GATA1 mutation who do not have a mutation in the UROS gene. GATA1 is located on the X chromosome, which means that males with a CEP-causing mutation in this gene will develop CEP symptoms while female mutation carriers may remain asymptomatic or have less severe manifestations than their male relatives. This is due to the fact that males have one X chromosome whereas females have two. Inheritance of GATA1-related CEP is X-linked, which means that all daughters of an affected male will carry the GATA1 mutation but none of his sons will. If a female carries the GATA1 mutation, the risk for any of her children to inherit the mutation is 50% regardless of gender. | Causes of Congenital Erythropoietic Porphyria. Congenital erythropoietic porphyria is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Mutations in the UROS gene cause CEP. The symptoms of CEP develop due to excessive levels of the specific porphyrins that accumulate in tissues of the body as a result of the markedly impaired function of the UROS enzyme. One female patient with very severe CEP symptoms was found to have two lesions in the UROS gene and in addition, she also had a genetic variant in a gene called ALAS2, which is usually associated with another form of cutaneous porphyria (X-linked protoporphyria). It is assumed that this additional gene variant in the ALAS2 gene is the reason why her CEP symptoms were more severe than expected.In very rare cases, one particular mutation in another gene called GATA1 has been found to cause CEP. So far, three CEP patients have been reported with the GATA1 mutation who do not have a mutation in the UROS gene. GATA1 is located on the X chromosome, which means that males with a CEP-causing mutation in this gene will develop CEP symptoms while female mutation carriers may remain asymptomatic or have less severe manifestations than their male relatives. This is due to the fact that males have one X chromosome whereas females have two. Inheritance of GATA1-related CEP is X-linked, which means that all daughters of an affected male will carry the GATA1 mutation but none of his sons will. If a female carries the GATA1 mutation, the risk for any of her children to inherit the mutation is 50% regardless of gender. | 303 | Congenital Erythropoietic Porphyria |
nord_303_3 | Affects of Congenital Erythropoietic Porphyria | CEP is a very rare genetic disorder that affects males and females in equal numbers. Over 200 cases have been reported worldwide. | Affects of Congenital Erythropoietic Porphyria. CEP is a very rare genetic disorder that affects males and females in equal numbers. Over 200 cases have been reported worldwide. | 303 | Congenital Erythropoietic Porphyria |
nord_303_4 | Related disorders of Congenital Erythropoietic Porphyria | Symptoms of the following disorders can be similar to those of CEP. Comparisons may be useful for a differential diagnosis:CEP is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular porphyrins in the body due to deficiencies of specific enzymes essential to the synthesis of heme for hemoglobin and other hemo-proteins. The symptoms associated with the various types of porphyria differ, depending upon which of the eight enzymes in the heme biosynthesis pathway is deficient. There are two major types of porphyria: The cutaneous porphyrias which present with skin involvement, and the acute porphyrias which are usually characterized by abdominal pain and neurological symptoms.The cutaneous porphyrias include CEP, erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLP), and porphyria cutanea tarda (PCT). EPP and XLP are rare cutaneous porphyrias due to deficiencies of the enzymes ferrochelatase or aminolevulinate synthase 2, respectively. Due to abnormally low levels of these enzymes, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. The major symptom of these disorders is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). However, they typically do not have the blistering lesions seen in CEP. After exposure to light, the skin may become itchy and red. Affected individuals may also experience a burning sensation on their skin. The hands, arms, and face are the most commonly affected areas. Some people with EPP/XLP may also have complications related to liver and gallbladder function. Individuals with PCT may develop skin lesions which resemble the skin findings in CEP. The acute porphyrias are characterized by the acute onset of neurologic attacks (especially abdominal pain, hypertension, etc.) and they include autosomal dominant acute intermittent porphyria, hereditary coproporphyria and variegate porphyria (the latter two acute porphyrias also may have cutaneous manifestations), as well as autosomal recessive aminolevulinate dehydratase deficient porphyria. It is important to note that individuals with one type of porphyria usually do not develop any of the other types, although rare patients have been reported to have inherited two porphyrias.In addition to the porphyrias, there are skin disorders characterized by hypersensitivity to artificial light and sunlight besides CEP, such as epidermolysis bullosa. The skin lesions in these disorders do not resemble the skin lesions in CEP. (For more information on these disorders, choose “porphyria” and “epidermolysis bullosa” as your search terms in the Rare Disease Database.) | Related disorders of Congenital Erythropoietic Porphyria. Symptoms of the following disorders can be similar to those of CEP. Comparisons may be useful for a differential diagnosis:CEP is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular porphyrins in the body due to deficiencies of specific enzymes essential to the synthesis of heme for hemoglobin and other hemo-proteins. The symptoms associated with the various types of porphyria differ, depending upon which of the eight enzymes in the heme biosynthesis pathway is deficient. There are two major types of porphyria: The cutaneous porphyrias which present with skin involvement, and the acute porphyrias which are usually characterized by abdominal pain and neurological symptoms.The cutaneous porphyrias include CEP, erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLP), and porphyria cutanea tarda (PCT). EPP and XLP are rare cutaneous porphyrias due to deficiencies of the enzymes ferrochelatase or aminolevulinate synthase 2, respectively. Due to abnormally low levels of these enzymes, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. The major symptom of these disorders is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). However, they typically do not have the blistering lesions seen in CEP. After exposure to light, the skin may become itchy and red. Affected individuals may also experience a burning sensation on their skin. The hands, arms, and face are the most commonly affected areas. Some people with EPP/XLP may also have complications related to liver and gallbladder function. Individuals with PCT may develop skin lesions which resemble the skin findings in CEP. The acute porphyrias are characterized by the acute onset of neurologic attacks (especially abdominal pain, hypertension, etc.) and they include autosomal dominant acute intermittent porphyria, hereditary coproporphyria and variegate porphyria (the latter two acute porphyrias also may have cutaneous manifestations), as well as autosomal recessive aminolevulinate dehydratase deficient porphyria. It is important to note that individuals with one type of porphyria usually do not develop any of the other types, although rare patients have been reported to have inherited two porphyrias.In addition to the porphyrias, there are skin disorders characterized by hypersensitivity to artificial light and sunlight besides CEP, such as epidermolysis bullosa. The skin lesions in these disorders do not resemble the skin lesions in CEP. (For more information on these disorders, choose “porphyria” and “epidermolysis bullosa” as your search terms in the Rare Disease Database.) | 303 | Congenital Erythropoietic Porphyria |
nord_303_5 | Diagnosis of Congenital Erythropoietic Porphyria | The diagnosis of CEP may be suspected when the reddish-colored urine is noted at birth or later in life. This finding, or the occurrence of skin blisters on sun or light exposure, should lead to a thorough clinical evaluation and specialized laboratory tests. The diagnosis can be made by testing the urine for increased levels of specific porphyrins. Diagnostic confirmation requires the demonstration of the specific UROS enzyme deficiency and/or the lesion(s) in the UROS gene.Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in CEP families if the underlying genetic mutations are known. | Diagnosis of Congenital Erythropoietic Porphyria. The diagnosis of CEP may be suspected when the reddish-colored urine is noted at birth or later in life. This finding, or the occurrence of skin blisters on sun or light exposure, should lead to a thorough clinical evaluation and specialized laboratory tests. The diagnosis can be made by testing the urine for increased levels of specific porphyrins. Diagnostic confirmation requires the demonstration of the specific UROS enzyme deficiency and/or the lesion(s) in the UROS gene.Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in CEP families if the underlying genetic mutations are known. | 303 | Congenital Erythropoietic Porphyria |
nord_303_6 | Therapies of Congenital Erythropoietic Porphyria | Treatment
Avoidance of sunlight is essential to prevent the skin lesions in individuals with CEP. The use of topical, zinc- or titanium-oxide containing sunscreens, protective clothing, long sleeves, hats, gloves, and sunglasses are strongly recommended. Individuals with CEP will benefit from window tinting or using vinyls or films to cover the windows in their car or home. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes.Individuals with CEP are at risk for low bone density and may therefore be more likely to experience bone fractures. Especially due to the avoidance of sun exposure, all CEP patients should therefore be taking vitamin D supplementation.In addition to protection from sunlight, anemia should be treated if present. Chronic blood transfusions have been useful in decreasing the bone marrow production of the phototoxic porphyrins but must be used with caution due to complications associated with chronic transfusion therapy.When successful, bone marrow or hematopoietic stem cell transplantation can cure patients with CEP, but these procedures have a risk for complications and demise. For more information on this treatment, contact the American Porphyria Foundation.Referral to an expert porphyria center is recommended for expert diagnosis, care and genetic counseling – see Resources, The Porphyrias Consortium. Genetic counseling is strongly recommended. Other treatment is symptomatic and supportive. | Therapies of Congenital Erythropoietic Porphyria. Treatment
Avoidance of sunlight is essential to prevent the skin lesions in individuals with CEP. The use of topical, zinc- or titanium-oxide containing sunscreens, protective clothing, long sleeves, hats, gloves, and sunglasses are strongly recommended. Individuals with CEP will benefit from window tinting or using vinyls or films to cover the windows in their car or home. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes.Individuals with CEP are at risk for low bone density and may therefore be more likely to experience bone fractures. Especially due to the avoidance of sun exposure, all CEP patients should therefore be taking vitamin D supplementation.In addition to protection from sunlight, anemia should be treated if present. Chronic blood transfusions have been useful in decreasing the bone marrow production of the phototoxic porphyrins but must be used with caution due to complications associated with chronic transfusion therapy.When successful, bone marrow or hematopoietic stem cell transplantation can cure patients with CEP, but these procedures have a risk for complications and demise. For more information on this treatment, contact the American Porphyria Foundation.Referral to an expert porphyria center is recommended for expert diagnosis, care and genetic counseling – see Resources, The Porphyrias Consortium. Genetic counseling is strongly recommended. Other treatment is symptomatic and supportive. | 303 | Congenital Erythropoietic Porphyria |
nord_304_0 | Overview of Congenital Fiber Type Disproportion | Congenital fiber type disproportion (CFTD) is a rare genetic muscle disease that is usually apparent at birth (congenital myopathy). It belongs to a group of muscle conditions called the congenital myopathies that tend to affect people in a similar pattern. Major symptoms may include loss of muscle tone (hypotonia) and generalized muscle weakness. Delays in motor development are common and people with more marked muscle weakness also have abnormal side-to-side curvature of the spine (scoliosis), dislocated hips, and the permanent fixation of certain joints in a flexed position (contractures), particularly at the ankle.The diagnosis of congenital fiber type disproportion is controversial. The changes to muscle tissue that characterize the disorder can also occur in association with many other disorders or conditions including other congenital muscle disorders, myotonic dystrophy nerve disorders (such as spinal muscular atrophy), metabolic conditions, and a variety of brain malformations such as cerebellar hypoplasia. These conditions should be considered and excluded before a diagnosis of CFTD is made. Most patients with CFTD have no other affected relatives (sporadic). Some cases are inherited as an autosomal recessive or dominant trait. In one family, CFTD was inherited as an X-linked recessive trait. | Overview of Congenital Fiber Type Disproportion. Congenital fiber type disproportion (CFTD) is a rare genetic muscle disease that is usually apparent at birth (congenital myopathy). It belongs to a group of muscle conditions called the congenital myopathies that tend to affect people in a similar pattern. Major symptoms may include loss of muscle tone (hypotonia) and generalized muscle weakness. Delays in motor development are common and people with more marked muscle weakness also have abnormal side-to-side curvature of the spine (scoliosis), dislocated hips, and the permanent fixation of certain joints in a flexed position (contractures), particularly at the ankle.The diagnosis of congenital fiber type disproportion is controversial. The changes to muscle tissue that characterize the disorder can also occur in association with many other disorders or conditions including other congenital muscle disorders, myotonic dystrophy nerve disorders (such as spinal muscular atrophy), metabolic conditions, and a variety of brain malformations such as cerebellar hypoplasia. These conditions should be considered and excluded before a diagnosis of CFTD is made. Most patients with CFTD have no other affected relatives (sporadic). Some cases are inherited as an autosomal recessive or dominant trait. In one family, CFTD was inherited as an X-linked recessive trait. | 304 | Congenital Fiber Type Disproportion |
nord_304_1 | Symptoms of Congenital Fiber Type Disproportion | The symptoms of CFTD are similar to other types of congenital myopathy and may vary from case to case. Most individuals have loss of muscle tone (hypotonia) and generalized muscle weakness that is present at or shortly after birth (congenital). In most cases, muscle weakness is a benign, nonprogressive condition that may even improve with age. Muscles closest to the trunk of the body (proximal muscles) such as those of the hip and shoulder area (limb-girdle) and muscles of the spine and neck (truncal muscles) are usually affected the most. A variety of additional abnormalities have been associated with CFTD including side-to-side curvature of the spine (scoliosis), dislocation of the hips, permanent fixation of certain joints in a flexed position (contractures), diminished reflexes, and delays in attaining motor milestones. Intelligence is typically unaffected. Some infants with CFTD may fail to grow and gain weight at the expected rate (failure to thrive). Infants with CFTD often have distinctive facial features including a long, thin face, an abnormally high roof of the mouth (highly arched palate), and weak facial muscles. CFTD cannot be diagnosed on physical characteristics alone since many other forms of congenital myopathy share these physical features. A combination of physical features and changes on muscle biopsy is used to make the diagnosis.In approximately 25 percent of cases, affected individuals may have a more severe form of CFTD characterized by severe weakness that may progress and that may cause serious complications including difficulty swallowing (dysphagia) and life-threatening respiratory muscle weakness. In rare cases, CFTD is associated with disease of the heart muscle (cardiomyopathy). In approximately 20 percent of cases, paralysis of certain eye muscles (ophthalmoplegia) may also occur. Ophthalmoplegia is often associated with a more severe form of the disorder. | Symptoms of Congenital Fiber Type Disproportion. The symptoms of CFTD are similar to other types of congenital myopathy and may vary from case to case. Most individuals have loss of muscle tone (hypotonia) and generalized muscle weakness that is present at or shortly after birth (congenital). In most cases, muscle weakness is a benign, nonprogressive condition that may even improve with age. Muscles closest to the trunk of the body (proximal muscles) such as those of the hip and shoulder area (limb-girdle) and muscles of the spine and neck (truncal muscles) are usually affected the most. A variety of additional abnormalities have been associated with CFTD including side-to-side curvature of the spine (scoliosis), dislocation of the hips, permanent fixation of certain joints in a flexed position (contractures), diminished reflexes, and delays in attaining motor milestones. Intelligence is typically unaffected. Some infants with CFTD may fail to grow and gain weight at the expected rate (failure to thrive). Infants with CFTD often have distinctive facial features including a long, thin face, an abnormally high roof of the mouth (highly arched palate), and weak facial muscles. CFTD cannot be diagnosed on physical characteristics alone since many other forms of congenital myopathy share these physical features. A combination of physical features and changes on muscle biopsy is used to make the diagnosis.In approximately 25 percent of cases, affected individuals may have a more severe form of CFTD characterized by severe weakness that may progress and that may cause serious complications including difficulty swallowing (dysphagia) and life-threatening respiratory muscle weakness. In rare cases, CFTD is associated with disease of the heart muscle (cardiomyopathy). In approximately 20 percent of cases, paralysis of certain eye muscles (ophthalmoplegia) may also occur. Ophthalmoplegia is often associated with a more severe form of the disorder. | 304 | Congenital Fiber Type Disproportion |
nord_304_2 | Causes of Congenital Fiber Type Disproportion | Most cases of CFTD occur without any previous family history. However, a number of familial cases have been reported and it is clear that CFTD can arise from changes (mutations) in one of different disease genes (genetic heterogeneity). Familial cases have indicated that the disorder may be inherited as an autosomal recessive or autosomal dominant trait. In one rare case, CFTD was inherited as an X-linked recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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 chance of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders are disorders in which individuals only develop the disorder when they inherit two abnormal copies of a gene, one from each parent. If an individual receives one normal copy of the gene and one abnormal gene copyfor the disease, the person will be a carrier for the disease, but usually will not show symptoms. The chance for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The chance of having a child who is a carrier like the parents is 50% with each pregnancy. The chance that a child will receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but in the cells of all normal females, 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 many cells in the body (usually around half) make use of the normal copy of the gene, and inactivate the X chromosome with the abnormal copy, which usually protects them from disease. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy of having a carrier daughter like themselves, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son. Investigators have determined that some cases of autosomal dominant CFTD are caused by disruptions or changes of several different genes. These are, in rough order of frequency, the i) alpha-tropomyosin-slow gene (TPM3), ii) alpha-skeletal actin gene (ACTA1), iii) beta-tropomyosin gene (TPM2) and iv) beta-myosin gene (MYH7).Investigators have identified that some families with autosomal recessive CFTD are caused by disruptions or changes in the ryanodine receptor type 1 gene (RYR1).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42.1” refers to band 42.1 on the long arm (q) of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Investigators have also determined that X-linked recessive CFTD may be caused by disruptions or changes of an unidentified gene located on the X chromosome. Previously, mutations of the selenoprotein N gene (SEPN1), also located on chromosome 1, were linked to some cases of autosomal recessive CFTD but these are not now usually diagnosed with CFTD based on new diagnostic criteria. At present, a specific genetic cause cannot be identified in around half of affected individuals.The symptoms and findings associated with CFTD are associated with abnormalities in the relative size and distribution of certain types of muscle fibers (i.e., fiber types I and II). Muscle fibers are the highly organized, specialized, contractile cells of skeletal or cardiac muscle tissue. In individuals with CFTD, type I fibers are abnormally, uniformly small (hypotrophic) and are usually (but not always) present in increased numbers (type I fiber predominance). Previously a diagnosis of CFTD was considered if type I muscle fibers were, on average, at least 12 percent smaller (in diameter) than type II muscle fibers. Now, CFTD is usually only when type I fibres are at least 35-40% smaller than type II fibres, on average. In many CFTD patient, this size disproportion arises because type I fibers are smaller than normal (hypotrophic) and type II fibers are larger than normal (hypertrophic) and often a class of type II fibers (called type IIB fibers) is absent. This same pattern of abnormalities can occur with a number of other, defined neurological conditions and it is important that these are considered before a diagnosis of CFTD is made. Since this pattern of muscle changes is not specific, some researchers have suggested using the term “fiber size disproportion” (FSD) to describe it and to reserve “congenital fiber size disproportion” for individuals with FSD and clinical features of a congenital myopathy when there is no other identifiable diagnosis. | Causes of Congenital Fiber Type Disproportion. Most cases of CFTD occur without any previous family history. However, a number of familial cases have been reported and it is clear that CFTD can arise from changes (mutations) in one of different disease genes (genetic heterogeneity). Familial cases have indicated that the disorder may be inherited as an autosomal recessive or autosomal dominant trait. In one rare case, CFTD was inherited as an X-linked recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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 chance of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders are disorders in which individuals only develop the disorder when they inherit two abnormal copies of a gene, one from each parent. If an individual receives one normal copy of the gene and one abnormal gene copyfor the disease, the person will be a carrier for the disease, but usually will not show symptoms. The chance for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The chance of having a child who is a carrier like the parents is 50% with each pregnancy. The chance that a child will receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but in the cells of all normal females, 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 many cells in the body (usually around half) make use of the normal copy of the gene, and inactivate the X chromosome with the abnormal copy, which usually protects them from disease. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy of having a carrier daughter like themselves, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son. Investigators have determined that some cases of autosomal dominant CFTD are caused by disruptions or changes of several different genes. These are, in rough order of frequency, the i) alpha-tropomyosin-slow gene (TPM3), ii) alpha-skeletal actin gene (ACTA1), iii) beta-tropomyosin gene (TPM2) and iv) beta-myosin gene (MYH7).Investigators have identified that some families with autosomal recessive CFTD are caused by disruptions or changes in the ryanodine receptor type 1 gene (RYR1).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42.1” refers to band 42.1 on the long arm (q) of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Investigators have also determined that X-linked recessive CFTD may be caused by disruptions or changes of an unidentified gene located on the X chromosome. Previously, mutations of the selenoprotein N gene (SEPN1), also located on chromosome 1, were linked to some cases of autosomal recessive CFTD but these are not now usually diagnosed with CFTD based on new diagnostic criteria. At present, a specific genetic cause cannot be identified in around half of affected individuals.The symptoms and findings associated with CFTD are associated with abnormalities in the relative size and distribution of certain types of muscle fibers (i.e., fiber types I and II). Muscle fibers are the highly organized, specialized, contractile cells of skeletal or cardiac muscle tissue. In individuals with CFTD, type I fibers are abnormally, uniformly small (hypotrophic) and are usually (but not always) present in increased numbers (type I fiber predominance). Previously a diagnosis of CFTD was considered if type I muscle fibers were, on average, at least 12 percent smaller (in diameter) than type II muscle fibers. Now, CFTD is usually only when type I fibres are at least 35-40% smaller than type II fibres, on average. In many CFTD patient, this size disproportion arises because type I fibers are smaller than normal (hypotrophic) and type II fibers are larger than normal (hypertrophic) and often a class of type II fibers (called type IIB fibers) is absent. This same pattern of abnormalities can occur with a number of other, defined neurological conditions and it is important that these are considered before a diagnosis of CFTD is made. Since this pattern of muscle changes is not specific, some researchers have suggested using the term “fiber size disproportion” (FSD) to describe it and to reserve “congenital fiber size disproportion” for individuals with FSD and clinical features of a congenital myopathy when there is no other identifiable diagnosis. | 304 | Congenital Fiber Type Disproportion |
nord_304_3 | Affects of Congenital Fiber Type Disproportion | CFTD affects males and females in equal numbers. The incidence of the disorder in the general population is unknown but it is uncommon. The disorder is usually present at birth (congenital) but may not be recognized for many months. Case reports describing children with the features of CFTD first appeared in the medical literature in the 1960s and 70s. The term congenital fiber type disproportion was first used in 1973. | Affects of Congenital Fiber Type Disproportion. CFTD affects males and females in equal numbers. The incidence of the disorder in the general population is unknown but it is uncommon. The disorder is usually present at birth (congenital) but may not be recognized for many months. Case reports describing children with the features of CFTD first appeared in the medical literature in the 1960s and 70s. The term congenital fiber type disproportion was first used in 1973. | 304 | Congenital Fiber Type Disproportion |
nord_304_4 | Related disorders of Congenital Fiber Type Disproportion | Symptoms of the following disorders can be similar to those of CFTD. Comparisons may be useful for a differential diagnosis.CFTD belongs to the group of muscle disorders (myopathies) called the congenital myopathies. These conditions are usually present at birth (congenital) and they are distinguished from other early-onset muscle disorders (such as the congenital muscular dystrophies) on the pattern of changes seen on a muscle biopsy. The congenital myopathies are characterized by muscle weakness, loss of muscle tone (hypotonia), diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some congenital myopathies, muscle weakness is slowly progressive and may result in life-threatening complications. This group of disorders includes nemaline rod myopathy, central core disease, centronuclear myopathy, and minimulticore myopathy. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life, even in adulthood. Inheritance of these disorders can be either autosomal recessive, autosomal dominant (inherited from a parent or new dominant), or X-linked recessive. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) is a group of inherited progressive neuromuscular disorders 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 (atrophy). 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 usually inherited as an autosomal recessive trait. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) | Related disorders of Congenital Fiber Type Disproportion. Symptoms of the following disorders can be similar to those of CFTD. Comparisons may be useful for a differential diagnosis.CFTD belongs to the group of muscle disorders (myopathies) called the congenital myopathies. These conditions are usually present at birth (congenital) and they are distinguished from other early-onset muscle disorders (such as the congenital muscular dystrophies) on the pattern of changes seen on a muscle biopsy. The congenital myopathies are characterized by muscle weakness, loss of muscle tone (hypotonia), diminished reflexes, and delays in reaching motor milestones (e.g., walking). In some congenital myopathies, muscle weakness is slowly progressive and may result in life-threatening complications. This group of disorders includes nemaline rod myopathy, central core disease, centronuclear myopathy, and minimulticore myopathy. Congenital myopathies are usually apparent in the newborn (neonatal) period, but may present much later in life, even in adulthood. Inheritance of these disorders can be either autosomal recessive, autosomal dominant (inherited from a parent or new dominant), or X-linked recessive. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) is a group of inherited progressive neuromuscular disorders 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 (atrophy). 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 usually inherited as an autosomal recessive trait. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) | 304 | Congenital Fiber Type Disproportion |
nord_304_5 | Diagnosis of Congenital Fiber Type Disproportion | A diagnosis of CFTD is one of exclusion. A diagnosis may be suspected based upon a thorough clinical evaluation, identification of characteristic findings (i.e., hypotonia and muscle weakness) and a variety of specialized tests including one that assesses muscle tissue (electromyography) and a muscle biopsy.During an electromyography, a needle with an attached electrode is inserted through the skin into the muscle. The electrode detects and records the electrical activity of the muscle at rest and when it contracts. This information can determine whether damage to muscle or nerves is present. During a muscle biopsy, muscle tissue is surgically removed and examined under a microscope to detect characteristic changes to muscle tissue (i.e., fiber size disproportion). | Diagnosis of Congenital Fiber Type Disproportion. A diagnosis of CFTD is one of exclusion. A diagnosis may be suspected based upon a thorough clinical evaluation, identification of characteristic findings (i.e., hypotonia and muscle weakness) and a variety of specialized tests including one that assesses muscle tissue (electromyography) and a muscle biopsy.During an electromyography, a needle with an attached electrode is inserted through the skin into the muscle. The electrode detects and records the electrical activity of the muscle at rest and when it contracts. This information can determine whether damage to muscle or nerves is present. During a muscle biopsy, muscle tissue is surgically removed and examined under a microscope to detect characteristic changes to muscle tissue (i.e., fiber size disproportion). | 304 | Congenital Fiber Type Disproportion |
nord_304_6 | Therapies of Congenital Fiber Type Disproportion | TreatmentNo specific therapy exists for individuals with CFTD. Treatment is directed toward the specific symptoms that are apparent in each individual. Physical therapy and orthopedic treatment (e.g., braces or surgery) of contractures may be necessary. Physical therapy may also help strengthen muscles.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Congenital Fiber Type Disproportion. TreatmentNo specific therapy exists for individuals with CFTD. Treatment is directed toward the specific symptoms that are apparent in each individual. Physical therapy and orthopedic treatment (e.g., braces or surgery) of contractures may be necessary. Physical therapy may also help strengthen muscles.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. | 304 | Congenital Fiber Type Disproportion |
nord_305_0 | Overview of Congenital Fibrosis of the Extraocular Muscles | Congenital fibrosis of the extraocular muscles (CFEOM) includes at least five rare genetic eye movement disorders present at birth that are characterized by incomitant strabismus. Specifically, there is an inability to move the eyes in certain directions (opthalmoplegia), droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. The oculomotor nucleus and nerve (cranial nerve III) and the muscles it serves and, in some cases the trochlear nucleus and nerve (cranial nerve IV) and/or the abducens nucleus and nerve (cranial nerve VI) and the muscles they serve are affected. | Overview of Congenital Fibrosis of the Extraocular Muscles. Congenital fibrosis of the extraocular muscles (CFEOM) includes at least five rare genetic eye movement disorders present at birth that are characterized by incomitant strabismus. Specifically, there is an inability to move the eyes in certain directions (opthalmoplegia), droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. The oculomotor nucleus and nerve (cranial nerve III) and the muscles it serves and, in some cases the trochlear nucleus and nerve (cranial nerve IV) and/or the abducens nucleus and nerve (cranial nerve VI) and the muscles they serve are affected. | 305 | Congenital Fibrosis of the Extraocular Muscles |
nord_305_1 | Symptoms of Congenital Fibrosis of the Extraocular Muscles | Affected individuals have limited ability to move their eyes vertically (upward and downward) and can have variable limitations in moving their eyes horizontally. CFEOM is also frequently associated with droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. Individuals with CFEOM often have their eyes fixed in a downward position, and elevate the chin so they can see. These disorders have been classified as CFEOM1, CFEOM2, and CFEOM3 based on ophthalmologic findings and molecular genetic testing. CFEOM3 can be characterized by additional involvement of the peripheral and central nervous system in addition to the eye findings. Tukel syndrome is characterized by missing and webbed fingers and toes in addition to the eye findings. These disorders do not worsen over time. | Symptoms of Congenital Fibrosis of the Extraocular Muscles. Affected individuals have limited ability to move their eyes vertically (upward and downward) and can have variable limitations in moving their eyes horizontally. CFEOM is also frequently associated with droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. Individuals with CFEOM often have their eyes fixed in a downward position, and elevate the chin so they can see. These disorders have been classified as CFEOM1, CFEOM2, and CFEOM3 based on ophthalmologic findings and molecular genetic testing. CFEOM3 can be characterized by additional involvement of the peripheral and central nervous system in addition to the eye findings. Tukel syndrome is characterized by missing and webbed fingers and toes in addition to the eye findings. These disorders do not worsen over time. | 305 | Congenital Fibrosis of the Extraocular Muscles |
nord_305_2 | Causes of Congenital Fibrosis of the Extraocular Muscles | CFEOM 1 and CFEOM 3 are inherited as autosomal dominant genetic conditions. CFEOM 2 and Tukel syndrome are inherited as autosomal recessive genetic conditions. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Several genes have been found to be associated with the CFEOM syndromes: KIF21A gene – CFEOM 1 and rarely CFEOM 3 PHOX2A gene – CFEOM 2 TUBB3 gene – CFEOM3 and rarely CFEOM1, and can be associated with additional findings, referred to as the TUBB3 syndromes. TUBB2B gene – CFEOM3 in association with polymicrogyriaFEOM4 locus on chromosome 13 – CFEOM 3TUKLS locus on chromosome 21 – Tukel syndrome | Causes of Congenital Fibrosis of the Extraocular Muscles. CFEOM 1 and CFEOM 3 are inherited as autosomal dominant genetic conditions. CFEOM 2 and Tukel syndrome are inherited as autosomal recessive genetic conditions. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Several genes have been found to be associated with the CFEOM syndromes: KIF21A gene – CFEOM 1 and rarely CFEOM 3 PHOX2A gene – CFEOM 2 TUBB3 gene – CFEOM3 and rarely CFEOM1, and can be associated with additional findings, referred to as the TUBB3 syndromes. TUBB2B gene – CFEOM3 in association with polymicrogyriaFEOM4 locus on chromosome 13 – CFEOM 3TUKLS locus on chromosome 21 – Tukel syndrome | 305 | Congenital Fibrosis of the Extraocular Muscles |
nord_305_3 | Affects of Congenital Fibrosis of the Extraocular Muscles | CFEOM are rare disorders that have been seen in a range of diverse ethnic populations and affect males and females. A minimum prevalence has been estimated to be 1 in 230,000. | Affects of Congenital Fibrosis of the Extraocular Muscles. CFEOM are rare disorders that have been seen in a range of diverse ethnic populations and affect males and females. A minimum prevalence has been estimated to be 1 in 230,000. | 305 | Congenital Fibrosis of the Extraocular Muscles |
nord_305_4 | Related disorders of Congenital Fibrosis of the Extraocular Muscles | Strabismus is a common group of eye movement disorders in which the eyes are not properly yoked together and one or both eyes are misaligned and cannot be voluntarily controlled. Strabismus is either concomitant or incomitant. Concomitant strabismus occurs when the misalignment, or the angle of deviation between the two eyes, remains constant and independent of the direction of gaze. Strabismus is incomitant when the misalignment varies with gaze direction. Congenital cranial dysinnervation disorders include the various forms of incomitant strabismus such as CFEOM, Duane syndrome, Moebius syndrome, and Brown syndrome. Strabismus may be an isolated finding or found in association with other birth defects. Duane syndrome is an eye movement disorder present at birth characterized by horizontal eye movement limitation (adduction), outward eye movement limitation toward the ear (abduction), or in both directions. In addition, when the affected eye moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some cases, when the eye attempts to look inward, it moves upward or downward. (For more information on this disorder, choose “Duane syndrome” as your search term in the Rare Disease Database.)Moebius syndrome is a congenital disorder in which the eye(s) cannot move fully outward toward the ear (abduction), and there is facial weakness. Brown syndrome is a rare eye movement disorder in which the affected eye is unable to look inward towards the nose (adduction) and upward, and may be out of alignment with the unaffected eye. Brown syndrome is thought to be caused by abnormalities in the superior oblique tendon sheath in the muscle that surrounds the eyeball. (For more information on this disorder, choose “Brown syndrome” as your search term in the Rare Disease Database.) | Related disorders of Congenital Fibrosis of the Extraocular Muscles. Strabismus is a common group of eye movement disorders in which the eyes are not properly yoked together and one or both eyes are misaligned and cannot be voluntarily controlled. Strabismus is either concomitant or incomitant. Concomitant strabismus occurs when the misalignment, or the angle of deviation between the two eyes, remains constant and independent of the direction of gaze. Strabismus is incomitant when the misalignment varies with gaze direction. Congenital cranial dysinnervation disorders include the various forms of incomitant strabismus such as CFEOM, Duane syndrome, Moebius syndrome, and Brown syndrome. Strabismus may be an isolated finding or found in association with other birth defects. Duane syndrome is an eye movement disorder present at birth characterized by horizontal eye movement limitation (adduction), outward eye movement limitation toward the ear (abduction), or in both directions. In addition, when the affected eye moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some cases, when the eye attempts to look inward, it moves upward or downward. (For more information on this disorder, choose “Duane syndrome” as your search term in the Rare Disease Database.)Moebius syndrome is a congenital disorder in which the eye(s) cannot move fully outward toward the ear (abduction), and there is facial weakness. Brown syndrome is a rare eye movement disorder in which the affected eye is unable to look inward towards the nose (adduction) and upward, and may be out of alignment with the unaffected eye. Brown syndrome is thought to be caused by abnormalities in the superior oblique tendon sheath in the muscle that surrounds the eyeball. (For more information on this disorder, choose “Brown syndrome” as your search term in the Rare Disease Database.) | 305 | Congenital Fibrosis of the Extraocular Muscles |
nord_305_5 | Diagnosis of Congenital Fibrosis of the Extraocular Muscles | The diagnosis of CFEOM is made by a thorough eye examination, with special attention to the presence of other eye or systemic malformations. Measurements of the ocular (eye) misalignment, ocular range of motion, head turn, glove (eyeball) retraction, palpebral fissure (eye opening) size, and upward and downward movement of the eye are taken. Forced duction (the rotation of the eye by its extraocular muscles) and vision tests are also recommended.Molecular genetic testing is available to identify mutations in the KIF21A, PHOX2A, TUBB3, and TUBB2B genes and confirms the diagnosis. | Diagnosis of Congenital Fibrosis of the Extraocular Muscles. The diagnosis of CFEOM is made by a thorough eye examination, with special attention to the presence of other eye or systemic malformations. Measurements of the ocular (eye) misalignment, ocular range of motion, head turn, glove (eyeball) retraction, palpebral fissure (eye opening) size, and upward and downward movement of the eye are taken. Forced duction (the rotation of the eye by its extraocular muscles) and vision tests are also recommended.Molecular genetic testing is available to identify mutations in the KIF21A, PHOX2A, TUBB3, and TUBB2B genes and confirms the diagnosis. | 305 | Congenital Fibrosis of the Extraocular Muscles |
nord_305_6 | Therapies of Congenital Fibrosis of the Extraocular Muscles | TreatmentEyeglasses and contact lenses are used to treat focusing problems (refractive errors). Reduced vision that is not correctable by these devices (amblyopia) can be treated by making the child use the eye with the reduced vision. This can be done by inserting a drop of atropine in the stronger eye once a day to temporarily blur the vision so that the child will prefer to use the eye with amblyopia or by placing a patch over the stronger eye.The standard management of CFEOM may involve surgery. The goal of surgery is the elimination or improvement of an unacceptable head position, the reduction of ptosis, and the elimination or reduction of significant misalignment of the eyes. Successful surgery at a young age may avoid loss of vision in one or both eyes. However, surgery does not eliminate the fundamental abnormality, and no surgical technique has been completely successful in eliminating the abnormal eye movements. The choice of procedure must be individualized. | Therapies of Congenital Fibrosis of the Extraocular Muscles. TreatmentEyeglasses and contact lenses are used to treat focusing problems (refractive errors). Reduced vision that is not correctable by these devices (amblyopia) can be treated by making the child use the eye with the reduced vision. This can be done by inserting a drop of atropine in the stronger eye once a day to temporarily blur the vision so that the child will prefer to use the eye with amblyopia or by placing a patch over the stronger eye.The standard management of CFEOM may involve surgery. The goal of surgery is the elimination or improvement of an unacceptable head position, the reduction of ptosis, and the elimination or reduction of significant misalignment of the eyes. Successful surgery at a young age may avoid loss of vision in one or both eyes. However, surgery does not eliminate the fundamental abnormality, and no surgical technique has been completely successful in eliminating the abnormal eye movements. The choice of procedure must be individualized. | 305 | Congenital Fibrosis of the Extraocular Muscles |
nord_306_0 | Overview of Congenital Generalized Lipodystrophy | Summary Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare genetic disorder characterized by the near total loss of body fat (adipose tissue) and extreme muscularity that is often present at birth or soon thereafter. CGL is associated with metabolic complications related to insulin resistance such as an inability to break down (metabolize) glucose intolerance (high blood glucose levels after oral glucose administration), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), and diabetes. Diabetes associated with CGL is often very difficult to treat. Additional complications such as those affecting the liver and heart can also occur. The symptoms and severity of CGL can vary greatly from one person to another. There are four different subtypes of CGL each caused by changes (called variants or mutations) in different genes. All of the known types of CGL are inherited in an autosomal recessive pattern.IntroductionLipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. In addition to CGL, there are other inherited forms of lipodystrophy. Some forms of lipodystrophy are not inherited but acquired at some point during life (acquired lipodystrophy). The degree of severity and the specific areas of the body affected can vary among the lipodystrophies. The loss of adipose tissue that characterizes these disorders is sometimes referred to as lipoatrophy rather than lipodystrophy by some physicians. CGL was first described in the medical literature by Dr. Berardinelli in 1954 and reviewed by Dr. Seip in 1959. | Overview of Congenital Generalized Lipodystrophy. Summary Congenital generalized lipodystrophy (CGL), also known as Berardinelli-Seip syndrome, is a rare genetic disorder characterized by the near total loss of body fat (adipose tissue) and extreme muscularity that is often present at birth or soon thereafter. CGL is associated with metabolic complications related to insulin resistance such as an inability to break down (metabolize) glucose intolerance (high blood glucose levels after oral glucose administration), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), and diabetes. Diabetes associated with CGL is often very difficult to treat. Additional complications such as those affecting the liver and heart can also occur. The symptoms and severity of CGL can vary greatly from one person to another. There are four different subtypes of CGL each caused by changes (called variants or mutations) in different genes. All of the known types of CGL are inherited in an autosomal recessive pattern.IntroductionLipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. In addition to CGL, there are other inherited forms of lipodystrophy. Some forms of lipodystrophy are not inherited but acquired at some point during life (acquired lipodystrophy). The degree of severity and the specific areas of the body affected can vary among the lipodystrophies. The loss of adipose tissue that characterizes these disorders is sometimes referred to as lipoatrophy rather than lipodystrophy by some physicians. CGL was first described in the medical literature by Dr. Berardinelli in 1954 and reviewed by Dr. Seip in 1959. | 306 | Congenital Generalized Lipodystrophy |
nord_306_1 | Symptoms of Congenital Generalized Lipodystrophy | Infants with all forms of CGL have a near total absence of body fat at birth or soon thereafter. They also have an extremely muscular appearance and may display prominent superficial veins. During early childhood, most children grow at an accelerated rate and have slightly enlarged hands, feet, and jaws (acromegaloid features). Infants and children have a markedly increased appetite and have been described as voracious eaters.In individuals with CGL, fat deposits build up in areas of the body such as the muscles and liver. Consequently, affected individuals may develop abnormal enlargement of the muscles (muscular hypertrophy) or the liver (hepatomegaly). Some individuals may also have an abnormally enlarged spleen (splenomegaly). Hepatomegaly is often noticed during infancy. Fat accumulation in the liver (known as fatty liver or hepatic steatosis) may eventually cause scarring and damage to the liver (cirrhosis) and liver dysfunction. Ultimately, liver failure may develop in some patient, necessitating a liver transplant.Individuals with CGL develop metabolic complications associated with insulin resistance. Some individuals with CGL have a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck, groin and armpits (axillae). Other complications of insulin resistance may occur at a young age (often between 15-20 years of age) including glucose intolerance, hypertriglyceridemia, and diabetes. These complications are often very difficult to control, and diabetes is often severe. Some individuals may experience extreme hypertriglyceridemia and chylomicronemia a condition characterized by the accumulation of chylomicrons (lipoprotein particles carrying fat) in the plasma. In some cases, this can result in episodes of acute inflammation of the pancreas (pancreatitis). Acute pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.Intellectual disability can occur in CGL, especially in cases caused by mutations of the BSCL2 gene (CGL type 2). However, the presence and/or severity of intellectual disability can vary dramatically from one person to another, even among members of the same family. Most cases have been associated with mild or moderate intellectual disability. Intellectual disability is not common in other forms of CGL.After puberty, some women with CGL may develop polycystic ovary syndrome (PCOS). PCOS is characterized by an imbalance of female sex hormones. Affected women may also have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, multiple cysts on the ovaries, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. Most women with CGL are unable to conceive. However, in a few reported cases, affected women have had successful pregnancies. While some affected men may have normal reproductive capabilities, others may have morphological defects of sperms or reduced sperm count.Heart irregularities may occur in some cases, especially abnormal thickening of the muscular walls of the left lower chamber of the heart (hypertrophic cardiomyopathy). This condition can obstruct the flow of blood in and out of the heart. Some individuals may have no associated symptoms; others may develop shortness of breath upon exertion, fatigue, and excessive sweating. As affected individuals age, they may experience chest pain or discomfort, irregular heartbeats, dizziness or fainting usually upon heavy exertion, and, eventually, life-threatening complications such as congestive heart failure. Hypertrophic cardiomyopathy is most common is individuals with CGL types 2 and 4. It often develops in individuals around the age of 30 but has been reported in infants as well.Additional findings have been reported in individuals with CGL including excessive sweating (hyperhidrosis). Some findings are more likely to be associated with a specific subtype of CGL such as the formation of bone cysts after puberty (more common in types 1 and 2), which can cause individuals to be prone to spontaneous fractures; bone marrow fat loss (more common in types 1 and 2); and osteoporosis and problems with vitamin D, reported patients with CGL type 3. CGL type 3 patients may have swallowing difficulty due to large esophagus with reduced motility (achalasia). Muscular dystrophy, a general term for disorders that cause muscle weakness and loss of muscle tissue, and pyloric stenosis (constriction of the opening of stomach into duodenum) is seen in individuals with CGL type 4. Irregular heartbeats (cardiac arrhythmias) and sudden death have also been associated with CGL type 4.Individuals with CGL type 1 lack metabolically active fat, which is the fat that plays a role in the storage and release of energy and is located in subcutaneous regions, intermuscular regions, the bone marrow and areas within the abdomen and chest (thoracic cavity), but mechanical fat is well preserved. Mechanical fat is the fat that supports and protects regions subjected to mechanical insults and is located in the palms, soles, eye sockets (orbits), scalp, and around the joints. Individuals with CGL type 2 are prone to having a more severe form of lipodystrophy because they also experience the loss of mechanical fat. | Symptoms of Congenital Generalized Lipodystrophy. Infants with all forms of CGL have a near total absence of body fat at birth or soon thereafter. They also have an extremely muscular appearance and may display prominent superficial veins. During early childhood, most children grow at an accelerated rate and have slightly enlarged hands, feet, and jaws (acromegaloid features). Infants and children have a markedly increased appetite and have been described as voracious eaters.In individuals with CGL, fat deposits build up in areas of the body such as the muscles and liver. Consequently, affected individuals may develop abnormal enlargement of the muscles (muscular hypertrophy) or the liver (hepatomegaly). Some individuals may also have an abnormally enlarged spleen (splenomegaly). Hepatomegaly is often noticed during infancy. Fat accumulation in the liver (known as fatty liver or hepatic steatosis) may eventually cause scarring and damage to the liver (cirrhosis) and liver dysfunction. Ultimately, liver failure may develop in some patient, necessitating a liver transplant.Individuals with CGL develop metabolic complications associated with insulin resistance. Some individuals with CGL have a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck, groin and armpits (axillae). Other complications of insulin resistance may occur at a young age (often between 15-20 years of age) including glucose intolerance, hypertriglyceridemia, and diabetes. These complications are often very difficult to control, and diabetes is often severe. Some individuals may experience extreme hypertriglyceridemia and chylomicronemia a condition characterized by the accumulation of chylomicrons (lipoprotein particles carrying fat) in the plasma. In some cases, this can result in episodes of acute inflammation of the pancreas (pancreatitis). Acute pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.Intellectual disability can occur in CGL, especially in cases caused by mutations of the BSCL2 gene (CGL type 2). However, the presence and/or severity of intellectual disability can vary dramatically from one person to another, even among members of the same family. Most cases have been associated with mild or moderate intellectual disability. Intellectual disability is not common in other forms of CGL.After puberty, some women with CGL may develop polycystic ovary syndrome (PCOS). PCOS is characterized by an imbalance of female sex hormones. Affected women may also have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, multiple cysts on the ovaries, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. Most women with CGL are unable to conceive. However, in a few reported cases, affected women have had successful pregnancies. While some affected men may have normal reproductive capabilities, others may have morphological defects of sperms or reduced sperm count.Heart irregularities may occur in some cases, especially abnormal thickening of the muscular walls of the left lower chamber of the heart (hypertrophic cardiomyopathy). This condition can obstruct the flow of blood in and out of the heart. Some individuals may have no associated symptoms; others may develop shortness of breath upon exertion, fatigue, and excessive sweating. As affected individuals age, they may experience chest pain or discomfort, irregular heartbeats, dizziness or fainting usually upon heavy exertion, and, eventually, life-threatening complications such as congestive heart failure. Hypertrophic cardiomyopathy is most common is individuals with CGL types 2 and 4. It often develops in individuals around the age of 30 but has been reported in infants as well.Additional findings have been reported in individuals with CGL including excessive sweating (hyperhidrosis). Some findings are more likely to be associated with a specific subtype of CGL such as the formation of bone cysts after puberty (more common in types 1 and 2), which can cause individuals to be prone to spontaneous fractures; bone marrow fat loss (more common in types 1 and 2); and osteoporosis and problems with vitamin D, reported patients with CGL type 3. CGL type 3 patients may have swallowing difficulty due to large esophagus with reduced motility (achalasia). Muscular dystrophy, a general term for disorders that cause muscle weakness and loss of muscle tissue, and pyloric stenosis (constriction of the opening of stomach into duodenum) is seen in individuals with CGL type 4. Irregular heartbeats (cardiac arrhythmias) and sudden death have also been associated with CGL type 4.Individuals with CGL type 1 lack metabolically active fat, which is the fat that plays a role in the storage and release of energy and is located in subcutaneous regions, intermuscular regions, the bone marrow and areas within the abdomen and chest (thoracic cavity), but mechanical fat is well preserved. Mechanical fat is the fat that supports and protects regions subjected to mechanical insults and is located in the palms, soles, eye sockets (orbits), scalp, and around the joints. Individuals with CGL type 2 are prone to having a more severe form of lipodystrophy because they also experience the loss of mechanical fat. | 306 | Congenital Generalized Lipodystrophy |
nord_306_2 | Causes of Congenital Generalized Lipodystrophy | CGL is caused by variants (mutations) of specific genes. Four genes that cause CGL have been identified including the AGPAT2 gene, which causes CGL type 1; the BSCL2 gene, which causes CGL type 2; the CAV1 gene, which causes CGL type 3; and the CAVIN1 gene, which causes CGL type 4. Some individuals with CGL do not have a mutation in any of these genes, suggesting that additional, as yet unidentified genes can cause the disorder.CGL is inherited as an autosomal recessive condition. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.The AGPAT2 gene contains instructions for creating (encoding) the enzyme AGPAT2, which is involved in the creation (synthesis) of triglycerides and fatty substances called phospholipids.The BSCL2 gene encodes a protein known as seipin. Recent data suggest a role of seipin in fusion of lipid droplets and in fat cell differentiation.The CAV1 gene encodes caveolin-1, which is expressed in caveolae, tiny structures on the surface of cells. Caveolae play a role in the formation of lipid droplets, most likely by transporting lipids and phospholipids from outside the cell to inside the cell. Lipid droplets are organelles, specialized subunits found within cells that have specific functions. One function of lipid droplets is the storage of lipids.The CAVIN1 (previously known as PTRF) gene encodes cavin 1, an essential protein factor in the creation (biogenesis) of caveolae.Researchers believe that various genes and gene products associated with CGL are involved with the proper creation, function and/or health of lipid droplets within adipocytes. Adipocytes are fat cells. Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Mutations in the above-mentioned genes ultimately lead to a loss of adipocytes and an inability to store fat. Consequently, fat is stored in other tissues of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. The cause of other symptoms sometimes associated with CGL such as cardiomyopathy is unknown. More research is necessary to understand the exact, underlying mechanisms that ultimately cause CGL and its associated symptoms. | Causes of Congenital Generalized Lipodystrophy. CGL is caused by variants (mutations) of specific genes. Four genes that cause CGL have been identified including the AGPAT2 gene, which causes CGL type 1; the BSCL2 gene, which causes CGL type 2; the CAV1 gene, which causes CGL type 3; and the CAVIN1 gene, which causes CGL type 4. Some individuals with CGL do not have a mutation in any of these genes, suggesting that additional, as yet unidentified genes can cause the disorder.CGL is inherited as an autosomal recessive condition. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.The AGPAT2 gene contains instructions for creating (encoding) the enzyme AGPAT2, which is involved in the creation (synthesis) of triglycerides and fatty substances called phospholipids.The BSCL2 gene encodes a protein known as seipin. Recent data suggest a role of seipin in fusion of lipid droplets and in fat cell differentiation.The CAV1 gene encodes caveolin-1, which is expressed in caveolae, tiny structures on the surface of cells. Caveolae play a role in the formation of lipid droplets, most likely by transporting lipids and phospholipids from outside the cell to inside the cell. Lipid droplets are organelles, specialized subunits found within cells that have specific functions. One function of lipid droplets is the storage of lipids.The CAVIN1 (previously known as PTRF) gene encodes cavin 1, an essential protein factor in the creation (biogenesis) of caveolae.Researchers believe that various genes and gene products associated with CGL are involved with the proper creation, function and/or health of lipid droplets within adipocytes. Adipocytes are fat cells. Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Mutations in the above-mentioned genes ultimately lead to a loss of adipocytes and an inability to store fat. Consequently, fat is stored in other tissues of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. The cause of other symptoms sometimes associated with CGL such as cardiomyopathy is unknown. More research is necessary to understand the exact, underlying mechanisms that ultimately cause CGL and its associated symptoms. | 306 | Congenital Generalized Lipodystrophy |
nord_306_3 | Affects of Congenital Generalized Lipodystrophy | Approximately 500-600 patients with CGL have been reported in the medical literature. The estimated worldwide prevalence ranges from 1 in a million to 1 in 10 million individuals in the general population. The disorder has been reported in individuals of every ethnic group. | Affects of Congenital Generalized Lipodystrophy. Approximately 500-600 patients with CGL have been reported in the medical literature. The estimated worldwide prevalence ranges from 1 in a million to 1 in 10 million individuals in the general population. The disorder has been reported in individuals of every ethnic group. | 306 | Congenital Generalized Lipodystrophy |
nord_306_4 | Related disorders of Congenital Generalized Lipodystrophy | Symptoms of the following disorders can be similar to those of CGL. Comparisons may be useful for a differential diagnosis.Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPLD often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most cases, adipose tissue loss begins during puberty. FPLD can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some cases. Eight genetically distinct subtypes of FPLD have been identified. Each subtype is caused by mutations in a different gene. Five forms of FPLD are inherited in an autosomal dominant pattern. Three forms are inherited in an autosomal recessive pattern. The mode of inheritance of one form is not fully understood. (For more information on this disorder, choose “familial partial lipodystrophy” as your search term in the Rare Disease Database.)Acquired lipodystrophy is a general term for types of lipodystrophy that are not inherited, but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies may be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include localized lipodystrophy, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome), and highly active antiretroviral therapy induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. Onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting certain areas of the body, especially the arms, legs, face, neck, and chest or thoracic regions. In some cases, metabolic complications associated with insulin resistance may occur. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), diabetes, and fat accumulation in the liver (fatty liver or hepatic steatosis). (For more information on these disorders, choose “acquired lipodystrophy” as your search term in the Rare Disease Database.)A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to CGL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Gilford progeria syndrome, Werner syndrome, and leprechaunism. Individuals with lipodystrophy should also be differentiated from individuals with anorexia nervosa, cachexia, diencephalic syndrome, multiple symmetric lipomatosis, and other disorders that affect growth and development. NORD has individual reports on most of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Congenital Generalized Lipodystrophy. Symptoms of the following disorders can be similar to those of CGL. Comparisons may be useful for a differential diagnosis.Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPLD often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most cases, adipose tissue loss begins during puberty. FPLD can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some cases. Eight genetically distinct subtypes of FPLD have been identified. Each subtype is caused by mutations in a different gene. Five forms of FPLD are inherited in an autosomal dominant pattern. Three forms are inherited in an autosomal recessive pattern. The mode of inheritance of one form is not fully understood. (For more information on this disorder, choose “familial partial lipodystrophy” as your search term in the Rare Disease Database.)Acquired lipodystrophy is a general term for types of lipodystrophy that are not inherited, but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies may be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include localized lipodystrophy, acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome), and highly active antiretroviral therapy induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. Onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting certain areas of the body, especially the arms, legs, face, neck, and chest or thoracic regions. In some cases, metabolic complications associated with insulin resistance may occur. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), diabetes, and fat accumulation in the liver (fatty liver or hepatic steatosis). (For more information on these disorders, choose “acquired lipodystrophy” as your search term in the Rare Disease Database.)A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to CGL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Gilford progeria syndrome, Werner syndrome, and leprechaunism. Individuals with lipodystrophy should also be differentiated from individuals with anorexia nervosa, cachexia, diencephalic syndrome, multiple symmetric lipomatosis, and other disorders that affect growth and development. NORD has individual reports on most of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 306 | Congenital Generalized Lipodystrophy |
nord_306_5 | Diagnosis of Congenital Generalized Lipodystrophy | A diagnosis of CGL is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A lipodystrophy diagnosis should be suspected in individuals who are lean or “non-obese” and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes and uric acid.The characteristic pattern of fat loss in CGL can be noted on magnetic resonance imaging (MRI). Radiographs can show the presence of lytic bones lesions that occur in some individuals with CGL.
Molecular genetic testing can confirm a diagnosis of CGL in most patients. Molecular genetic testing can detect mutations in specific genes that cause CGL and is available on a clinical basis or in some research laboratories.Individuals with CGL may be evaluated to determine their leptin levels. Leptin is a hormone found in adipocytes. Some affected individuals have low levels of leptin. Although not a diagnostic test, determining leptin levels may help physicians predict a person’s response to leptin replacement therapy. | Diagnosis of Congenital Generalized Lipodystrophy. A diagnosis of CGL is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A lipodystrophy diagnosis should be suspected in individuals who are lean or “non-obese” and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes and uric acid.The characteristic pattern of fat loss in CGL can be noted on magnetic resonance imaging (MRI). Radiographs can show the presence of lytic bones lesions that occur in some individuals with CGL.
Molecular genetic testing can confirm a diagnosis of CGL in most patients. Molecular genetic testing can detect mutations in specific genes that cause CGL and is available on a clinical basis or in some research laboratories.Individuals with CGL may be evaluated to determine their leptin levels. Leptin is a hormone found in adipocytes. Some affected individuals have low levels of leptin. Although not a diagnostic test, determining leptin levels may help physicians predict a person’s response to leptin replacement therapy. | 306 | Congenital Generalized Lipodystrophy |
nord_306_6 | Therapies of Congenital Generalized Lipodystrophy | Treatment
The treatment of CGL is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Individuals with CGL and their families are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety, stress and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling is recommended for affected individuals and their families as well.Despite the lack of clinical trial evaluation, individuals with CGL are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. However, such diets may also raise very low-density lipoprotein triglyceride concentration. It is important that children still consume sufficient energy for proper growth and development. Regular exercise and maintaining a healthy weight are also encouraged to decrease the chances of developing diabetes.Leptin is a hormone found in adipocytes. Severe lipodystrophy is sometimes associated with leptin deficiency. In 2014, the U.S. Food and Drug Administration approved Myalept (metreleptin for injection) as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. Myalept is a recombinant analogue (laboratory-created form) of human leptin and is taken once a day by subcutaneous (under the skin) injection. It has been found to be beneficial for improving metabolic complications, such as diabetes and hypertriglyceridemia. The most common side effects are low blood sugar (hypoglycemia), headache and decreased weight. Other side effects can be local reactions at injection site, possibility of developing leptin antibodies (which could result in severe infections or loss of treatment effectiveness) and rare cases of T- cell lymphoma. It is contraindicated in patients with general obesity not associated with congenital leptin deficiency and with prior severe hypersensitivity reactions to metreleptin or any of the product components. Myalept is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) which requires prescriber and pharmacy certification and special documentation. Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids from fish oils. The characteristic loss of adipose tissue in individuals with CGL cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance. Individuals with severe facial lipodystrophy can undergo reconstructive facial surgery including fascial grafts from the thighs, free flaps from the anterolateral thigh, anterior abdomen or temporalis muscle.In some patients, liver disease can ultimately require a liver transplantation.Additional therapies to treat individuals with CGL are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin and sulfonylureas may be recommended to treat hyperglycemia. Insulin can also be used to treat individuals with CGL and diabetes, although extremely high doses are often required. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications associated with CGL.Special remedial education may be necessary for individuals with intellectual disability. Psychosocial support for the entire family is essential as well. | Therapies of Congenital Generalized Lipodystrophy. Treatment
The treatment of CGL is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.Individuals with CGL and their families are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety, stress and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling is recommended for affected individuals and their families as well.Despite the lack of clinical trial evaluation, individuals with CGL are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. However, such diets may also raise very low-density lipoprotein triglyceride concentration. It is important that children still consume sufficient energy for proper growth and development. Regular exercise and maintaining a healthy weight are also encouraged to decrease the chances of developing diabetes.Leptin is a hormone found in adipocytes. Severe lipodystrophy is sometimes associated with leptin deficiency. In 2014, the U.S. Food and Drug Administration approved Myalept (metreleptin for injection) as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. Myalept is a recombinant analogue (laboratory-created form) of human leptin and is taken once a day by subcutaneous (under the skin) injection. It has been found to be beneficial for improving metabolic complications, such as diabetes and hypertriglyceridemia. The most common side effects are low blood sugar (hypoglycemia), headache and decreased weight. Other side effects can be local reactions at injection site, possibility of developing leptin antibodies (which could result in severe infections or loss of treatment effectiveness) and rare cases of T- cell lymphoma. It is contraindicated in patients with general obesity not associated with congenital leptin deficiency and with prior severe hypersensitivity reactions to metreleptin or any of the product components. Myalept is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) which requires prescriber and pharmacy certification and special documentation. Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids from fish oils. The characteristic loss of adipose tissue in individuals with CGL cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance. Individuals with severe facial lipodystrophy can undergo reconstructive facial surgery including fascial grafts from the thighs, free flaps from the anterolateral thigh, anterior abdomen or temporalis muscle.In some patients, liver disease can ultimately require a liver transplantation.Additional therapies to treat individuals with CGL are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin and sulfonylureas may be recommended to treat hyperglycemia. Insulin can also be used to treat individuals with CGL and diabetes, although extremely high doses are often required. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications associated with CGL.Special remedial education may be necessary for individuals with intellectual disability. Psychosocial support for the entire family is essential as well. | 306 | Congenital Generalized Lipodystrophy |
nord_307_0 | Overview of Congenital Heart Block | Congenital heart block (CHB), or atrioventricular block (AVB), is characterized by interference of the transfer of the electrical nerve impulses (conduction) that regulate the normal and rhythmic pumping action of the heart muscle. The severity of such conduction abnormalities varies among affected individuals.The normal heart has four chambers. The two upper chambers are the atria and the two lower chambers are the ventricles. In order for the heart to contract and pump blood to the body, it needs an electrical stimulus to signal contraction. The SA (sinoatrial) node, which is located in the right atrium, acts as a natural pacemaker that initiates and controls the heartbeat. The electrical stimulus travels from the SA node in the atrium to the ventricles along a very specific path of conducting tissue via the AV (atrioventricular) node located at the junction between the atria and ventricles. The AV node mediates proper transmission between the top and bottom chambers so that every atrial contraction is accompanied by ventricular contraction. To allow for ventricular contraction, the signal travels down the bundle branches in the His-Purkinje system, which is the electrical pathway located in the septum (the heart muscle between the two ventricles). To summarize, the SA node allows for atrial contraction, the AV node allows for transmission of the signal between the atria and ventricles, and the His-Purkinje system allows for ventricular contraction. As long as the electrical impulse is transmitted normally, the heart behaves and contracts normally allowing for blood to be pumped out to the body.If the transmission of the signal is impeded, the blocked electrical transmission is known as a heart block or an AV block. The disturbance may be transient or permanent. This condition does not affect the flow of blood and does not lead to the blockage of coronary arteries (which would lead to a heart attack). It is an electrical problem rather than a hydraulic one.Heart blocks are categorized according to the degree of impairment of the patient and the pattern of conduction abnormality. The categories are first, second, and third degree heart block. Second degree heart block is further characterized into two types: Mobitz type I and Mobitz type II. CHB can happen at any age but is termed congenital when it occurs in the fetus or newborn up to 28 days of life. Individuals may progress from one type of heart block to a more severe degree. | Overview of Congenital Heart Block. Congenital heart block (CHB), or atrioventricular block (AVB), is characterized by interference of the transfer of the electrical nerve impulses (conduction) that regulate the normal and rhythmic pumping action of the heart muscle. The severity of such conduction abnormalities varies among affected individuals.The normal heart has four chambers. The two upper chambers are the atria and the two lower chambers are the ventricles. In order for the heart to contract and pump blood to the body, it needs an electrical stimulus to signal contraction. The SA (sinoatrial) node, which is located in the right atrium, acts as a natural pacemaker that initiates and controls the heartbeat. The electrical stimulus travels from the SA node in the atrium to the ventricles along a very specific path of conducting tissue via the AV (atrioventricular) node located at the junction between the atria and ventricles. The AV node mediates proper transmission between the top and bottom chambers so that every atrial contraction is accompanied by ventricular contraction. To allow for ventricular contraction, the signal travels down the bundle branches in the His-Purkinje system, which is the electrical pathway located in the septum (the heart muscle between the two ventricles). To summarize, the SA node allows for atrial contraction, the AV node allows for transmission of the signal between the atria and ventricles, and the His-Purkinje system allows for ventricular contraction. As long as the electrical impulse is transmitted normally, the heart behaves and contracts normally allowing for blood to be pumped out to the body.If the transmission of the signal is impeded, the blocked electrical transmission is known as a heart block or an AV block. The disturbance may be transient or permanent. This condition does not affect the flow of blood and does not lead to the blockage of coronary arteries (which would lead to a heart attack). It is an electrical problem rather than a hydraulic one.Heart blocks are categorized according to the degree of impairment of the patient and the pattern of conduction abnormality. The categories are first, second, and third degree heart block. Second degree heart block is further characterized into two types: Mobitz type I and Mobitz type II. CHB can happen at any age but is termed congenital when it occurs in the fetus or newborn up to 28 days of life. Individuals may progress from one type of heart block to a more severe degree. | 307 | Congenital Heart Block |
nord_307_1 | Symptoms of Congenital Heart Block | The presentation of congenital heart block varies with age of onset, underlying etiology, and type of heart block. In newborns affected by CHB, the primary finding is a slow heart rate (bradycardia). Individuals may also appear pale or diaphoretic, have intermittent gallops and murmurs, and show signs of congestive heart failure (e.g. crackles in lungs, peripheral edema, etc.). Some individuals may present with CHB later in childhood. The primary finding is also a slow heart rate (bradycardia), which may or may not be present with bradycardia-related symptoms such as decreased exercise tolerance and presyncope or syncope (Stokes-Adams attacks). Heart block may be intermittent at first and become persistent over time. In first degree heart block, the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) slightly lag behind because it takes a longer time for the electrical impulse to move from the SA node to the AV node. If the time taken for the impulse to move from the atria to the ventricles is longer than 0.2 seconds, but no other abnormalities are present, first degree heart block is present. Most people with this mild form of the disorder do not experience any symptoms (asymptomatic). Some affected individuals may fatigue quickly and experience difficulty breathing (dyspnea). Second degree heart block is characterized by dropped or skipped beats. This signifies that some signals sent from the SA node in the atrium do not reach the ventricles because they are “blocked” or “stopped” at the AV node. Therefore, not all contractions of the atria will be followed by contractions of the ventricles. This form of the disorder may be separated into two subgroups which have different presentations: Mobitz type I (Wenckebach) and Mobitz type II.In Mobitz type I AV block, there is a progressive delay between heartbeats until a beat is dropped or skipped. Because the consequences are usually limited to short-term dizziness and modest fatigue, the condition is not considered dangerous and has excellent prognosis.Mobitz type II AV block is more rarely encountered and usually carries greater risks. It is characterized by an extremely low heart rate because most of the electrical impulses generated by the SA node in the atrium cannot get to the ventricles. Thus, the number of heartbeats is reduced. Often, affected individuals may fatigue quickly and/or experience difficulty breathing (dyspnea) and/or episodes of unconsciousness (syncope). It is, however, not uncommon for affected individuals to be symptomless (asymptomatic). In some people, a pacemaker may be inserted into the upper chest to restore normal heart rhythm.In third degree or complete heart block, none of the electrical signals from the SA node in the upper chamber reach the lower chambers. In order for the ventricles to contract, the His-Purkinje system (bundles of specialized nerves in the electrical conduction system) takes over as a natural pacemaker in the lower chambers. Thus, the atria and ventricles beat independently of one another and are not in sync because they are controlled by two different areas that do not communicate (the SA node controls the atria and the His-Purkinje system controls the ventricles). Individuals with complete heart block may experience episodes of unconsciousness (syncope), breathlessness, lack of energy (lethargy), and/or low blood pressure (hypotension). In addition, complete heart block may be associated with an impaired ability of the heart to pump blood effectively (congestive heart failure); chest pain and/or palpitations; episodes of dizziness with or without loss of consciousness due to heart fluttering (fibrillation) or cessation (asystole) of the heart (Stokes-Adams attacks); and/or enlargement of the heart (cardiomegaly). In rare cases, infants born with complete heart block may have abnormal accumulation of fluid within tissues of the body (hydrops fetalis). Treatment with a pacemaker is necessary to restore natural heart rhythm. | Symptoms of Congenital Heart Block. The presentation of congenital heart block varies with age of onset, underlying etiology, and type of heart block. In newborns affected by CHB, the primary finding is a slow heart rate (bradycardia). Individuals may also appear pale or diaphoretic, have intermittent gallops and murmurs, and show signs of congestive heart failure (e.g. crackles in lungs, peripheral edema, etc.). Some individuals may present with CHB later in childhood. The primary finding is also a slow heart rate (bradycardia), which may or may not be present with bradycardia-related symptoms such as decreased exercise tolerance and presyncope or syncope (Stokes-Adams attacks). Heart block may be intermittent at first and become persistent over time. In first degree heart block, the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) slightly lag behind because it takes a longer time for the electrical impulse to move from the SA node to the AV node. If the time taken for the impulse to move from the atria to the ventricles is longer than 0.2 seconds, but no other abnormalities are present, first degree heart block is present. Most people with this mild form of the disorder do not experience any symptoms (asymptomatic). Some affected individuals may fatigue quickly and experience difficulty breathing (dyspnea). Second degree heart block is characterized by dropped or skipped beats. This signifies that some signals sent from the SA node in the atrium do not reach the ventricles because they are “blocked” or “stopped” at the AV node. Therefore, not all contractions of the atria will be followed by contractions of the ventricles. This form of the disorder may be separated into two subgroups which have different presentations: Mobitz type I (Wenckebach) and Mobitz type II.In Mobitz type I AV block, there is a progressive delay between heartbeats until a beat is dropped or skipped. Because the consequences are usually limited to short-term dizziness and modest fatigue, the condition is not considered dangerous and has excellent prognosis.Mobitz type II AV block is more rarely encountered and usually carries greater risks. It is characterized by an extremely low heart rate because most of the electrical impulses generated by the SA node in the atrium cannot get to the ventricles. Thus, the number of heartbeats is reduced. Often, affected individuals may fatigue quickly and/or experience difficulty breathing (dyspnea) and/or episodes of unconsciousness (syncope). It is, however, not uncommon for affected individuals to be symptomless (asymptomatic). In some people, a pacemaker may be inserted into the upper chest to restore normal heart rhythm.In third degree or complete heart block, none of the electrical signals from the SA node in the upper chamber reach the lower chambers. In order for the ventricles to contract, the His-Purkinje system (bundles of specialized nerves in the electrical conduction system) takes over as a natural pacemaker in the lower chambers. Thus, the atria and ventricles beat independently of one another and are not in sync because they are controlled by two different areas that do not communicate (the SA node controls the atria and the His-Purkinje system controls the ventricles). Individuals with complete heart block may experience episodes of unconsciousness (syncope), breathlessness, lack of energy (lethargy), and/or low blood pressure (hypotension). In addition, complete heart block may be associated with an impaired ability of the heart to pump blood effectively (congestive heart failure); chest pain and/or palpitations; episodes of dizziness with or without loss of consciousness due to heart fluttering (fibrillation) or cessation (asystole) of the heart (Stokes-Adams attacks); and/or enlargement of the heart (cardiomegaly). In rare cases, infants born with complete heart block may have abnormal accumulation of fluid within tissues of the body (hydrops fetalis). Treatment with a pacemaker is necessary to restore natural heart rhythm. | 307 | Congenital Heart Block |
nord_307_2 | Causes of Congenital Heart Block | Over half the cases of congenital heart block (60-90 percent) are associated with an autoimmune disorder in the affected individual’s mother such as systemic lupus erythematosus or Sjogren's syndrome. This results in a passively acquired autoimmune disease in the child termed neonatal lupus. Autoimmune disorders occur when the body’s natural defenses against foreign or invading organisms (antibodies) begin to attack healthy tissue for unknown reasons. Congenital heart block may result when maternal antibodies cross the placenta, enter the fetus, and attack the fetal cardiac conduction system. The antibodies that were originally produced by the mother’s body to fight infections recognize parts of the conduction system in the fetal heart as foreign and abnormally attack and damage the tissues, resulting in inflammation and scarring which leads to faulty conduction. Neonatal lupus may present with other symptoms such as cutaneous lupus lesions and liver abnormalities, though these symptoms normally resolve after a few months of age when the maternal antibodies have been cleared. The heart conduction system abnormalities, on the other hand, are irreversible. Autoimmune heart block is typically of the third degree and begins in utero, while heart block due to other causes tends to present after birth and may be first, second, or third degree. In fact, up to 40 percent of AV block cases do not present until later in childhood, out of which only around 5 percent are of autoimmune origin. (For information on neonatal lupus, choose “lupus” as your search term in the Rare Disease Database.)Congenital heart blocks may or may not be associated with structural abnormalities of the heart. Almost half of children diagnosed in utero (during pregnancy have structural heart disease. When diagnosed in the postnatal period (after birth), approximately one-third have structural heart disease. There are several types of heart anomalies that can occur with abnormal fetal development, some of which are more prone to accompanying developmental anomalies of the AV conduction tissues. These include L-looped (levo) transposition of the great arteries, endocardial cushion defects, and atrial septal defects (ASDs). The most common congenital heart diseases associated with AV block are levo transposition and left atrial isomerism, which is often associated with an ASD. Presence or absence of structural heart defects significantly impact prognosis and treatment. There is also a genetic form of congenital heart block that is seen in non-immune cases without structural heart defects, which is described as an idiopathic disorder having a familial tendency. It may be inherited in an autosomal recessive pattern, although some researchers do not rule out an autosomal dominant pattern of inheritance.In some cases, congenital heart block may occur as a secondary characteristic of certain disorders or tumours of the heart muscle (myocardium). | Causes of Congenital Heart Block. Over half the cases of congenital heart block (60-90 percent) are associated with an autoimmune disorder in the affected individual’s mother such as systemic lupus erythematosus or Sjogren's syndrome. This results in a passively acquired autoimmune disease in the child termed neonatal lupus. Autoimmune disorders occur when the body’s natural defenses against foreign or invading organisms (antibodies) begin to attack healthy tissue for unknown reasons. Congenital heart block may result when maternal antibodies cross the placenta, enter the fetus, and attack the fetal cardiac conduction system. The antibodies that were originally produced by the mother’s body to fight infections recognize parts of the conduction system in the fetal heart as foreign and abnormally attack and damage the tissues, resulting in inflammation and scarring which leads to faulty conduction. Neonatal lupus may present with other symptoms such as cutaneous lupus lesions and liver abnormalities, though these symptoms normally resolve after a few months of age when the maternal antibodies have been cleared. The heart conduction system abnormalities, on the other hand, are irreversible. Autoimmune heart block is typically of the third degree and begins in utero, while heart block due to other causes tends to present after birth and may be first, second, or third degree. In fact, up to 40 percent of AV block cases do not present until later in childhood, out of which only around 5 percent are of autoimmune origin. (For information on neonatal lupus, choose “lupus” as your search term in the Rare Disease Database.)Congenital heart blocks may or may not be associated with structural abnormalities of the heart. Almost half of children diagnosed in utero (during pregnancy have structural heart disease. When diagnosed in the postnatal period (after birth), approximately one-third have structural heart disease. There are several types of heart anomalies that can occur with abnormal fetal development, some of which are more prone to accompanying developmental anomalies of the AV conduction tissues. These include L-looped (levo) transposition of the great arteries, endocardial cushion defects, and atrial septal defects (ASDs). The most common congenital heart diseases associated with AV block are levo transposition and left atrial isomerism, which is often associated with an ASD. Presence or absence of structural heart defects significantly impact prognosis and treatment. There is also a genetic form of congenital heart block that is seen in non-immune cases without structural heart defects, which is described as an idiopathic disorder having a familial tendency. It may be inherited in an autosomal recessive pattern, although some researchers do not rule out an autosomal dominant pattern of inheritance.In some cases, congenital heart block may occur as a secondary characteristic of certain disorders or tumours of the heart muscle (myocardium). | 307 | Congenital Heart Block |
nord_307_3 | Affects of Congenital Heart Block | Congenital heart block is a rare disorder that appears to affect males and females in equal numbers. In the general population, the incidence varies between 1 in 15,000 to 1 in 22,000 live births. The incidence of complete (third degree) congenital heart block is one in approximately 20,000 to 25,000 live births. The recurrence rate of congenital heart block in subsequent pregnancies in women who have had an affected child is 15 percent. | Affects of Congenital Heart Block. Congenital heart block is a rare disorder that appears to affect males and females in equal numbers. In the general population, the incidence varies between 1 in 15,000 to 1 in 22,000 live births. The incidence of complete (third degree) congenital heart block is one in approximately 20,000 to 25,000 live births. The recurrence rate of congenital heart block in subsequent pregnancies in women who have had an affected child is 15 percent. | 307 | Congenital Heart Block |
nord_307_4 | Related disorders of Congenital Heart Block | Symptoms of bundle branch block, another disorder affecting the heart’s electrical activity, can be similar to those of congenital heart block. Comparison may be useful for a differential diagnosis.Bundle branch block is a heart block caused by a lesion in one of the bundle branches located in the septum (the heart muscle between the two ventricles). There is a right and a left bundle branch, and damage to either will affect the electrical system of the respective side of the heart. It usually indicates cardiovascular disease; though right bundle branch block may be recorded in persons showing no clinical evidence of cardiovascular disease. In either case, it is characterized by a slowing of the conduction in the bundle branches of the heart. Often times patients do not show symptoms (asymptomatic), but may have fainting episodes (syncope) or feel they are going to faint (presyncope). | Related disorders of Congenital Heart Block. Symptoms of bundle branch block, another disorder affecting the heart’s electrical activity, can be similar to those of congenital heart block. Comparison may be useful for a differential diagnosis.Bundle branch block is a heart block caused by a lesion in one of the bundle branches located in the septum (the heart muscle between the two ventricles). There is a right and a left bundle branch, and damage to either will affect the electrical system of the respective side of the heart. It usually indicates cardiovascular disease; though right bundle branch block may be recorded in persons showing no clinical evidence of cardiovascular disease. In either case, it is characterized by a slowing of the conduction in the bundle branches of the heart. Often times patients do not show symptoms (asymptomatic), but may have fainting episodes (syncope) or feel they are going to faint (presyncope). | 307 | Congenital Heart Block |
nord_307_5 | Diagnosis of Congenital Heart Block | The prenatal diagnosis of congenital heart block is more common as cardiac imaging techniques are improving. A growing number of autoimmune cases are being diagnosed between 18 and 24 weeks of pregnancy, leading to a better prognosis. Diagnosis depends on the results of one or more cardiac imaging tests such as fetal electrocardiography (ECG) and fetal echocardiography. This may help determine the type of heart block and may rule out any structural heart anomalies. If congenital heart block is overlooked during pregnancy or if the physician prefers to wait for the birth of the baby, diagnosis is commonly confirmed during infancy or early childhood. | Diagnosis of Congenital Heart Block. The prenatal diagnosis of congenital heart block is more common as cardiac imaging techniques are improving. A growing number of autoimmune cases are being diagnosed between 18 and 24 weeks of pregnancy, leading to a better prognosis. Diagnosis depends on the results of one or more cardiac imaging tests such as fetal electrocardiography (ECG) and fetal echocardiography. This may help determine the type of heart block and may rule out any structural heart anomalies. If congenital heart block is overlooked during pregnancy or if the physician prefers to wait for the birth of the baby, diagnosis is commonly confirmed during infancy or early childhood. | 307 | Congenital Heart Block |
nord_307_6 | Therapies of Congenital Heart Block | TreatmentThere are limited management options for congenital heart block in utero, but fetuses are often able to tolerate slow escape rhythms. If a more severe degree of heart block is present, adrenocorticosteroids such as dexamethasone may be prescribed to the mother as this class of medication is not metabolized by the placenta. Dexamethasone works to decrease inflammation and the number of circulating maternal antibodies in the fetus. If signs of fetal distress such as hydrops fetalis (abnormal accumulation of fluid within tissues of the body) are present, dexamethasone is also given but an early delivery may be required with emergency pacing.For newborns and children with CHB, the main therapy is insertion of a pacemaker. In affected individuals who exhibit mild forms of heart block (such as first degree or second degree Mobitz I), treatment may not be required. More severe cases (such as second degree Mobitz II and third degree heart block) may require a temporary or permanent pacemaker. Permanent insertion of a pacemaker may be recommended for individuals with Stokes-Adams attacks, congestive heart failure or significant cardiomegaly, or infants with a ventricular rate of less than 55 beats per minute. Ultimately, most (~90 percent) people with congenital heart block will require a pacemaker regardless of the age of onset of symptoms. The type of pacemaker needed depends primarily on the age of onset and the presence or absence of congenital heart defects. If hypotension and bradycardia occur alongside Mobitz type I, treatment can consist of the administration of atropine, a drug that temporarily increases the AV conduction in the heart. Patients with other types of CHB are usually unresponsive to atropine. The prognosis of patients with congenital heart block depends largely on the following factors: presence or absence of underlying structural heart disease, rate of ventricular activation and presence or absence of congestive heart failure. Presence of bradycardia (slow heart rate), congestive heart failure and structural heart disease are usually poor prognostic markers. Prognosis is better for infants diagnosed after the newborn period. | Therapies of Congenital Heart Block. TreatmentThere are limited management options for congenital heart block in utero, but fetuses are often able to tolerate slow escape rhythms. If a more severe degree of heart block is present, adrenocorticosteroids such as dexamethasone may be prescribed to the mother as this class of medication is not metabolized by the placenta. Dexamethasone works to decrease inflammation and the number of circulating maternal antibodies in the fetus. If signs of fetal distress such as hydrops fetalis (abnormal accumulation of fluid within tissues of the body) are present, dexamethasone is also given but an early delivery may be required with emergency pacing.For newborns and children with CHB, the main therapy is insertion of a pacemaker. In affected individuals who exhibit mild forms of heart block (such as first degree or second degree Mobitz I), treatment may not be required. More severe cases (such as second degree Mobitz II and third degree heart block) may require a temporary or permanent pacemaker. Permanent insertion of a pacemaker may be recommended for individuals with Stokes-Adams attacks, congestive heart failure or significant cardiomegaly, or infants with a ventricular rate of less than 55 beats per minute. Ultimately, most (~90 percent) people with congenital heart block will require a pacemaker regardless of the age of onset of symptoms. The type of pacemaker needed depends primarily on the age of onset and the presence or absence of congenital heart defects. If hypotension and bradycardia occur alongside Mobitz type I, treatment can consist of the administration of atropine, a drug that temporarily increases the AV conduction in the heart. Patients with other types of CHB are usually unresponsive to atropine. The prognosis of patients with congenital heart block depends largely on the following factors: presence or absence of underlying structural heart disease, rate of ventricular activation and presence or absence of congestive heart failure. Presence of bradycardia (slow heart rate), congestive heart failure and structural heart disease are usually poor prognostic markers. Prognosis is better for infants diagnosed after the newborn period. | 307 | Congenital Heart Block |
nord_308_0 | Overview of Congenital Hepatic Fibrosis | Congenital hepatic fibrosis (CHF) is a rare disease that is present at birth (congenital) and affects the liver. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that affect the kidneys, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others. Typical liver abnormalities include an enlarged liver (hepatomegaly), increased pressure in the venous system that carries blood from different organs to the liver (portal hypertension), and fiber-like connective tissue that spreads over and through the liver (hepatic fibrosis). Gastrointestinal (stomach and intestine) bleeding, splenomegaly (enlarged spleen) and hypersplenism (decreased platelet and other blood counts due to enlarged spleen) may be early signs of this condition. | Overview of Congenital Hepatic Fibrosis. Congenital hepatic fibrosis (CHF) is a rare disease that is present at birth (congenital) and affects the liver. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that affect the kidneys, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others. Typical liver abnormalities include an enlarged liver (hepatomegaly), increased pressure in the venous system that carries blood from different organs to the liver (portal hypertension), and fiber-like connective tissue that spreads over and through the liver (hepatic fibrosis). Gastrointestinal (stomach and intestine) bleeding, splenomegaly (enlarged spleen) and hypersplenism (decreased platelet and other blood counts due to enlarged spleen) may be early signs of this condition. | 308 | Congenital Hepatic Fibrosis |
nord_308_1 | Symptoms of Congenital Hepatic Fibrosis | The more obvious symptoms are a swollen abdomen, a firm, slightly enlarged and abnormally shaped liver and vomiting blood (hematemesis) due to bleeding from the enlarged blood vessels (varices) under the inner lining of the esophagus, stomach, and intestines. There is an increased risk for inflamed bile ducts (cholangitis) as well. The main findings in this disorder are identified through diagnostic testing. Many of the following signs are present in affected individuals with this disorder:Portal Hypertension: increased pressure in the venous system that carries blood from multiple organs to the liver (portal system). This increased blood pressure is caused by the probable congenital abnormality of the portal vein as well as blockage of the portal blood supply to the liver due to excess connective tissue growth in the liver. Portal hypertension can cause enlargement of the spleen and swollen or dilated veins of the esophagus. Hepatic Fibrosis: a fiber-like connective tissue that spreads through the liver. Nephromegaly: enlarged kidney. Gastrointestinal Bleeding: bleeding from the esophagus, and/or stomach and intestines that may cause the affected individual to vomit red blood or have dark black stools. Polycystic Kidney Disease: an inherited disorder in which cysts invade both kidneys. This causes enlargement in the size of the kidney while at the same time, reducing the amount of functional kidney tissue by compression. (For more information on this disorder choose “Polycystic Kidney Disease” as your search term in the Rare Disease Database). Splenomegaly: an enlarged spleen. Liver function tests are usually normal in people with CHF. | Symptoms of Congenital Hepatic Fibrosis. The more obvious symptoms are a swollen abdomen, a firm, slightly enlarged and abnormally shaped liver and vomiting blood (hematemesis) due to bleeding from the enlarged blood vessels (varices) under the inner lining of the esophagus, stomach, and intestines. There is an increased risk for inflamed bile ducts (cholangitis) as well. The main findings in this disorder are identified through diagnostic testing. Many of the following signs are present in affected individuals with this disorder:Portal Hypertension: increased pressure in the venous system that carries blood from multiple organs to the liver (portal system). This increased blood pressure is caused by the probable congenital abnormality of the portal vein as well as blockage of the portal blood supply to the liver due to excess connective tissue growth in the liver. Portal hypertension can cause enlargement of the spleen and swollen or dilated veins of the esophagus. Hepatic Fibrosis: a fiber-like connective tissue that spreads through the liver. Nephromegaly: enlarged kidney. Gastrointestinal Bleeding: bleeding from the esophagus, and/or stomach and intestines that may cause the affected individual to vomit red blood or have dark black stools. Polycystic Kidney Disease: an inherited disorder in which cysts invade both kidneys. This causes enlargement in the size of the kidney while at the same time, reducing the amount of functional kidney tissue by compression. (For more information on this disorder choose “Polycystic Kidney Disease” as your search term in the Rare Disease Database). Splenomegaly: an enlarged spleen. Liver function tests are usually normal in people with CHF. | 308 | Congenital Hepatic Fibrosis |
nord_308_2 | Causes of Congenital Hepatic Fibrosis | CHF is caused by abnormal development of the portal veins and bile ducts that begins with a malformation in the embryonic structure called the ductal plate. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that are associated with kidney disease, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others. FCDs are caused by defects in proteins on the primary (immotile) cilia that interfere with receiving signals from other cells or fluids nearby. FCDs can be inherited as autosomal recessive, autosomal dominant or X-linked disorders. Mutations in many different genes are associated with the various FCDs. No specific genes have been associated with isolated CHF.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene with a disease-causing mutation (gene change). The person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 5-10 abnormal recessively inherited trait genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.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 in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one X chromosome carries the defective gene. Males have only one X chromosome and it is inherited from their mother. If a male inherits an X chromosome that contains a defective gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | Causes of Congenital Hepatic Fibrosis. CHF is caused by abnormal development of the portal veins and bile ducts that begins with a malformation in the embryonic structure called the ductal plate. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that are associated with kidney disease, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others. FCDs are caused by defects in proteins on the primary (immotile) cilia that interfere with receiving signals from other cells or fluids nearby. FCDs can be inherited as autosomal recessive, autosomal dominant or X-linked disorders. Mutations in many different genes are associated with the various FCDs. No specific genes have been associated with isolated CHF.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene with a disease-causing mutation (gene change). The person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry 5-10 abnormal recessively inherited trait genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.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 in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one X chromosome carries the defective gene. Males have only one X chromosome and it is inherited from their mother. If a male inherits an X chromosome that contains a defective gene, he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. | 308 | Congenital Hepatic Fibrosis |
nord_308_3 | Affects of Congenital Hepatic Fibrosis | The frequency of CHF is not known. The prevalence has been estimated to be 1/10,000 -20,000 based on the prevalence of ciliopathies that are associated with CHF. | Affects of Congenital Hepatic Fibrosis. The frequency of CHF is not known. The prevalence has been estimated to be 1/10,000 -20,000 based on the prevalence of ciliopathies that are associated with CHF. | 308 | Congenital Hepatic Fibrosis |
nord_308_4 | Related disorders of Congenital Hepatic Fibrosis | Symptoms of the following disorders can be similar to those of CHF. Comparisons may be useful for a differential diagnosis.Cirrhosis (liver scarring) can be similar to CHF on a liver biopsy, but people with CHF usually have normal liver function tests.Caroli syndrome is a rare congenital liver disorder marked by enlargement (dilatation) of the bile ducts inside the liver. Major symptoms may include abdominal pain, yellowing of the skin (jaundice) and fever. Caroli syndrome is a birth defect which is usually associated with ciliopathies. (For more information on this disorder choose “Caroli syndrome” as your search term in the Rare Disease Database.) | Related disorders of Congenital Hepatic Fibrosis. Symptoms of the following disorders can be similar to those of CHF. Comparisons may be useful for a differential diagnosis.Cirrhosis (liver scarring) can be similar to CHF on a liver biopsy, but people with CHF usually have normal liver function tests.Caroli syndrome is a rare congenital liver disorder marked by enlargement (dilatation) of the bile ducts inside the liver. Major symptoms may include abdominal pain, yellowing of the skin (jaundice) and fever. Caroli syndrome is a birth defect which is usually associated with ciliopathies. (For more information on this disorder choose “Caroli syndrome” as your search term in the Rare Disease Database.) | 308 | Congenital Hepatic Fibrosis |
nord_308_5 | Diagnosis of Congenital Hepatic Fibrosis | CHF is diagnosed by ultrasound exam and magnetic resonance imaging of the liver and kidneys, and rarely, by liver biopsy. CHF and Caroli’s syndrome are often associated with cystic disease of the kidneys. Family history, physical exam, and various tests including kidney ultrasound exam, kidney function tests, X-rays, eye exam, brain MRI, and molecular genetic testing can help to determine the underlying FCD syndrome. | Diagnosis of Congenital Hepatic Fibrosis. CHF is diagnosed by ultrasound exam and magnetic resonance imaging of the liver and kidneys, and rarely, by liver biopsy. CHF and Caroli’s syndrome are often associated with cystic disease of the kidneys. Family history, physical exam, and various tests including kidney ultrasound exam, kidney function tests, X-rays, eye exam, brain MRI, and molecular genetic testing can help to determine the underlying FCD syndrome. | 308 | Congenital Hepatic Fibrosis |
nord_308_6 | Therapies of Congenital Hepatic Fibrosis | Treatment
Treatment of CHF is symptomatic and supportive. Complications of CHF including gastrointestinal bleeding, hypersplenism and cholangitis can be routinely treated. Treatment is not available to correct the developmental abnormalities in the portal veins and bile ducts or reverse the fibrosis.Affected individuals should avoid alcohol, medications known to impair liver function, and nonsteroidal anti-inflammatory drugs (NSAIDS).Genetic counseling is recommended for affected individuals and their families. | Therapies of Congenital Hepatic Fibrosis. Treatment
Treatment of CHF is symptomatic and supportive. Complications of CHF including gastrointestinal bleeding, hypersplenism and cholangitis can be routinely treated. Treatment is not available to correct the developmental abnormalities in the portal veins and bile ducts or reverse the fibrosis.Affected individuals should avoid alcohol, medications known to impair liver function, and nonsteroidal anti-inflammatory drugs (NSAIDS).Genetic counseling is recommended for affected individuals and their families. | 308 | Congenital Hepatic Fibrosis |
nord_309_0 | Overview of Congenital Hyperinsulinism | Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies, infants, and children. In most countries it occurs in approximately 1/25,000 to 1/50,000 births. About 60% of babies with HI are diagnosed during the first month of life. An additional 30% will be diagnosed later in the first year and the remainder after that. With early treatment and aggressive prevention of hypoglycemia, brain damage can be prevented. However, brain damage can occur in children with HI if the condition is not recognized or if treatment is ineffective in the prevention of hypoglycemia.Insulin is the most important hormone for controlling the concentration of glucose in the blood. As food is eaten, blood glucose rises and the pancreas secretes insulin to keep blood glucose in the normal range. Insulin acts by driving glucose into the cells of the body. This action of insulin maintains blood glucose levels and stores glucose as glycogen in the liver. Once feeding is completed and glucose levels fall, insulin secretion is turned off, allowing the stores of glucose in glycogen to be released into the bloodstream to keep blood glucose normal. In addition, with the switching off of insulin secretion, protein and fat stores become accessible and can be used instead of glucose as sources of fuel. In this manner, whether one eats or is fasting blood glucose levels remain in the normal range and the body has access to energy at all times.This close regulation of blood glucose and insulin secretion does not occur normally in people who have HI. The beta cells in the pancreas, which are responsible for insulin secretion, are blind to the blood glucose level and secrete insulin regardless of the blood glucose concentration. As a result, the baby or child with HI can develop hypoglycemia at any time but particularly when fasting. In the most severe form of HI this glucose blindness causes frequent, random episodes of hypoglycemia.HI causes a particularly damaging form of hypoglycemia because it denies the brain of all the fuels on which it is critically dependent. These fuels are glucose, ketones, and lactate. The usual protective measures against hypoglycemia, such as release of glycogen stores from the liver (called glycogenolysis), conversion of protein to glucose (called gluconeogenesis) and conversion of fat into ketones (called fatty acid oxidation and ketogenesis) are prevented by insulin. Once the brain cells are deprived of these important fuels, they cannot make the energy they need to work and so they stop working. The lack of appropriate fuel to the brain may result in seizures and coma and if prolonged may result in death of the brain cells. It is this cell damage which can manifest as a permanent seizure disorder, learning disabilities, cerebral palsy, blindness or even death. | Overview of Congenital Hyperinsulinism. Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies, infants, and children. In most countries it occurs in approximately 1/25,000 to 1/50,000 births. About 60% of babies with HI are diagnosed during the first month of life. An additional 30% will be diagnosed later in the first year and the remainder after that. With early treatment and aggressive prevention of hypoglycemia, brain damage can be prevented. However, brain damage can occur in children with HI if the condition is not recognized or if treatment is ineffective in the prevention of hypoglycemia.Insulin is the most important hormone for controlling the concentration of glucose in the blood. As food is eaten, blood glucose rises and the pancreas secretes insulin to keep blood glucose in the normal range. Insulin acts by driving glucose into the cells of the body. This action of insulin maintains blood glucose levels and stores glucose as glycogen in the liver. Once feeding is completed and glucose levels fall, insulin secretion is turned off, allowing the stores of glucose in glycogen to be released into the bloodstream to keep blood glucose normal. In addition, with the switching off of insulin secretion, protein and fat stores become accessible and can be used instead of glucose as sources of fuel. In this manner, whether one eats or is fasting blood glucose levels remain in the normal range and the body has access to energy at all times.This close regulation of blood glucose and insulin secretion does not occur normally in people who have HI. The beta cells in the pancreas, which are responsible for insulin secretion, are blind to the blood glucose level and secrete insulin regardless of the blood glucose concentration. As a result, the baby or child with HI can develop hypoglycemia at any time but particularly when fasting. In the most severe form of HI this glucose blindness causes frequent, random episodes of hypoglycemia.HI causes a particularly damaging form of hypoglycemia because it denies the brain of all the fuels on which it is critically dependent. These fuels are glucose, ketones, and lactate. The usual protective measures against hypoglycemia, such as release of glycogen stores from the liver (called glycogenolysis), conversion of protein to glucose (called gluconeogenesis) and conversion of fat into ketones (called fatty acid oxidation and ketogenesis) are prevented by insulin. Once the brain cells are deprived of these important fuels, they cannot make the energy they need to work and so they stop working. The lack of appropriate fuel to the brain may result in seizures and coma and if prolonged may result in death of the brain cells. It is this cell damage which can manifest as a permanent seizure disorder, learning disabilities, cerebral palsy, blindness or even death. | 309 | Congenital Hyperinsulinism |
nord_309_1 | Symptoms of Congenital Hyperinsulinism | It is often difficult to identify symptoms of HI because they are often confused with typical behaviors of newborns and infants. Common symptoms include irritability, sleepiness, lethargy, excessive hunger and rapid heart rate. More severe symptoms, such as seizures and coma, can occur with a prolonged or extremely low blood sugar level. Common symptoms of low blood sugar in older children and adults include feelings of shakiness, weakness, or tiredness, confusion and rapid pulse. More severe symptoms include seizures or coma. | Symptoms of Congenital Hyperinsulinism. It is often difficult to identify symptoms of HI because they are often confused with typical behaviors of newborns and infants. Common symptoms include irritability, sleepiness, lethargy, excessive hunger and rapid heart rate. More severe symptoms, such as seizures and coma, can occur with a prolonged or extremely low blood sugar level. Common symptoms of low blood sugar in older children and adults include feelings of shakiness, weakness, or tiredness, confusion and rapid pulse. More severe symptoms include seizures or coma. | 309 | Congenital Hyperinsulinism |
nord_309_2 | Causes of Congenital Hyperinsulinism | A number of causes exist. Some forms will resolve and are considered transient. Others arise from genetic defects and persist for life. These genetic forms of HI do not go away, but in some cases, may become easier to treat as the child gets much older.Transient Hyperinsulinism
Babies born small for gestational age, or prematurely, may develop hypoglycemia due to excessive insulin secretion. In addition, infants who experience fetal distress due to lack of oxygen to the brain may develop hypoglycemia. The cause of this inappropriate insulin secretion is unclear, but it can last a few days to months. Once recognized, this form of hypoglycemia is usually easy to treat. Many affected infants will not have hypoglycemia once they are fed every 3-4 hours. In the more severely affected children, intravenous glucose is needed to prevent hypoglycemia. Occasionally, drug therapy is required; in which case, diazoxide is usually a very effective treatment. Children with this form of hyperinsulinism have a fasting study done when medications have been weaned, to prove that the hyperinsulinism has resolved and therefore was transient. A small number of babies born to mothers with diabetes mellitus may have transient hypoglycemia. This tends to occur if the mother’s diabetes was not under good control. The mother’s high blood glucose levels are transmitted across the placenta to the fetus. The fetus compensates by secreting extra insulin. This step-up in insulin secretion does not cause hypoglycemia while the fetus is inside the mother, but after birth, the constant supply of high glucose from the placenta is gone and the blood sugar in the newborn falls precipitously. This form of hyperinsulinism should resolve within a few days with frequent feeding or in some cases intensive intravenous drip of glucose. Once the hypoglycemia resolves, it should never recur.Persistent HI
A number of different genetic defects causing HI have been identified. In the past, before the different genetic forms of HI were recognized, HI was referred to by many names, including nesidioblastosis, islet cell dysregulation syndrome, idiopathic hypoglycemia of infancy, and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). With the identification of the genes responsible for these disorders, the naming of the different forms of HI has become more exact.KATP-HI Diffuse or Focal Disease
The KATP form of HI was formerly known as “nesidioblastosis” or “PHHI”. Neonates with this form of hyperinsulinism are frequently, although not always, larger than normal birth weight (many weigh above 9lbs) and present in the first days of life. It is called KATP-HI because its genetic cause is due to defects in either of two genes that make up the potassium channel (called KATP channel) in the insulin secreting beta-cells of the pancreas. These two genes are the SUR1 gene (known as ABCC8) and the Kir6.2 gene (known as KCNJ11). Normally, when the beta cell senses that glucose levels are elevated, closure of the KATP channel triggers insulin secretion. When the KATP channel is defective, inappropriate insulin secretion occurs and causes hypoglycemia. Two forms of KATP-HI exist: diffuse KATP-HI and focal KATP-HI. When these mutations are inherited in an autosomal recessive manner (one mutation in the gene inherited from each parent, neither of whom is affected) they cause diffuse disease, meaning every beta-cell in the pancreas is abnormal. Recently autosomal dominant mutations (a mutation in a single copy of the gene) have been found to cause diffuse disease. When a recessive mutation is inherited from the father and loss of heterozygosity for the maternal copy of the gene (loss of the mother’s unaffected gene from a few cells in the pancreas) occurs, a focal lesion arises. Abnormal beta cells are limited to this focal lesion and are surrounded by normal beta-cells.Children with either form of KATP-HI are identical in their appearance and behavior. They tend to have significant hypoglycemia within the first few days of life and require large amounts of glucose to keep their blood glucose normal. They may have seizures due to hypoglycemia. Diazoxide is often an ineffective treatment for these children because diazoxide works on the KATP channel and it cannot fix the broken channels. Octreotide given by injection every 6 to 8 hours or by continuous infusion may be successful (sometimes only in the short term). Glucagon may be given by intravenous infusion to stabilize the blood sugar as a temporary measure in the hospital setting. Some centers prefer the surgical approach. With the recent discovery of diffuse and focal KATP-HI, attempts to differentiate these two forms are very important: surgical therapy will cure focal HI but not diffuse HI (see below).GDH-HI
GDH-HI has also been known as the hyperinsulinism/hyperammonemia syndrome (HI/HA), leucine-sensitive hypoglycemia, and protein-sensitive hypoglycemia. GDH-HI is caused by a mutation in the enzyme glutamate dehydrogenase (GDH). It is inherited in either an autosomal dominant manner or may arise as a sporadically new mutation in a child with no family history. GDH plays an important role in regulating insulin secretion stimulated by amino acids (especially leucine). Individuals with GDH-HI develop hypoglycemia after eating a high protein meal or after fasting. GDH-HI affected individuals can have significant hypoglycemia if they eat protein (for instance eggs or meat) without eating carbohydrate containing foods such as bread, juice or pasta. GDH-HI is also associated with elevated blood concentrations of ammonia, which is derived from protein. Patients with GDH-HI often present later than KATP channel HI, typically, not until three to four months of age when they wean from low protein containing breast milk to infant formula. Others do not have recognizable hypoglycemia until they sleep overnight without a middle of the night feed or after they start higher protein-containing solid foods. In addition, GDH-HI can be successfully treated with diazoxide and the avoidance of protein loads without carbohydrates. Most children with GDH-HI will do very well once recognized, but if the diagnosis is delayed, they may also suffer brain damage from untreated hypoglycemia.GK-HI
This defect is inherited in an autosomal dominant fashion but can also arise sporadically. Glucokinase is the “glucose sensor” for the beta-cell. It tells the beta-cell how high the blood glucose is and when to secrete insulin. Glucokinase mutations that cause HI instruct the beta-cell to secrete insulin at a lower blood glucose than is normal. Like GDH-HI, GK-HI can be treated with diazoxide, but sometimes, it may be severe and unresponsive to diazoxide.Other forms of HI, responsive to diazoxide include: 1) HI due to mutations in SCHAD, an enzyme that regulates GDH. Children with SCHAD HI, are also protein-sensitive. 2) HNF4A and HNF1A HI are caused by mutations in HNF4A and HNF1A, transcription factors that play an important role in the beta-cells. These mutations cause hyperinsulinism in infancy and familial diabetes (also known as MODY, or maturity onset diabetes of the young) later in life. 3) Exercise-induced hyperinsulinism is a rare form of HI in which hypoglycemia is triggered by exercise.Other forms of HI are known to exist, but the genetic mutations are not yet well described. Their clinical features and response to therapy vary. HI can also be associated with syndromes such as Beckwith Wiedemann syndrome, Kabuki syndrome, and Turner syndrome among others. In these cases, HI is only one of the features that characterize the clinical picture. | Causes of Congenital Hyperinsulinism. A number of causes exist. Some forms will resolve and are considered transient. Others arise from genetic defects and persist for life. These genetic forms of HI do not go away, but in some cases, may become easier to treat as the child gets much older.Transient Hyperinsulinism
Babies born small for gestational age, or prematurely, may develop hypoglycemia due to excessive insulin secretion. In addition, infants who experience fetal distress due to lack of oxygen to the brain may develop hypoglycemia. The cause of this inappropriate insulin secretion is unclear, but it can last a few days to months. Once recognized, this form of hypoglycemia is usually easy to treat. Many affected infants will not have hypoglycemia once they are fed every 3-4 hours. In the more severely affected children, intravenous glucose is needed to prevent hypoglycemia. Occasionally, drug therapy is required; in which case, diazoxide is usually a very effective treatment. Children with this form of hyperinsulinism have a fasting study done when medications have been weaned, to prove that the hyperinsulinism has resolved and therefore was transient. A small number of babies born to mothers with diabetes mellitus may have transient hypoglycemia. This tends to occur if the mother’s diabetes was not under good control. The mother’s high blood glucose levels are transmitted across the placenta to the fetus. The fetus compensates by secreting extra insulin. This step-up in insulin secretion does not cause hypoglycemia while the fetus is inside the mother, but after birth, the constant supply of high glucose from the placenta is gone and the blood sugar in the newborn falls precipitously. This form of hyperinsulinism should resolve within a few days with frequent feeding or in some cases intensive intravenous drip of glucose. Once the hypoglycemia resolves, it should never recur.Persistent HI
A number of different genetic defects causing HI have been identified. In the past, before the different genetic forms of HI were recognized, HI was referred to by many names, including nesidioblastosis, islet cell dysregulation syndrome, idiopathic hypoglycemia of infancy, and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). With the identification of the genes responsible for these disorders, the naming of the different forms of HI has become more exact.KATP-HI Diffuse or Focal Disease
The KATP form of HI was formerly known as “nesidioblastosis” or “PHHI”. Neonates with this form of hyperinsulinism are frequently, although not always, larger than normal birth weight (many weigh above 9lbs) and present in the first days of life. It is called KATP-HI because its genetic cause is due to defects in either of two genes that make up the potassium channel (called KATP channel) in the insulin secreting beta-cells of the pancreas. These two genes are the SUR1 gene (known as ABCC8) and the Kir6.2 gene (known as KCNJ11). Normally, when the beta cell senses that glucose levels are elevated, closure of the KATP channel triggers insulin secretion. When the KATP channel is defective, inappropriate insulin secretion occurs and causes hypoglycemia. Two forms of KATP-HI exist: diffuse KATP-HI and focal KATP-HI. When these mutations are inherited in an autosomal recessive manner (one mutation in the gene inherited from each parent, neither of whom is affected) they cause diffuse disease, meaning every beta-cell in the pancreas is abnormal. Recently autosomal dominant mutations (a mutation in a single copy of the gene) have been found to cause diffuse disease. When a recessive mutation is inherited from the father and loss of heterozygosity for the maternal copy of the gene (loss of the mother’s unaffected gene from a few cells in the pancreas) occurs, a focal lesion arises. Abnormal beta cells are limited to this focal lesion and are surrounded by normal beta-cells.Children with either form of KATP-HI are identical in their appearance and behavior. They tend to have significant hypoglycemia within the first few days of life and require large amounts of glucose to keep their blood glucose normal. They may have seizures due to hypoglycemia. Diazoxide is often an ineffective treatment for these children because diazoxide works on the KATP channel and it cannot fix the broken channels. Octreotide given by injection every 6 to 8 hours or by continuous infusion may be successful (sometimes only in the short term). Glucagon may be given by intravenous infusion to stabilize the blood sugar as a temporary measure in the hospital setting. Some centers prefer the surgical approach. With the recent discovery of diffuse and focal KATP-HI, attempts to differentiate these two forms are very important: surgical therapy will cure focal HI but not diffuse HI (see below).GDH-HI
GDH-HI has also been known as the hyperinsulinism/hyperammonemia syndrome (HI/HA), leucine-sensitive hypoglycemia, and protein-sensitive hypoglycemia. GDH-HI is caused by a mutation in the enzyme glutamate dehydrogenase (GDH). It is inherited in either an autosomal dominant manner or may arise as a sporadically new mutation in a child with no family history. GDH plays an important role in regulating insulin secretion stimulated by amino acids (especially leucine). Individuals with GDH-HI develop hypoglycemia after eating a high protein meal or after fasting. GDH-HI affected individuals can have significant hypoglycemia if they eat protein (for instance eggs or meat) without eating carbohydrate containing foods such as bread, juice or pasta. GDH-HI is also associated with elevated blood concentrations of ammonia, which is derived from protein. Patients with GDH-HI often present later than KATP channel HI, typically, not until three to four months of age when they wean from low protein containing breast milk to infant formula. Others do not have recognizable hypoglycemia until they sleep overnight without a middle of the night feed or after they start higher protein-containing solid foods. In addition, GDH-HI can be successfully treated with diazoxide and the avoidance of protein loads without carbohydrates. Most children with GDH-HI will do very well once recognized, but if the diagnosis is delayed, they may also suffer brain damage from untreated hypoglycemia.GK-HI
This defect is inherited in an autosomal dominant fashion but can also arise sporadically. Glucokinase is the “glucose sensor” for the beta-cell. It tells the beta-cell how high the blood glucose is and when to secrete insulin. Glucokinase mutations that cause HI instruct the beta-cell to secrete insulin at a lower blood glucose than is normal. Like GDH-HI, GK-HI can be treated with diazoxide, but sometimes, it may be severe and unresponsive to diazoxide.Other forms of HI, responsive to diazoxide include: 1) HI due to mutations in SCHAD, an enzyme that regulates GDH. Children with SCHAD HI, are also protein-sensitive. 2) HNF4A and HNF1A HI are caused by mutations in HNF4A and HNF1A, transcription factors that play an important role in the beta-cells. These mutations cause hyperinsulinism in infancy and familial diabetes (also known as MODY, or maturity onset diabetes of the young) later in life. 3) Exercise-induced hyperinsulinism is a rare form of HI in which hypoglycemia is triggered by exercise.Other forms of HI are known to exist, but the genetic mutations are not yet well described. Their clinical features and response to therapy vary. HI can also be associated with syndromes such as Beckwith Wiedemann syndrome, Kabuki syndrome, and Turner syndrome among others. In these cases, HI is only one of the features that characterize the clinical picture. | 309 | Congenital Hyperinsulinism |
nord_309_3 | Affects of Congenital Hyperinsulinism | HI affects both males and females and has been reported in many countries. In most countries it occurs in approximately 1/25,000 to 1/50,000 births. | Affects of Congenital Hyperinsulinism. HI affects both males and females and has been reported in many countries. In most countries it occurs in approximately 1/25,000 to 1/50,000 births. | 309 | Congenital Hyperinsulinism |
nord_309_4 | Related disorders of Congenital Hyperinsulinism | Due to the similarity in names people often confuse hyperinsulinemia with hyperinsulinism. Hyperinsulinemia is something completely different but over production of insulin is also involved and the names are similar.An insulinoma also causes hypoglycemia.Reactive or post-prandrial hypoglycemia caused by gastric surgery is also something completely different but results in hypoglycemia because of inappropriate insulin secretion. | Related disorders of Congenital Hyperinsulinism. Due to the similarity in names people often confuse hyperinsulinemia with hyperinsulinism. Hyperinsulinemia is something completely different but over production of insulin is also involved and the names are similar.An insulinoma also causes hypoglycemia.Reactive or post-prandrial hypoglycemia caused by gastric surgery is also something completely different but results in hypoglycemia because of inappropriate insulin secretion. | 309 | Congenital Hyperinsulinism |
nord_309_5 | Diagnosis of Congenital Hyperinsulinism | The diagnosis of HI may be quite difficult if one relies on demonstrating a detectable blood insulin concentration at the time of hypoglycemia because insulin levels fluctuate widely over time in patients with HI. Other signs and chemical markers must be used to provide clues to excess insulin action and are often easier to demonstrate.Hypoglycemia which occurs while an infant is on a glucose infusion is strongly suggestive of HI. Other clues to excess insulin action are low free fatty acids and ketones at the time of hypoglycemia. Another indicator of excess insulin can be demonstrated by the glucagon stimulation test. Glucagon is a hormone that opposes insulin action and stimulates release of glucose from liver glycogen stores. A rise in blood glucose after glucagon administration at the time of hypoglycemia is a sensitive marker for hyperinsulinism. Ketones, free fatty acids, and the glucagon stimulation test may all be performed if a random episode of hypoglycemia occurs. A fasting test done in a safe setting in an experienced hospital is sometimes required to provoke hypoglycemia and confirm the diagnosis of HI.Distinguishing between focal and diffuse disease is an important aspect of diagnosis. Genetic testing is the most useful test in determining the likelihood of focal hyperinsulinism. Special radiologic testing is used in some centers to help localize focal lesions. The 18-F-DOPA PET scan which involves use of a radioactive drug is the most effective way to localize focal lesions. 18-F-DOPA is not yet approved by the FDA, so this work is being done under research protocols in the U.S. The 18-F-DOPA PET scan is more widely available in some centers in Europe. Other imaging modalities such as ultrasound, CT scans, or MRIs are not useful to localize these lesions. | Diagnosis of Congenital Hyperinsulinism. The diagnosis of HI may be quite difficult if one relies on demonstrating a detectable blood insulin concentration at the time of hypoglycemia because insulin levels fluctuate widely over time in patients with HI. Other signs and chemical markers must be used to provide clues to excess insulin action and are often easier to demonstrate.Hypoglycemia which occurs while an infant is on a glucose infusion is strongly suggestive of HI. Other clues to excess insulin action are low free fatty acids and ketones at the time of hypoglycemia. Another indicator of excess insulin can be demonstrated by the glucagon stimulation test. Glucagon is a hormone that opposes insulin action and stimulates release of glucose from liver glycogen stores. A rise in blood glucose after glucagon administration at the time of hypoglycemia is a sensitive marker for hyperinsulinism. Ketones, free fatty acids, and the glucagon stimulation test may all be performed if a random episode of hypoglycemia occurs. A fasting test done in a safe setting in an experienced hospital is sometimes required to provoke hypoglycemia and confirm the diagnosis of HI.Distinguishing between focal and diffuse disease is an important aspect of diagnosis. Genetic testing is the most useful test in determining the likelihood of focal hyperinsulinism. Special radiologic testing is used in some centers to help localize focal lesions. The 18-F-DOPA PET scan which involves use of a radioactive drug is the most effective way to localize focal lesions. 18-F-DOPA is not yet approved by the FDA, so this work is being done under research protocols in the U.S. The 18-F-DOPA PET scan is more widely available in some centers in Europe. Other imaging modalities such as ultrasound, CT scans, or MRIs are not useful to localize these lesions. | 309 | Congenital Hyperinsulinism |
nord_309_6 | Therapies of Congenital Hyperinsulinism | TreatmentPrompt treatment of hypoglycemia due to HI is essential to prevent brain damage. Unlike other hypoglycemia-causing conditions in which alternative fuels, such as ketones or lactate, may be available for the brain during periods of hypoglycemia, HI prevents the production of these fuels and leaves the brain without a source of energy. Hypoglycemia can be treated by giving a carbohydrate-containing drink by mouth or if severe, by giving glucose through the vein or by injecting glucagon. A child with a feeding tube can have glucose given through the tube. The goal of treatment is to prevent hypoglycemia while the child has a normal feeding pattern for age with a little extra safety built in, e.g., a one year old who normally would not eat overnight for 10-12 hours should be able to fast for at least 14 -15 hours on a successful medical regimen. Medications used to treat HI include diazoxide, octreotide, and glucagon.Diazoxide
Diazoxide is given by mouth 2-3 times per day. The dose varies from 5 to 15mg/kg/day. Usually, if 15 mg/kg/day does not work, higher doses will not work. Diazoxide acts on the KATP channel to prevent insulin secretion. It is generally effective for infants with stress-induced hyperinsulinism, infants with GDH-HI or GK-HI, and in a subgroup of infants whose basic defect is not known. Diazoxide often does not work in children with KATP-HI. Side effects of diazoxide include fluid retention, a particular problem for the newborn who is receiving large amounts of intravenous glucose to maintain the blood glucose in the normal range. A diuretic medication is sometimes used with diazoxide in anticipation of such a problem. Diazoxide also causes excessive hair growth of the eyebrows, forehead, and back (referred to medically as hypertrichosis). This hair growth resolves several months after diazoxide therapy is stopped. Some patients choose to shave the hair occasionally and this does not intensify hair growth.Octreotide
Octreotide is a drug that also inhibits insulin secretion. It is administered by injection. It can be given periodically throughout the day by subcutaneous injection or may be administered continuously under the skin by a pump that is commonly used for insulin therapy in individuals with diabetes. Octreotide is often very effective initially, but it may become less effective over time. In addition, more is not always better as the higher the dose (higher than 20 micrograms/kg/day), the less effective it may become. Side effects include alteration of gut motility, which may cause poor feeding. It may also cause gallstones and very rarely may produce hypothyroidism, and short stature. As with any injection, risks of pain, infection, and bruising exist. Additionally, octreotide is not currently recommended in neonates already at risk for NEC (necrotizing enterocolitis). There other drugs similar to octreotide that have a longer duration of action and can be used once a month, these include octreotide LAR and lanreotide. These longer acting preparations are reserved for use in those patients that have responded to the short acting octreotide and are on a stable regimen.Glucagon
Glucagon stimulates release of glucose from the liver. It is given through a vein or by injection under the skin or into the muscle. Glucagon can be used in cases of emergency when a child with HI has low blood glucose levels and cannot be fed. It can also be given in the hospital as a continuous infusion through a vein. It is most effective as a holding therapy while the child is prepared for surgery.Surgery
Children with diffuse KATP-HI often require 95-99% pancreatectomies. These surgeries are not curative and KATP-HI children who have undergone such surgeries may continue to require frequent feeds and medications to prevent hypoglycemia. They also may need repeat surgeries. The hope with such surgery is to lessen the intense medical regimen that otherwise would be needed to protect the child from recurrent, severe hypoglycemia.In children with focal KATP channel HI, surgery to remove only the small part of the pancreas that is affected is the procedure of choice. This requires a multidisciplinary team of endocrinologists, radiologists, pathologists and surgeons, specialized in the treatment of these children. Therefore it is generally only available in the major centers treating patients with HI. The majority of patients with focal HI will be cured or will not require any medical therapy after the surgery. This is in stark contrast to those with diffuse disease in whom medical therapy after surgery is the rule. | Therapies of Congenital Hyperinsulinism. TreatmentPrompt treatment of hypoglycemia due to HI is essential to prevent brain damage. Unlike other hypoglycemia-causing conditions in which alternative fuels, such as ketones or lactate, may be available for the brain during periods of hypoglycemia, HI prevents the production of these fuels and leaves the brain without a source of energy. Hypoglycemia can be treated by giving a carbohydrate-containing drink by mouth or if severe, by giving glucose through the vein or by injecting glucagon. A child with a feeding tube can have glucose given through the tube. The goal of treatment is to prevent hypoglycemia while the child has a normal feeding pattern for age with a little extra safety built in, e.g., a one year old who normally would not eat overnight for 10-12 hours should be able to fast for at least 14 -15 hours on a successful medical regimen. Medications used to treat HI include diazoxide, octreotide, and glucagon.Diazoxide
Diazoxide is given by mouth 2-3 times per day. The dose varies from 5 to 15mg/kg/day. Usually, if 15 mg/kg/day does not work, higher doses will not work. Diazoxide acts on the KATP channel to prevent insulin secretion. It is generally effective for infants with stress-induced hyperinsulinism, infants with GDH-HI or GK-HI, and in a subgroup of infants whose basic defect is not known. Diazoxide often does not work in children with KATP-HI. Side effects of diazoxide include fluid retention, a particular problem for the newborn who is receiving large amounts of intravenous glucose to maintain the blood glucose in the normal range. A diuretic medication is sometimes used with diazoxide in anticipation of such a problem. Diazoxide also causes excessive hair growth of the eyebrows, forehead, and back (referred to medically as hypertrichosis). This hair growth resolves several months after diazoxide therapy is stopped. Some patients choose to shave the hair occasionally and this does not intensify hair growth.Octreotide
Octreotide is a drug that also inhibits insulin secretion. It is administered by injection. It can be given periodically throughout the day by subcutaneous injection or may be administered continuously under the skin by a pump that is commonly used for insulin therapy in individuals with diabetes. Octreotide is often very effective initially, but it may become less effective over time. In addition, more is not always better as the higher the dose (higher than 20 micrograms/kg/day), the less effective it may become. Side effects include alteration of gut motility, which may cause poor feeding. It may also cause gallstones and very rarely may produce hypothyroidism, and short stature. As with any injection, risks of pain, infection, and bruising exist. Additionally, octreotide is not currently recommended in neonates already at risk for NEC (necrotizing enterocolitis). There other drugs similar to octreotide that have a longer duration of action and can be used once a month, these include octreotide LAR and lanreotide. These longer acting preparations are reserved for use in those patients that have responded to the short acting octreotide and are on a stable regimen.Glucagon
Glucagon stimulates release of glucose from the liver. It is given through a vein or by injection under the skin or into the muscle. Glucagon can be used in cases of emergency when a child with HI has low blood glucose levels and cannot be fed. It can also be given in the hospital as a continuous infusion through a vein. It is most effective as a holding therapy while the child is prepared for surgery.Surgery
Children with diffuse KATP-HI often require 95-99% pancreatectomies. These surgeries are not curative and KATP-HI children who have undergone such surgeries may continue to require frequent feeds and medications to prevent hypoglycemia. They also may need repeat surgeries. The hope with such surgery is to lessen the intense medical regimen that otherwise would be needed to protect the child from recurrent, severe hypoglycemia.In children with focal KATP channel HI, surgery to remove only the small part of the pancreas that is affected is the procedure of choice. This requires a multidisciplinary team of endocrinologists, radiologists, pathologists and surgeons, specialized in the treatment of these children. Therefore it is generally only available in the major centers treating patients with HI. The majority of patients with focal HI will be cured or will not require any medical therapy after the surgery. This is in stark contrast to those with diffuse disease in whom medical therapy after surgery is the rule. | 309 | Congenital Hyperinsulinism |
nord_310_0 | Overview of Congenital Lactic Acidosis | Lactate is a chemical compound normally produced by all cells and plays important roles in several chemical processes in the body. Lactic acidosis occurs when lactate and other molecules, called protons, accumulate in bodily tissues and fluids faster than the body can remove them. Consequently, tissues and fluids may become acidic and impair the normal functioning of cells. Lactic acidosis can have many different causes and is often present in severely ill patients hospitalized in intensive care units. Congenital lactic acidosis is a rare form of lactic acidosis. The word “congenital” means that the underlying condition that increases risk of developing lactic acidosis is present at birth. In most cases, the cause of congenital lactic acidosis is due to a defect in an enzyme responsible for helping the body convert carbohydrates and fats into energy. Most of these enzymes are located in specialized structures within the cell called mitochondria. Therefore, most causes of congenital lactic acidosis are due to genetic mitochondrial enzyme deficiencies. These are either inherited from one or both parents or arise spontaneously in the developing embryo. | Overview of Congenital Lactic Acidosis. Lactate is a chemical compound normally produced by all cells and plays important roles in several chemical processes in the body. Lactic acidosis occurs when lactate and other molecules, called protons, accumulate in bodily tissues and fluids faster than the body can remove them. Consequently, tissues and fluids may become acidic and impair the normal functioning of cells. Lactic acidosis can have many different causes and is often present in severely ill patients hospitalized in intensive care units. Congenital lactic acidosis is a rare form of lactic acidosis. The word “congenital” means that the underlying condition that increases risk of developing lactic acidosis is present at birth. In most cases, the cause of congenital lactic acidosis is due to a defect in an enzyme responsible for helping the body convert carbohydrates and fats into energy. Most of these enzymes are located in specialized structures within the cell called mitochondria. Therefore, most causes of congenital lactic acidosis are due to genetic mitochondrial enzyme deficiencies. These are either inherited from one or both parents or arise spontaneously in the developing embryo. | 310 | Congenital Lactic Acidosis |
nord_310_1 | Symptoms of Congenital Lactic Acidosis | The enzyme deficiencies that give rise to congenital lactic acidosis can potentially affect many different organ systems of the body and, therefore, lead to a wide variety of symptoms and signs. Whereas some individuals may have persistently elevated levels of lactic acid in blood, cerebrospinal fluid and urine, other people may have only occasional increases in lactic acid that are brought on by another illness, such as an infection, a seizure or an asthmatic attack.In some children (especially those with a severe enzyme defect), clinical manifestations of congenital lactic acidosis appear within the first hours or days of life and may include loss of muscle tone (hypotonia), lethargy, vomiting and abnormally rapid breathing (tachypnea). Eventually, the condition may progress to cause developmental delay, intellectual disability, motor abnormalities, behavioral issues, abnormalities of the face and head and, ultimately, multi-organ failure. In some individuals in whom the disease is due to a mutation in mitochondrial DNA, the complications of congenital lactic acidosis may not appear until adolescence or adulthood. | Symptoms of Congenital Lactic Acidosis. The enzyme deficiencies that give rise to congenital lactic acidosis can potentially affect many different organ systems of the body and, therefore, lead to a wide variety of symptoms and signs. Whereas some individuals may have persistently elevated levels of lactic acid in blood, cerebrospinal fluid and urine, other people may have only occasional increases in lactic acid that are brought on by another illness, such as an infection, a seizure or an asthmatic attack.In some children (especially those with a severe enzyme defect), clinical manifestations of congenital lactic acidosis appear within the first hours or days of life and may include loss of muscle tone (hypotonia), lethargy, vomiting and abnormally rapid breathing (tachypnea). Eventually, the condition may progress to cause developmental delay, intellectual disability, motor abnormalities, behavioral issues, abnormalities of the face and head and, ultimately, multi-organ failure. In some individuals in whom the disease is due to a mutation in mitochondrial DNA, the complications of congenital lactic acidosis may not appear until adolescence or adulthood. | 310 | Congenital Lactic Acidosis |
nord_310_2 | Causes of Congenital Lactic Acidosis | Most cases of congenital lactic acidosis are caused by one or more inherited mutations of genes in DNA located in the nucleus (nDNA) or in genes in the mitochondria (mtDNA) of cells. Genes carry the genetic instructions for cells. A mutation (also called a pathogenic variant) is a change in a gene located in nuclear or mitochondrial DNA that may cause disease. Mutations in nDNA, which occur in cellular chromosomes, can be inherited in different patterns, including autosomal recessive, autosomal dominant or X-linked recessive inheritance.Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. The mtDNA in sperm cells is typically lost during fertilization and as a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production.As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable pattern in different tissues. Consequently, mutated mtDNA accumulates at different rates in different tissues in the same individual. Therefore, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity.Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease of carbohydrate metabolism that is due to a mutation in nDNA. It is generally considered to be the most common cause of biochemically proven cases of congenital lactic acidosis. PDC deficiency can be inherited in an autosomal recessive or X-linked recessive pattern.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children. X-linked dominant disorders are caused by a mutated gene on the X chromosome and mostly affect females. Females are affected when they have an X chromosome with the mutated gene for the disease. Males with a mutated gene for an X-linked dominant disorder are more severely affected than females and often do not survive. Although genetic mitochondrial diseases are the most common causes of congenital lactic acidosis, additional conditions that are present at birth can result in the disorder. These include biotin deficiency, bacterial infection in the bloodstream or body tissues (sepsis), certain types of glycogen storage disease, Reye syndrome, short-bowel syndrome, liver failure, a defect in the heart or blood vessels that leads to a deficiency in the amount of oxygen reaching the body’s tissues (hypoxia) and bacterial meningitis (which causes elevated lactic acid in cerebrospinal fluid). | Causes of Congenital Lactic Acidosis. Most cases of congenital lactic acidosis are caused by one or more inherited mutations of genes in DNA located in the nucleus (nDNA) or in genes in the mitochondria (mtDNA) of cells. Genes carry the genetic instructions for cells. A mutation (also called a pathogenic variant) is a change in a gene located in nuclear or mitochondrial DNA that may cause disease. Mutations in nDNA, which occur in cellular chromosomes, can be inherited in different patterns, including autosomal recessive, autosomal dominant or X-linked recessive inheritance.Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. The mtDNA in sperm cells is typically lost during fertilization and as a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production.As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable pattern in different tissues. Consequently, mutated mtDNA accumulates at different rates in different tissues in the same individual. Therefore, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity.Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease of carbohydrate metabolism that is due to a mutation in nDNA. It is generally considered to be the most common cause of biochemically proven cases of congenital lactic acidosis. PDC deficiency can be inherited in an autosomal recessive or X-linked recessive pattern.Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children. X-linked dominant disorders are caused by a mutated gene on the X chromosome and mostly affect females. Females are affected when they have an X chromosome with the mutated gene for the disease. Males with a mutated gene for an X-linked dominant disorder are more severely affected than females and often do not survive. Although genetic mitochondrial diseases are the most common causes of congenital lactic acidosis, additional conditions that are present at birth can result in the disorder. These include biotin deficiency, bacterial infection in the bloodstream or body tissues (sepsis), certain types of glycogen storage disease, Reye syndrome, short-bowel syndrome, liver failure, a defect in the heart or blood vessels that leads to a deficiency in the amount of oxygen reaching the body’s tissues (hypoxia) and bacterial meningitis (which causes elevated lactic acid in cerebrospinal fluid). | 310 | Congenital Lactic Acidosis |
nord_310_3 | Affects of Congenital Lactic Acidosis | Congenital lactic acidosis affects males and females in equal numbers. The exact incidence of congenital lactic acidosis is unknown. One estimate is that the incidence is 250-300 live births per 1,000 per year in the United States. However, it is likely that many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of congenital lactic acidosis in the general population. | Affects of Congenital Lactic Acidosis. Congenital lactic acidosis affects males and females in equal numbers. The exact incidence of congenital lactic acidosis is unknown. One estimate is that the incidence is 250-300 live births per 1,000 per year in the United States. However, it is likely that many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of congenital lactic acidosis in the general population. | 310 | Congenital Lactic Acidosis |
nord_310_4 | Related disorders of Congenital Lactic Acidosis | Related disorders of Congenital Lactic Acidosis. | 310 | Congenital Lactic Acidosis |
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nord_310_5 | Diagnosis of Congenital Lactic Acidosis | A diagnosis of congenital lactic acidosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood and cerebrospinal fluid tests can reveal certain findings associated with congenital lactic acidosis such as elevated levels of lactate. An enzyme deficiency may be diagnosed by tests conducted on white blood cells or on skin or muscle cells obtained by biopsy. Genetic testing can be used to determine the molecular cause (pathogenic variants or mutations) of congenital lactic acidosis in many patients. | Diagnosis of Congenital Lactic Acidosis. A diagnosis of congenital lactic acidosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood and cerebrospinal fluid tests can reveal certain findings associated with congenital lactic acidosis such as elevated levels of lactate. An enzyme deficiency may be diagnosed by tests conducted on white blood cells or on skin or muscle cells obtained by biopsy. Genetic testing can be used to determine the molecular cause (pathogenic variants or mutations) of congenital lactic acidosis in many patients. | 310 | Congenital Lactic Acidosis |
nord_310_6 | Therapies of Congenital Lactic Acidosis | Treatment
There is no proven treatment for congenital lactic acidosis that is due to a genetic mitochondrial disease. Therefore, treatment is directed toward the specific symptoms and signs that are present in each individual. Vitamins and certain co-factors (for example, carnitine and coenzyme Q) are frequently administered to patients with congenital lactic acidosis, but there is no proof that such agents are effective, except in extremely rare cases of PDC deficiency that respond to high doses of thiamine or in biochemically proven cases of coenzyme Q deficiency.For many years so-called “ketogenic” diets that are very high in fat and very low in carbohydrate have been used in patients with PDC deficiency, with beneficial effects reported in the scientific literature. However, the long-term safety and effectiveness of ketogenic diets have not been studied in a rigorous fashion.Additional therapies for individuals with congenital lactic acidosis are directed at specific complications, such as anti-seizure medications (anti-convulsants) for seizures. Genetic counseling is recommended for affected individuals and their families. | Therapies of Congenital Lactic Acidosis. Treatment
There is no proven treatment for congenital lactic acidosis that is due to a genetic mitochondrial disease. Therefore, treatment is directed toward the specific symptoms and signs that are present in each individual. Vitamins and certain co-factors (for example, carnitine and coenzyme Q) are frequently administered to patients with congenital lactic acidosis, but there is no proof that such agents are effective, except in extremely rare cases of PDC deficiency that respond to high doses of thiamine or in biochemically proven cases of coenzyme Q deficiency.For many years so-called “ketogenic” diets that are very high in fat and very low in carbohydrate have been used in patients with PDC deficiency, with beneficial effects reported in the scientific literature. However, the long-term safety and effectiveness of ketogenic diets have not been studied in a rigorous fashion.Additional therapies for individuals with congenital lactic acidosis are directed at specific complications, such as anti-seizure medications (anti-convulsants) for seizures. Genetic counseling is recommended for affected individuals and their families. | 310 | Congenital Lactic Acidosis |
nord_311_0 | Overview of Congenital Leptin Deficiency | SummaryCongenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. People affected with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by changes (pathogenic variants or mutations) in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.IntroductionCLD is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing. | Overview of Congenital Leptin Deficiency. SummaryCongenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. People affected with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by changes (pathogenic variants or mutations) in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.IntroductionCLD is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing. | 311 | Congenital Leptin Deficiency |
nord_311_1 | Symptoms of Congenital Leptin Deficiency | Most babies with CLD have a normal weight at birth. The earliest symptoms of CLD are constant hunger and excessive eating leading to rapid weight gain and obesity before one year of age. People with CLD always feel hungry even after eating a full meal and often have abnormal behaviors related to food. Many have low levels of sex hormones (hypogonadotropic hypogonadism) causing delayed or absent puberty and infertility. Other symptoms include low energy levels, low blood pressure and insulin resistance, which can lead to type 2 diabetes. Children with CLD are often prone to infections, due to an immune system that doesn’t work correctly. Excessive weight gain can lead to other symptoms such as abnormal bone growth, liver disease and difficultly walking. | Symptoms of Congenital Leptin Deficiency. Most babies with CLD have a normal weight at birth. The earliest symptoms of CLD are constant hunger and excessive eating leading to rapid weight gain and obesity before one year of age. People with CLD always feel hungry even after eating a full meal and often have abnormal behaviors related to food. Many have low levels of sex hormones (hypogonadotropic hypogonadism) causing delayed or absent puberty and infertility. Other symptoms include low energy levels, low blood pressure and insulin resistance, which can lead to type 2 diabetes. Children with CLD are often prone to infections, due to an immune system that doesn’t work correctly. Excessive weight gain can lead to other symptoms such as abnormal bone growth, liver disease and difficultly walking. | 311 | Congenital Leptin Deficiency |
nord_311_2 | Causes of Congenital Leptin Deficiency | CLD is caused by pathogenic variants (mutations) in the LEP gene. The LEP gene is responsible for making the protein, leptin. Leptin is made by fat cells and helps regulate energy storage in the body by balancing how much fat is made and how much is burned for energy. Without leptin, the body doesn’t recognize when the body has enough energy and it’s time to stop eating.CLD is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Congenital Leptin Deficiency. CLD is caused by pathogenic variants (mutations) in the LEP gene. The LEP gene is responsible for making the protein, leptin. Leptin is made by fat cells and helps regulate energy storage in the body by balancing how much fat is made and how much is burned for energy. Without leptin, the body doesn’t recognize when the body has enough energy and it’s time to stop eating.CLD is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 311 | Congenital Leptin Deficiency |
nord_311_3 | Affects of Congenital Leptin Deficiency | Congenital leptin deficiency is a very rare disorder. It has been estimated that 1 in 4.4 million people may have this condition. Many come from parts of the world where it is customary for relatives to marry. | Affects of Congenital Leptin Deficiency. Congenital leptin deficiency is a very rare disorder. It has been estimated that 1 in 4.4 million people may have this condition. Many come from parts of the world where it is customary for relatives to marry. | 311 | Congenital Leptin Deficiency |
nord_311_4 | Related disorders of Congenital Leptin Deficiency | CLD is one of several rare inherited conditions that include early-onset extreme obesity with few or no other signs or symptoms. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and growth of body fat. These conditions may be difficult to diagnose based solely on clinical examination and sometimes genetic testing is the only way to tell the difference between them.Some of these conditions include:PCSK1 deficiencyPCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms which tend to diminish slightly with time, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. PCSK1 deficiency is caused by variants in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and the results of genetic testing. Treatment is available for this condition using a drug called setmelanotide. This drug has been approved for treating people age six and over with PCSK1 deficiency and reverses the symptoms including obesity. Less than 50 people have been reported with PCSK1 deficiency.POMC deficiencyPOMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age, and without treatment, people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by variants in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide. This drug reverses the constant hunger and allows people with POMC deficiency to lose weight. This condition is very rare, and it is difficult to predict how this condition will impact someone with a new diagnosis.Leptin receptor deficiency (LEPR deficiency) Individuals with LEPR deficiency have almost the same symptoms as individuals with congenital leptin deficiency. Early symptoms of both conditions include constant hunger and feeding (hyperphagia) and rapid weight gain leading to obesity in the first few months of life. In addition, endocrine gland abnormalities affecting levels of sex hormones are common, and puberty may be absent or delayed. This condition is caused by variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and the results of genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.Obesity due to melanocortin 4 receptor (MC4R) gene variantsThis is the most common cause of early-onset obesity due to a single gene. People with only one MC4R gene variant are affected. Affected people show severe hunger and develop obesity during childhood. Weight and length are normal at birth. People with MC4R deficiency are often taller than average, which is one of the distinguishing features of this condition.People with two MC4R gene variants develop an extreme form of obesity comparable to people with leptin or leptin receptor deficiency. During the first year of life, affected babies develop extreme hunger and rapidly gain weight. Other symptoms include increased insulin in the blood which can lead to type 2 diabetes. For more information see: Welcome to the Melanocortin 4 Receptor website at https://www.mc4r.org.uk/There are other inherited conditions that include obesity in childhood as one of several features. People with these conditions have other signs and symptoms along with excess weight. These conditions include:Bardet-Biedl syndrome (BBS)BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/Alström syndrome Alström syndrome is a rare complex disorder that includes a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/Beckwith-Wiedemann syndromeBeckwith-Wiedemann syndrome (BWS) is characterized by symptoms and physical findings that vary in range and severity from person to person. Associated features include above-average birth weight, increased growth after birth (macrosomia), a large tongue (macroglossia), enlargement of certain internal organs (organomegaly) and abdominal wall defects (omphalocele, umbilical hernia or diastasis recti). BWS may also be associated with low blood sugar levels, distinctive grooves in the ear lobes (ear creases and ear pits), facial abnormalities and abnormal enlargement of one side or structure of the body (lateralized overgrowth). People with BWS also have an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor). Beckwith-Wiedemann syndrome has been recently reclassified as Beckwith-Wiedemann spectrum as the clinical presentation can vary from patient to patient. Approximately 80% of BWS occurs due to genetic changes that occur randomly. Inherited forms occur in about 5-10% of people with BWS. About 14% of people with BWS have an unknown cause. BWS affects at least one in 10,340 live births. Researchers have determined that BWS results from various abnormalities affecting the normal expression of certain genes that control growth on one part of chromosome 11 (BWS critical region). For more information on this disorder, choose “Beckwith-Wiedemann syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/beckwith-wiedemann-syndrome/Prader-Willi syndromePrader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. People with PWS do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to changes of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/ | Related disorders of Congenital Leptin Deficiency. CLD is one of several rare inherited conditions that include early-onset extreme obesity with few or no other signs or symptoms. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and growth of body fat. These conditions may be difficult to diagnose based solely on clinical examination and sometimes genetic testing is the only way to tell the difference between them.Some of these conditions include:PCSK1 deficiencyPCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms which tend to diminish slightly with time, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. PCSK1 deficiency is caused by variants in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and the results of genetic testing. Treatment is available for this condition using a drug called setmelanotide. This drug has been approved for treating people age six and over with PCSK1 deficiency and reverses the symptoms including obesity. Less than 50 people have been reported with PCSK1 deficiency.POMC deficiencyPOMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age, and without treatment, people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by variants in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide. This drug reverses the constant hunger and allows people with POMC deficiency to lose weight. This condition is very rare, and it is difficult to predict how this condition will impact someone with a new diagnosis.Leptin receptor deficiency (LEPR deficiency) Individuals with LEPR deficiency have almost the same symptoms as individuals with congenital leptin deficiency. Early symptoms of both conditions include constant hunger and feeding (hyperphagia) and rapid weight gain leading to obesity in the first few months of life. In addition, endocrine gland abnormalities affecting levels of sex hormones are common, and puberty may be absent or delayed. This condition is caused by variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and the results of genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.Obesity due to melanocortin 4 receptor (MC4R) gene variantsThis is the most common cause of early-onset obesity due to a single gene. People with only one MC4R gene variant are affected. Affected people show severe hunger and develop obesity during childhood. Weight and length are normal at birth. People with MC4R deficiency are often taller than average, which is one of the distinguishing features of this condition.People with two MC4R gene variants develop an extreme form of obesity comparable to people with leptin or leptin receptor deficiency. During the first year of life, affected babies develop extreme hunger and rapidly gain weight. Other symptoms include increased insulin in the blood which can lead to type 2 diabetes. For more information see: Welcome to the Melanocortin 4 Receptor website at https://www.mc4r.org.uk/There are other inherited conditions that include obesity in childhood as one of several features. People with these conditions have other signs and symptoms along with excess weight. These conditions include:Bardet-Biedl syndrome (BBS)BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/Alström syndrome Alström syndrome is a rare complex disorder that includes a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/Beckwith-Wiedemann syndromeBeckwith-Wiedemann syndrome (BWS) is characterized by symptoms and physical findings that vary in range and severity from person to person. Associated features include above-average birth weight, increased growth after birth (macrosomia), a large tongue (macroglossia), enlargement of certain internal organs (organomegaly) and abdominal wall defects (omphalocele, umbilical hernia or diastasis recti). BWS may also be associated with low blood sugar levels, distinctive grooves in the ear lobes (ear creases and ear pits), facial abnormalities and abnormal enlargement of one side or structure of the body (lateralized overgrowth). People with BWS also have an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor). Beckwith-Wiedemann syndrome has been recently reclassified as Beckwith-Wiedemann spectrum as the clinical presentation can vary from patient to patient. Approximately 80% of BWS occurs due to genetic changes that occur randomly. Inherited forms occur in about 5-10% of people with BWS. About 14% of people with BWS have an unknown cause. BWS affects at least one in 10,340 live births. Researchers have determined that BWS results from various abnormalities affecting the normal expression of certain genes that control growth on one part of chromosome 11 (BWS critical region). For more information on this disorder, choose “Beckwith-Wiedemann syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/beckwith-wiedemann-syndrome/Prader-Willi syndromePrader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. People with PWS do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to changes of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/ | 311 | Congenital Leptin Deficiency |
nord_311_5 | Diagnosis of Congenital Leptin Deficiency | Congenital leptin deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations. | Diagnosis of Congenital Leptin Deficiency. Congenital leptin deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations. | 311 | Congenital Leptin Deficiency |
nord_311_6 | Therapies of Congenital Leptin Deficiency | Congenital leptin deficiency is treatable with leptin replacement using recombinant human leptin, also known as metreleptin. Treatment results in a decreased appetite and significant weight and fat loss. In addition, leptin replacement leads to normal sexual development, decreased insulin levels and restores the immune system.People with congenital leptin deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition. | Therapies of Congenital Leptin Deficiency. Congenital leptin deficiency is treatable with leptin replacement using recombinant human leptin, also known as metreleptin. Treatment results in a decreased appetite and significant weight and fat loss. In addition, leptin replacement leads to normal sexual development, decreased insulin levels and restores the immune system.People with congenital leptin deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition. | 311 | Congenital Leptin Deficiency |
nord_312_0 | Overview of Congenital Muscular Dystrophy | Congenital muscular dystrophy (CMD) is a general term for a group of genetic muscle diseases that occur at birth (congenital) or early during infancy. CMDs are generally characterized by diminished muscle tone (hypotonia), which is sometimes referred to as “floppy baby”; progressive muscle weakness and degeneration (atrophy); abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected area (contractures); spinal rigidity, and delays in reaching motor milestones such as sitting or standing unassisted. Feeding difficulties and breathing (respiratory) complications can develop in some cases. Muscle weakness may improve, remain stable or worsen. Some forms of CMD may be associated with structural brain defects and, potentially, intellectual disability. The severity, specific symptoms, and progression of these disorders vary greatly. Most forms of CMD are inherited as autosomal recessive traits. Collage type VI-related disorders can be inherited as either autosomal dominant or autosomal recessive conditions. LMNA-related CMD is inherited in an autosomal dominant manner, with all mutations reported to date being new mutations (de novo).CMDs belong to a larger group of disorders known as the muscular dystrophies. The muscular dystrophies characterized by weakness and degeneration of various voluntary muscles of the body. More than 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns. As researchers have learned more about the CMDs, such as identifying many of the specific genes involved, a broader picture of these diseases has emerged. The subtypes of CMD have considerable overlap with other disease classifications including the congenital myopathies, disorders of glycosylation, and the limb-girdle muscular dystrophies. CMDs are a rapidly growing disease family and information about these disorders is constantly changing. | Overview of Congenital Muscular Dystrophy. Congenital muscular dystrophy (CMD) is a general term for a group of genetic muscle diseases that occur at birth (congenital) or early during infancy. CMDs are generally characterized by diminished muscle tone (hypotonia), which is sometimes referred to as “floppy baby”; progressive muscle weakness and degeneration (atrophy); abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected area (contractures); spinal rigidity, and delays in reaching motor milestones such as sitting or standing unassisted. Feeding difficulties and breathing (respiratory) complications can develop in some cases. Muscle weakness may improve, remain stable or worsen. Some forms of CMD may be associated with structural brain defects and, potentially, intellectual disability. The severity, specific symptoms, and progression of these disorders vary greatly. Most forms of CMD are inherited as autosomal recessive traits. Collage type VI-related disorders can be inherited as either autosomal dominant or autosomal recessive conditions. LMNA-related CMD is inherited in an autosomal dominant manner, with all mutations reported to date being new mutations (de novo).CMDs belong to a larger group of disorders known as the muscular dystrophies. The muscular dystrophies characterized by weakness and degeneration of various voluntary muscles of the body. More than 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns. As researchers have learned more about the CMDs, such as identifying many of the specific genes involved, a broader picture of these diseases has emerged. The subtypes of CMD have considerable overlap with other disease classifications including the congenital myopathies, disorders of glycosylation, and the limb-girdle muscular dystrophies. CMDs are a rapidly growing disease family and information about these disorders is constantly changing. | 312 | Congenital Muscular Dystrophy |
nord_312_1 | Symptoms of Congenital Muscular Dystrophy | The onset, specific symptoms, and severity of CMD varies considerably even among affected members of the same family. Several different methods of classifying the CMDs have been proposed. One classification separates these disorders based upon the primary genetic defect. This classification has three main categories: CMDs caused by defective genes that produce structural proteins of the basement membrane or the extracellular matrix, a complex structure that surrounds and supports cells; CMDs caused by defective genes that produce proteins essential for the normal attachment or binding (glycosylation) of sugar molecules to dystroglycan, a protein found on the membrane (sarcolemma) of muscle cells; or CMDs caused by a defective selenoprotein 1 (SEPN1) gene, which produces a protein without a currently known function. Recently, defective genes that produce proteins of the nuclear envelope, the double-layered membrane that covers the nucleus of certain cells, have also been linked to CMD. CMDS RESULTING FROM DEFECTIVE STRUCTURAL PROTEINS OF THE BASAL MEMBRANE OR EXTRACELLUAR MATRIX OF MUSCLE FIBERS. * Congenital Muscular Dystrophy Type 1A (MDC1A; Merosin-Deficient CMD; CMD with Laminin Alpha 2 Deficiency) This form of CMD may be associated with a complete deficiency of the protein merosin in muscle, a protein found in the tissue that surrounds muscle fibers. Infants usually exhibit diminished muscle tone (hypotonia) and muscle weakness at birth. Some infants may experience respiratory and feeding difficulties shortly after birth (neonatal period). Feeding difficulties may result in affected children failing to gain weight and grow at the expected rate (failure to thrive). Muscle weakness is severe and most affected infants experience delays in reaching or fail to reach many motor milestones. Most affected infants can sit unsupported and some can stand without assistance. Only a few children with the severe form of MDC1A eventually are able to walk without assistance. Additional symptoms may occur including joint contractures, congenital dislocation of the hip, progressive curvature of the spine (scoliosis), and weakness of muscles around the eyes that gradually restricts the movements of the eyes (ophthalmoplegia). Some individuals with MDC1A experience seizures. As affected children age, breathing difficulties may progress and cause complications such as inadequate breathing at night (nocturnal hypoventilation). Seizures have been reported in approximately 20%-30% of affected individuals. Although less common, some affected children only have a partial deficiency of merosin. The severity of partial merosin deficiency varies greatly and can be much milder. Muscle weakness may be absent. The age of onset may be during infancy, adolescence, or adulthood. During infancy, affected individuals may have diminished muscle tone (hypotonia), contractures, and delays in attaining motor milestones. Although rare, partial deficiency of merosin can resemble classic MDC1A, onset of symptoms usually doesn’t occur until the second decade and feeding or ventilation support is usually not required or not required until much later in life. Adolescence or adult onset usually resembles a similar muscle disorder known as limb-girdle muscular dystrophy. (For more information on this disorder, see the related disorders section of this report.) * Collagen Type VI-Related Disorders Collagen type VI-related disorders is a spectrum of disease encompasses two disorders formerly thought to be separate conditions, Bethlem myopathy and Ullrich congenital muscular dystrophy. Bethlem myopathy represents the mild end of this spectrum; Ullrich congenital muscular dystrophy represents the severe end this spectrum. Intermediate forms are common. (For more information, see the individual NORD entry on “collagen type VI-related disorders” in NORD's Rare Disease Database.) The characteristic symptoms of this form of CMD are diminished muscle tone (hypotonia), muscle weakness, abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), and abnormally flexible (hyperelastic) joints of the wrists and ankles as well as in the fingers and toes. Contractures may be present at birth or occur later. Additional symptoms may be present and severity is highly variable. In some cases, congenital dislocation of the hip, muscles spasms of the neck (torticollis), or lower bone density may develop. Affected individuals may also experience breathing (respiratory) difficulties and failure to thrive. Intelligence is normal in most cases. The amount of motor development varies from case to case. Some children are able to walk independently; others require assistance to walk. In some cases, affected children may never be able to walk. In addition, some children who develop the ability to walk independently lose that ability because of the progression of the disease and worsening of the contractures. Others maintain the ability to walk through adulthood. Additional symptoms may occur including breathing insufficiency and a skin condition characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules) on the skin. However, skin on the palms of the hands and soles of the feet is velvety and very soft. Individuals with this form of CMD develop rigidity of the spin, often with scoliosis. * Congenital Muscular Dystrophy with Integrin 7 Alpha Deficiency This is an extremely rare form of CMD that has been described in only a few individuals. Symptoms include muscles weakness and delays in attaining motor milestones. * Congenital Muscular Dystrophy with Integrin 9 Alpha DeficiencyThis extremely rare form of CMD has only been described in a handful of individuals. Affected individuals may experience hypotonia, contractures, joint hyperlaxity, and scoliosis. In this form of CMD, intelligence has been unaffected and individuals retain the ability to walk into adulthood. Some affected individuals may develop decreased respiratory function, but usually do not require ventilator support.CMDS THAT RESULT FROM DEFECTIVE PROTEINS THAT ARE ESSENTIAL FOR THE BINDING OF SUGAR MOLECULES TO DYSTROGLYCAN, KNOWN COLLECTIVELY AS THE DYSTROGLYCANOPATHIES. Several different genes have been associated with the dystroglycanopathies and researchers have determined that these individual genes can potentially be associated with more than one of the disorders described below. Although these disorders were once considered separate conditions, this subgroup of CMD is now considered a spectrum of disease that ranges from mild presentations (phenotypes) to severe ones. Mutations in certain genes that cause these dystroglycanopathies can also causes mild forms of limb-girdle muscular dystrophy. * Congenital Muscular Dystrophy Type 1C (MDC1C; CMD with secondary merosin deficiency type 2) MDC1C is a potentially severe form of CMD that is characterized by diminished muscle tone (hypotonia) and muscle weakness at birth. Affected infants may also develop respiratory and feeding difficulties. Respiratory difficulties are progressive and often cause breathing insufficiency (respiratory failure). Delays in reaching motor milestones also occur. Affected infants usually are able to sit up without assistance, but only a few are able to walk unassisted. Additional symptoms may occur including overgrowth (hypertrophy) of the muscles of the legs, an abnormally enlarged tongue (macroglossia), weakness and wasting (atrophy) of the muscles of the arms, and contractures, especially of the Achilles tendon, hip flexor, and fingers. Weakness and wasting may also affect the muscles of the face and shoulders. Some individuals eventually develop disease of the heart muscle, specifically dilated cardiomyopathy. This condition is characterized by abnormal enlargement or widening (dilatation) of one or more of the chambers of the heart resulting in weakening of the heart's pumping action, causing a limited ability to circulate blood to the lungs and the rest of the body and resulting in fluid buildup in the heart, lung, and various body tissues (congestive heart failure). Most cases of MDC1C are not associated with structural brain abnormalities and intelligence is normal. However, in some rare cases, affected individuals do have such abnormalities and often have mild intellectual disability. Seizures have also been reported in some cases. * Muscle-Eye-Brain (MEB) Disease Spectrum The symptoms and severity of MEB disease may vary. Affected infants usually exhibit profoundly diminished muscle tone (hypotonia) and muscle weakness at birth. Muscle weakness often affects the arms, legs, and trunk. Affected infants may fail to gain weight and grow at the expected rate (failure to thrive). Developmental delays and eye (ocular) abnormalities are also common findings. In mild forms of MEB, affected individuals experience delays in attaining developmental milestones, but eventually may be able to walk independently. In severe cases, few motor milestones are attained (e.g., no head control or ability to hold the head up). MEB is usually progressive and some individuals will lose previously acquired skills such as walking independently. Motor decline can also occur as a result of increasing spasticity. Affected infants may have a large head with a prominent forehead and wide “soft spot” (fontanelle) and distinctive facial features including an abnormally small jaw (micrognathia), underdevelopment of middle portion of the face (midface hypoplasia), a short nose, and an abnormally small groove between the upper lip and tip of the nose (philtrum). Ocular abnormalities associated MEB disease include increased pressure within the eyes (infantile glaucoma), clouding of the lenses of the eyes (cataracts), rapid, involuntary eye movements (nystagmus), underdevelopment of the nerve-rich membrane lining the eyes (retinal hypoplasia), and severe nearsightedness (congenital myopia). Central nervous system involvement such as increased reflexes or involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs may also develop. Mental retardation and seizures may also occur in individuals with MEB disease. All individuals with MEB have a small brainstem and cerebellum and some have cerebral cortex abnormalities such as pachygyria or lissencephaly, a structural brain defect in which the brain is smooth, lacking the normal folds. * Fukuyama Type Congenital Muscular Dystrophy and Walker-Warburg Syndrome Like MEB disease, Fukuyama congenital muscular dystrophy (FCMD) and Walker-Warburg syndrome (WSS) are multisystem disorders characterized by muscle weakness, structural brain defects, and eye abnormalities. Infants with FCMD have generalized muscle weakness, diminished muscle tone (hypotonia), poor sucking ability, and a weak cry. Contractures of the hip, knee, ankles, and elbows are common findings within the first year of life. Individuals with FCMD also have eye (ocular) abnormalities such as crossed eyes (strabismus), cataracts, nearsightedness (myopia), abnormal eye movements, and, in severe cases, retinal detachment and abnormally small eyes (microphthalmos). FCMD is also characterized by seizures, mental retardation, and speech problems. Eventually, affected individuals develop respiratory difficulties and disease of the heart muscle (dilated cardiomyopathy). Walker-Warburg syndrome is characterized by muscle weakness, type II lissencephaly, and the abnormal development of the nerve-rich membrane at the back of the eyes (retinal dysplasia). Affected individuals also have obstructive hydrocephalus, a condition in which blockage of the normal circulation of cerebrospinal fluid results in pressure on the brain. Occipital encephalocele can also occur. Affected infants also typically have severe growth failure; an unusually small head; seizures; and additional abnormalities of the eyes including detachment of the retinas, abnormally small eyes (microphthalmia), and clouding of the lenses (cataracts) and the corneas. (For more information, see the individual entries for FCMD and WSS in NORD's Rare Disease Database.) * Congenital Muscular Dystrophy Type 1D (MDC1D) As of 2012, MDC1D has been reported in several individuals from four different families (kindreds). Affected individuals have developed severe intellectual disability, hypotonia, developmental delays, mild contractures, and muscle weakness and degeneration (atrophy). Structural defects of the brain have also been reported. CMDS RESULTING FROM DEFECTS OF THE SELENOPROTEIN1 (SEPN1) GENE. * SEPN1-Related MyopathyIndividuals with this form of CMD were initially referred to as having rigid spine muscular dystrophy (RSMD1) or CMD with early rigidity of the spine. However, individuals with a rigid spine and a mutation of the selenoprotein N1 (SEPN1) gene have been seen who fit the criteria for four different muscle conditions including rigid spine muscular dystrophy (rigid spine syndrome), congenital fiber type disproportion, desmin-related myopathy, and multiminicore myopathy. Researchers now refer to these individuals collectively as having SEPN1-related myopathy. The hallmark of this form of CMD is early rigidity of the spine that often develops during the first year of life and slowly progressive curvature of the spine (scoliosis), which develops from 3 to 12 years of age. Additional symptoms include progressive muscle weakness, diminished muscle tone (hypotonia), early breathing (respiratory) difficulties, contractures of the Achilles tendons, and weakness of the neck muscles resulting in poor head control. Muscle weakness is mild compared to other forms of CMD. Breathing difficulties are progressive and by the teen-age years, muscles within the lungs may become affected. Eventually, affected individuals experience inadequate breathing at night (nocturnal hypoventilation) and, potentially, respiratory failure. The onset of breathing difficulties is highly variable, usually occurring during adolescence, but also occurring during infancy and as late as the fourth decade of life. Individuals with SEPN1-related myopathy usually do not experience delays in attaining motor milestones. Most individuals are able to walk independently although because of progressive spinal rigidity and scoliosis they may experience difficulties walking later during life. CMDS RESULTING FROM DEFECTIVE PROTEINS OF THE NUCLEAR ENVELOPE. * LMNA-Related CMDThis form of CMD is often associated with a severe presentation that occurs during the first 6 months of life. Affected infants may experience hypotonia, absence of head/trunk support (dropped head syndrome), spinal rigidity, and generalized muscle wasting and weakness that is prominent in the neck, arms and feet. Scoliosis and lower limb contractures may also develop. As muscle weakness progresses, lung disease can develop resulting in breathing difficulties. Severely affected individuals may require breathing assistance (mechanical ventilation).This form of CMD is caused by mutations of the LMNA gene. Mutations of this gene have also been shown to cause a wide variety of other disorders (allelic disorders) including familial partial lipodystrophy type 2 (Dunnigan lipodystrophy), mandibuloacral dysplasia, a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and some cases of Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)* SYNE1-Related CMDThis extremely rare form of CMD has only been reported in two siblings who had adducted thumbs, intellectual disability, cataracts, and ophthalmoplegia. These siblings also had underdevelopment of the cerebellum (cerebellar hypoplasia), which can cause problems with balance and coordination. This form of the CMD is caused by mutations of the SYNE1 gene. ADDITIONAL RARE FORMS OF CMDS WITH OR WITHOUT A KNOWN GENETIC DEFECT. Several additional forms of CMD exist, but cannot be linked to a specific genetic defect. These forms include cases of WSS not linked to mutations in any known gene associated with glycosyltransferase enzymes and cases with rigid spine syndrome not linked to mutations in the SEPN1 gene. Cases associated with cerebellar involvement have also been reported.* Congenital Muscular Dystrophy Type 1B (MDC1B; CMD with secondary merosin deficiency type 1) MDC1B is characterized by diminished muscle tone (hypotonia), muscle weakness of the muscles closer to the center of the body (proximal muscles), generalized overgrowth of some muscles (hypertrophy), rigidity of the spine, and contractures especially of the Achilles tendon. This form of CMD has been linked to an as yet unidentified gene on chromosome 1 and is classified as a subtype of the dystroglycanopathies.* CHKB-Related Muscle DiseaseThis extremely rare form of CMD has been reported in fewer than twenty individuals. Affected individuals experience intellectual disability, hypotonia, and generalized muscle weakness. Affected individuals were able to walk without assistance. Additional symptoms that may occur include dilated cardiomyopathy and structural abnormalities to the mitochondria, the parts of the cell that release energy. This disorder is also known as megaconial type CMD or CMD with mitochondrial structural abnormalities (CMDmt). | Symptoms of Congenital Muscular Dystrophy. The onset, specific symptoms, and severity of CMD varies considerably even among affected members of the same family. Several different methods of classifying the CMDs have been proposed. One classification separates these disorders based upon the primary genetic defect. This classification has three main categories: CMDs caused by defective genes that produce structural proteins of the basement membrane or the extracellular matrix, a complex structure that surrounds and supports cells; CMDs caused by defective genes that produce proteins essential for the normal attachment or binding (glycosylation) of sugar molecules to dystroglycan, a protein found on the membrane (sarcolemma) of muscle cells; or CMDs caused by a defective selenoprotein 1 (SEPN1) gene, which produces a protein without a currently known function. Recently, defective genes that produce proteins of the nuclear envelope, the double-layered membrane that covers the nucleus of certain cells, have also been linked to CMD. CMDS RESULTING FROM DEFECTIVE STRUCTURAL PROTEINS OF THE BASAL MEMBRANE OR EXTRACELLUAR MATRIX OF MUSCLE FIBERS. * Congenital Muscular Dystrophy Type 1A (MDC1A; Merosin-Deficient CMD; CMD with Laminin Alpha 2 Deficiency) This form of CMD may be associated with a complete deficiency of the protein merosin in muscle, a protein found in the tissue that surrounds muscle fibers. Infants usually exhibit diminished muscle tone (hypotonia) and muscle weakness at birth. Some infants may experience respiratory and feeding difficulties shortly after birth (neonatal period). Feeding difficulties may result in affected children failing to gain weight and grow at the expected rate (failure to thrive). Muscle weakness is severe and most affected infants experience delays in reaching or fail to reach many motor milestones. Most affected infants can sit unsupported and some can stand without assistance. Only a few children with the severe form of MDC1A eventually are able to walk without assistance. Additional symptoms may occur including joint contractures, congenital dislocation of the hip, progressive curvature of the spine (scoliosis), and weakness of muscles around the eyes that gradually restricts the movements of the eyes (ophthalmoplegia). Some individuals with MDC1A experience seizures. As affected children age, breathing difficulties may progress and cause complications such as inadequate breathing at night (nocturnal hypoventilation). Seizures have been reported in approximately 20%-30% of affected individuals. Although less common, some affected children only have a partial deficiency of merosin. The severity of partial merosin deficiency varies greatly and can be much milder. Muscle weakness may be absent. The age of onset may be during infancy, adolescence, or adulthood. During infancy, affected individuals may have diminished muscle tone (hypotonia), contractures, and delays in attaining motor milestones. Although rare, partial deficiency of merosin can resemble classic MDC1A, onset of symptoms usually doesn’t occur until the second decade and feeding or ventilation support is usually not required or not required until much later in life. Adolescence or adult onset usually resembles a similar muscle disorder known as limb-girdle muscular dystrophy. (For more information on this disorder, see the related disorders section of this report.) * Collagen Type VI-Related Disorders Collagen type VI-related disorders is a spectrum of disease encompasses two disorders formerly thought to be separate conditions, Bethlem myopathy and Ullrich congenital muscular dystrophy. Bethlem myopathy represents the mild end of this spectrum; Ullrich congenital muscular dystrophy represents the severe end this spectrum. Intermediate forms are common. (For more information, see the individual NORD entry on “collagen type VI-related disorders” in NORD's Rare Disease Database.) The characteristic symptoms of this form of CMD are diminished muscle tone (hypotonia), muscle weakness, abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), and abnormally flexible (hyperelastic) joints of the wrists and ankles as well as in the fingers and toes. Contractures may be present at birth or occur later. Additional symptoms may be present and severity is highly variable. In some cases, congenital dislocation of the hip, muscles spasms of the neck (torticollis), or lower bone density may develop. Affected individuals may also experience breathing (respiratory) difficulties and failure to thrive. Intelligence is normal in most cases. The amount of motor development varies from case to case. Some children are able to walk independently; others require assistance to walk. In some cases, affected children may never be able to walk. In addition, some children who develop the ability to walk independently lose that ability because of the progression of the disease and worsening of the contractures. Others maintain the ability to walk through adulthood. Additional symptoms may occur including breathing insufficiency and a skin condition characterized by thickening and hardening (hyperkeratosis) of hair follicles, resulting in the development of rough, elevated growths (papules) on the skin. However, skin on the palms of the hands and soles of the feet is velvety and very soft. Individuals with this form of CMD develop rigidity of the spin, often with scoliosis. * Congenital Muscular Dystrophy with Integrin 7 Alpha Deficiency This is an extremely rare form of CMD that has been described in only a few individuals. Symptoms include muscles weakness and delays in attaining motor milestones. * Congenital Muscular Dystrophy with Integrin 9 Alpha DeficiencyThis extremely rare form of CMD has only been described in a handful of individuals. Affected individuals may experience hypotonia, contractures, joint hyperlaxity, and scoliosis. In this form of CMD, intelligence has been unaffected and individuals retain the ability to walk into adulthood. Some affected individuals may develop decreased respiratory function, but usually do not require ventilator support.CMDS THAT RESULT FROM DEFECTIVE PROTEINS THAT ARE ESSENTIAL FOR THE BINDING OF SUGAR MOLECULES TO DYSTROGLYCAN, KNOWN COLLECTIVELY AS THE DYSTROGLYCANOPATHIES. Several different genes have been associated with the dystroglycanopathies and researchers have determined that these individual genes can potentially be associated with more than one of the disorders described below. Although these disorders were once considered separate conditions, this subgroup of CMD is now considered a spectrum of disease that ranges from mild presentations (phenotypes) to severe ones. Mutations in certain genes that cause these dystroglycanopathies can also causes mild forms of limb-girdle muscular dystrophy. * Congenital Muscular Dystrophy Type 1C (MDC1C; CMD with secondary merosin deficiency type 2) MDC1C is a potentially severe form of CMD that is characterized by diminished muscle tone (hypotonia) and muscle weakness at birth. Affected infants may also develop respiratory and feeding difficulties. Respiratory difficulties are progressive and often cause breathing insufficiency (respiratory failure). Delays in reaching motor milestones also occur. Affected infants usually are able to sit up without assistance, but only a few are able to walk unassisted. Additional symptoms may occur including overgrowth (hypertrophy) of the muscles of the legs, an abnormally enlarged tongue (macroglossia), weakness and wasting (atrophy) of the muscles of the arms, and contractures, especially of the Achilles tendon, hip flexor, and fingers. Weakness and wasting may also affect the muscles of the face and shoulders. Some individuals eventually develop disease of the heart muscle, specifically dilated cardiomyopathy. This condition is characterized by abnormal enlargement or widening (dilatation) of one or more of the chambers of the heart resulting in weakening of the heart's pumping action, causing a limited ability to circulate blood to the lungs and the rest of the body and resulting in fluid buildup in the heart, lung, and various body tissues (congestive heart failure). Most cases of MDC1C are not associated with structural brain abnormalities and intelligence is normal. However, in some rare cases, affected individuals do have such abnormalities and often have mild intellectual disability. Seizures have also been reported in some cases. * Muscle-Eye-Brain (MEB) Disease Spectrum The symptoms and severity of MEB disease may vary. Affected infants usually exhibit profoundly diminished muscle tone (hypotonia) and muscle weakness at birth. Muscle weakness often affects the arms, legs, and trunk. Affected infants may fail to gain weight and grow at the expected rate (failure to thrive). Developmental delays and eye (ocular) abnormalities are also common findings. In mild forms of MEB, affected individuals experience delays in attaining developmental milestones, but eventually may be able to walk independently. In severe cases, few motor milestones are attained (e.g., no head control or ability to hold the head up). MEB is usually progressive and some individuals will lose previously acquired skills such as walking independently. Motor decline can also occur as a result of increasing spasticity. Affected infants may have a large head with a prominent forehead and wide “soft spot” (fontanelle) and distinctive facial features including an abnormally small jaw (micrognathia), underdevelopment of middle portion of the face (midface hypoplasia), a short nose, and an abnormally small groove between the upper lip and tip of the nose (philtrum). Ocular abnormalities associated MEB disease include increased pressure within the eyes (infantile glaucoma), clouding of the lenses of the eyes (cataracts), rapid, involuntary eye movements (nystagmus), underdevelopment of the nerve-rich membrane lining the eyes (retinal hypoplasia), and severe nearsightedness (congenital myopia). Central nervous system involvement such as increased reflexes or involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs may also develop. Mental retardation and seizures may also occur in individuals with MEB disease. All individuals with MEB have a small brainstem and cerebellum and some have cerebral cortex abnormalities such as pachygyria or lissencephaly, a structural brain defect in which the brain is smooth, lacking the normal folds. * Fukuyama Type Congenital Muscular Dystrophy and Walker-Warburg Syndrome Like MEB disease, Fukuyama congenital muscular dystrophy (FCMD) and Walker-Warburg syndrome (WSS) are multisystem disorders characterized by muscle weakness, structural brain defects, and eye abnormalities. Infants with FCMD have generalized muscle weakness, diminished muscle tone (hypotonia), poor sucking ability, and a weak cry. Contractures of the hip, knee, ankles, and elbows are common findings within the first year of life. Individuals with FCMD also have eye (ocular) abnormalities such as crossed eyes (strabismus), cataracts, nearsightedness (myopia), abnormal eye movements, and, in severe cases, retinal detachment and abnormally small eyes (microphthalmos). FCMD is also characterized by seizures, mental retardation, and speech problems. Eventually, affected individuals develop respiratory difficulties and disease of the heart muscle (dilated cardiomyopathy). Walker-Warburg syndrome is characterized by muscle weakness, type II lissencephaly, and the abnormal development of the nerve-rich membrane at the back of the eyes (retinal dysplasia). Affected individuals also have obstructive hydrocephalus, a condition in which blockage of the normal circulation of cerebrospinal fluid results in pressure on the brain. Occipital encephalocele can also occur. Affected infants also typically have severe growth failure; an unusually small head; seizures; and additional abnormalities of the eyes including detachment of the retinas, abnormally small eyes (microphthalmia), and clouding of the lenses (cataracts) and the corneas. (For more information, see the individual entries for FCMD and WSS in NORD's Rare Disease Database.) * Congenital Muscular Dystrophy Type 1D (MDC1D) As of 2012, MDC1D has been reported in several individuals from four different families (kindreds). Affected individuals have developed severe intellectual disability, hypotonia, developmental delays, mild contractures, and muscle weakness and degeneration (atrophy). Structural defects of the brain have also been reported. CMDS RESULTING FROM DEFECTS OF THE SELENOPROTEIN1 (SEPN1) GENE. * SEPN1-Related MyopathyIndividuals with this form of CMD were initially referred to as having rigid spine muscular dystrophy (RSMD1) or CMD with early rigidity of the spine. However, individuals with a rigid spine and a mutation of the selenoprotein N1 (SEPN1) gene have been seen who fit the criteria for four different muscle conditions including rigid spine muscular dystrophy (rigid spine syndrome), congenital fiber type disproportion, desmin-related myopathy, and multiminicore myopathy. Researchers now refer to these individuals collectively as having SEPN1-related myopathy. The hallmark of this form of CMD is early rigidity of the spine that often develops during the first year of life and slowly progressive curvature of the spine (scoliosis), which develops from 3 to 12 years of age. Additional symptoms include progressive muscle weakness, diminished muscle tone (hypotonia), early breathing (respiratory) difficulties, contractures of the Achilles tendons, and weakness of the neck muscles resulting in poor head control. Muscle weakness is mild compared to other forms of CMD. Breathing difficulties are progressive and by the teen-age years, muscles within the lungs may become affected. Eventually, affected individuals experience inadequate breathing at night (nocturnal hypoventilation) and, potentially, respiratory failure. The onset of breathing difficulties is highly variable, usually occurring during adolescence, but also occurring during infancy and as late as the fourth decade of life. Individuals with SEPN1-related myopathy usually do not experience delays in attaining motor milestones. Most individuals are able to walk independently although because of progressive spinal rigidity and scoliosis they may experience difficulties walking later during life. CMDS RESULTING FROM DEFECTIVE PROTEINS OF THE NUCLEAR ENVELOPE. * LMNA-Related CMDThis form of CMD is often associated with a severe presentation that occurs during the first 6 months of life. Affected infants may experience hypotonia, absence of head/trunk support (dropped head syndrome), spinal rigidity, and generalized muscle wasting and weakness that is prominent in the neck, arms and feet. Scoliosis and lower limb contractures may also develop. As muscle weakness progresses, lung disease can develop resulting in breathing difficulties. Severely affected individuals may require breathing assistance (mechanical ventilation).This form of CMD is caused by mutations of the LMNA gene. Mutations of this gene have also been shown to cause a wide variety of other disorders (allelic disorders) including familial partial lipodystrophy type 2 (Dunnigan lipodystrophy), mandibuloacral dysplasia, a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and some cases of Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)* SYNE1-Related CMDThis extremely rare form of CMD has only been reported in two siblings who had adducted thumbs, intellectual disability, cataracts, and ophthalmoplegia. These siblings also had underdevelopment of the cerebellum (cerebellar hypoplasia), which can cause problems with balance and coordination. This form of the CMD is caused by mutations of the SYNE1 gene. ADDITIONAL RARE FORMS OF CMDS WITH OR WITHOUT A KNOWN GENETIC DEFECT. Several additional forms of CMD exist, but cannot be linked to a specific genetic defect. These forms include cases of WSS not linked to mutations in any known gene associated with glycosyltransferase enzymes and cases with rigid spine syndrome not linked to mutations in the SEPN1 gene. Cases associated with cerebellar involvement have also been reported.* Congenital Muscular Dystrophy Type 1B (MDC1B; CMD with secondary merosin deficiency type 1) MDC1B is characterized by diminished muscle tone (hypotonia), muscle weakness of the muscles closer to the center of the body (proximal muscles), generalized overgrowth of some muscles (hypertrophy), rigidity of the spine, and contractures especially of the Achilles tendon. This form of CMD has been linked to an as yet unidentified gene on chromosome 1 and is classified as a subtype of the dystroglycanopathies.* CHKB-Related Muscle DiseaseThis extremely rare form of CMD has been reported in fewer than twenty individuals. Affected individuals experience intellectual disability, hypotonia, and generalized muscle weakness. Affected individuals were able to walk without assistance. Additional symptoms that may occur include dilated cardiomyopathy and structural abnormalities to the mitochondria, the parts of the cell that release energy. This disorder is also known as megaconial type CMD or CMD with mitochondrial structural abnormalities (CMDmt). | 312 | Congenital Muscular Dystrophy |
nord_312_2 | Causes of Congenital Muscular Dystrophy | Most of the congenital muscular dystrophies are inherited as autosomal recessive conditions. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Collagen type VI disorders can be inherited as either autosomal recessive conditions or as autosomal dominant conditions. LMNA-related CMD is caused by autosomal dominant mutations that occur spontaneously (de novo) with no previous family history of the disorder (i.e. new mutations. Some cases of autosomal dominant collagen type VI-related disorders occur as de novo mutations. 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 (de novo gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. The CMDs are caused by deficiency or lack of specific proteins that play an essential role in the proper function and health of muscle cells. Some CMDs are involved with genes that contain instructions to produce (encode) proteins associated with the basement membrane and extracellular matrix of muscle cells. Investigators have determined that MDC1A is caused by disruptions or changes (mutations) in the laminin alpha-2 (LAMA2) gene located on long arm of chromosome 6 (6q22-23). The LAMA2 gene encodes merosin, a protein found in the tissue that surrounds muscle fibers. Three disease genes have been identified for collagen type VI disorders. These genes, two of which are located on the long arm of chromosome 21 and one on the long arm of chromosome 2, encode for types of a known as collagen VI. A disease gene (ITGA7) for CMD with integrin alpha 7 has been located on the long arm of chromosome 12 (12q13). A disease gene (ITGA9) for CMD with integrin alpha 9 has been located on the short arm of chromosome 3 (3p23-p221). Some CMD are involved with genes that encode proteins (enzymes) that play a role in the binding of sugar molecules to proteins (glycosylation). In these particular disorders, improper glycosylation of a protein found on the membrane of muscle cells (dystroglycan) occurs. These disorders are collectively termed the dystroglycanopathies and include Fukuyama CMD, muscle-eye-brain disease, Walker-Warburg syndrome, MDC1C, and MDC1D. A disease gene (FCMD) for Fukuyama CMD has been located on the long arm of chromosome 9 (9q31). The FCMD gene encodes for the protein fukutin. A disease gene (FKRP) for MDC1C has been located on the long arm of chromosome 19 (19q13.3). The FKRP gene encodes for the fukutin-related protein. A disease gene (LARGE), which causes MDC1D, has been located on the long arm of chromosome 22 (22q12.3-13.1). The function of the protein encoded by the LARGE gene is unknown. Although researchers initially believed that the dystroglycanopathies followed a “one gene, one disorder” pattern, they have learned that individual genes can be associated with different phenotypes and the same phenotype can be found associated with different genes. For example, both muscle-eye-brain disease and Walker-Warburg syndrome can be caused by mutations of more than one gene (genetic heterogeneity). A disease gene (POMGnT1) for muscle-eye-brain disease has been located on the long arm of chromosome 1 (1q32-34). Some rare cases of muscle-eye-brain disease are caused by mutations of the FKRP gene. A disease gene (POMT1) for Walker-Warburg syndrome has been located on the long arm of chromosome 9 (9q34.1).Walker-Warburg syndrome can also be caused by mutations of the FCMD and FKRP genes and the POMT2 gene, which is located on the long arm of chromosome 14 (14q24.3). Although four genes have been identified in causing Walker-Warburg syndrome, they only account for 10-20 percent of all cases, meaning that additional, as yet unidentified, genes cause the majority of Walker-Warburg syndrome cases. In fact, researchers estimate that approximately 40-60% of the individuals classified as having a dystroglycanopathy do not have a mutation in a known gene. In 2012, researchers reported on a group of affected individuals with CMD of the Walker-Warburg phenotype who had mutations of the isoprenoid synthase domain containing (ISPD) gene. The ISPD gene is located on the short arm of chromosome 7 (7p21.2)The SEPN1 gene is located on the short arm of chromosome 1 (1p35-36) and encodes for a protein found in the extensive membrane network (endoplasmic reticulum) located in all cells including muscle cells. The function of this protein is not fully understood. The LMNA gene is located on the long arm of chromosome 1 (1q21-q22). The gene encodes the proteins lamin A and lamin C. The CHKB gene is located on the long arm of chromosome 22 (22q13). The gene encodes the protein choline kinase beta. The synaptic nuclear envelope 1 (SYNE1) gene is located on the long arm of chromosome 6 (6q25.1-q25.2). The gene encodes the protein nesprin 1. The range of effect (phenotypic spectrum) for the genes associated with the CMDs is still being defined. As discussed above, many of the CMDs can be caused by a number of the involved genes. Additional forms of CMD exist that cannot be linked to any known defective gene, suggesting that other, as yet unidentified, genes exist that cause CMD. | Causes of Congenital Muscular Dystrophy. Most of the congenital muscular dystrophies are inherited as autosomal recessive conditions. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Collagen type VI disorders can be inherited as either autosomal recessive conditions or as autosomal dominant conditions. LMNA-related CMD is caused by autosomal dominant mutations that occur spontaneously (de novo) with no previous family history of the disorder (i.e. new mutations. Some cases of autosomal dominant collagen type VI-related disorders occur as de novo mutations. 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 (de novo gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. The CMDs are caused by deficiency or lack of specific proteins that play an essential role in the proper function and health of muscle cells. Some CMDs are involved with genes that contain instructions to produce (encode) proteins associated with the basement membrane and extracellular matrix of muscle cells. Investigators have determined that MDC1A is caused by disruptions or changes (mutations) in the laminin alpha-2 (LAMA2) gene located on long arm of chromosome 6 (6q22-23). The LAMA2 gene encodes merosin, a protein found in the tissue that surrounds muscle fibers. Three disease genes have been identified for collagen type VI disorders. These genes, two of which are located on the long arm of chromosome 21 and one on the long arm of chromosome 2, encode for types of a known as collagen VI. A disease gene (ITGA7) for CMD with integrin alpha 7 has been located on the long arm of chromosome 12 (12q13). A disease gene (ITGA9) for CMD with integrin alpha 9 has been located on the short arm of chromosome 3 (3p23-p221). Some CMD are involved with genes that encode proteins (enzymes) that play a role in the binding of sugar molecules to proteins (glycosylation). In these particular disorders, improper glycosylation of a protein found on the membrane of muscle cells (dystroglycan) occurs. These disorders are collectively termed the dystroglycanopathies and include Fukuyama CMD, muscle-eye-brain disease, Walker-Warburg syndrome, MDC1C, and MDC1D. A disease gene (FCMD) for Fukuyama CMD has been located on the long arm of chromosome 9 (9q31). The FCMD gene encodes for the protein fukutin. A disease gene (FKRP) for MDC1C has been located on the long arm of chromosome 19 (19q13.3). The FKRP gene encodes for the fukutin-related protein. A disease gene (LARGE), which causes MDC1D, has been located on the long arm of chromosome 22 (22q12.3-13.1). The function of the protein encoded by the LARGE gene is unknown. Although researchers initially believed that the dystroglycanopathies followed a “one gene, one disorder” pattern, they have learned that individual genes can be associated with different phenotypes and the same phenotype can be found associated with different genes. For example, both muscle-eye-brain disease and Walker-Warburg syndrome can be caused by mutations of more than one gene (genetic heterogeneity). A disease gene (POMGnT1) for muscle-eye-brain disease has been located on the long arm of chromosome 1 (1q32-34). Some rare cases of muscle-eye-brain disease are caused by mutations of the FKRP gene. A disease gene (POMT1) for Walker-Warburg syndrome has been located on the long arm of chromosome 9 (9q34.1).Walker-Warburg syndrome can also be caused by mutations of the FCMD and FKRP genes and the POMT2 gene, which is located on the long arm of chromosome 14 (14q24.3). Although four genes have been identified in causing Walker-Warburg syndrome, they only account for 10-20 percent of all cases, meaning that additional, as yet unidentified, genes cause the majority of Walker-Warburg syndrome cases. In fact, researchers estimate that approximately 40-60% of the individuals classified as having a dystroglycanopathy do not have a mutation in a known gene. In 2012, researchers reported on a group of affected individuals with CMD of the Walker-Warburg phenotype who had mutations of the isoprenoid synthase domain containing (ISPD) gene. The ISPD gene is located on the short arm of chromosome 7 (7p21.2)The SEPN1 gene is located on the short arm of chromosome 1 (1p35-36) and encodes for a protein found in the extensive membrane network (endoplasmic reticulum) located in all cells including muscle cells. The function of this protein is not fully understood. The LMNA gene is located on the long arm of chromosome 1 (1q21-q22). The gene encodes the proteins lamin A and lamin C. The CHKB gene is located on the long arm of chromosome 22 (22q13). The gene encodes the protein choline kinase beta. The synaptic nuclear envelope 1 (SYNE1) gene is located on the long arm of chromosome 6 (6q25.1-q25.2). The gene encodes the protein nesprin 1. The range of effect (phenotypic spectrum) for the genes associated with the CMDs is still being defined. As discussed above, many of the CMDs can be caused by a number of the involved genes. Additional forms of CMD exist that cannot be linked to any known defective gene, suggesting that other, as yet unidentified, genes exist that cause CMD. | 312 | Congenital Muscular Dystrophy |
nord_312_3 | Affects of Congenital Muscular Dystrophy | CMD affects males and females in equal numbers. The exact incidence and prevalence of CMD is unknown. One estimate based upon findings within an Italian population place the incidence at 1 in 125,000. Another study placed the incidence in western Sweden at 1 in 16,000. However, these findings may not be applicable in other parts of the world. The muscular dystrophies as a whole are estimated to affect approximately 250,000 people in the United States. Some forms of CMD occur with greater frequency in certain parts of the world. Fukuyama CMD is found almost exclusively in Japan. MEB occurs with greatest frequency in Finland. MDC1A is generally considered to be the most common form of CMD worldwide. | Affects of Congenital Muscular Dystrophy. CMD affects males and females in equal numbers. The exact incidence and prevalence of CMD is unknown. One estimate based upon findings within an Italian population place the incidence at 1 in 125,000. Another study placed the incidence in western Sweden at 1 in 16,000. However, these findings may not be applicable in other parts of the world. The muscular dystrophies as a whole are estimated to affect approximately 250,000 people in the United States. Some forms of CMD occur with greater frequency in certain parts of the world. Fukuyama CMD is found almost exclusively in Japan. MEB occurs with greatest frequency in Finland. MDC1A is generally considered to be the most common form of CMD worldwide. | 312 | Congenital Muscular Dystrophy |
nord_312_4 | Related disorders of Congenital Muscular Dystrophy | Symptoms of the following disorders can be similar to those of congenital muscular dystrophy. Comparisons may be useful for a differential diagnosis. Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 24 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability. The term limb-girdle muscular dystrophy is a general term encompasses several disorders. These disorders can now be distinguished by genetic and protein analysis. At least 24 subtypes have been identified. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMD1A-H). Autosomal recessive LGMD is known as LGMD2 and has 16 subtypes (LGMD2A-Q). There is no LGMD2P. (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.) Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 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. 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. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) Prader-Willi syndrome is a genetic disorder characterized in infancy by diminished muscle tone (hypotonia), feeding difficulties, and failure to grow and gain weight (failure to thrive). In childhood, features of the disorder include short stature, genital abnormalities and an excessive appetite. Progressive obesity results because of a lack of feeling satisfied after completing a meal (satiety) that leads to overeating. Without appropriate treatment, individuals with severe progressive obesity may have an increased risk of cardiac insufficiency, diabetes or other serious conditions that may lead to potentially life-threatening complications. All individuals with Prader-Willi syndrome have some cognitive impairment that ranges from borderline normal with learning disabilities to mild mental retardation. Behavior problems are common and can include temper tantrums, obsessive/compulsive behavior, and skin picking. Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. The abnormal genes usually result from random errors in development, but are sometimes inherited. (For more information on this disorder, choose “Prader Willi” as your search term in the Rare Disease Database.) Multiminicore disease is an autosomal recessive genetic condition that affects skeletal muscles. There are at least four different types of multiminicore disease that result in a wide range of muscle weakness and other symptoms. The most common type is the classic form that is associated with progressive muscle weakness in infancy or early childhood and most noticeable in the trunk and neck. Additional symptoms include low muscle tone (hypotonia), breathing difficulties that can be life threatening and curvature of the spine (scoliosis) that becomes progressively worse over time. Other forms of multiminicore disease are milder and less common. Muscle fibers in affected individuals have small, disorganized areas called minicores that are visible under a microscope. Additional forms of muscle disease (myopathy) are considered differential diagnoses for or overlap with CMD including myotonic dystrophy type 1; congenital disorder of glycosylation; metabolic myopathies such as Pompe disease; mitochondrial myopathies; congenital myasthenic syndromes; inflammatory myopathies such as dermatomyositis or polymyositis; and distinct congenital myopathies such as nemaline myopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Congenital Muscular Dystrophy. Symptoms of the following disorders can be similar to those of congenital muscular dystrophy. Comparisons may be useful for a differential diagnosis. Limb-girdle muscular dystrophy (LGMD) is a generic term for a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Approximately 24 different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age of onset, severity, and progression of symptoms of these subtypes varies greatly even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability. The term limb-girdle muscular dystrophy is a general term encompasses several disorders. These disorders can now be distinguished by genetic and protein analysis. At least 24 subtypes have been identified. The various forms of LGMD may be inherited as an autosomal dominant or recessive trait. Autosomal dominant LGMD is known as LGMD1 and has five subtypes (LGMD1A-H). Autosomal recessive LGMD is known as LGMD2 and has 16 subtypes (LGMD2A-Q). There is no LGMD2P. (For more information on this disorder, choose “limb-girdle muscular dystrophy” as your search term in the Rare Disease Database.) Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 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. 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. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.) Prader-Willi syndrome is a genetic disorder characterized in infancy by diminished muscle tone (hypotonia), feeding difficulties, and failure to grow and gain weight (failure to thrive). In childhood, features of the disorder include short stature, genital abnormalities and an excessive appetite. Progressive obesity results because of a lack of feeling satisfied after completing a meal (satiety) that leads to overeating. Without appropriate treatment, individuals with severe progressive obesity may have an increased risk of cardiac insufficiency, diabetes or other serious conditions that may lead to potentially life-threatening complications. All individuals with Prader-Willi syndrome have some cognitive impairment that ranges from borderline normal with learning disabilities to mild mental retardation. Behavior problems are common and can include temper tantrums, obsessive/compulsive behavior, and skin picking. Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. The abnormal genes usually result from random errors in development, but are sometimes inherited. (For more information on this disorder, choose “Prader Willi” as your search term in the Rare Disease Database.) Multiminicore disease is an autosomal recessive genetic condition that affects skeletal muscles. There are at least four different types of multiminicore disease that result in a wide range of muscle weakness and other symptoms. The most common type is the classic form that is associated with progressive muscle weakness in infancy or early childhood and most noticeable in the trunk and neck. Additional symptoms include low muscle tone (hypotonia), breathing difficulties that can be life threatening and curvature of the spine (scoliosis) that becomes progressively worse over time. Other forms of multiminicore disease are milder and less common. Muscle fibers in affected individuals have small, disorganized areas called minicores that are visible under a microscope. Additional forms of muscle disease (myopathy) are considered differential diagnoses for or overlap with CMD including myotonic dystrophy type 1; congenital disorder of glycosylation; metabolic myopathies such as Pompe disease; mitochondrial myopathies; congenital myasthenic syndromes; inflammatory myopathies such as dermatomyositis or polymyositis; and distinct congenital myopathies such as nemaline myopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 312 | Congenital Muscular Dystrophy |
nord_312_5 | Diagnosis of Congenital Muscular Dystrophy | A diagnosis of CMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry); magnetic resonance imaging (MRI), and molecular genetic testing.Clinical Testing and WorkupDuring an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy. Muscle imaging with MRI, CT and ultrasound may also be used.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. CK levels are usually elevated in CMD. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of CMD.In some cases, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific muscle proteins within muscle cells. Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain muscle proteins. Tissue samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present and in what quantity. For example, such procedures can demonstrate complete merosin deficiency thereby confirming a diagnosis of MDC1A.A brain MRI may be used to aid in a diagnosis of CMD associated with structural brain defects such as muscle-eye-brain disease, Fukuyama CMD, and Walker-Warburg syndrome. A MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as the brain.Molecular genetic testing involves the examination of deoxyribonucleic acid (DNA) to identify specific genetic mutations and can be used to confirm a diagnosis of some forms of CMD. | Diagnosis of Congenital Muscular Dystrophy. A diagnosis of CMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry); magnetic resonance imaging (MRI), and molecular genetic testing.Clinical Testing and WorkupDuring an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy. Muscle imaging with MRI, CT and ultrasound may also be used.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. CK levels are usually elevated in CMD. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of CMD.In some cases, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific muscle proteins within muscle cells. Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain muscle proteins. Tissue samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present and in what quantity. For example, such procedures can demonstrate complete merosin deficiency thereby confirming a diagnosis of MDC1A.A brain MRI may be used to aid in a diagnosis of CMD associated with structural brain defects such as muscle-eye-brain disease, Fukuyama CMD, and Walker-Warburg syndrome. A MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as the brain.Molecular genetic testing involves the examination of deoxyribonucleic acid (DNA) to identify specific genetic mutations and can be used to confirm a diagnosis of some forms of CMD. | 312 | Congenital Muscular Dystrophy |
nord_312_6 | Therapies of Congenital Muscular Dystrophy | TreatmentNo cure exists for CMD. Treatment is aimed at the specific symptoms present in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, surgeons, orthopedists, cardiologists, ophthalmologists, psychiatrists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Specific treatment options may include physical and occupational therapy to improve muscle strength and prevent contractures; speech therapy; the use of various devices (e.g., canes, braces, walkers, wheelchairs) to assist with walking (ambulation) and mobility; surgery to correct skeletal abnormalities such as scoliosis; and regular monitoring of the heart and the respiratory system for the development of such complications potentially associated with some forms of CMD. Overnight sleep studies are used to monitor breathing quality. In cases of respiratory insufficiency, noninvasive ventilation or mechanical ventilation may become necessary. For severe failure to thrive or feeding difficulties, gastrostomy tube feedings may be needed. If seizures are present, medical management may be needed.Genetic counseling will be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. | Therapies of Congenital Muscular Dystrophy. TreatmentNo cure exists for CMD. Treatment is aimed at the specific symptoms present in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, surgeons, orthopedists, cardiologists, ophthalmologists, psychiatrists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Specific treatment options may include physical and occupational therapy to improve muscle strength and prevent contractures; speech therapy; the use of various devices (e.g., canes, braces, walkers, wheelchairs) to assist with walking (ambulation) and mobility; surgery to correct skeletal abnormalities such as scoliosis; and regular monitoring of the heart and the respiratory system for the development of such complications potentially associated with some forms of CMD. Overnight sleep studies are used to monitor breathing quality. In cases of respiratory insufficiency, noninvasive ventilation or mechanical ventilation may become necessary. For severe failure to thrive or feeding difficulties, gastrostomy tube feedings may be needed. If seizures are present, medical management may be needed.Genetic counseling will be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. | 312 | Congenital Muscular Dystrophy |
nord_313_0 | Overview of Congenital Myasthenic Syndromes | Summary
The congenital myasthenic syndromes (CMS) are a diverse group of disorders that have an underlying defect in the transmission of signals from nerve cells to muscles. These disorders are characterized by muscle weakness, which is worsened upon exertion. The age of onset, severity of presenting symptoms, and distribution of muscle weakness can vary from one patient to another. A variety of additional symptoms affecting other organ systems can be present in specific subtypes. Severity can range from minor symptoms such as mild exercise intolerance to severe, disabling ones. Most CMS are transmitted by autosomal recessive inheritance; a few specific subtypes are transmitted by autosomal dominant inheritance. Genetic diagnosis these disorders is important because therapy that benefits one type CMS can worsen another type.Introduction
The CMS involve the neuromuscular junction which is a synapse where signals from motor nerves are passed to muscle fibers and tell the muscles fibers when to contract.The normal neuromuscular junction consists of a presynaptic region, a synaptic space, and a postsynaptic region. The presynaptic region contains the end of a motor nerve cell called the motor nerve terminal. The motor nerve terminal overlies a specialized region of the muscle fiber called the postsynaptic region. The space between the motor nerve terminal and the postsynaptic region is called the synaptic space or synaptic cleft. The postsynaptic region displays multiple folds, known as junctional folds. The motor nerve terminal contains small vesicles that are filled by the neurotransmitter, acetylcholine, or ACh for short that acts as a chemical ‘messenger’ with instructions for the muscles to contract.The membrane covering the motor nerve terminal and facing the synaptic space is known as the presynaptic membrane. The membrane covering the postsynaptic region is known as the postsynaptic membrane. The segment of the postsynaptic membrane that covers the tips of junctional folds is lined by molecules of the acetylcholine receptor, or AChR for short. The synaptic space is lined by a membrane known as the synaptic basement membrane. This membrane anchors molecules of acetylcholinesterase, or AChE for short, an enzyme that converts ACh to acetate and choline.The process of how the motor nerve endings communicate with the muscle fibers is a highly specialized process and a genetic defect that impairs that communication can result in a congenital myasthenic syndrome. Understanding this process helps to understand myasthenic disorders.When muscles are in the resting state, there is a randomly occurring release of acetylcholine from single synaptic vesicles in the motor nerve terminal. This release is known as exocytosis. The amount of ACh released from a single synaptic vesicle is referred to as a quantum of ACh.ACh released from a synaptic vesicle travels through the synaptic space and binds to the AChRs that are concentrated on the tips of the junctional folds. When this binding occurs, it causes a channel in the center of AChR to and allows positively charged sodium and lesser amounts of calcium ions to enter the muscle fiber. This process briefly changes the electric charge across the postsynaptic membrane from negative to positive (small postsynaptic depolarization) which is referred to as a miniature endplate potential (MEPP).When a person wants to perform a voluntary action, (e.g. raising one’s hand, dancing, kicking a ball, etc.), a series of successive nerve impulses are sent to the motor nerve terminal where they depolarize the presynaptic membrane, causing structures called voltage-gated calcium channels to open which allows calcium to enter the motor nerve terminal. This calcium influx results in a nearly synchronous release of the contents of several synaptic vesicles which results in a larger depolarization of the postsynaptic membrane, known as the endplate potential (EPP). When the EP reaches a certain threshold, it opens voltage-gated sodium channels found along the entire muscle fiber outside of the motor endplate area and this triggers a propagated muscle fiber action potential which causes the muscle fiber to contract.The difference between the endplate potential and the depolarization required to activate the voltage-gated sodium channels is known as the safety margin of neuromuscular transmission. In healthy individuals, the amplitude of the EPP is quite large. With continued activity the EPP begins to decrease but still remains large enough to trigger a muscle fiber action potential.After the muscle contracts, ACh is released from the AChRs into the synaptic space) where it is broken down (hydrolyzed) by AChE into two molecules, acetate and choline. Choline is transported back into the nerve terminal where it recombines with acetate under the influence of an enzyme known as choline acetyltransferase to be stored once again within the synaptic vesicles.The factors governing the safety margin of neuromuscular transmission fall into four major categories: (1) factors that affect the number of ACh molecules in the synaptic vesicle; (2) factors that affect quantal release mechanisms; (3) the density of AChE in the synaptic space; and (4) factors that affect the efficacy of individual quanta. The efficacy of individual quanta depends on the endplate geometry, the packing density of AChRs on the tips of the junctional folds, the affinity of AChRs for ACh, and the kinetic properties of the AChR ion channel.Congenital myasthenic syndromes are caused when there is an alteration (mutation) in a specific gene. This results in an abnormal protein or even loss of a protein that impairs some part of the process described above. The abnormal protein (disease protein) can reside in the motor nerve terminal, or the synaptic space, or in the postsynaptic region that underlies the nerve terminal, but in some patients the disease protein is also present in others tissues or organs causing not only CMS but also a variety of other symptoms. | Overview of Congenital Myasthenic Syndromes. Summary
The congenital myasthenic syndromes (CMS) are a diverse group of disorders that have an underlying defect in the transmission of signals from nerve cells to muscles. These disorders are characterized by muscle weakness, which is worsened upon exertion. The age of onset, severity of presenting symptoms, and distribution of muscle weakness can vary from one patient to another. A variety of additional symptoms affecting other organ systems can be present in specific subtypes. Severity can range from minor symptoms such as mild exercise intolerance to severe, disabling ones. Most CMS are transmitted by autosomal recessive inheritance; a few specific subtypes are transmitted by autosomal dominant inheritance. Genetic diagnosis these disorders is important because therapy that benefits one type CMS can worsen another type.Introduction
The CMS involve the neuromuscular junction which is a synapse where signals from motor nerves are passed to muscle fibers and tell the muscles fibers when to contract.The normal neuromuscular junction consists of a presynaptic region, a synaptic space, and a postsynaptic region. The presynaptic region contains the end of a motor nerve cell called the motor nerve terminal. The motor nerve terminal overlies a specialized region of the muscle fiber called the postsynaptic region. The space between the motor nerve terminal and the postsynaptic region is called the synaptic space or synaptic cleft. The postsynaptic region displays multiple folds, known as junctional folds. The motor nerve terminal contains small vesicles that are filled by the neurotransmitter, acetylcholine, or ACh for short that acts as a chemical ‘messenger’ with instructions for the muscles to contract.The membrane covering the motor nerve terminal and facing the synaptic space is known as the presynaptic membrane. The membrane covering the postsynaptic region is known as the postsynaptic membrane. The segment of the postsynaptic membrane that covers the tips of junctional folds is lined by molecules of the acetylcholine receptor, or AChR for short. The synaptic space is lined by a membrane known as the synaptic basement membrane. This membrane anchors molecules of acetylcholinesterase, or AChE for short, an enzyme that converts ACh to acetate and choline.The process of how the motor nerve endings communicate with the muscle fibers is a highly specialized process and a genetic defect that impairs that communication can result in a congenital myasthenic syndrome. Understanding this process helps to understand myasthenic disorders.When muscles are in the resting state, there is a randomly occurring release of acetylcholine from single synaptic vesicles in the motor nerve terminal. This release is known as exocytosis. The amount of ACh released from a single synaptic vesicle is referred to as a quantum of ACh.ACh released from a synaptic vesicle travels through the synaptic space and binds to the AChRs that are concentrated on the tips of the junctional folds. When this binding occurs, it causes a channel in the center of AChR to and allows positively charged sodium and lesser amounts of calcium ions to enter the muscle fiber. This process briefly changes the electric charge across the postsynaptic membrane from negative to positive (small postsynaptic depolarization) which is referred to as a miniature endplate potential (MEPP).When a person wants to perform a voluntary action, (e.g. raising one’s hand, dancing, kicking a ball, etc.), a series of successive nerve impulses are sent to the motor nerve terminal where they depolarize the presynaptic membrane, causing structures called voltage-gated calcium channels to open which allows calcium to enter the motor nerve terminal. This calcium influx results in a nearly synchronous release of the contents of several synaptic vesicles which results in a larger depolarization of the postsynaptic membrane, known as the endplate potential (EPP). When the EP reaches a certain threshold, it opens voltage-gated sodium channels found along the entire muscle fiber outside of the motor endplate area and this triggers a propagated muscle fiber action potential which causes the muscle fiber to contract.The difference between the endplate potential and the depolarization required to activate the voltage-gated sodium channels is known as the safety margin of neuromuscular transmission. In healthy individuals, the amplitude of the EPP is quite large. With continued activity the EPP begins to decrease but still remains large enough to trigger a muscle fiber action potential.After the muscle contracts, ACh is released from the AChRs into the synaptic space) where it is broken down (hydrolyzed) by AChE into two molecules, acetate and choline. Choline is transported back into the nerve terminal where it recombines with acetate under the influence of an enzyme known as choline acetyltransferase to be stored once again within the synaptic vesicles.The factors governing the safety margin of neuromuscular transmission fall into four major categories: (1) factors that affect the number of ACh molecules in the synaptic vesicle; (2) factors that affect quantal release mechanisms; (3) the density of AChE in the synaptic space; and (4) factors that affect the efficacy of individual quanta. The efficacy of individual quanta depends on the endplate geometry, the packing density of AChRs on the tips of the junctional folds, the affinity of AChRs for ACh, and the kinetic properties of the AChR ion channel.Congenital myasthenic syndromes are caused when there is an alteration (mutation) in a specific gene. This results in an abnormal protein or even loss of a protein that impairs some part of the process described above. The abnormal protein (disease protein) can reside in the motor nerve terminal, or the synaptic space, or in the postsynaptic region that underlies the nerve terminal, but in some patients the disease protein is also present in others tissues or organs causing not only CMS but also a variety of other symptoms. | 313 | Congenital Myasthenic Syndromes |
nord_313_1 | Symptoms of Congenital Myasthenic Syndromes | The cardinal symptom of all myasthenic disorders is muscle weakness that is induced or worsened by exertion. This is referred to as fatigable weakness. In healthy people, physical activity causes a small decrease in the number of ACh quanta released from the nerve terminal that does not impair the safety margin of neuromuscular transmission, but it is incapacitating in myasthenic patients in whom the safety margin is already reduced.In some patients with CMS, the weakness is confined to muscles supplied (innervated) by the cranial nerves causing double vison, droopy eyelids (eyelid ptosis), facial weakness, hypernasal or slurred speech, and swallowing difficulties. In other patients, the above symptoms are combined with weakness of the limb and torso muscles causing generalized myasthenia. In still others, the weakness is limited to the limb and torso muscles causing ‘limb-girdle myasthenia’.The myasthenic disorders caused by defects in enzymes required for protein glycosylation can also be associated with development delay, seizures, intellectual disability, neuropathy, and metabolic abnormalities of different organs.Several different types of CMS have been identified.1 The currently identified types are:Each type can be subdivided into several subtypes that are discussed below.PRESYNAPTIC CMS
Endplate Choline Acetyltransferase (ChAT) Deficiency
After acetylcholine is released from the nerve terminal, it binds to acetylcholine receptor for a brief period; when it is released from the receptor, it is rapidly broken down (hydrolyzed) by the enzyme acetylcholinesterase into choline and acetate. The released choline is transported to the nerve terminal where the enzyme choline acetyltransferase (ChAT) reforms (resynthesizes) acetylcholine. The resynthesized acetylcholine is then transported into the synaptic vesicles, where it becomes available to be released into the synaptic space as needed. Deleterious mutations in the CHAT gene, alone or in combination, alter the expression, catalytic efficiency, or stability of the ChAT protein.2,3The defect in ChAT causes progressive decrease of the acetylcholine content of the synaptic vesicles during activity and hence reduces the amplitude of the EPP, which reduces the safety margin of neuromuscular transmission.Some patients present with hypotonia (low muscle tone), paralysis of cranial and limb muscles and apnea (failure to breathe) at birth. Others are normal at birth and develop attacks of apnea during infancy or childhood precipitated by infection, excitement, or no apparent cause.3-7 In some children an acute attack is followed by respiratory failure that lasts for weeks.8 A few patients are respirator-dependent and paralyzed since birth3 and some develop brain atrophy caused by lack of oxygen (hypoxia) during episodes of apnea.3,7 Others improve with age, but still have variable eyelid drooping (ptosis), impaired movement of the ocular muscles, fatigable weakness, and recurrent episodes of cyanosis, in which there is bluish discoloration of the skin due to impaired respiration and inadequate oxygenation of the blood. Some patients complain only of mild to moderately severe fatigable weakness. The weakness is worsened by exposure to cold because this further reduces the efficiency of the mutant enzyme.5Treatment consists of preventive (prophylactic) therapy with pyridostigmine (Mestinon) which is a medication that inhibits the activity of acetylcholinesterase (which breaks down acetylcholine in the synaptic space). This prolongs the life time of acetylcholine in the synaptic space and, consequently, the number of acetylcholine receptors it can activate. Parents of affected infants should be provided an inflatable rescue bag and a fitted mask, and should be instructed in the intramuscular injection of neostigmine methylsulfate (another inhibitor of acetylcholinesterase), and are advised to install an apnea monitor in their home.SNAP25B Myasthenia
A single patient reported to date had a severe CMS associated with an unusually exaggerated response to brain stimuli (cerebral cortical hyperexcitability), ataxia (lack of coordination), and intellectual disability.9 Genetic studies revealed a dominant single amino acid change in the gene SNAP25B, which produces an essential protein required by the synaptic vesicles to release acetylcholine (exocytosis). The endplates were structurally normal on examination by the electron microscope. Treatment with 3,4-diaminopyridine (3,4-DAP), which increases the number of quanta released by nerve impulse, improved the patient’s weakness but not her ataxia or intellectual disability.Synaptotagmin 2 Deficiency
Synaptotagmin 2 is another presynaptic protein. It senses the calcium concentration in the nerve terminal; when this is increased, it acts on other proteins to initiate the release of acetylcholine into the synaptic space (exocytosis). In two kinships, mutations in this gene caused limb muscle weakness, loss of the tendon reflexes, and a reduced amplitude of the muscle fiber action potential that precedes muscle fiber contraction. This response as well as the weakness was transiently improved by exercise. The treatment of this condition has not been described.10Paucity of Synaptic Vesicles and Impaired Quantal Release
The clinical features resemble that of autoimmune myasthenic gravis, but the onset is at birth or in early infancy and tests for anti-acetylcholine receptor antibodies are negative. A specific diagnosis requires electron microscopy and electrophysiology studies of the motor endplate. A presynaptic defect is revealed by a severe decrease (to approximately 20% of normal) in quantal release of acetylcholine by nerve impulse accompanied by a proportionate decrease in the number of synaptic vesicles in the nerve terminal. This CMS responds to treatment with pyridostigmine.11SYNAPTIC BASAL LAMINA-ASSOCIATED
Endplate Acetylcholinesterase (AChE) Deficiency
The endplate species of acetylcholinesterase (AChE) is composed of 12 catalytic subunits, which rapidly breaks down (hydrolyzes) acetylcholine, plus a collagenic subunit, called ColQ, which anchors the entire molecule to the basal lamina of the endplate. Subunits are single protein molecules that combine with other proteins to form a larger protein complex.The ColQ protein is composed of three identical strands each of which binds to 4 catalytic subunits. Histochemical and electron microscopy studies reveal absence of acetylcholinesterase from the endplate and smaller than normal nerve terminals. Severely affected patients present at birth with apnea and generalized weakness that persists throughout life. Less severely affected patients present later in childhood.12 The patients do not respond to, or are worsened by, pyridostigmine which acts by inhibiting acetylcholinesterase. Therapy is still unsatisfactory, but ephedrine13 and albuterol14 have a gradually developing beneficial effect.CMS Associated with β2-Laminin Deficiency
β2-laminin is a component of the basal lamina of different tissues and is highly expressed in kidney, eye, and at the endplate where the protein is important for the appropriate alignment of the nerve terminal with the postsynaptic region. β2-laminin also contributes to the development and organization of the two regions. Mutations in β2-laminin result in Pierson syndrome, a rare disorder associated with malformations of the kidneys and eyes. A patient with Pierson syndrome had a myasthenic syndrome. The kidney defect was corrected by renal transplant at age 15 months. Quantal release by nerve impulse and the MEPP amplitude were both reduced. Electron microscopy revealed abnormally small nerve endings accounting for the decreased quantal release. The synaptic space was widened and the junctional folds were simplified, accounting for the decreased MEPP amplitude.15DEFECTS IN ACETYLCHOLINE RECEPTOR (AChR)Primary AChR Deficiency
The acetylcholine receptor is made up 5 subunits. Subunits are single protein molecules that combine with other proteins to form a larger protein complex; in this case, the acetylcholine receptor. Two of these subunits are called alpha (α) and the remaining 3 are called beta (β), delta (δ) and epsilon (ε) in adults. Before birth, the fetal subunit contains a gamma (γ) instead of a ε subunit.In primary AChR deficiency, the amount of AChR expressed at the endplate is reduced and the safety margin of neuromuscular transmission is impaired by the decreased amplitude of the EPP. The clinical deficits vary from mild to severe. Patients with recessive mutations in the ε subunit are generally less severely affected than those with mutations in other subunits because compensatory expression of the fetal γ subunit can partially substitute for the defective ε subunit.The sickest patients have severe ocular, bulbar and respiratory muscle weakness from birth and survive only with respiratory support and gavage feeding. Gavage feeding is the use of a small, narrow tube inserted through an infant’s nostrils and run down the throat to the stomach to directly supply nourishment to an affected infant. Infants may be weaned from a respirator and begin to tolerate oral feedings during the first year of life, but have bouts of aspiration pneumonia and may need intermittent respiratory support during childhood and adult life.Motor development is severely delayed; they seldom learn to take steps and can walk for only for a short distance. Older patients close their mouths by supporting their jaw with their hand and elevate their eyelids with their fingers. Facial deformities, protruding jaw, misalignment teeth (malocclusion), and abnormal curvature of the spine such as scoliosis or kyphoscoliosis become noticeable during the second decade. Muscle bulk is reduced. The tendon reflexes are normal or hypoactive.Less severely affected patients experience moderate physical handicaps from early childhood. Limited eye movements and ptosis of the lids become apparent during the first year of life. They fatigue easily, walk and negotiate stairs with difficulty, cannot keep up with their peers in sports, but can perform most activities of daily living. Mutations in the AChR α, β, and δ subunits that reduce or prevent the expression of AChR are either lethal in embryonic life or cause marked disability and high mortality after birth.In the least affected patients motor development is only slightly delayed; they only have mild eyelid ptosis and limitation of eye movements. They are often clumsy in sports, fatigue easily, and cannot run well, climb rope, or do pushups. In some patients, a myasthenic disorder is suspected only when they develop prolonged respiratory arrest on exposure to a neuromuscular blocking agent drug during a surgical procedure.Treatment consists of pyridostigmine an inhibitor of acetylcholinesterase. This medication increases the lifetime of acetylcholine in the synaptic space which allows each acetylcholine molecule to bind to different acetylcholine receptors repeatedly before it leaves the synaptic space by diffusion. Many patients derive additional benefit from the use of 3,4-diaminopyridine (3,4-DAP)16 which prolongs the depolarization of the presynaptic membrane by nerve impulse. This allows more calcium to enter the nerve terminal which increases the number of acetylcholine quanta released by each nerve impulse. Finally, some patients derive still additional benefit from albuterol. 17Kinetic Defect in AChR: The Slow-Channel Syndrome
This syndrome is caused by dominant mutations in the acetylcholine receptor (AChR) gene that leads to the abnormally slow closure of the AChR ion channel. The prolonged openings of the ion channel cause overloading of the postsynaptic region with positively charged ions, including calcium. The local increase in calcium concentration damages the junctional folds, and can damage the muscle fiber nuclei under the folds. The onset of symptoms ranges from infancy to early adult life. The disease causes selectively severe weakness and loss of bulk (atrophy) of the cervical, scapular, and of the wrist and finger extensor muscles.18The safety margin of synaptic transmission is compromised by damage to the junctional folds with loss of acetylcholine receptors, and by the receptors becoming desensitized (unresponsive) during physiologic activity due to prolonged exposure to acetylcholine.This syndrome does not respond to, or is worsened by, pyridostigmine but is improved by relatively high doses of fluoxetine (Prozac) which blocks (plugs) the acetylcholine receptor ion channel and thereby reduces the length of channel openings.19Kinetic Defect in AChR: The Fast-Channel Syndrome
This syndrome is transmitted by recessive inheritance and is the physiologic and anatomic opposite of the slow-channel syndrome.18 The length of the AChR channel openings is decreased because the mutations reduce the ability of AChR to bind acetylcholine, or because they hinder the opening of the AChR ion channel, or because they cause the ion channel to become intermittently unstable. The structural integrity of the endplate is unaffected.This syndrome becomes manifest only if the second copy of the AChR subunit gene is not expressed, or if both copies of the gene harbor the same mutation, so that the fast- channel mutation dictates the clinical consequences. The safety margin of neuromuscular transmission is reduced because the mutant gene reduces the probability and length of channel openings, which reduce the amplitude and duration of EPP. The clinical consequences vary from mild to severe. Most patients respond to combined treatment with pyridostigmine and 3,4-DAP.Prenatal CMS Caused by Mutations in AChR Subunits and Other Specific Proteins
The first identified prenatal myasthenic syndrome was traced to mutations in the fetal AChR γ subunit. In humans, AChR harboring the fetal subunit appears on developing muscle fibers around the ninth week of gestation and becomes concentrated at early nerve-muscle junctions around the sixteenth week of gestation. Subsequently, the γ subunit is replaced by the adult ε subunit and is no longer present at fetal endplates after the thirty-first week of gestation. Thus harmful mutations of the γ-subunit reduce fetal movements (hypomotility) between the sixteenth and thirty-first week of gestation.20The clinical consequences at birth are contractures of large joints, small muscle bulk, webbing around the neck, armpits, elbows, fingers, or behind the knees, flexion contractures of the fingers, rocker-bottom feet with prominent heels, and a characteristic facial appearance with mild eyelid ptosis and a small mouth with downturned corners. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.Myasthenic symptoms are absent after birth because by then the normal adult ε subunit is expressed at the endplates.21 Recent studies also identified lethal fetal akinesia syndromes arising from deleterious null mutations in both copies of the AChR α, β, and δ subunits as well as in other CMS disease genes.CMS CAUSED BY DEFECTS IN ENDPLATE DEVELOPMENT OR MAINTENANCETo date, mutations have been detected in genes for proteins that are essential for motor endplate development and maintenance. As with the communication of nerve signals from nerve cells to muscle fibers described above, the health and development of the motor endplate depends upon a sequence of interrelated, chemical reactions involving multiple genes and their protein products.These genes are MuSK, Agrin, LRP4, and DOK-7. Agrin is secreted into the synaptic space by the nerve terminal where it binds to the lipoprotein-related protein LRP4 in the postsynaptic membrane creating an agrin-LRP4 protein complex. The Agrin-LRP4 complex then binds to and activates MuSK. This enhances MuSK phosphorylation and leads to clustering of LRP4 and MuSK. Activated MuSK in concert with postsynaptic DOK-7 and other postsynaptic proteins acts on Rapsyn to concentrate AChR in the postsynaptic membrane, enhances synapse specific gene expression by postsynaptic nuclei, and promotes postsynaptic differentiation. Clustered LRP4, in turn, promotes differentiation of motor axons. The agrin-LRP4-MuSK-Dok-7 signaling system is also essential for maintaining the structure of the adult neuromuscular junction.22Agrin Deficiency
Only a few patients with agrin-related CMS have been reported. The severity of the symptoms varies according to the location of the mutations in the agrin gene and whether or not the mutations affect agrin expression.23,24,25 The consequences are severe when a mutation that hinders attachment of agrin to LRP4 dominates the clinical picture. In such a patient the synaptic contacts were dispersed, the postsynaptic regions were poorly differentiated, the nerve terminals were small, and there were degenerative changes in the muscle fibers under the junctional folds.24 Another report describes three kinships in which the agrin mutations were associated with slowly progressive wasting of the distal leg and later of the upper arm muscles.25 Treatment of the agrin-related CMS is unsatisfactory, but one patient responded partially to ephedrine.24LRP4 Deficiency
There are only two reports of LRP4-related CMS. The first report described a 17-year-old girl with moderately severe fatigable limb-girdle weakness, irregularly shaped synaptic contacts, and mild endplate AChR deficiency. In a muscle located between the ribs (intercostal muscle) of this patient the MEPPs and EPPs were of normal amplitude indicating the identified mutations could spare neuromuscular transmission in some muscles.26 Subsequently, two sisters with moderately severe CMS and harboring a homozygous mutation that hinders LRP4 from activating MuSK were shown to have structurally and functionally abnormal endplates and endplate AChR deficiency.27MuSK Deficiency
This disease presents at birth or in early life with eyelid ptosis or respiratory distress. Subsequently, it involves the ocular, facial and proximal limb muscles, and in some kinships the bulbar muscles as well.28,29,30,31,32 Introduction of the mutant gene in mice results in recurrent cycles of focal loss of nerve supply (denervation) and reestablishment of nerve supply (reinnervation) resulting in extensive remodeling of the endplates.33 Pyridostigmine therapy is ineffective or worsens the disease.31 A recent report indicates that therapy with albuterol has been highly effective in two brothers.34 No clear genotype-phenotype correlations (correlation between a given mutation and the clinical features) have been observed.DOK-7 Deficiency
DOK-7 is expressed within developing and mature muscle fibers. In developing muscle fibers it serves as an intrinsic activator of MuSK.35 In mature muscle, it is activated by MuSK to activate rapsyn to concentrate acetylcholine receptors on the junctional folds and to promote the development and maintenance of the endplate. This CMS can be mild or severe. The pathogenic mutations can curtail DOK-7 expression or prevent DOK-7 to activate, or be activated by, other intracellular proteins. There appears to be no consistent correlation between the identified mutations and the clinical features.All affected patients have limb-girdle weakness with lesser facial and neck muscle weakness but a few have severe bulbar weakness and few have significant limitation of the eye movements.36,37 The clinical course is mild to severe. Impaired maintenance of the endplates is evidenced by ongoing destruction and remodeling of the endplates. Neuromuscular transmission is compromised by the decreased quantal release from the nerve terminal by nerve impulse and by a reduced amplitude of the MEPP.37 Importantly, this CMS is rapidly worsened by pyridostigmine but responds well over a period of time to ephedrine38 or albuterol.37Rapsyn Deficiency
Rapsyn concentrates and anchors acetylcholine receptors on the junctional folds39 and is required for development of the junctional folds.40 Most patients present in the first year of life.41 Joint contractures at birth and other congenital malformations occur in close to one-third.42 Intercurrent infections or fever can trigger respiratory crises that can cause brain damage due to lack of oxygen (anoxia). 43,44 The eye movements are intact in most patients.42 Multiple synaptic contacts appear on single muscle fibers. The endplate acetylcholine receptor deficiency is milder than in primary acetylcholine receptor deficiency42 and the junctional folds are not well differentiated. Most patients respond well to pyridostigmine; some derive additional benefit from ephedrine or albuterol43 and some are further improved by 3,4-DAP.Indo-Europeans harbor a common N88K mutation in the gene that produces rapsyn, which involves replacement of an asparagine molecule (N) by a lysine molecule (K) at codon 8845 (codon: a sequence of 3 adjacent nucleotides that constitutes a genetic code for a specific amino acid). Different mutations hinder self-association of rapsyn molecules, or their binding to acetylcholine receptors, or impede agrin-MuSK-LRP4-mediated clustering of these receptors, or decrease rapsyn expression.40,46 There are no genotype-phenotype correlations (correlation between a given mutation and the clinical features) except that Near-Eastern Jewish patients with a homozygous E-box mutation (E-box: a sequence before the coding region of a gene involved in regulating gene expression) have a milder course with eyelid ptosis, a large protruding jaw, severe weakness of the masticatory and facial muscle, and hypernasal speech.47MYASTHENIC SYNDROMES ASSOCIATED WITH CONGENITAL DEFECTS OF GLYCOSYLATIONGlycosylation is the process by which sugar ‘trees’ or residues (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems.Glycosylation to nascent peptides increases their solubility, folding, stability, assembly, and intracellular transport. Peptides are amino acid compounds and can perform a wide range of functions in the body. O-glycosylation involves addition of sugar residues to the amino acids serine and threonine; N-glycosylation occurs in sequential steps that decorate the amino group of the amino acid asparagine.48,49To date, defects in four enzymes subserving N-glycosylation have been shown to cause a CMS: GFPT1,50,51 DPAGT1,52,53 ALG2, and ALG14.54 Accumulation of small tubules within the muscle fibers, referred to as tubular aggregates, are a clue to the diagnosis but are not seen in all patients. Because glycosylated proteins are present at all endplate sites, the safety margin of neuromuscular transmission is likely compromised by a combination of pre- and postsynaptic defects.GFPT1Deficiency
GFPT1 controls the entry of glucose into the glycosylation pathway. A defect in GFPT1 predicts reduced glycosylation, and therefore defective function, of several endplate- associated proteins.50 The synaptic contacts are small and the postsynaptic regions are poorly developed .51 One patient whose mutations abolished expression of the muscle- specific exon of GFPT1 had severe facial, bulbar, and respiratory muscle weakness, and has been paralyzed since birth. She has a vacuolar myopathy, reduced quantal release evoked by nerve impulse, and low MEPP amplitude. A vacuolar myopathy is a muscle disease that is associated with the development of abnormal pockets or spaces called vacuoles within muscle tissue.DPAGT1 Deficiency
DPAGT1 catalyzes the first committed step of N-linked protein glycosylation. DPAGT1 deficiency predicts impaired asparagine glycosylation of multiple proteins distributed throughout the organism, but in the first 5 patients harboring DPAGT1 gene mutations only neuromuscular transmission was adversely affected.52 A subsequent study of two siblings and of a third patient showed the DPAGT1 deficiency associated with intellectual disability.9 The siblings respond poorly to pyridostigmine and 3,4-DAP; the third patient was partially improved by pyridostigmine and albuterol. Intercostal muscle studies showed fiber type disproportion, small tubular aggregates in some muscle fibers, and autophagic vacuoles (vacuoles that degrade and digest subcellular structures). Evoked quantal release, the MEPP amplitude, and the endplate acetylcholine receptor content were all reduced to ~50% of normal.ALG2 AND ALG14 Deficiency
ALG2 catalyzes the second and third committed steps of N-glycosylation. In one family, four affected siblings had a deleterious homozygous mutation, and a third patient was homozygous for a low-expressor mutation. ALG14 forms an enzyme complex with ALG13 and DPAGT1 and also contributes to the first committed step of N-glycosylation. In one family two affected siblings carried two different recessive mutations. Endplate ultrastructure and parameters of neuromuscular transmission were not investigated.54OTHER CONGENITAL MYASTHENIC SYNDROMESPREPL Deletion Syndrome
The hypotonia-cystinuria syndrome is caused by recessive deletions involving the SLC3A1 and PREPL genes at chromosome 2p21. The major clinical features are cystinuria, growth hormone deficiency, muscle weakness, eyelid ptosis, and feeding problems. Cystinuria is an inherited metabolic disorder characterized by the abnormal movement (transport) in the intestines and kidneys, of certain organic chemical compounds (amino acids).A patient with isolated PREPL deficiency had myasthenic symptoms since birth and growth hormone deficiency but no cystinuria, and responded transiently to pyridostigmine during infancy.55 She harbors a paternally inherited nonsense mutation in the PREPL gene and a maternally inherited deletion involving both PREPL and SLC3A1; therefore the PREPL deficiency determines the phenotype. PREPL expression was absent from the patient’s muscles and endplates. Endplate studies revealed decreased evoked quantal release and small MEPP amplitude despite robust endplate acetylcholine receptor expression.55 Because PREPL is an essential activator of the clathrin associated adaptor protein 1 (AP1),56 and AP1 is required by the vesicular acetylcholine transporter to fill the synaptic vesicles with acetylcholine,57 the small MEPP is attributed to a decreased vesicular content of acetylcholine.Na-Channel Myasthenia
Two patients with this syndrome have been identified to date. The first patient had abrupt episodes of respiratory and facial weakness associated with weakness of muscles required for speaking and swallowing since birth lasting from 3 to 30 minutes typical of periodic paralysis as well as a myasthenic disorder. Studies of neuromuscular transmission revealed normal amplitude EPPs that frequently failed generate muscle action potentials pointing to voltage-gated sodium channels (SCN4A gene) as the culprit. The gene for voltage-gated sodium channels (SCN4A) harbored two recessive mutations which caused the sodium channel to become inactive soon after it was activated by the EPP.58 A second patient with similar clinical findings was recently identified. In this patient two different recessive mutations in voltage-gated sodium channel caused abnormal inactivation of the sodium (Na) channel by activity.59CMS Caused by Plectin Deficiency
Plectin, encoded by the PLEC gene, has different tissue-specific and organelle-specific forms (known as isoforms) that serve to link cytoskeletal filaments to target organelles.60-62 Organelles are a general term for any number of organized or specialized structures within a living cell.Plectin is concentrated at sites of mechanical stress. For example, in skeletal muscle it is present under the junctional folds of the endplates, under the surface membrane of the muscle fiber, at the Z-disks (thin protein bands that mark the boundaries of adjoining contractile units), and around nuclei and mitochondria, which are found by the hundreds within virtually every cell of the body and which generate most of the cellular energy.In skin, it is associated with hemidesmosomes (peg-like structures that link epithelial cells to the underlying basement membrane). Alone or in combination, mutations in plectin can result in a blistering skin disease known as epidermolysis bullosa simplex (EBS), in progressive muscular dystrophy, and sometimes in a myasthenic syndrome. The two patients investigated by the author had EBS, a myasthenic syndrome due to low amplitude MEPPs caused by degenerating junctional folds, as well as muscular dystrophy associated with dislocation of the muscle fiber nuclei, mitochondria and myofibrils (basic rod-like units of muscle cells) as well as defects in the muscle fiber surface membrane causing calcium overloading and degeneration of the muscle fibers.63CMS Associated with Defects in the Mitochondrial Citrate Synthase Carrier SLC25A1The SLC25A1 gene encodes a transporter protein that is responsible for the movement of citrate across the inner membranes of mitochondria. Mutations in the SLC25A1 gene interfere with brain, eye, and psychomotor development.64Two siblings born to consanguineous parents had a CMS associated with intellectual disability and whole exome sequencing revealed they carried a homozygous mutation in SLC25A1. Subsequent studies showed that the mutation impairs the transport activity of the enzyme, and that knockdown of the gene equivalent to SLC25A1 in zebra fish hindered motor axons from innervating muscle fibers.65 A third patient who harbored two recessive mutations in SLC25A1 had myasthenic symptoms as well underdeveloped optical nerves, undeveloped corpus callosum (a structure connecting the two cerebral hemispheres), and excessive urinary excretion of 2-hydroxyglutaric acid.64CMS Associated with Centronuclear Myopathies
Eyelid ptosis, weakness of the external ocular and facial muscles, exercise intolerance, a decremental EMG study, and response to pyridostigmine have been documented in patients with centronuclear myopathies (CNM) caused by mutations in amphiphysin (BIN1),66 myotubularin (MTM1),67 and dynamin 2 (DNM2)68 as well as in other CNM patients with no identified mutations.69 | Symptoms of Congenital Myasthenic Syndromes. The cardinal symptom of all myasthenic disorders is muscle weakness that is induced or worsened by exertion. This is referred to as fatigable weakness. In healthy people, physical activity causes a small decrease in the number of ACh quanta released from the nerve terminal that does not impair the safety margin of neuromuscular transmission, but it is incapacitating in myasthenic patients in whom the safety margin is already reduced.In some patients with CMS, the weakness is confined to muscles supplied (innervated) by the cranial nerves causing double vison, droopy eyelids (eyelid ptosis), facial weakness, hypernasal or slurred speech, and swallowing difficulties. In other patients, the above symptoms are combined with weakness of the limb and torso muscles causing generalized myasthenia. In still others, the weakness is limited to the limb and torso muscles causing ‘limb-girdle myasthenia’.The myasthenic disorders caused by defects in enzymes required for protein glycosylation can also be associated with development delay, seizures, intellectual disability, neuropathy, and metabolic abnormalities of different organs.Several different types of CMS have been identified.1 The currently identified types are:Each type can be subdivided into several subtypes that are discussed below.PRESYNAPTIC CMS
Endplate Choline Acetyltransferase (ChAT) Deficiency
After acetylcholine is released from the nerve terminal, it binds to acetylcholine receptor for a brief period; when it is released from the receptor, it is rapidly broken down (hydrolyzed) by the enzyme acetylcholinesterase into choline and acetate. The released choline is transported to the nerve terminal where the enzyme choline acetyltransferase (ChAT) reforms (resynthesizes) acetylcholine. The resynthesized acetylcholine is then transported into the synaptic vesicles, where it becomes available to be released into the synaptic space as needed. Deleterious mutations in the CHAT gene, alone or in combination, alter the expression, catalytic efficiency, or stability of the ChAT protein.2,3The defect in ChAT causes progressive decrease of the acetylcholine content of the synaptic vesicles during activity and hence reduces the amplitude of the EPP, which reduces the safety margin of neuromuscular transmission.Some patients present with hypotonia (low muscle tone), paralysis of cranial and limb muscles and apnea (failure to breathe) at birth. Others are normal at birth and develop attacks of apnea during infancy or childhood precipitated by infection, excitement, or no apparent cause.3-7 In some children an acute attack is followed by respiratory failure that lasts for weeks.8 A few patients are respirator-dependent and paralyzed since birth3 and some develop brain atrophy caused by lack of oxygen (hypoxia) during episodes of apnea.3,7 Others improve with age, but still have variable eyelid drooping (ptosis), impaired movement of the ocular muscles, fatigable weakness, and recurrent episodes of cyanosis, in which there is bluish discoloration of the skin due to impaired respiration and inadequate oxygenation of the blood. Some patients complain only of mild to moderately severe fatigable weakness. The weakness is worsened by exposure to cold because this further reduces the efficiency of the mutant enzyme.5Treatment consists of preventive (prophylactic) therapy with pyridostigmine (Mestinon) which is a medication that inhibits the activity of acetylcholinesterase (which breaks down acetylcholine in the synaptic space). This prolongs the life time of acetylcholine in the synaptic space and, consequently, the number of acetylcholine receptors it can activate. Parents of affected infants should be provided an inflatable rescue bag and a fitted mask, and should be instructed in the intramuscular injection of neostigmine methylsulfate (another inhibitor of acetylcholinesterase), and are advised to install an apnea monitor in their home.SNAP25B Myasthenia
A single patient reported to date had a severe CMS associated with an unusually exaggerated response to brain stimuli (cerebral cortical hyperexcitability), ataxia (lack of coordination), and intellectual disability.9 Genetic studies revealed a dominant single amino acid change in the gene SNAP25B, which produces an essential protein required by the synaptic vesicles to release acetylcholine (exocytosis). The endplates were structurally normal on examination by the electron microscope. Treatment with 3,4-diaminopyridine (3,4-DAP), which increases the number of quanta released by nerve impulse, improved the patient’s weakness but not her ataxia or intellectual disability.Synaptotagmin 2 Deficiency
Synaptotagmin 2 is another presynaptic protein. It senses the calcium concentration in the nerve terminal; when this is increased, it acts on other proteins to initiate the release of acetylcholine into the synaptic space (exocytosis). In two kinships, mutations in this gene caused limb muscle weakness, loss of the tendon reflexes, and a reduced amplitude of the muscle fiber action potential that precedes muscle fiber contraction. This response as well as the weakness was transiently improved by exercise. The treatment of this condition has not been described.10Paucity of Synaptic Vesicles and Impaired Quantal Release
The clinical features resemble that of autoimmune myasthenic gravis, but the onset is at birth or in early infancy and tests for anti-acetylcholine receptor antibodies are negative. A specific diagnosis requires electron microscopy and electrophysiology studies of the motor endplate. A presynaptic defect is revealed by a severe decrease (to approximately 20% of normal) in quantal release of acetylcholine by nerve impulse accompanied by a proportionate decrease in the number of synaptic vesicles in the nerve terminal. This CMS responds to treatment with pyridostigmine.11SYNAPTIC BASAL LAMINA-ASSOCIATED
Endplate Acetylcholinesterase (AChE) Deficiency
The endplate species of acetylcholinesterase (AChE) is composed of 12 catalytic subunits, which rapidly breaks down (hydrolyzes) acetylcholine, plus a collagenic subunit, called ColQ, which anchors the entire molecule to the basal lamina of the endplate. Subunits are single protein molecules that combine with other proteins to form a larger protein complex.The ColQ protein is composed of three identical strands each of which binds to 4 catalytic subunits. Histochemical and electron microscopy studies reveal absence of acetylcholinesterase from the endplate and smaller than normal nerve terminals. Severely affected patients present at birth with apnea and generalized weakness that persists throughout life. Less severely affected patients present later in childhood.12 The patients do not respond to, or are worsened by, pyridostigmine which acts by inhibiting acetylcholinesterase. Therapy is still unsatisfactory, but ephedrine13 and albuterol14 have a gradually developing beneficial effect.CMS Associated with β2-Laminin Deficiency
β2-laminin is a component of the basal lamina of different tissues and is highly expressed in kidney, eye, and at the endplate where the protein is important for the appropriate alignment of the nerve terminal with the postsynaptic region. β2-laminin also contributes to the development and organization of the two regions. Mutations in β2-laminin result in Pierson syndrome, a rare disorder associated with malformations of the kidneys and eyes. A patient with Pierson syndrome had a myasthenic syndrome. The kidney defect was corrected by renal transplant at age 15 months. Quantal release by nerve impulse and the MEPP amplitude were both reduced. Electron microscopy revealed abnormally small nerve endings accounting for the decreased quantal release. The synaptic space was widened and the junctional folds were simplified, accounting for the decreased MEPP amplitude.15DEFECTS IN ACETYLCHOLINE RECEPTOR (AChR)Primary AChR Deficiency
The acetylcholine receptor is made up 5 subunits. Subunits are single protein molecules that combine with other proteins to form a larger protein complex; in this case, the acetylcholine receptor. Two of these subunits are called alpha (α) and the remaining 3 are called beta (β), delta (δ) and epsilon (ε) in adults. Before birth, the fetal subunit contains a gamma (γ) instead of a ε subunit.In primary AChR deficiency, the amount of AChR expressed at the endplate is reduced and the safety margin of neuromuscular transmission is impaired by the decreased amplitude of the EPP. The clinical deficits vary from mild to severe. Patients with recessive mutations in the ε subunit are generally less severely affected than those with mutations in other subunits because compensatory expression of the fetal γ subunit can partially substitute for the defective ε subunit.The sickest patients have severe ocular, bulbar and respiratory muscle weakness from birth and survive only with respiratory support and gavage feeding. Gavage feeding is the use of a small, narrow tube inserted through an infant’s nostrils and run down the throat to the stomach to directly supply nourishment to an affected infant. Infants may be weaned from a respirator and begin to tolerate oral feedings during the first year of life, but have bouts of aspiration pneumonia and may need intermittent respiratory support during childhood and adult life.Motor development is severely delayed; they seldom learn to take steps and can walk for only for a short distance. Older patients close their mouths by supporting their jaw with their hand and elevate their eyelids with their fingers. Facial deformities, protruding jaw, misalignment teeth (malocclusion), and abnormal curvature of the spine such as scoliosis or kyphoscoliosis become noticeable during the second decade. Muscle bulk is reduced. The tendon reflexes are normal or hypoactive.Less severely affected patients experience moderate physical handicaps from early childhood. Limited eye movements and ptosis of the lids become apparent during the first year of life. They fatigue easily, walk and negotiate stairs with difficulty, cannot keep up with their peers in sports, but can perform most activities of daily living. Mutations in the AChR α, β, and δ subunits that reduce or prevent the expression of AChR are either lethal in embryonic life or cause marked disability and high mortality after birth.In the least affected patients motor development is only slightly delayed; they only have mild eyelid ptosis and limitation of eye movements. They are often clumsy in sports, fatigue easily, and cannot run well, climb rope, or do pushups. In some patients, a myasthenic disorder is suspected only when they develop prolonged respiratory arrest on exposure to a neuromuscular blocking agent drug during a surgical procedure.Treatment consists of pyridostigmine an inhibitor of acetylcholinesterase. This medication increases the lifetime of acetylcholine in the synaptic space which allows each acetylcholine molecule to bind to different acetylcholine receptors repeatedly before it leaves the synaptic space by diffusion. Many patients derive additional benefit from the use of 3,4-diaminopyridine (3,4-DAP)16 which prolongs the depolarization of the presynaptic membrane by nerve impulse. This allows more calcium to enter the nerve terminal which increases the number of acetylcholine quanta released by each nerve impulse. Finally, some patients derive still additional benefit from albuterol. 17Kinetic Defect in AChR: The Slow-Channel Syndrome
This syndrome is caused by dominant mutations in the acetylcholine receptor (AChR) gene that leads to the abnormally slow closure of the AChR ion channel. The prolonged openings of the ion channel cause overloading of the postsynaptic region with positively charged ions, including calcium. The local increase in calcium concentration damages the junctional folds, and can damage the muscle fiber nuclei under the folds. The onset of symptoms ranges from infancy to early adult life. The disease causes selectively severe weakness and loss of bulk (atrophy) of the cervical, scapular, and of the wrist and finger extensor muscles.18The safety margin of synaptic transmission is compromised by damage to the junctional folds with loss of acetylcholine receptors, and by the receptors becoming desensitized (unresponsive) during physiologic activity due to prolonged exposure to acetylcholine.This syndrome does not respond to, or is worsened by, pyridostigmine but is improved by relatively high doses of fluoxetine (Prozac) which blocks (plugs) the acetylcholine receptor ion channel and thereby reduces the length of channel openings.19Kinetic Defect in AChR: The Fast-Channel Syndrome
This syndrome is transmitted by recessive inheritance and is the physiologic and anatomic opposite of the slow-channel syndrome.18 The length of the AChR channel openings is decreased because the mutations reduce the ability of AChR to bind acetylcholine, or because they hinder the opening of the AChR ion channel, or because they cause the ion channel to become intermittently unstable. The structural integrity of the endplate is unaffected.This syndrome becomes manifest only if the second copy of the AChR subunit gene is not expressed, or if both copies of the gene harbor the same mutation, so that the fast- channel mutation dictates the clinical consequences. The safety margin of neuromuscular transmission is reduced because the mutant gene reduces the probability and length of channel openings, which reduce the amplitude and duration of EPP. The clinical consequences vary from mild to severe. Most patients respond to combined treatment with pyridostigmine and 3,4-DAP.Prenatal CMS Caused by Mutations in AChR Subunits and Other Specific Proteins
The first identified prenatal myasthenic syndrome was traced to mutations in the fetal AChR γ subunit. In humans, AChR harboring the fetal subunit appears on developing muscle fibers around the ninth week of gestation and becomes concentrated at early nerve-muscle junctions around the sixteenth week of gestation. Subsequently, the γ subunit is replaced by the adult ε subunit and is no longer present at fetal endplates after the thirty-first week of gestation. Thus harmful mutations of the γ-subunit reduce fetal movements (hypomotility) between the sixteenth and thirty-first week of gestation.20The clinical consequences at birth are contractures of large joints, small muscle bulk, webbing around the neck, armpits, elbows, fingers, or behind the knees, flexion contractures of the fingers, rocker-bottom feet with prominent heels, and a characteristic facial appearance with mild eyelid ptosis and a small mouth with downturned corners. A contracture is a condition in which a joint becomes permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.Myasthenic symptoms are absent after birth because by then the normal adult ε subunit is expressed at the endplates.21 Recent studies also identified lethal fetal akinesia syndromes arising from deleterious null mutations in both copies of the AChR α, β, and δ subunits as well as in other CMS disease genes.CMS CAUSED BY DEFECTS IN ENDPLATE DEVELOPMENT OR MAINTENANCETo date, mutations have been detected in genes for proteins that are essential for motor endplate development and maintenance. As with the communication of nerve signals from nerve cells to muscle fibers described above, the health and development of the motor endplate depends upon a sequence of interrelated, chemical reactions involving multiple genes and their protein products.These genes are MuSK, Agrin, LRP4, and DOK-7. Agrin is secreted into the synaptic space by the nerve terminal where it binds to the lipoprotein-related protein LRP4 in the postsynaptic membrane creating an agrin-LRP4 protein complex. The Agrin-LRP4 complex then binds to and activates MuSK. This enhances MuSK phosphorylation and leads to clustering of LRP4 and MuSK. Activated MuSK in concert with postsynaptic DOK-7 and other postsynaptic proteins acts on Rapsyn to concentrate AChR in the postsynaptic membrane, enhances synapse specific gene expression by postsynaptic nuclei, and promotes postsynaptic differentiation. Clustered LRP4, in turn, promotes differentiation of motor axons. The agrin-LRP4-MuSK-Dok-7 signaling system is also essential for maintaining the structure of the adult neuromuscular junction.22Agrin Deficiency
Only a few patients with agrin-related CMS have been reported. The severity of the symptoms varies according to the location of the mutations in the agrin gene and whether or not the mutations affect agrin expression.23,24,25 The consequences are severe when a mutation that hinders attachment of agrin to LRP4 dominates the clinical picture. In such a patient the synaptic contacts were dispersed, the postsynaptic regions were poorly differentiated, the nerve terminals were small, and there were degenerative changes in the muscle fibers under the junctional folds.24 Another report describes three kinships in which the agrin mutations were associated with slowly progressive wasting of the distal leg and later of the upper arm muscles.25 Treatment of the agrin-related CMS is unsatisfactory, but one patient responded partially to ephedrine.24LRP4 Deficiency
There are only two reports of LRP4-related CMS. The first report described a 17-year-old girl with moderately severe fatigable limb-girdle weakness, irregularly shaped synaptic contacts, and mild endplate AChR deficiency. In a muscle located between the ribs (intercostal muscle) of this patient the MEPPs and EPPs were of normal amplitude indicating the identified mutations could spare neuromuscular transmission in some muscles.26 Subsequently, two sisters with moderately severe CMS and harboring a homozygous mutation that hinders LRP4 from activating MuSK were shown to have structurally and functionally abnormal endplates and endplate AChR deficiency.27MuSK Deficiency
This disease presents at birth or in early life with eyelid ptosis or respiratory distress. Subsequently, it involves the ocular, facial and proximal limb muscles, and in some kinships the bulbar muscles as well.28,29,30,31,32 Introduction of the mutant gene in mice results in recurrent cycles of focal loss of nerve supply (denervation) and reestablishment of nerve supply (reinnervation) resulting in extensive remodeling of the endplates.33 Pyridostigmine therapy is ineffective or worsens the disease.31 A recent report indicates that therapy with albuterol has been highly effective in two brothers.34 No clear genotype-phenotype correlations (correlation between a given mutation and the clinical features) have been observed.DOK-7 Deficiency
DOK-7 is expressed within developing and mature muscle fibers. In developing muscle fibers it serves as an intrinsic activator of MuSK.35 In mature muscle, it is activated by MuSK to activate rapsyn to concentrate acetylcholine receptors on the junctional folds and to promote the development and maintenance of the endplate. This CMS can be mild or severe. The pathogenic mutations can curtail DOK-7 expression or prevent DOK-7 to activate, or be activated by, other intracellular proteins. There appears to be no consistent correlation between the identified mutations and the clinical features.All affected patients have limb-girdle weakness with lesser facial and neck muscle weakness but a few have severe bulbar weakness and few have significant limitation of the eye movements.36,37 The clinical course is mild to severe. Impaired maintenance of the endplates is evidenced by ongoing destruction and remodeling of the endplates. Neuromuscular transmission is compromised by the decreased quantal release from the nerve terminal by nerve impulse and by a reduced amplitude of the MEPP.37 Importantly, this CMS is rapidly worsened by pyridostigmine but responds well over a period of time to ephedrine38 or albuterol.37Rapsyn Deficiency
Rapsyn concentrates and anchors acetylcholine receptors on the junctional folds39 and is required for development of the junctional folds.40 Most patients present in the first year of life.41 Joint contractures at birth and other congenital malformations occur in close to one-third.42 Intercurrent infections or fever can trigger respiratory crises that can cause brain damage due to lack of oxygen (anoxia). 43,44 The eye movements are intact in most patients.42 Multiple synaptic contacts appear on single muscle fibers. The endplate acetylcholine receptor deficiency is milder than in primary acetylcholine receptor deficiency42 and the junctional folds are not well differentiated. Most patients respond well to pyridostigmine; some derive additional benefit from ephedrine or albuterol43 and some are further improved by 3,4-DAP.Indo-Europeans harbor a common N88K mutation in the gene that produces rapsyn, which involves replacement of an asparagine molecule (N) by a lysine molecule (K) at codon 8845 (codon: a sequence of 3 adjacent nucleotides that constitutes a genetic code for a specific amino acid). Different mutations hinder self-association of rapsyn molecules, or their binding to acetylcholine receptors, or impede agrin-MuSK-LRP4-mediated clustering of these receptors, or decrease rapsyn expression.40,46 There are no genotype-phenotype correlations (correlation between a given mutation and the clinical features) except that Near-Eastern Jewish patients with a homozygous E-box mutation (E-box: a sequence before the coding region of a gene involved in regulating gene expression) have a milder course with eyelid ptosis, a large protruding jaw, severe weakness of the masticatory and facial muscle, and hypernasal speech.47MYASTHENIC SYNDROMES ASSOCIATED WITH CONGENITAL DEFECTS OF GLYCOSYLATIONGlycosylation is the process by which sugar ‘trees’ or residues (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems.Glycosylation to nascent peptides increases their solubility, folding, stability, assembly, and intracellular transport. Peptides are amino acid compounds and can perform a wide range of functions in the body. O-glycosylation involves addition of sugar residues to the amino acids serine and threonine; N-glycosylation occurs in sequential steps that decorate the amino group of the amino acid asparagine.48,49To date, defects in four enzymes subserving N-glycosylation have been shown to cause a CMS: GFPT1,50,51 DPAGT1,52,53 ALG2, and ALG14.54 Accumulation of small tubules within the muscle fibers, referred to as tubular aggregates, are a clue to the diagnosis but are not seen in all patients. Because glycosylated proteins are present at all endplate sites, the safety margin of neuromuscular transmission is likely compromised by a combination of pre- and postsynaptic defects.GFPT1Deficiency
GFPT1 controls the entry of glucose into the glycosylation pathway. A defect in GFPT1 predicts reduced glycosylation, and therefore defective function, of several endplate- associated proteins.50 The synaptic contacts are small and the postsynaptic regions are poorly developed .51 One patient whose mutations abolished expression of the muscle- specific exon of GFPT1 had severe facial, bulbar, and respiratory muscle weakness, and has been paralyzed since birth. She has a vacuolar myopathy, reduced quantal release evoked by nerve impulse, and low MEPP amplitude. A vacuolar myopathy is a muscle disease that is associated with the development of abnormal pockets or spaces called vacuoles within muscle tissue.DPAGT1 Deficiency
DPAGT1 catalyzes the first committed step of N-linked protein glycosylation. DPAGT1 deficiency predicts impaired asparagine glycosylation of multiple proteins distributed throughout the organism, but in the first 5 patients harboring DPAGT1 gene mutations only neuromuscular transmission was adversely affected.52 A subsequent study of two siblings and of a third patient showed the DPAGT1 deficiency associated with intellectual disability.9 The siblings respond poorly to pyridostigmine and 3,4-DAP; the third patient was partially improved by pyridostigmine and albuterol. Intercostal muscle studies showed fiber type disproportion, small tubular aggregates in some muscle fibers, and autophagic vacuoles (vacuoles that degrade and digest subcellular structures). Evoked quantal release, the MEPP amplitude, and the endplate acetylcholine receptor content were all reduced to ~50% of normal.ALG2 AND ALG14 Deficiency
ALG2 catalyzes the second and third committed steps of N-glycosylation. In one family, four affected siblings had a deleterious homozygous mutation, and a third patient was homozygous for a low-expressor mutation. ALG14 forms an enzyme complex with ALG13 and DPAGT1 and also contributes to the first committed step of N-glycosylation. In one family two affected siblings carried two different recessive mutations. Endplate ultrastructure and parameters of neuromuscular transmission were not investigated.54OTHER CONGENITAL MYASTHENIC SYNDROMESPREPL Deletion Syndrome
The hypotonia-cystinuria syndrome is caused by recessive deletions involving the SLC3A1 and PREPL genes at chromosome 2p21. The major clinical features are cystinuria, growth hormone deficiency, muscle weakness, eyelid ptosis, and feeding problems. Cystinuria is an inherited metabolic disorder characterized by the abnormal movement (transport) in the intestines and kidneys, of certain organic chemical compounds (amino acids).A patient with isolated PREPL deficiency had myasthenic symptoms since birth and growth hormone deficiency but no cystinuria, and responded transiently to pyridostigmine during infancy.55 She harbors a paternally inherited nonsense mutation in the PREPL gene and a maternally inherited deletion involving both PREPL and SLC3A1; therefore the PREPL deficiency determines the phenotype. PREPL expression was absent from the patient’s muscles and endplates. Endplate studies revealed decreased evoked quantal release and small MEPP amplitude despite robust endplate acetylcholine receptor expression.55 Because PREPL is an essential activator of the clathrin associated adaptor protein 1 (AP1),56 and AP1 is required by the vesicular acetylcholine transporter to fill the synaptic vesicles with acetylcholine,57 the small MEPP is attributed to a decreased vesicular content of acetylcholine.Na-Channel Myasthenia
Two patients with this syndrome have been identified to date. The first patient had abrupt episodes of respiratory and facial weakness associated with weakness of muscles required for speaking and swallowing since birth lasting from 3 to 30 minutes typical of periodic paralysis as well as a myasthenic disorder. Studies of neuromuscular transmission revealed normal amplitude EPPs that frequently failed generate muscle action potentials pointing to voltage-gated sodium channels (SCN4A gene) as the culprit. The gene for voltage-gated sodium channels (SCN4A) harbored two recessive mutations which caused the sodium channel to become inactive soon after it was activated by the EPP.58 A second patient with similar clinical findings was recently identified. In this patient two different recessive mutations in voltage-gated sodium channel caused abnormal inactivation of the sodium (Na) channel by activity.59CMS Caused by Plectin Deficiency
Plectin, encoded by the PLEC gene, has different tissue-specific and organelle-specific forms (known as isoforms) that serve to link cytoskeletal filaments to target organelles.60-62 Organelles are a general term for any number of organized or specialized structures within a living cell.Plectin is concentrated at sites of mechanical stress. For example, in skeletal muscle it is present under the junctional folds of the endplates, under the surface membrane of the muscle fiber, at the Z-disks (thin protein bands that mark the boundaries of adjoining contractile units), and around nuclei and mitochondria, which are found by the hundreds within virtually every cell of the body and which generate most of the cellular energy.In skin, it is associated with hemidesmosomes (peg-like structures that link epithelial cells to the underlying basement membrane). Alone or in combination, mutations in plectin can result in a blistering skin disease known as epidermolysis bullosa simplex (EBS), in progressive muscular dystrophy, and sometimes in a myasthenic syndrome. The two patients investigated by the author had EBS, a myasthenic syndrome due to low amplitude MEPPs caused by degenerating junctional folds, as well as muscular dystrophy associated with dislocation of the muscle fiber nuclei, mitochondria and myofibrils (basic rod-like units of muscle cells) as well as defects in the muscle fiber surface membrane causing calcium overloading and degeneration of the muscle fibers.63CMS Associated with Defects in the Mitochondrial Citrate Synthase Carrier SLC25A1The SLC25A1 gene encodes a transporter protein that is responsible for the movement of citrate across the inner membranes of mitochondria. Mutations in the SLC25A1 gene interfere with brain, eye, and psychomotor development.64Two siblings born to consanguineous parents had a CMS associated with intellectual disability and whole exome sequencing revealed they carried a homozygous mutation in SLC25A1. Subsequent studies showed that the mutation impairs the transport activity of the enzyme, and that knockdown of the gene equivalent to SLC25A1 in zebra fish hindered motor axons from innervating muscle fibers.65 A third patient who harbored two recessive mutations in SLC25A1 had myasthenic symptoms as well underdeveloped optical nerves, undeveloped corpus callosum (a structure connecting the two cerebral hemispheres), and excessive urinary excretion of 2-hydroxyglutaric acid.64CMS Associated with Centronuclear Myopathies
Eyelid ptosis, weakness of the external ocular and facial muscles, exercise intolerance, a decremental EMG study, and response to pyridostigmine have been documented in patients with centronuclear myopathies (CNM) caused by mutations in amphiphysin (BIN1),66 myotubularin (MTM1),67 and dynamin 2 (DNM2)68 as well as in other CNM patients with no identified mutations.69 | 313 | Congenital Myasthenic Syndromes |
nord_313_2 | Causes of Congenital Myasthenic Syndromes | Congenital myasthenic syndromes are caused by alterations (mutations) in specific genes. 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.Approximately 30 different genes are known to cause CMS. These genes contain instructions for proteins that are essential for the proper function or health of the neuromuscular junction and the motor endplate. Some of these proteins are found in other areas of the body and, in those subtypes, other areas of the body in addition to the neuromuscular junction can be affected.In some individuals with CMS, no altered gene has been found indicating that additional, as-yet-unidentified genes exist that can cause a congenital myasthenic syndrome.In most subtypes, CMS are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Specific CMS subtypes, specifically SNAP25, synaptotagmin 2, and the slow-channel-myasthenic syndrome are transmitted by autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a 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. | Causes of Congenital Myasthenic Syndromes. Congenital myasthenic syndromes are caused by alterations (mutations) in specific genes. 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.Approximately 30 different genes are known to cause CMS. These genes contain instructions for proteins that are essential for the proper function or health of the neuromuscular junction and the motor endplate. Some of these proteins are found in other areas of the body and, in those subtypes, other areas of the body in addition to the neuromuscular junction can be affected.In some individuals with CMS, no altered gene has been found indicating that additional, as-yet-unidentified genes exist that can cause a congenital myasthenic syndrome.In most subtypes, CMS are inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Specific CMS subtypes, specifically SNAP25, synaptotagmin 2, and the slow-channel-myasthenic syndrome are transmitted by autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a 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. | 313 | Congenital Myasthenic Syndromes |
nord_313_3 | Affects of Congenital Myasthenic Syndromes | Affects of Congenital Myasthenic Syndromes. | 313 | Congenital Myasthenic Syndromes |
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nord_313_4 | Related disorders of Congenital Myasthenic Syndromes | Related disorders of Congenital Myasthenic Syndromes. | 313 | Congenital Myasthenic Syndromes |
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nord_313_5 | Diagnosis of Congenital Myasthenic Syndromes | A generic diagnosis of a CMS can be made on clinical grounds from a history of fatigable weakness involving ocular muscles, bulbar muscles (muscles of the face, and muscles used for speaking and swallowing), and limb muscles since infancy or early childhood, a history of similarly affected relatives, and a variety of tests.Such tests include a decremental electromyographic (EMG) response, and negative tests for antibodies against the acetylcholine receptor (AChR) and the muscle specific receptor tyrosine kinase (MuSK). However, in many CMS patients the family history is negative; in others the onset is delayed, the EMG abnormalities are not present in all muscles or are present only intermittently, and the weakness has a restricted distribution.An electromyography or EMG test records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. The decremental EMG response is measured by stimulation of a motor nerve to muscle at a rate of 2 to 3 times per second; the evoked electrical responses from muscle, known as compound muscle action potentials, or CMAPs, are recorded by electrodes placed on skin overlying the stimulated muscle. The response is abnormal if the fourth evoked CMAP is more than 10% smaller than the first evoked CMAP. Single fiber EMG is a more sensitive but less specific test for a myasthenic disorder. In this test, single intramuscular nerve fibers are stimulated repetitively and the evoked single fiber action potentials are recorded simultaneously from 2 to 4 muscle fibers at a time. An abnormally increased variability in the time-locked firing of individual action potentials is an early indicator of a defect in neuromuscular transmission.1A specific diagnosis of a CMS depends on identifying the disease gene and the pathologic mutations in that gene. Commercially available studies can readily detect mutations in previously identified types of CMS. Mutations in previously unrecognized types of CMS can be detected by whole exome sequencing or whole genome sequencing but the bioinformatic analysis of the obtained result remains challenging. Genetic diagnosis of the CMS is important because therapy that benefits one type CMS can worsen another type. | Diagnosis of Congenital Myasthenic Syndromes. A generic diagnosis of a CMS can be made on clinical grounds from a history of fatigable weakness involving ocular muscles, bulbar muscles (muscles of the face, and muscles used for speaking and swallowing), and limb muscles since infancy or early childhood, a history of similarly affected relatives, and a variety of tests.Such tests include a decremental electromyographic (EMG) response, and negative tests for antibodies against the acetylcholine receptor (AChR) and the muscle specific receptor tyrosine kinase (MuSK). However, in many CMS patients the family history is negative; in others the onset is delayed, the EMG abnormalities are not present in all muscles or are present only intermittently, and the weakness has a restricted distribution.An electromyography or EMG test records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. The decremental EMG response is measured by stimulation of a motor nerve to muscle at a rate of 2 to 3 times per second; the evoked electrical responses from muscle, known as compound muscle action potentials, or CMAPs, are recorded by electrodes placed on skin overlying the stimulated muscle. The response is abnormal if the fourth evoked CMAP is more than 10% smaller than the first evoked CMAP. Single fiber EMG is a more sensitive but less specific test for a myasthenic disorder. In this test, single intramuscular nerve fibers are stimulated repetitively and the evoked single fiber action potentials are recorded simultaneously from 2 to 4 muscle fibers at a time. An abnormally increased variability in the time-locked firing of individual action potentials is an early indicator of a defect in neuromuscular transmission.1A specific diagnosis of a CMS depends on identifying the disease gene and the pathologic mutations in that gene. Commercially available studies can readily detect mutations in previously identified types of CMS. Mutations in previously unrecognized types of CMS can be detected by whole exome sequencing or whole genome sequencing but the bioinformatic analysis of the obtained result remains challenging. Genetic diagnosis of the CMS is important because therapy that benefits one type CMS can worsen another type. | 313 | Congenital Myasthenic Syndromes |
nord_313_6 | Therapies of Congenital Myasthenic Syndromes | Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the CMS overall and that fact that certain subtypes have only been identified in a handful or fewer individuals, 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 CMS.As stated above, it is critically important to identify the specific subtype in each individual as medications that prove effective for one type of CMS may be ineffective or even harmful in another. More detailed treatment information for specific subtypes of CMS is discussed in the “Signs and Symptoms” section above under each individual subtype listing.Current therapies for CMS include medications known as cholinergic agonists such as pyridostigmine or amifampridine (3,4-diaminopyridine), long-lived open channel blockers of acetylcholine receptor ion channel fluoxetine and quinidine, and adrenergic agonists such as salbutamol and ephedrine. | Therapies of Congenital Myasthenic Syndromes. Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the CMS overall and that fact that certain subtypes have only been identified in a handful or fewer individuals, 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 CMS.As stated above, it is critically important to identify the specific subtype in each individual as medications that prove effective for one type of CMS may be ineffective or even harmful in another. More detailed treatment information for specific subtypes of CMS is discussed in the “Signs and Symptoms” section above under each individual subtype listing.Current therapies for CMS include medications known as cholinergic agonists such as pyridostigmine or amifampridine (3,4-diaminopyridine), long-lived open channel blockers of acetylcholine receptor ion channel fluoxetine and quinidine, and adrenergic agonists such as salbutamol and ephedrine. | 313 | Congenital Myasthenic Syndromes |
nord_314_0 | Overview of Congenital Myopathy | SummaryCongenital myopathy (CM) is an extremely rare, inherited disease that affects the muscles (myopathy) and is characterized by the lack of muscle tone or floppiness at birth. There are several different subtypes of congenital myopathy and many are caused by changes (mutations) in specific genes. They differ in severity and onset of symptoms, cellular characteristics under a microscope, and prognosis. Symptoms can be present from birth or slowly progress throughout infancy and childhood, but this disorder does not typically get more severe in adulthood. Experimental treatments are still under development therefore CM disease management involves treatment of symptoms, prevention of possible life-threatening complications, and orthopedic, physical, occupational, speech or other forms of therapy. | Overview of Congenital Myopathy. SummaryCongenital myopathy (CM) is an extremely rare, inherited disease that affects the muscles (myopathy) and is characterized by the lack of muscle tone or floppiness at birth. There are several different subtypes of congenital myopathy and many are caused by changes (mutations) in specific genes. They differ in severity and onset of symptoms, cellular characteristics under a microscope, and prognosis. Symptoms can be present from birth or slowly progress throughout infancy and childhood, but this disorder does not typically get more severe in adulthood. Experimental treatments are still under development therefore CM disease management involves treatment of symptoms, prevention of possible life-threatening complications, and orthopedic, physical, occupational, speech or other forms of therapy. | 314 | Congenital Myopathy |
nord_314_1 | Symptoms of Congenital Myopathy | The subtypes of CM have highly variable severity of muscle loss symptoms and differ in the age of onset.General symptoms of congenital myopathy in a newborn are the slow, progressive loss of muscle tone characterized by floppiness (hypotonia) and general weakness. Early motor skills and other critical developmental milestones may be delayed. Toddlers with this disorder usually have mild muscle weakness and may be prone to falling or stumbling. The muscles of the pelvis, neck, and shoulder area are most commonly affected. Since the symptoms of this disease are not progressive during adulthood, most people with congenital myopathy walk normally as adults. However, some physical activities may be slightly impaired.Typically, diagnosis of CM subtypes requires the use of muscle biopsy and looking at the structural make-up of the muscles under a microscope. Symptoms seen in one subtype are generally seen in other subtypes with slight exceptions and nuances.Nemaline myopathy (NM) is also known as rod myopathy. NM is characterized by abnormal rod- or thread-like structures present in muscle fibers under a microscope. These abnormal rod structures are associated with problems in the contraction and tone of affected skeletal muscles, ultimately leading to muscle weakness.There are six different types of NM which are based on age and severity: severe congenital, Amish, intermediate congenital, typical congenital, childhood-onset, and adult-onset. Severe cases of NM are typically seen in young children, while milder versions of NM are seen in adulthood. Muscle weakness is caused by decreased muscle tone in NM which generally occurs throughout the body and is most severe in the neck, face, and skin muscles. One symptom of NM includes bulbar muscle weakness indicated by difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and excess saliva production (sialorrhea). In infants, bulbar muscle weakness is mainly presented as difficulty feeding while older children and adults exhibit difficulty swallowing. Other symptoms include foot deformities, curvature of the spine (scoliosis), as well as joint deformities (contractures). (For more information, search for “nemaline myopathy” in the Rare Disease Database.)Core myopathies are characterized by areas in the muscle fiber that lack oxidative enzymatic activity. There are two types of muscle fiber core myopathy: central core disease (CCD) and multiminicore disease (MmD). CCD is characterized by the presence of single, well-circumscribed circular regions in the middle of type 1 fibers of the muscle that do not contain mitochondria. CCD is more common in infants who have hypotonia or seen in children with delays in motor development. CCD mainly affects the proximal and axial muscles. Orthopedic and joint deformities seen in nemaline myopathy are not seen in these patients. Eye muscles are not affected in this type of congenital myopathy. Pathologically, CCD can be observed in the tissue fibers by staining sections of the muscle fiber for oxidative enzyme activity. Patients with MmD also exhibit similar severity of symptoms compared to CCD with the exception of axial muscle weakness, especially in the head and neck muscle, which is much more severe in MmD. (For more information, search for “central core disease” in the Rare Disease Database.)Centronuclear myopathy (CNM) is characterized by the abundant amount of centralized nuclei in muscle fibers when viewed in the microscope. One type of CNM, XLMTM, affects newborn boys and is generally clinical severe. Symptoms of XLMTM include an excess of amniotic fluid (polyhydramnios) and reduced fetal movements during pregnancy, thin ribs, weak eye muscles (ophthalmoplegia), drooping upper eyelid (ptosis), pyloric stenosis, knee, and hip contractures, and muscle wasting. Other forms of CNM can affect either males or females and tend to show more mild clinical signs. (For more information, search for “centronuclear myopathy” in the Rare Disease Database.)Congenital fiber-type disproportion (CFTD) occurs when an abundant amount of type I (slow twitch) muscle fibers are 35-40% smaller than type II (fast twitch) muscle fibers. Many symptoms from the previous three myopathy types can be seen in CFTD as well. Additional symptoms include respiratory failure and nocturnal hypoventilation. (For more information, search for “CFTD” in the Rare Disease Database.) | Symptoms of Congenital Myopathy. The subtypes of CM have highly variable severity of muscle loss symptoms and differ in the age of onset.General symptoms of congenital myopathy in a newborn are the slow, progressive loss of muscle tone characterized by floppiness (hypotonia) and general weakness. Early motor skills and other critical developmental milestones may be delayed. Toddlers with this disorder usually have mild muscle weakness and may be prone to falling or stumbling. The muscles of the pelvis, neck, and shoulder area are most commonly affected. Since the symptoms of this disease are not progressive during adulthood, most people with congenital myopathy walk normally as adults. However, some physical activities may be slightly impaired.Typically, diagnosis of CM subtypes requires the use of muscle biopsy and looking at the structural make-up of the muscles under a microscope. Symptoms seen in one subtype are generally seen in other subtypes with slight exceptions and nuances.Nemaline myopathy (NM) is also known as rod myopathy. NM is characterized by abnormal rod- or thread-like structures present in muscle fibers under a microscope. These abnormal rod structures are associated with problems in the contraction and tone of affected skeletal muscles, ultimately leading to muscle weakness.There are six different types of NM which are based on age and severity: severe congenital, Amish, intermediate congenital, typical congenital, childhood-onset, and adult-onset. Severe cases of NM are typically seen in young children, while milder versions of NM are seen in adulthood. Muscle weakness is caused by decreased muscle tone in NM which generally occurs throughout the body and is most severe in the neck, face, and skin muscles. One symptom of NM includes bulbar muscle weakness indicated by difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and excess saliva production (sialorrhea). In infants, bulbar muscle weakness is mainly presented as difficulty feeding while older children and adults exhibit difficulty swallowing. Other symptoms include foot deformities, curvature of the spine (scoliosis), as well as joint deformities (contractures). (For more information, search for “nemaline myopathy” in the Rare Disease Database.)Core myopathies are characterized by areas in the muscle fiber that lack oxidative enzymatic activity. There are two types of muscle fiber core myopathy: central core disease (CCD) and multiminicore disease (MmD). CCD is characterized by the presence of single, well-circumscribed circular regions in the middle of type 1 fibers of the muscle that do not contain mitochondria. CCD is more common in infants who have hypotonia or seen in children with delays in motor development. CCD mainly affects the proximal and axial muscles. Orthopedic and joint deformities seen in nemaline myopathy are not seen in these patients. Eye muscles are not affected in this type of congenital myopathy. Pathologically, CCD can be observed in the tissue fibers by staining sections of the muscle fiber for oxidative enzyme activity. Patients with MmD also exhibit similar severity of symptoms compared to CCD with the exception of axial muscle weakness, especially in the head and neck muscle, which is much more severe in MmD. (For more information, search for “central core disease” in the Rare Disease Database.)Centronuclear myopathy (CNM) is characterized by the abundant amount of centralized nuclei in muscle fibers when viewed in the microscope. One type of CNM, XLMTM, affects newborn boys and is generally clinical severe. Symptoms of XLMTM include an excess of amniotic fluid (polyhydramnios) and reduced fetal movements during pregnancy, thin ribs, weak eye muscles (ophthalmoplegia), drooping upper eyelid (ptosis), pyloric stenosis, knee, and hip contractures, and muscle wasting. Other forms of CNM can affect either males or females and tend to show more mild clinical signs. (For more information, search for “centronuclear myopathy” in the Rare Disease Database.)Congenital fiber-type disproportion (CFTD) occurs when an abundant amount of type I (slow twitch) muscle fibers are 35-40% smaller than type II (fast twitch) muscle fibers. Many symptoms from the previous three myopathy types can be seen in CFTD as well. Additional symptoms include respiratory failure and nocturnal hypoventilation. (For more information, search for “CFTD” in the Rare Disease Database.) | 314 | Congenital Myopathy |
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