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Copyright 2007, 2013
NORD is very grateful to Susan E. Sparks, MD, PhD, Clinical Genetics/Department of Pediatrics, Levine Children's Hospital at Carolinas Medical Center, for assistance in the preparation of this report.
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.
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 Deficiency
This 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 Myopathy
Individuals 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 CMD
This 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 CMD
This 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 Disease
This 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).
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.
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.
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.)
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 Workup
During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy. 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.
No 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
There are anecdotal reports of corticosteroid drugs being tried in individuals with dystroglycanopathies. Dosages were based upon the guidelines used for another rare muscle disorder known as Duchenne muscular dystrophy. In individuals who responded to such treatment, it appears to improve the ability to walk. However, clinical studies have not yet been undertaken and more research is necessary to determine the long-term safety and effectiveness of this potential treatment for individuals with dystroglycanopathies.
Members of the CMD community, specifically individuals with the nonprofit section and from academic institutions have created a website to provide information and support for individuals with CMD. These individuals maintain a registry, a database that catalogues information on affected individuals. The registry is a patient self-report registry with the goal of registering the global CMD population. For more information, contact:
Congenital Muscular Dystrophy International Registry (CMDIR)
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FROM THE INTERNET
Sparks S, Quijano-Roy S, Harper A, et al. Updated:08/23/2012. Congenital Muscular Dystrophy Overview. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at: http://www.genetests.org.
Quijano-Roy S. Congenital Muscular Dystrophy. Orphanet Encyclopedia, September 2009. Available at: http://www.orpha.net Accessed on: February 3, 2013.
Report last updated: 2013/05/08 00:00:00 GMT+0