Information on the following diseases can be found in the Related Disorders section of this report:

• None

The onset, specific symptoms, and severity of CMD varies considerably even among 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.

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 is characterized by complete deficiency of the protein merosin in muscle, a protein found in the tissue that surrounds muscle fibers. MDC1A is the most common form of CMD . 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 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).

Although less common, some affected children only have a partial deficiency of merosin. The severity of partial merosin deficiency varies greatly and 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. 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.)

Ullrich Congenital Muscular Dystrophy
The characteristic symptoms of this form of CMD are diminished muscle tone (hypotonia), muscle weakness, contractures, abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), and abnormally flexible (hyperelasticity) joints of the wrists and ankles as well as in the fingers and toes. Additional symptoms and severity is highly variable. In some cases, congenital dislocation of the hip and muscles spasms of the neck (torticollis) 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 (e.g., worsening contractures).

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.

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.

CMDs that result from defective proteins that are essential for the binding of sugar molecules to dystroglycan, known collectively as the dystroglycanopathies.

Congenital Muscular Dystrophy Type 1C (MDC1C; CMD with secondary merosin deficiency type 2). MDC1C is a 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 mental retardation.

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. .

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 a 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. Individuals with MEB often have lissencephaly, a structural brain defect in which the brain is smooth, lacking the normal folds.

Fukuyama Type Congenital Muscular Dystrophy (FCMD) and Walker-Warburg Syndrome (WSS). 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. 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 loss of transparency 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 2007, MDC1D has been reported in one individual with severe mental retardation, developmental delays, and muscle weakness and degeneration (atrophy).

CMDs resulting from defects of the selenoprotein1 (SEPN1) gene:

Rigid Spine Muscular Dystrophy (RSMD1; Rigid Spine Syndrome; CMD with early rigidity of the spine)
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.

Individuals with RSMD1 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.

Additional forms of CMDs without a known genetic defect:
Several additional forms of CMD exists, 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 of rigid spine syndrome not linked to mutations in the SEPN1 gene.

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.

Almost all of the congenital muscular dystrophies 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.

Ullrich CMD is the only form of CMD that is known to also be inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

The CMDs are caused by deficiency or lack of specific proteins (enzymes) 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 Ullrich CMD. 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).

Some CMD are involved with genes that encode proteins 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) for MDC1D has been located on the long arm of chromosome 22 (22q12.3-13.1).

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.

A disease gene (selenoprotein N; SEPN1) for rigid spine muscular dystrophy has been located on the short arm of chromosome 1 (1p35-36). The SEPN1 gene 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 unknown.

Additional forms of CMD exist that cannot be linked to any known defective gene, suggesting that additional, 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. However, this finding 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.

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 17 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 17 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 (LGMDA-E). Autosomal recessive LGMD is known as LGMD2 and has 10 subtypes (LGMDA-J). (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. 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.
(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.)

Additional forms of muscle disease (myopathy) are considered differential diagnoses for LGMD including metabolic myopathies such as Pompe disease; 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.)

Diagnosis
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.

During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy.

Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. 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.

An 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 a genetic mutation and can be used to confirm a diagnosis of some forms of CMD.

Treatment
No cure exists for CMD. Treatment is aimed at the specific symptoms present in each individual. Specific treatment options may include physical and occupational therapy to improve muscle strength and prevent contractures; 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. In cases of respiratory insufficiency, noninvasive ventilation or mechanical ventilation may become necessary.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

TEXTBOOKS
Walsh CA. Walker-Warburg Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:597-8.

Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin's Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:3253-63.

JOURNAL ARTICLES
Martin PT. Mechanisms of disease: congenital muscular dystrophies-glycosylation takes center stage. Nat Clin Pract Neurol. 2006;2:222-30.

Mercuri E, Longman C. Congenital muscular dystrophy. Pediatr Ann. 2005;34:560-2, 564-8.

Scheffer H, Brockington M, Muntoni F, et al., POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet. 2005;42:907-12.

Muntoni F, Voit T. 133rd ENMC International Workshop on Congenital Muscular Dystrophy (IXth International CMD Workshop). Neuromuscul Disord. 2005;15:794-801.

Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. Neuromuscul Disord. 15:207-17.

Muntoni F, Voit T. The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord. 2004;14;635-49.

Beltran-Valero de Bernabe D, Voit T, Longman C, et al., Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004;41:e61.

Longman C, Brockington M, Torelli S, et al., Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mutat. 2003;12:2853-61.

Mercuri E, Brockington C, Straub V, et al., Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol. 2003;53:537-42.

Taniguchi K, Kobayashi K, Saito K, et al., Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum Mol Genet. 2003;12:527-34.

Brockington M, Sewry CA, Herrmann R, et al., Assignement of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. Am J Hum Genet. 2000;66:428-35.

Toda T, Kobayashi K, Kondo-Iida E, et al., The Fukuyama congenital muscular dystrophy story. Neuromuscul Disord. 2000;10:153-9.

Hayashi YK, Chou FL, Engvall E, et al., Mutations in the integrin alpha 7 gene cause congenital myopathy. Nat Genet. 1998;19:94-7.

ON THE INTERNET
Gordon E, Hoffman EP, Pegoraro E. Updated:12/22/2006. 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.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:607855; Last Update:10/18/2006. Entry No:602771; Last Update:06/30/2005. Entry No:254090; Last Update:12/28/2005. Entry No:606612; Last Update:08/13/2004. Entry No:604801; Last Update:03/19/2004. Entry No:608840; Last Update:08/30/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM Accessed on: January 6, 2007.