AUTHOR INFORMATION

Section 1 of 11

Authored by Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCar; Consulting Staff, Barnes Jewish Hospital

Glenn Lopate, MD, is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Edited by Robert S Rust, Jr, MD, Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, University of Virginia School; Clinical and Residency Training, Child Neurology, University of Virginia Hospital and Clinics; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Kenneth J Mack, MD, PhD, Visiting Associate Professor, Department of Neurology, University of Wisconsin at Madison; Associate Professor and Consultant, Department of Neurology, Division of Child and Adolescent Neurology, Mayo Medical School; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Glenn Lopate, MD
Editor's Email:	Robert S Rust, Jr, MD

eMedicine Journal, January 26 2007, VOLUME 8, Number 1

INTRODUCTION

Section 2 of 11

Background: In 1903, Batten described 3 children who had proximal muscle weakness from birth. Biopsy of their muscles showed evidence of chronic myopathy without distinguishing characteristics. In 1908, Howard coined the term congenital muscular dystrophy (CMD) when he described another infant with similar features. Ullrich first described the combination of joint hyperlaxity and proximal contractures in 1930 in the German literature; this was the first case of what is now known as Ullrich CMD. In 1960, Fukuyama et al described a common CMD in Japan that always had features of muscular dystrophy and brain pathology. Other muscle-eye-brain (MEB) diseases were subsequently described: a Finnish variant and Walker-Warburg syndrome (WWS). All of these are caused by a similar molecular pathologic event.

Classifications of CMD

Several authors of review articles have proposed classifications for the CMDs. In 2004, Muntoni and Voit suggested the following scheme:

• Extracellular matrix protein defects
  • Laminin-alpha2–deficient CMD (MDC1A)

  • Ullrich CMD (UCMDs 1,2, and 3)

• Integrin-alpha7 deficiency (ITGA7)

• Glycosyltransferases (abnormal O-glycosylation [O-linked mannose pathway] of alpha-dystroglycan)
  • Walker-Warburg syndrome

  • MEB disease

  • Fukuyama CMD (FCMD)

  • CMD plus secondary laminin deficiency 1 (MDC1B)

  • CMD plus secondary laminin deficiency 2 (mutation in fukitin-related protein, MDC1C)

  • CMD with mental retardation and pachygyria (mutation in LARGE, MDC1D)

• Proteins of the endoplasmic reticulum - Rigid-spine syndrome (RSMD1)

CLINICAL

Section 3 of 11

History:

• Defects of extracellular matrix proteins



• CMD with laminin-alpha2 deficiency (MDC1A, classic CMD, merosin-deficient CMD)
  • This is the most common CMD and accounts for approximately 40% of all cases.

  • Reduced fetal movements may be noted in utero.

  • At birth or in the first few months of life, patients may have severe hypotonia, weakness, feeding difficulty, and respiratory insufficiency.

  • Contractures are common.

  • External ophthalmoplegia may occur late.

  • Most infants eventually sit unsupported, but standing is rare.

  • Weakness is static or minimally progressive.

  • Complications are related to respiratory compromise, feeding difficulty, scoliosis, and (in approximately one third) cardiopulmonary disease.

  • A sensory motor demyelinating neuropathy is present in many patients, but it may not be clinically relevant.

  • CNS manifestations may be present.
    • Mild mental retardation or perceptual-motor difficulties are observed in a few cases.

    • Seizures occur in up to 30% of patients.

    • White-matter changes, most often in periventricular areas, as noted on MRI, are invariably present after age 6 months, even in patients with normal intelligence.

    • White-matter changes are not correlated with the amount of laminin-alpha2, the patient’s intelligence, or the presence of seizures.

    • Structural brain changes have been reported in a few patients and include enlargement of the lateral ventricles, focal cortical dysplasia, occipital polymicrogyria and/or agyria, and hypoplasia of the pons and/or cerebellum.


• • Clinical variants of MDC1A occur with some mutations when only partial laminin-alpha2 deficiency is present.
    • Patients may present with hypotonia during infancy, but they become ambulatory and maintain ambulation for many years.

    • The phenotype of limb-girdle dystrophy may also be present; this includes RSMD (see below) or Emery-Dreifuss muscular dystrophy–type syndrome.

    • Clues to the presence of laminin-alpha2 deficiency include MRI abnormalities, seizures, and demyelinating neuropathy. (Leukodystrophies may result in a similar phenotype.)
  
  
  
• Ullrich CMD
  • Typical features include presentation in the neonatal period with hypotonia, kyphosis of the spine, proximal joint contractures, torticollis, and hip dislocation.

  • Combined with the above is distal joint hyperlaxity with a protruding calcaneus. Patients with severe disease may lack hyperlaxity.

  • Kyphosis and proximal contractures may improve with therapy, but contractures recur and eventually involve previously lax distal joints.

  • Most patients never walk, but some walk for a short time. However, progressive disability, usually due to contractures, leads to loss of ambulation after 2-10 years.

  • Respiratory insufficiency invariably develops in the first or second decade.

  • Facial dysmorphism is common and includes micrognathia, a round face with drooping of the lower lids, and prominent ears.

  • Skin changes typically include follicular hyperkeratosis.

  • Intelligence and brain MRIs are normal.

  • Cardiac function is normal.

  • UCMD is allelic and shares several features with a more mild myopathy termed Bethlem myopathy. UCMD is typically due to an autosomal recessive mutation in the gene for collagen type VI, whereas Bethlem myopathy is due to autosomal dominant mutations. Typical features of Bethlem myopathy include the following:
    • Onset occurs in the first or second decade.

    • Flexion contractures of the fingers, wrists, elbows, and ankles are noted.

    • Joint laxity occurs and may precede the contractures.

    • Patients have proximal muscle weakness and wasting, including respiratory muscles. In rare cases, patients have no weakness.

    • Weakness is slowly progressive, with patients usually having a normal life expectancy. However, some may need aid for ambulation after 40 years.

    • In severe cases, congenital contractures, torticollis, hip dislocation, delayed motor milestones, and late loss of ambulation are similar to findings in UCMD



• Integrin-alpha7 deficiency
  • This rare disorder has been described in only a few children, who presented with hypotonia in infancy and delayed motor milestones (eg, walked at age 2-3 y).

  • One patient had mental retardation, and another had contractures and respiratory failure.



• Presentation is at birth or within the first year of life, with variable degrees of proximal weakness and hypotonia.


• • Presentation is at birth or within the first year of life with variable degrees of proximal weakness and hypotonia.

  • Most patients eventually walk, but in rare and severe cases, patients never gain independent ambulation.

  • In contrast to UCMD, contractures are not present at birth, but they usually develop at age 3-10 years.
    • The most characteristic pattern is spinal rigidity and scoliosis.

    • Contractures of the face, proximal limbs, and finger extensors may also be present.
  
  
  
  • Respiratory insufficiency is common and progressive and may be more severe than limb weakness. Ventilatory assistance may be needed as early as the first decade of life in order to treat nocturnal hypoventilation.

  • Muscle weakness is slowly progressive, and ambulation may be maintained for many years.

  • The cardiac system is usually normal.

  • Intelligence and brain MRIs are normal.
  
  
  
• Glycosyltransferases (abnormal O-glycosylation of alpha-dystroglycan)


• • Mutations in 6 genes involved in O-glycosylation of alpha-dystroglycan are known to cause CMD.

  • Initially, mutations in different genes were thought to cause separate disorders. However, it has now been clearly demonstrated that mutations in each of the different genes can result in overlapping phenotypes with a wide range of phenotypic variability. Similarly, many of the originally described phenotypes can be caused by more than one gene mutation.

  • In these CMDs, the severity of changes in affected tissue has a rank order. This order is possibly related to the degree of preserved alpha-dystroglycan function.

  • In the mildest disease, only the skeletal muscle is affected.

  • As severity progresses, the cerebellum and then the pons, eyes, and cerebrum are affected.



• An order of worsening severity in each affected tissue is also observed.
  • In mild disease, patients may have normal muscle and only mild eye and cerebellar abnormalities.

  • In intermediate disease, patients may have myopia, pontocerebellar hypoplasia, and focal pachygyria.

  • In severe disease, patients may have active muscle fiber degeneration and necrosis, nonfunctioning eyes, severe pontocerebellar hypoplasia, and agyria.

Physical: See History above.

Causes:

• CMD with laminin-alpha2 deficiency


• • This is an autosomal recessive disease caused by a mutation on chromosome 6 in the LAMA2 gene that codes for laminin-alpha2.

  • More than 90 different missense, nonsense, splice-site, and deletion mutations have been described.

  • Expression of laminin-alpha2 is related to disease severity. Complete lack of expression is always associated with a severe phenotype. Partial loss of expression is often associated with a mild phenotype, but severe phenotypes have also been described.

  • Laminin-alpha2 is expressed in the basement membrane of striated muscle, cerebral blood vessels, Schwann cells, and skin.

  • Laminins are glycoproteins that form the backbone of the basement membrane in almost every cell type.
    • Seven laminin genes (4 alpha, 2 beta, 1 gamma) are known.

    • Each laminin is a heterotrimer (alpha-beta-gamma). Laminin 2 (alpha2-beta1-gamma1) and laminin 4 (alpha2-beta2-gamma1) are expressed in muscle.

    • Laminins bind to a number of molecules, most importantly to the 2 main transmembrane receptors: alpha-dystroglycan and various integrins.

    • They are thought to play a role in cell-to-cell recognition, cell shape, differentiation, movement, transmission of force, and tissue survival.

    • Loss of laminin-alpha2 results in a secondary loss of alpha-dystroglycan and integrin-alpha7 (not dystrophin or sarcoglycans), with resultant impairment of myogenesis, synaptogenesis, force generation, and mechanical stability.
  
  
  
• Ullrich CMD


• • This is an autosomal recessive (or more rarely dominant) disorder caused by a mutation in 1 of the 3 collagen type VI genes (COL6A1, COL6A2, COL6A3).

  • Collagen type VI is expressed in the extracellular matrix of nearly all cell types and is composed of alpha1, alpha2, and alpha3 chains, which intracellularly form a triple helix monomer.

  • Six-chain dimers and then 12-chain tetramers are formed with stabilization by disulfide bonds. The tetramers are excreted into the extracellular space.

  • Tetramers aggregate into beaded collagen microfibrils, which require the presence of all 3 alpha chains.

  • Mutations in all 3 alpha chains have been associated with UCMD (and Bethlem myopathy).

  • Collagen type VI has cell adhesion properties and binds to numerous extracellular matrix proteins, including decorin, biglycan, perlecan, fibronectin, proteoglycans, and other collagens.

  • The major role of collagen type VI is likely to assist in anchoring the basement membrane to the underlying connective tissue and to act as a scaffold for the formation of the collagen fibrillar network. It also plays a role in cell-cycle signaling during cellular proliferation and differentiation. Lastly, it likely has a role in tissue homeostasis by assisting in interactions between cells and the extracellular matrix and by its role in the development of the extracellular matrix supramolecular structure.

  • How mutations cause disease and why some mutations cause UCMD and others cause Bethlem myopathy is unclear. However, it is becoming clear that UCMD and Bethlem myopathy are likely 2 ends of a spectrum of collagen type VI diseases. This is based on the finding of "severe" Bethlem myopathy patients and "mild" UCMD patients with a great deal of clinically similarity. Furthermore, some mutations in collagen type VI can cause both diseases. Lastly, cases of UCMD have now been described with an autosomal dominant inheritance similar to that associated with Bethlem myopathy.
    • Hypotheses include site-specific mutation effects relating to different domains in each alpha chain or different, tissue-specific transcriptional regulation events.

    • These effects may lead to improper assembly of tetramers, reduced secretion of normal tetramers, or reduced secretion of abnormal monomers and/or tetramers that subsequently form abnormal tetramers and/or collagen microfibrils.

DIFFERENTIALS

Section 4 of 11

Congenital Myopathies
Dystrophinopathies
Emery-Dreifuss Muscular Dystrophy
Limb-Girdle Muscular Dystrophy
Metabolic Myopathies
Spinal Muscular Atrophy

Other Problems to be Considered:

Congenital myopathy
Congenital myotonic dystrophy
Congenital fascioscapulohumeral dystrophy
Congenital myasthenic syndromes
Leukodystrophies
Mitochondrial myopathies
Ehlers-Danlos and Marfan syndromes for UCMD

WORKUP

Section 5 of 11

Lab Studies:

• Persons with UCMD, rigid spine with muscular dystrophy (deficiency of selenoprotein N), and integrin-alpha7 deficiency have creatine kinase (CK) levels that are normal to mildly elevated (<5 times normal).



• CK levels are mildly to markedly elevated (2-150 times normal) in persons with CMD1C or any other CMD due to abnormal glycosylation.

Imaging Studies:

• Persons with CMDs due to mutations in genes for selenoprotein N and in genes for the extracellular matrix proteins integrin-alpha7 and collagen type VI have normal brain MRI findings.



• In those with CMDs due to mutations in laminin-alpha2 or with any other CMD due to abnormal O-glycosylation, brain MRI findings are abnormal.


• • The mildest changes are seen in deficiency of laminin-alpha2, with periventricular white matter changes being the most common abnormality.
  
  
  
  • In the CMDs due to abnormalities in O-glycosylation, the abnormalities vary, even in patients with mutations in the same gene. The widest spectrum is seen in mutations in the FKRP gene. Brain MRIs can be normal, or they can show severe changes, such as agyria and severe pontocerebellar hypoplasia.
  
  
  
  • All patients with MEB disease and FCMD have abnormal MRIs, which show a range from mild changes of only cerebellar hypoplasia or cysts to severe disease, as described above.
  
  
  
  • The most severe changes are seen in WWS, with most patients having severe agyria, pontocerebellar hypoplasia, and, in many patients, encephalocele or myelomeningocele.
  
  
  

Other Tests:

• Electromyography (EMG) and nerve conduction study (NCS)


• • EMG and NCS should be performed in all patients with suspected CMD to confirm myopathy and to exclude other diseases.
  
  
  
  • NCS results are normal except in some cases of MDC1A, in which mild neuropathic changes may be seen (some with demyelinating features).
  
  
  
  • EMG usually shows typical small-amplitude, narrow-duration motor-unit potentials with early recruitment.
    
  
  
  
• Prenatal diagnosis


• • Prenatal diagnosis had been performed most commonly in families with MDC1A, in part, because this is the most common CMD.
  
  
  
  • Laminin-alpha2 is expressed in 9-week trophoblasts, allowing immunohistochemical detection of protein in chorionic villus. However, in families with partial laminin-alpha2 deficiency, protein detection may not be reliable. Linkage analysis can also be performed but is also at times unreliable, especially in families with partial laminin-alpha2 deficiency or no brain MRI abnormalities. However, the combination of these 2 techniques along with rigorous controls has been shown to be highly accurate and reliable in the prenatal diagnosis of MDC1A. The most reliable technique is direct mutation analysis, although this is more time consuming because the entire gene sequence must be analyzed.
  
  
  

Procedures:

• Muscle biopsy is indicated in all cases of suspected CMD to help confirm the diagnosis and exclude other causes of weakness.


• • CMD with laminin-alpha2 deficiency
    • Complete laminin-alpha2 deficiency
      • Patients may have severe dystrophic pathology with muscle-fiber degeneration and regeneration, fiber necrosis, and endomysial and perimysial fibrosis.

      • Mononuclear cell infiltrates may be present in biopsy samples obtained from infants.

      • Immunohistochemical studies show complete loss of staining for laminin-alpha2.
      • Antibodies must be used against both the 300- and 80-kd subunits.

      • Alpha-dystroglycan and beta-laminin staining is also absent.

      • Approximately 95% of biopsy samples with absent laminin-alpha2 staining have a mutation in the LAMA2 gene.

    • Partial laminin-alpha2 deficiency
      • Mild myopathic features often occur with little or no necrosis.

      • Partial staining for laminin-alpha2 may be seen in patients with laminin-alpha2-deficient CMD and in those with any CMD associated with glycosyltransferase enzyme deficiency.



• Ullrich CMD
  • Variation ranges from mildly myopathic to dystrophic in terms of muscle fiber size, muscle fiber necrosis, and fibrosis.

  • Reduced or absent staining for collagen type VI is observed.

  • In Bethlem myopathy, routine muscle biopsy and collagen type VI immunohistochemistry usually are normal.



• Integrin-alpha7 deficiency
  • Mild variations in muscle-fiber size are noted.

  • Staining for integrin-alpha7 is decreased. This may also be seen in CMD with laminin-alpha2 deficiency.



• Rigid spine with muscular dystrophy (deficiency of selenoprotein N)
  • Myopathic features include small, round muscle fibers; endomysial fibrosis; type 1 fiber predominance; and hypotrophy.

  • Regenerating and degenerating muscle fibers and fiber necrosis are rare.

  • Minicores may be present.

  • Severe cases may have significant fibrosis but still little or no necrosis.



• Glycotransferases (abnormal O-glycosylation of alpha-dystroglycan)
  • All of the alpha-dystroglycanopathies have similar muscle pathologies that differ in the degree of severity, which is likely correlated with the degree of preserved alpha-dystroglycan function.

  • Patients have muscle fiber degeneration and/or necrosis and regeneration, variability in muscle fiber size, and endomysial and/or perimysial fibrosis

  • Muscle tissue may look fairly normal in persons with MEB disease and MDC1A (FKRP deficiency) shortly after birth.

  • Immunohistochemical studies show decreased staining for alpha-dystroglycan, which is localized correctly to the muscle cell surface. Western blot studies show a decreased molecular weight of alpha-dystroglycan in affected patients. A secondary decrease in staining for laminin-alpha2 may be noted in some biopsy samples.

TREATMENT

Section 6 of 11

Medical Care:

• No specific treatment is available for any of the CMDs.



• Aggressive supportive care is essential to preserve muscle activity, to allow for maximal functional ability, and to prolong the patient's life expectancy.


• • The primary neuromuscular concerns include prevention and correction of skeletal abnormalities, such as scoliosis, foot deformities, and contractures, to maintain ambulation.

  • Aggressive use of passive stretching, bracing, and orthopedic procedures, such as spinal fusion, allows the patient to remain independent for as long as possible.
  
  
  
• Pulmonary complications are the other main concern.


• • Early monitoring and intervention to treat respiratory insufficiency is important because effective therapies can help to improve function and prolong life expectancy.

  • Such therapies include noninvasive bilevel positive airway pressure and/or continuous positive airway pressure or permanent ventilation via a tracheostomy.
  
  
  
• Cardiac complications are especially common in patients with a mutation in FKRP and occasionally in patients with laminin-alpha2 deficiency. Treatment of dilated cardiomyopathy with ACE inhibitors and beta-blockers may be necessary.

• Children with CMD may have other neurologic treatment issues, including seizure management, need for supplementary gastric tube feedings, ophthalmologic care, and general medical concerns that occur in profoundly retarded children.

• As with other hereditary myopathies, a team approach, including a neurologist, pulmonologist, ophthalmologist, cardiologist, orthopedic surgeon, physical medicine specialist, orthotist, and counselors, is required to ensure the best possible care.

Surgical Care: Orthopedic surgery is often necessary in patients who live several years with their disease to prevent contractures and scoliosis.

Consultations:

• Ophthalmologist



• Pulmonologist



• Cardiologist



• Orthopedic surgeon



• Epileptologist



• Physical medicine specialist

FOLLOW-UP

Section 7 of 11

Further Inpatient Care:

• Patients with alpha-dystroglycanopathies may require prolonged hospitalization. For example, neonates or infants may have progressive disease and have feeding difficulties, cardiopulmonary complications, seizures, or profound mental retardation.



• Older children may need admission for orthopedic care or cardiopulmonary complications.

Further Outpatient Care:

• Muscle function, contractures, visual function, seizures, the ability to perform activities of daily living, and cardiopulmonary functions should be assessed at each follow-up visit.

Complications:

• Feeding difficulties



• Respiratory failure



• Seizures



• Contractures and/or scoliosis



• Blindness

Prognosis:

• The prognosis depends on the type of CMD.



• With severe disease, such as WWS, patients usually die within the first few years of life.



• In CMD with laminin-alpha2 deficiency and in some patients with mutations in FKRP, patients occasionally have a relatively normal life span.

Patient Education:

• Genetic counseling is often helpful to patients and their families to assist in family planning.

MISCELLANEOUS

Section 8 of 11

Special Concerns:

• For additional information, visit the Web site of the Muscular Dystrophy Association.

TEST QUESTIONS

Section 9 of 11

CME Question 1: Which of the following statements about disease related to the glycosyltransferases is false?

A: Mutations in the FKRP gene can result in the least severe disease, and no CNS or ocular abnormalities may be present.
B: Weakness, hypotonia, seizures, mental retardation, and blindness can be present.
C: Creatine kinase levels are mildly to moderately elevated, and muscle biopsy shows dystrophic changes.
D: Primary deficiency of laminin-alpha2 is the cause of the congenital muscular dystrophies due to abnormal glycosylation of alpha-dystroglycan.
E: These congenital muscular dystrophies are transmitted in an autosomal recessive inheritance pattern.

The correct answer is D: None of the disease related to glycosyltransferases is due to a primary deficiency of laminin-alpha2. They are due to known or putative O-glycotransferases that result in primary deficiency of glycosylated alpha-dystroglycan. Mutations in the FKRP gene can result in a limb-girdle phenotype allelic with limb-girdle muscular dystrophy type 2I.

CME Question 2: Which of the following is not characteristic of congenital muscular dystrophy (CMD) associated with a mutation in the gene for laminin-alpha2?

A: Weakness correlates with the level of residual laminin-alpha2, as detected on immunocytochemical analysis.
B: No white-matter abnormalities are present on MRIs.
C: Intelligence is normal.
D: Muscle biopsy specimens show inflammation in young patients.
E: Weakness is presumably caused by disruption of the linkage between dystrophin and the extracellular matrix.

The correct answer is B: Although most patients with laminin-alpha2 deficiency have normal intelligence, T2-weighted MRIs usually show abnormal white matter hyperintensity. This finding corresponds to hypomyelination of the cerebral white matter.

Pearl Question 1 (T/F): Holoprosencephaly is the migrational defect in the muscle-eye-brain congenital muscular dystrophies (CMDs).

The correct answer is False: Lissencephaly, a term which means smooth brain and which refers to the lack of normal gyral patterns, is the migrational defect seen in disease related to O-glycosyltransferases. The cobblestone appearance characteristic of these CMDs is likely due to migrational defects resulting in nodular heterotopia.

Pearl Question 2 (T/F): In congenital muscular dystrophy (CMD) with integrin-alpha7 deficiency, immunostaining for laminin-alpha2 is reduced.

The correct answer is False: Although integrin-alpha7-beta1 (the main integrin isoform in muscle) binds to laminin-alpha2, immunostaining for laminin-alpha2 is preserved. This is probably because laminin-alpha2 also binds alpha-dystroglycan and because its localization to the muscle basement membrane is maintained through linkage to this dystroglycan.

Pearl Question 3 (T/F): In congenital muscular dystrophy (CMD) with laminin-alpha2 deficiency, the level of residual muscle laminin-alpha2 is correlated with the clinical phenotype.

The correct answer is True: The severity of weakness correlates to the level of laminin-alpha2. Absent laminin-alpha2 results in severe weakness, whereas partial loss of laminin-alpha2 usually results in mildly to moderately severe weakness.

Pearl Question 4 (T/F): In congenital muscular dystrophy (CMD), laminin-alpha2 is expressed and can be measured in the liver.

The correct answer is False: Laminin-alpha2 is expressed in muscle, brain, peripheral nerves (Schwann cells), and skin. This results in the clinical manifestations of weakness, brain MRI abnormalities, and, occasionally, neuropathy. Muscle biopsy must be performed to evaluate all CMDs to measure protein concentrations by means of immunostaining or Western blotting.

PICTURES

Section 10 of 11

Caption: Picture 1. Dystrophin-glycoprotein complex. The complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in laminin-alpha2, integrin alpha7, and O-glycosyltransferases that glycosylate alpha-dystroglycan all can cause congenital muscular dystrophy (CMD). Furthermore, mutations in collagen (not shown), which binds alpha-dystroglycan through perlecan and other proteoglycans, can cause CMD. Mutations in dystrophin, the sarcoglycans, dysferlin, and caveolin-3 can also cause muscular dystrophies. Reprinted with permission from Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. In: Neuromuscular Disorders. Vol. 15. Cohn RD. Elsevier; 2005: 207-17. 7, 20
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BIBLIOGRAPHY

Section 11 of 11

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