Congenital Muscular Dystrophy Workup

  • Author: Glenn Lopate, MD; Chief Editor: Amy Kao, MD   more...
 
Updated: Aug 17, 2011
 

Laboratory Studies

  • Persons with Ullrich congenital muscular dystrophy, rigid spine with muscular dystrophy (deficiency of selenoprotein N), and integrin-α7 deficiency have creatine kinase (CK) levels that are normal to mildly elevated (≤5 times normal).
  • CK levels are usually more than 1000 in patients with congenital muscular dystrophy with familial junctional epidermolysis bullosa.
  • CK levels are mildly to markedly elevated (2-150 times normal) in most patients with congenital muscular dystrophy due to abnormal glycosylation or with laminin-α2 mutations.
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Imaging Studies

  • Persons with congenital muscular dystrophies due to mutations in genes for selenoprotein N and in genes for the extracellular matrix proteins integrin-α7 and collagen type VI have normal brain MRI findings.
  • Patients CMD with familial junctional epidermolysis bullosa often have brain atrophy and enlarged ventricles on MRI.
  • In those with congenital muscular dystrophies due to mutations in laminin-α2 or with any other congenital muscular dystrophy due to abnormal O-glycosylation, brain MRI findings are abnormal.
    • The mildest changes are seen in deficiency of laminin-α2, with periventricular white matter changes being the most common abnormality (increased T2 signal).
    • In the congenital muscular dystrophies due to abnormalities in O-glycosylation, the abnormalities vary, even in patients with mutations in the same gene. Brain MRIs can be normal, or they can show severe changes, such as agyria and severe pontocerebellar hypoplasia.
    • All patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy 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 Walker-Warburg syndrome, with most patients having severe agyria, pontocerebellar hypoplasia, and, in many patients, encephalocele or myelomeningocele.
  • Muscle MRI can help differentiate muscular dystrophies with rigidity of the spine[32]
    • SEPN1 – Selective involvement of the sartorius, gastrocnemius spared
    • COL6A – Bethlem myopathy (BM) patients had concentric atrophy and peripheral involvement, most obvious in vasti and gastrocnemius
    • COL6A - Ullrich CMD patients had diffuse involvement of thigh muscles with selective sparing of anteromedial thigh muscles; more diffuse than BM, but similar peripheral involvement of gastrocnemius
    • LMNA – Involvement of vasti at thigh level, medial > lateral gastrocnemius, soleus involved
    • LGMD2A (CAPN3) – Selective involvement of adductor magnus and posterior thigh muscles, medial > lateral gastrocnemius, soleus involved
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Other Tests

  • Electromyography (EMG) and nerve conduction study (NCS)
    • EMG and NCS should be performed in all patients with suspected congenital muscular dystrophy to confirm myopathy and to exclude other diseases.
    • NCS results are normal except in some cases with mutations in laminin-α2, 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 mutations in laminin-α2, in part, because this is the most common congenital muscular dystrophy.
    • Laminin-α2 is expressed in 9-week trophoblasts, allowing immunohistochemical detection of protein in chorionic villus. However, in families with partial laminin-α2 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-α2 deficiency or no brain MRI abnormalities. However, the combination of these 2 techniques along with rigorous controls has been highly accurate and reliable in the prenatal diagnosis of laminin-α2 mutations. The most reliable technique is direct mutation analysis, although this is more time consuming because the entire gene sequence must be analyzed.
  • Genetic testing is available for all congenital muscular dystrophies (see http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests)
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Procedures

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

  • Congenital muscular dystrophy with laminin-α2 deficiency
    • Complete laminin-α2 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-α2.
      • Antibodies must be used against both the 300- and 80-kd subunits.
      • α-dystroglycan staining is also absent.
      • Approximately 95% of biopsy samples with absent laminin-α2 staining have a mutation in the LAMA2 gene.
    • Partial laminin-α2 deficiency
      • Mild myopathic features often occur with little or no necrosis.
      • Partial staining for laminin-α2 may be seen in patients with laminin-α2-deficient congenital muscular dystrophy and in those with any congenital muscular dystrophy associated with a glycosyltransferase enzyme deficiency.

Ullrich congenital muscular dystrophy

  • Variation ranges from mildly myopathic to dystrophic in terms of muscle fiber size, muscle fiber necrosis, and fibrosis.
  • Collagen type VI staining around surface of muscle fiber is usually reduced or absent, but staining may occur in connective tissue.
  • In Bethlem myopathy, routine muscle biopsy and collagen type VI immunohistochemistry usually are normal.

Integrin-α7 deficiency

  • Mild variations in muscle-fiber size are noted.
  • Staining for integrin-α7 is decreased. This may also be seen in congenital muscular dystrophy with laminin-α2 deficiency.

Congenital muscular dystrophy with familial junctional epdermolysis bullosa

  • Variation in muscle fiber size, internal nuclei, increased connective tissue, muscle fiber necrosis and regeneration
  • Plectin immunostaining is reduced in muscle Z-lines and skin

Rigid spine with muscular dystrophy (deficiency of selenoprotein N)

  • Myopathic features include small, round muscle fibers, endomysial fibrosis and type 1 fiber predominance or atrophy.
  • Regenerating and degenerating muscle fibers and fiber necrosis are rare. Severe cases may have significant fibrosis but still little or no necrosis.
  • Minicores may be present.

Glycotransferases (abnormal O-glycosylation of α-dystroglycan)

  • All of the α-dystroglycanopathies have similar muscle pathologies that differ in the degree of severity, which is likely correlated with the degree of preserved α-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 muscle-eye-brain disease and with mutations in FKRP shortly after birth.
  • Immunohistochemical studies show decreased staining for α-dystroglycan, which is localized correctly to the muscle cell surface. Western blot studies show a decreased molecular weight of α-dystroglycan in affected patients. A secondary decrease in staining for laminin-α2 may be noted in some biopsy samples.
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Histologic Findings

See Background and Procedures.

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Contributor Information and Disclosures
Author

Glenn Lopate, MD  Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; Consulting Staff, Department of Neurology, 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

Disclosure: Baxter Grant/research funds Other; Amgen Grant/research funds None

Specialty Editor Board

Robert Stanley Rust Jr, MD, MA  Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology

Robert Stanley Rust Jr, MD, MA is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Neurological Association, Child Neurology Society, International Child Neurology Association, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Kenneth J Mack, MD, PhD  Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD  Attending Neurologist, Children's National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose.

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Dystrophin-glycoprotein complex. The complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in laminin-α2, integrin α7, 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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