eMedicine Specialties > Neurology > Pediatric Neurology

Congenital Muscular Dystrophy: Differential Diagnoses & Workup

Author: Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Contributor Information and Disclosures

Updated: Feb 12, 2009

Differential Diagnoses

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

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 mildly to markedly elevated (2-150 times normal) in most patients with congenital muscular dystrophy due to abnormal glycosylation or with laminin-α2 mutations.

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.
  • 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.

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.

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 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.
  • 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.

Histologic Findings

See Background and Procedures.

More on Congenital Muscular Dystrophy

Overview: Congenital Muscular Dystrophy
Differential Diagnoses & Workup: Congenital Muscular Dystrophy
Treatment & Medication: Congenital Muscular Dystrophy
Follow-up: Congenital Muscular Dystrophy
Multimedia: Congenital Muscular Dystrophy
References
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Further Reading

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Keywords

Finnish-type congenital muscular dystrophy, Fukuyama congenital muscular dystrophy, integrin-alpha7 beta1-deficiency disease, laminin-alpha2 merosin-deficiency disease, muscle-eye-brain disease, Walker-Warburg congenital muscular dystrophy, CMD, Walker-Warburg syndrome, WWS, WW syndrome, MEB disease

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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; Chief of Neurology, St Louis ConnectCare, 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
Disclosure: Nothing to disclose.

Medical Editor

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; 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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

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.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children
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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