What are the signs and symptoms of classic congenital muscular dystrophy (CMD)?

Updated: Jul 03, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Amy Kao, MD  more...
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This is the most common congenital muscular dystrophy in some countries and may account for approximately 40% of all cases.

MDC1A is caused by mutations in the laminin α2 gene (LAMA2) linked to chromosome 6q22-q23 and inherited as autosomal recessive. Laminins are extracellular glycoproteins that bind with other extracellular and transmembrane proteins to form the frame of the basal lamina that surrounds individual myofibers. Each laminin is a heterodimer composed of a heavy chain (α) and two light chains (β and γ). The major laminin of adult skeletal muscle is laminin-2 (also known as merosin), and only mutations of LAMA2 gene encoding laminin α2 cause muscular dystrophy.

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 but is rare.

Most infants eventually sit unsupported, but standing and walking with support is achieved in only about 25%.

Weakness is static or minimally progressive, but death often occurs after 10–30 years due to respiratory failure.

Complications are related to respiratory compromise, feeding difficulty, scoliosis, and (in approximately one third) cardiac abnormalities,

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 hypomyelination and hypodensity, 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-α2, the patient's intelligence, or the presence of seizures. However, patients with severe abnormalities may have low intelligence quotient (IQ) scores.

  • 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-α2 deficiency is present.

  • Patients may present with hypotonia during infancy, but they become ambulatory and maintain ambulation for many years.

  • Others may present in childhood with a limb-girdle phenotype or with a phenotype resembling rigid spine muscular dystrophy (RSMD) (see below) or Emery-Dreifuss muscular dystrophy.

  • Clues to the presence of laminin-α2 deficiency include MRI abnormalities, seizures, and demyelinating neuropathy. (Leukodystrophies may result in a similar phenotype.)

A large series of patients with LAMA2 mutations was described, highlighting the differences between the severe homogenous presentation typical of patients with absent merosinimmunostaining with the more heterogeneous presentation of those with residual merosin expression. [8] Patients with complete lack of merosin were more severely affected, often presenting within the first week of life; however, 46% of patients with residual merosin also had a severe course indistinguishable from patients with complete lack of merosin. These patients were rarely able to achieve independent ambulation (6% did walk), were more likely to need ventilator support (39% vs 8%) and enteral feeding (48% vs 6%) as compared to patients with residual merosin, and were more likely to have nonsense mutations.

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