Merosin-Deficient Type Congenital Muscular Dystrophy

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Background    Histopathology & Immunohistochemistry    Differential Diagnosis

BACKGROUND AND CLINICAL INFORMATION: Head  

Useful Web Sites: Muscular Dystrophy Association (MDA) web site

Summary: Classic congenital muscular dystrophy consists of the merosin-deficient type and merosin-positive type. Merosin-deficient congenital muscular dystrophy (MDCMD) is the most common cases of neonatal onset congenital muscular dystrophy outside Japan. It is autosomal recessive. The clinical manifestation is more severe than merosin positive congenital muscular dystrophy. Clinically, it is characterized by infantile hypotonia and, often but not always, with joint contractures. Neuroimaging often reveals abnormal high-intensity T2-weighted signals in the white matter of the brain. There may also be demyelination in the peripheral nerves. The histological picture is that of dystrophic myopathy. Inflammatory cell infiltration can often be seen at the early stage of disease and should be distinguished from inflammatory myopathy.

Incidence: 30-40% of neonatal onset cases of classic congenital muscular dystrophy outside Japan.

Laminins-2 (formerly known as merosin): Laminins are heterotrimers consistinct of three distinct laminin chains (a, b, and g; each chain with its isoforms). In skeletal muscle and Creatine kinase (CK) level: high, in the thousands. peripheral nerve, a-dystroglycan mainly binds to the a₂-chain of laminin-2. Laminins are molecules that link the dystrophin-glycoprotein complex within the extrecellar matrix.

EMG: Myopathic pattern.

Genetics: Autosomal recessive. Mutations in the a₂-chain (LAMA2) gene on chromosome 6q32-33, a large gene of 10 kb of cDNA and 64 exons.

Prenatal diagnosis: Linage analysis or analysis of a₂-laminin of chorionic villus samples.

Clinical:

·        Neonatal onset: Hypotonic at birth, generalized muscle weakness. Some cases have multiple contractures. Many patients never ambulate.

·        Late onset: A small number of patients have later onset in the childhood and has a limb-girdle pattern of dystrophy.

·        Distribution: Muscles of the limbs are very weak. The facial, neck, and chaest musculature is variably involved. The tendon reflexes are decreased or absent.

·        Normal mentation inspite of abnormal MRI findings in white matter. Some patients have seizures.

NEUROIMAGING: Head  

There is characteristic abnormal high T2-weighted intensity in the white matter, presumably a result of increased water content of the white matter.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Myopathic picture: The histologic picture is essentially that of a striking dystrophic process. There are increased variation in fiber diameter, fibrosis, and replacement of muscle by adipose tissue.

Inflammatory cell infiltration: Marked inflammatory cell infiltration is seen in many cases, particularly those in earlier stages of the disease.

Immunostaining: Staining for merosin is completely negative in most cases. In some patients, however, there is only a reduction in staining. 

DIFFERENTIAL DIAGNOSIS: Head

Inflammatory myopathies: History, histology, and immunostaining are helpful. Inflammatory myopathies usually do not demonstrate a striking picture of dystrophic myopathic changes.

Fukuyama congenital dystrophy: Inflammatory cell infiltration may also be seen and there is always anormal brain development. It is rare outside Japan.