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  • Updated 08.03.2020
  • Released 01.17.2001
  • Expires For CME 08.03.2023

Congenital muscular dystrophy: merosin deficient form

Introduction

Overview

Congenital muscular dystrophies occur with a frequency of 1 in 20,000 births, with a prevalence of 1 in 100,000. They manifest as hypotonia and muscle atrophy at birth, but there is significant clinical and genetic variation. Merosin (laminin alpha-2, also known as LAMA2), is a component of the basal lamina in muscle that is tightly bound to the dystrophin-associated membrane complex, and is responsible for about half of the “classical” cases of congenital muscular dystrophy. Brain MRIs of these patients show diffuse white matter signal abnormality, but it does not affect cognition. In this article, the authors describe the clinical and molecular aspects of this disease. Implementation of new care standards, aids in diagnosis, and gene-based therapies that could likely improve the outcome of this disease will also be discussed. Hereafter, the merosin deficient form of congenital muscular dystrophy will be referred to as LAMA2-related congenital muscular dystrophy (LAMA2-CMD) for the rest of the article.

Key points

• LAMA2 (merosin) is a component of the basal lamina of skeletal muscles, and is associated with the most frequent form of congenital muscular dystrophy.

• Elevated creatine kinase level and white matter signal abnormality on brain MRI are the hallmarks of this disorder.

• The availability of genetic testing has simplified and expedited the diagnosis of this disorder.

• Supportive treatment provides long-term clinical benefit.

• Gene-based research into putative treatments is ongoing.

Historical note and terminology

Congenital muscular dystrophy was first described in detail by FE Batten in 1903. The article included 3 cases with clinical features of muscular dystrophy, which was termed "infantile myopathy" (08). Congenital muscular dystrophy was then referred to as amyotonia congenita to distinguish this group of atrophic muscle diseases from "myotonia congenita" or Thomsen disease. Further histological observations led to the current term of "congenital muscular dystrophy" in the late 1960s. Since then, various forms have been recognized with or without brain involvement, demonstrating the clinical heterogeneity of congenital muscular dystrophy (06). Congenital muscular dystrophy was traditionally classified as a subgroup of congenital myopathies with an onset in the first 6 months of life by the Research Group on Neuromuscular Diseases of the World Federation of Neurology (59) but with continued advances in our knowledge of the disease, it was found to present within the first 2 years of life (41). Additionally, congenital muscular dystrophies with cerebral involvement (Fukuyama disease, Walker-Warburg syndrome, and muscle-eye-brain disease) were separated into a distinct category of congenital muscular dystrophy associated with glycosylation defects (31). The most prevalent type of congenital muscular dystrophy without clinical involvement of the central nervous system was called "classical" or "occidental" congenital muscular dystrophy (88). Gene discoveries for dystrophin and related membrane or basal lamina proteins revealed the genetic basis of the various forms of congenital muscular dystrophies, including merosin (LAMA2)-deficient form (Tome at al 1994). In light of these genetic findings, muscular dystrophies, including congenital muscular dystrophies, are now best classified according to the genetic and protein defects they harbor (60). Close to half of these cases are related to primary or secondary LAMA2 deficiency (MDC1 A-D) best identified by laminin-alpha 2 staining of muscle biopsies (39). Primary LAMA2-CMD (MDC1A) is an autosomal recessive form of muscular dystrophy due to mutations in the laminin alpha-2 (LAMA2) gene and shows a clinical onset within the first 6 months of life. Congenital inflammatory myopathy, described in the past, has similar clinical presentation and histological features; therefore, it is a fair assumption that most cases of “congenital inflammatory myopathy” actually represented cases of LAMA2-CMD (71). Late-onset, limb-girdle type of muscular dystrophy has also been reported in patients with partial LAMA2 deficiency with missense mutations in the LAMA2 gene (03; 85). Secondary LAMA2 deficient congenital muscular dystrophy can be associated with glycosylation related gene defects of fukutin (Fukuyama muscular dystrophy), fukutin related protein (FKRP) gene (MDC1C), and LARGE gene (MDC1D).

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