Congenital muscular dystrophy: merosin deficient form

Gyula Acsadi MD PhD (Dr. Acsadi, Chief of Pediatric Neurology at the Departments of Pediatrics and Neurology at the University of Connecticut, has no relevant financial relationships to disclose.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released January 17, 2001; last updated September 10, 2014; expires September 10, 2017

This article includes discussion of congenital muscular dystrophy: merosin deficient form and laminin alpha2 deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Congenital muscular dystrophies present with hypotonia and muscle atrophy at birth, but there is a significant clinical and genetic variation. Merosin (laminin alpha-2), a component of the basal lamina in muscle, is tightly bound to the dystrophin-associated membrane complex, and it is responsible for about half of the occidental cases. Brain MRIs of patients show diffuse white matter signal abnormality, but it does not affect the cognition. In this article, the author describes the clinical and molecular aspects of this disease. Implementation of new care standards and genetic-based therapies will likely improve the outcome of this disease.

Key points

 

• Merosin (laminin-alpha 2) is a component of the basal lamina of skeletal muscles, and it is associated with the most frequent form of congenital muscular dystrophy.

 

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

 

• There is no significant progression of the muscle weakness over time, but supportive treatment will provide long-term clinical benefit.

Historical note and terminology

Congenital muscular dystrophy (CMD) was first described in detail by FE Batten in 1903. In the same year, he also reported the juvenile form of neuronal ceroid lipofuscinosis (Tome 1999). His article included 3 cases with clinical features of muscular dystrophy, which he called "infantile myopathy" (Batten 1903). However, congenital muscular dystrophy was referred to as amyotonia congenita to distinguish this group of atrophic muscle diseases from "myotonia congenita" or Thomsen disease. After more detailed histological observations, the name "congenital muscular dystrophy" emerged in the late 1960s. Since then, various forms have been recognized with or without brain involvement, showing the clinical heterogeneity of congenital muscular dystrophy (Banker 1994). Congenital muscular dystrophy was 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 (Muntoni et al 2003). Also, congenital muscular dystrophies with cerebral involvement (Fukuyama disease, Walker-Warburg syndrome, and muscle-eye-brain disease) were separated into distinct categories, and these forms are associated with glycosylation defects (Grewal and Hewitt 2003). The most prevalent type of congenital muscular dystrophy without clinical involvement of the central nervous system was called "classical" or "occidental" congenital muscular dystrophy (Parano et al 1995; Tubridy et al 2001). In the past 10 years, gene discoveries for dystrophin and related membrane or basal lamina proteins revealed the genetic bases of various forms of congenital muscular dystrophies, including the merosin (laminin alpha2; LAMA2)-deficient form (Tome at al 1994). In the light of these genetic findings, muscular dystrophies, including congenital muscular dystrophy, are best classified according to genetic and protein defect (Muntoni and Voit 2004). Close to one half of the cases are related to primary or secondary merosin deficiency (MDC1 A-D) best identified on laminin-alpha 2 staining of muscle biopsies (Jimenez-Mallebrera et al 2005). Primary merosin-deficient muscular dystrophy (MDC1A) is an autosomal recessive form of muscular dystrophy due to mutations in the laminin alpha-2 gene LAMA2) and shows a clinical onset within the first 6 months of life. Congenital inflammatory myopathy described in the old literature has similar clinical presentation and histological features therefore, it is a fair assumption that most cases of “congenital inflammatory myopathy” represented actually cases of MDC1A (Pegoraro et al 1996). Late-onset, limb-girdle type of muscular dystrophy has also been reported in patients with partial merosin deficiency with misense mutations in LAMA2 (Allamand et al 1997; Cohn et al 1998; Tezak et al 2003). Secondary merosin deficient CMD can be associated with glycosylation related gene defects of fukutin (Fukuyama muscular dystrophy), fukutin related protein (FKRP) gene (MDC1C), LARGE gene (MDC1D).

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