CONGENITAL MUSCULAR DYSTROPHIES: AN OVERVIEW

Abstract

The congenital muscular dystrophies (CMD) have long been known as a heterogeneous group of disorders. The extent of this clinical and genetic heterogeneity is becoming increasingly apparent as novel genes are identified. Currently, fourteen genes are known to cause CMD, and the resulting disorders can be broadly divided into three groups. The largest group results from mutations in genes encoding structural proteins. The commonest form, merosin deficient CMD (MDC1A), results from mutations in LAMA2, encoding the laminin-? 2 chain of laminin-2 (merosin), a key component of the muscle cell basement membrane. Another common condition, Ullrich syndrome, results from mutations in the collagen VI chain genes, COL6A1, COL6A2 or COL6A3, which comprise the extracellular matrix protein, collagen VI. CMD due to mutations in the integrin A7 (ITGA) gene is extremely rare and is confined to only a few patients in Japan. The second group, collectively termed the dystroglycanopathies, result from mutations in genes encoding known or putative glycosyltransferase enzymes involved in glycosylation of the sarcolemmal protein?-dystroglycan. Muscle biopsy clearly shows reduction or absence of this protein. These include Fukuyama CMD, Walker Warburg syndrome, Muscle Eye Brain disease, MDC1C and MDC1D, due to mutations in FCMD, POMT1, POMGnT1, FKRP and LARGE, respectively. Affected children have severe features with have mental retardation and a neuronal migration defect on brain magnetic resonance imaging. The FKRP mutations are exceptional, because the CNS involvement do not constitute the majority of cases. The POMT2 gene has been identified as a second gene for the Walker-Warburg syndrome, Another dystroglycanopathy locus (MDC1B) maps to chromosome 1q42, but the gene responsible has not yet been identified. As the third group, mutations in SEPN1, encoding an endoplasmic reticulum resident selenoprotein of unknown function, result in CMD with spinal rigidity (RSMD1). There are several other clinically recognizable CMD phenotypes in which the molecular defect is unknown. Recently, a milder from of merosin positive CMD has been mapped to chromosome 4p16.3. It has been estimated that at least seven or eight new genes should be in the pipeline for the CMD saga.