From CureCMD
The congenital muscular dystrophies (CMDs) are a group of rare heterogeneous muscle diseases caused by genetically defined mutations leading to protein deficiencies that result in disturbed interactions between the extracellular matrix (ECM) and muscle cells. In CMD, ECM involvement leads to traditional muscular dystrophy mechanisms of sarcolemmal instability and novel mechanisms driven by primary matrix, intracellular and intranuclear pathology leading to degeneration, fibrosis, apoptosis, failed regeneration and failed muscle differentiation. In the CMDs, common pathology at the level of the muscle basal lamina of defective ECM-muscle interaction creates a shared CMD phenotype, with infant to childhood onset of hypotonia and muscle weakness typically followed by progressive contractures, nutritional deficiencies, scoliosis and respiratory insufficiency. Brain involvement may be present in certain subtypes and may manifest as seizures, mental retardation, learning and speech disability with or without structural brain malformation. Possible additional eye abnormalities include cataracts, myopia and retinal detachment. CMD onset within the first 2 years of life presumes intrauterine muscle disease pathology (developmental hit) compounded by ongoing postnatal stresses and perturbations. CMD subtypes can be subdivided into extracellular and intracellular localization of the affected protein. The three most common forms of CMD affect proteins localized in the extracellular matrix with abnormalities in the three genes coding for collagen 6, laminin a2 (part of laminin 211 heterotrimer) and hypoglycosylation of a-dystroglycan, an important receptor for laminin 211 and other ECM components on the surface of muscle cells and in the brain. Intracellularly localized proteins include RYR1, the calcium release channel of the sarcoplasmic reticulum and selenoprotein 1 (SEPN1), likely involved in the cellular response to oxidative stress. Lamin A/C, an intermediate filament of the inner nuclear envelope protein also may present with a congenital muscular dystrophy phenotype.