Molecular Genetics of Limb‐Girdle Muscular Dystrophies

Abstract

Abstract The limb‐girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous neuromuscular disorders caused by specific protein defects in muscle fibres and characterised by predominant weakness and wasting in proximal limb and axial muscles. Most of these diseases present with wide clinical heterogeneity and the limb‐girdle phenotype should be regarded as one of the possible phenotypic expressions of a specific protein defect. Therefore, a precise clinical evaluation is often difficult, and an appropriate diagnostic approach using clinical, pathological, biochemical and genetic resources is essential to achieve the correct diagnosis. The current classification of LGMDs is based on inheritance pattern. Dominant forms are classified as type 1 (LGMD1), whereas the recessive forms are classified as type 2 (LGMD2). A progressive alphabetical letter identifies the different involved genes and indicates the order of identification. This review reports a comprehensive update on the genetic bases and the main clinical aspects of these groups of diseases according to protein defect and transmission modality. Key Concepts The limb‐girdle muscular dystrophies (LGMDs) are a heterogeneous group of hereditary neuromuscular disorders caused by specific protein defects in muscle fibres and characterised by predominant weakness and wasting in proximal limb and axial muscles. The current classification of LGMDs is based on inheritance pattern. Dominant forms are classified as type 1 (LGMD1), whereas the recessive forms are classified as type 2 (LGMD2). A progressive alphabetical letter identifies the different involved genes and indicates the order of identification. LGMDs are diseases having wide inter‐ and intra‐familial phenotypic heterogeneity and therefore the limb‐girdle phenotype is often the only one of the possible phenotypic expressions of a specific protein defect. Four recessive LGMDs are caused by mutations in the genes encoding the four members of the skeletal muscle sarcoglycan complex which is a part of the large macromolecular complex of proteins named the dystrophin‐associated protein complex (DAPC) which is thought to have structural functions in providing membrane stability, maintaining the integrity of sarcolemma and in ensuring transduction during muscle contraction. Eight genes have been found to be responsible for an LGMD‐dystroglycanopathy until now. Mutations in these genes reduce dystroglycan glycosylation and cause different phenotypes ranging from mild to dramatic conditions. Limb‐girdle muscular dystrophies should to be considered the mildest expression of the phenotypic spectrum of dystroglycanopathies.