Limb girdle muscular dystrophies (LGMD) are a group of inherited muscular disorders mainly affecting proximal muscles of the limbs. They are inherited according autosomal dominant or recessive pattern.
Clinical presentations show great heterogeneity ranging from severe infantile-onset forms to milder presentations in adult life. Some of these defects may also strike cardiopulmonary system. The loss of deambulation is consistent but variable. Phenotypic variability reflects the complex scenario of the underlining genetic defects.
Autosomal dominant forms (LGMD1 forms) are rare representing 10% of the affected patients. They are generally characterized by adult-onset and delayed loss of deambulation. The remaining 90% of patients harbor recessive mutations (LGMD2 forms). Until now, researchers have identified 24 genetic defects underlining LGMD but molecular diagnosis is not achieved in a relevant (30%) proportion of patients.
Most of the mutations fall within genes encoding for proteins, which are present in the sarcolemma, the cell membrane of skeletal muscle cells. They are structural proteins (alpha, beta, gamma and delta sarcoglycans, caveolin 3 and titin), proteins of alpha dystroglycan glycosilation complex (FKRP, POMT1, Fukutin, POMT2, POMGnT1, DAG1 and ISPD), constituent of the sarcomeres (telethonin, plectin, merosin, myotilin) and of the nuclear inner envelope (lamin A/C). Other proteins feature muscle enzymatic activity (calpain 3, dysferlin, anoctamin, DNAJB6 and Trim 32).