Limb-Girdle Muscular Dystrophies

This article reviews the current classification system, common subtypes, differential diagnosis, diagnostic algorithms, current management strategies, and evolving therapeutic areas for limb-girdle muscular dystrophies (LGMDs).

There are currently five dominantly inherited LGMDs (LGMD-D1 to D5) and 29 recessively inherited LGMDs (LGMD-R1 to R29). Progress in molecular genetics makes next-generation sequencing gene panels the initial step in diagnosing LGMD and, in some cases, obviates the need for muscle biopsy. The panel should include LGMD genes and genes responsible for other hereditary myopathies and congenital myasthenic syndromes. Whole-exome sequencing or whole-genome sequencing can be performed before or after a muscle biopsy, depending on the specifics of each case. Once a diagnosis of LGMD is established, genetic counseling, symptomatic and supportive care, and cardiopulmonary surveillance remain the cornerstones of management. However, results from preclinical studies and early-stage clinical trials of genetic therapies for common LGMD-R subtypes are promising.

Progressive proximal weakness and hyperCKemia are hallmark features of LGMDs; however, they are not specific and can also be observed in many acquired and hereditary myopathies. Muscle biopsy is typically reserved for patients with negative or inconclusive genetic testing and can be particularly useful for verifying the pathogenicity of variants of uncertain significance. Advances in molecular genetics and genetic therapies have revolutionized the diagnostic landscape of LGMDs and paved the way for future disease-specific treatments.