The Classification, Natural History and Treatment of the Limb Girdle Muscular Dystrophies

Abstract

Over sixty years ago JohnWalton and Frederick Nattrass defined limb girdle muscular dystrophy (LGMD) as a separate entity from the X-linked dystrophinopathies such as Duchenne and Becker muscular dystrophies. LGMD is a highly heterogeneous group of very rare neuromuscular disorders whose common factor is their autosomal inheritance. Sixty years later, with the development of increasingly advanced molecular genetic investigations, a more precise classification and understanding of the pathogenesis is possible. To date, over 30 distinct subtypes of LGMD have been identified, most of them inherited in an autosomal recessive fashion. There are significant differences in the frequency of subtypes of LGMDbetween different ethnic populations, providing evidence of founder mutations. Clinically there is phenotypic heterogeneity between subtypes of LGMD with varying severity and age of onset of symptoms. The first natural history studies into subtypes of LGMD are in process, but large scale longitudinal data have been lacking due to the rare nature of these diseases. Following natural history data collection, the next challenge is to develop more effective, disease specific treatments. Current management is focussed on symptomatic and supportive treatments. Advances in the application of new omics technologies and the generation of large-scale biomedical data will help to better understand disease mechanisms in LGMD and should ultimately help to accelerate the development of novel and more effective therapeutic approaches.