Distal Muscular Dystrophies

Abstract

Distal muscular dystrophies are primary hereditary muscle disorders with progressive loss of muscle tissue causing prominent weakness in hands and/or feet at onset. Some may progress to involve proximal muscles, while others remain mainly restricted to distal muscles. The age of onset and the histopathological findings are extremely variable. High throughput sequencing has further expanded the long list of genes associated with a distal muscular dystrophy. Currently, 19 genes (CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KLHL9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPC1, RILPL1) have been associated with an autosomal dominant form and four genes (ADSSL, ANO5, DYSF, GNE) are known causes of autosomal recessive forms. Disease-causing variants in five genes (ACTN2, DES, MYH7, NEB, RYR1 and TTN) result in either dominant or recessive distal muscular dystrophy and we have recently identified the first X-linked form due to SMPX mutations. An even more complex digenic mechanism has also been reported; rare pathogenic mutations in SQSTM1, previously identified with Paget disease of the bone, cause a distal muscular dystrophy when inherited in combination with a common polymorphism in TIA1. This chapter describes the genetic background and the main clinical features of the currently known different forms of distal muscular dystrophy.