Facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline. In about 5% of individuals with phenotypic FSHD, there is no contraction in the D4Z4 repeats and yet similar chromatin changes are present, resulting in the inappropriate expression of the DUX4 gene. The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation. The recent identification of aberrant activation of DUX4 transcription in FSHD as the root cause of FSHD now allows for a targeted approach to therapeutic development.