ABSTRACT: Purpose of Review: This article describes the clinical characteristics, diagnosis, molecular pathogenesis, and treatment of facioscapulohumeral muscular dystrophy (FSHD).
Recent Findings: FSHD comprises two genetically distinct types that converge on a common downstream pathway of the expression of the toxic protein DUX4. Approximately 95% of patients have FSHD type 1 (FSHD1), in which loss of DNA repetitive elements (D4Z4 repeats) in the subtelomeric region of chromosome 4q causes decreased methylation and epigenetic derepression of DUX4, a gene contained within each D4Z4 repeat. FSHD type 2 (FSHD2) occurs through a deletion-independent mechanism but, similar to FSHD1, leads to decreased methylation and epigenetic derepression in the same region of chromosome 4q. Whereas FSHD1 is dominantly inherited, FSHD2 shows digenic inheritance, and about 80% of patients will have a mutation in the SMCHD1 gene. DUX4 lacks a polyadenylation signal, so both FSHD1 and FSHD2 only occur in the presence of permissive 4q polymorphisms, which provide a stabilizing polyadenylation sequence. FSHD is an epigenetic disease, and penetrance and severity are related to both the number of residual D4Z4 units and D4Z4 methylation.
Summary: Recent consensus guidelines outline standards for care for FSHD, and identification of potential therapeutic targets have shifted emphasis in the research community toward drug development and clinical trial planning.