Facioscapulohumeral dystrophy (FSHD) originally named as Landouzy-Dejerine is the third common form of muscular dystrophy, characterized by a wide variability of clinical phenotypes.
The diagnosis of FSHD is challenging, especially in the early phase, and the natural course of the disease is largely variable also within the same family, where some members can be wheelchair bound children, while others stay asymptomatic until late adulthood. The disease is inherited as autosomal dominant and is associated with epigenetic depression of the polymorphic D4Z4 repeat on chromosome 4q. In the most common (95%) form of FSHD (type 1), the disease is associated with a reduction of D4Z4 repeat units to a size of 1–10 (normal range from 11-150). In almost 5% of cases, FSHD (type 2) presents with normal size of D4Z4 repeat units but defects in D4Z4 chromatin modifiers. In both FSHD 1 and 2 excessive expression of DUX4, a transcriptional regulator toxic for skeletal muscles.
Recent studies clinical data with detailed genetic analysis, suggesting that FSHD 1 and 2 may represent opposite ends of a disease spectrum. Currently there are no curative treatment for FSHD but, based on recently increased understanding of disease’s pathophysiology, gene therapy has been successfully explored in vitro to reduce pathogenic DUX4 levels. Therapies with antisense oligonucleotides seem the be promising and new therapeutic agents for FSHD are expected in the next few years. However, the clinical and genetic variability can represent an obstacle for the interpretation of genotype-phenotype correlations and for stratification of patients eligible for therapeutic trials. With this purpose, international collaborative networks are currently working on reliable outcome measures for FSHD.
