This article reviews the current knowledge on the clinical characteristics and disease mechanism of facioscapulohumeral muscular dystrophy (FSHD), as well as advances in targeted therapy development.
FSHD has a wide range of severity, yet a distinct phenotype characterized by weakness of the facial, shoulder, and upper arm muscles, followed by weakness of the trunk and leg muscles. It can be caused by two genetic mechanisms that share a common downstream pathway, namely, the epigenetic derepression and subsequent misexpression of the myotoxic DUX4 transcription factor. Treatment is currently supportive and outlined in evidence-based guidelines. Advances in the understanding of the pathogenic mechanism of FSHD are paving the way for targeted therapy development. Approaches for targeted therapies to reduce DUX4 expression that are currently being explored include small molecules, antisense oligonucleotides, vector-based RNA interference, and gene therapy. In anticipation of more clinical trials, “clinical trial preparedness,” including the development of sensitive biomarkers and clinical outcome measures, are needed.
The cornerstones of the diagnosis of FSHD are clinical observation and genetic testing. Management is currently supportive, but progress in the understanding of the disease mechanism has shifted the field of FSHD toward targeted therapy development.