Biomarkers in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy is one of the most frequent myopathies. Its clinical presentation and genetic background are unique. FSHD needs reliable and measurable biomarkers to monitor the disease and assess the efficacy of therapeutic approaches. The purpose of this review is to summarize and focus on the most recent evidence regarding the different available biomarkers at the level of muscle imaging, circulating molecules and muscle-based markers that currently are the main potential candidates in FSHD.

A large phase III trial testing losmapimod (a small molecule inhibitor of p38α MAPK, which regulates DUX4 expression) in FSHD patients failed to demonstrate clear clinical benefits, highlighting concerns about trial readiness. KHDC1L, a recently identified direct transcriptional target of DUX4, is a candidate circulating protein biomarker directly associated with DUX4 activity, although independent replication and analytical validation are still awaited. Quantitative muscle MRI and, increasingly, quantitative muscle ultrasound provide complementary imaging biomarkers that are now being compared head-to-head. Artificial intelligence-based tools are increasingly being used to capture disease heterogeneity and support patient stratification.

Facing the genetic and phenotypic complexity of FSHD, robust biomarkers must be used to assess the efficacy of the experimental treatments, and individuals must be selected and stratified to minimize variability, in order to prepare for future clinical trials.