Assessment of the Muscle Excitability Properties in Facioscapulohumeral Dystrophy and Their Use as a Novel Disease Biomarker

Abstract

Facioscapulohumeral dystrophy (FSHD) is a common genetic dystrophic condition. Despite the high prevalence of disease there are no disease modifying therapies available. One of the major limitations in the development of effective therapies is the natural history of the disease itself. Functional impairment is acquired over decades. The slow clinical progression makes it challenging to measure improvements over the timeframe that therapeutic clinical trials are typically performed. As a result, there is significant interest in developing biomarkers that more sensitively measure treatment response.

The aim of this thesis was to define the muscle excitability profile of FSHD and provide a preliminary assessment of muscle excitability techniques as a novel biomarker of disease severity. The more commonly studied tibialis anterior (TA) is spared in early FSHD. We first studied the trapezius in normal subjects, as a more targeted muscle for study in FSHD. The muscle excitability profiles of the trapezius and TA were similar, suggesting comparable sarcolemmal function.

Muscle excitability techniques were then applied to the trapezius and TA in FSHD. This unveiled a pattern consistent with relative depolarisation of the muscle fibre membrane, a finding seen in a range of previously studied primary and secondary muscle diseases. These changes were more marked in the trapezius than the TA, suggesting that the trapezius may be a more sensitive target in conditions affecting the proximal musculature.

The excitability changes in FSHD were then correlated with validated clinical trial endpoints. Several correlations were identified, with the strongest and most reproducible seen for measures of lower limb function and balance. This suggests that muscle excitability parameters do provide a measure of disease severity in FSHD, but further research is required, with repeated longitudinal assessments, to determine their utility as a novel clinical trial biomarker.