Methylation Percentage Among FSHD Type 1 Relates To Gait Impairment Analyzed Using Custom Gait Application

FacioScapuloHumeral Dystrophy (FSHD) effects around 1:15,000 people; making it the third most common type of muscular dystrophy worldwide. Gait is becoming a possible marker of disease progression however this may vary by the type of FSHD. It is important to understand if a relationship exists between the epigenetics status at the FSHD pathogenic locus and gait. PURPOSE: The purpose of this study is to measure the relationship between gait and DNA methylation percentage in 4A allele FSDH type 1 patients. METHODS: 5 participants (2 males; 3 females; 58 ± 15 years) who were diagnosed clinically and genetically with 4A allele (FSHD 1) were recruited for the study. All participants were mailed a smart-phone (LG KG40) loaded with our custom Gait Analyzer application, a belt for holding the phone, instructions, and a saliva testing kit. All participants completed 12 consecutive ten-meter walking trials with a 3-second pause over a flat level surface between trials for 5 days straight. Participants used the custom application to rate fatigue pre- and post-gait trials and take pictures of their shoes and walking surface. Upon return, gait data were further analyzed controlling for shoe type and walking surface. In addition, saliva samples were bisulfite converted, and assayed using our FSHD epigenetic analysis to determine the DNA methylation of the shortest 4q35 D4Z4 array (DRA: D4Z4 reduced allele). Spearman rho correlation coefficients determined the relationship between methylation percentage, gait velocity, and cadence after controlling for walking surface and shoe type. RESULTS: A strong positive relationship between methylation percentage and gait velocity (average = 0.92 ± 0.19 m/s; r = 0.74, p < 0.05) with a moderate negative relationship to cadence (average = 88.78 ± 8.8 steps/min; r = -0.42, p < 0.5) was observed. CONCLUSIONS: These results suggest that methylation percentage of the 4q35 D4Z4 distal repeat region in FSHD type 1 patients is related to gait impairments. Low methylation status in FSHD type 1 patients is associated with greater gait impairments. The findings of this study should be expanded to other forms of FSHD and muscular dystrophy but may serve as a candidate clinical outcome measure for future clinical trials.