Gait analysis reveals new outcome measures for monitoring disease progression in individuals with late-onset Pompe disease

Background Late-onset Pompe disease (LOPD) presents with progressive muscle weakness, often leading to functional impairment that is challenging to monitor with conventional assessments. This study aims to develop and validate novel gait-based outcome measures for monitoring disease progression in individuals with LOPD. Methods Longitudinal study with genetically confirmed LOPD patients and age-and gait velocity-matched healthy controls that were assessed over a two-year period using the Ephion Mobility system, which integrates inertial sensors, plantar pressure insoles, and surface electromyography. All participants completed a free walking test (10–15 m at self-selected pace) and the 6-minute walk test (6MWT). Differences in gait features were identified using a three-stage feature selection framework that includes linear mixed-effects model, ElasticNet-regularized and bootstrap analysis. To explore intra-group variability within the LOPD cohort, we performed a clustering analysis. Based on the selected features and their weighted temporal changes, we developed a Pompe Mobility-Derived Progression Index (Pompe-MDPI) by training a Linear Discriminant Analysis (LDA) to discriminate between control and LOPD data. We calculated the Minimum Clinically Important Difference and compared its performance against the 6MWT distance. Results 24 LOPD and 39 healthy controls were included in the study. 46 gait features were found to significantly differentiate individuals with LOPD from controls (Holm-corrected p < 0.05), comprising 16 from trunk and pelvis joints, 18 from lower limb joints, 4 from force profiles, and 8 from EMG.Hierarchical clustering analysis revealed two distinct subgroups within the LOPD cohort, based on nine gait features. The computed Pompe-MDPI successfully discriminated between LOPD and healthy controls (AUC = 0.95), outperforming the 6MWT distance (AUC = 0.84). The Pompe-MDPI was also strongly associated with the 6MWT (p < 0.0001) and demonstrated significant change over time in the LOPD group (p = 0.02). Conclusions The Pompe Mobility-Derived Progression Index (Pompe-MDPI) was developed and validated as a sensitive biomarker of disease progression. Longitudinal analysis demonstrated that Pompe-MDPI captured gait deterioration over one year, outperforming traditional measures like the six-minute walk test in sensitivity. These findings support the use of wearable gait analysis as a clinically meaningful, scalable tool for monitoring motor function in LOPD, with implications for both patient care and therapeutic trials.