Physical Fitness and Physical Function in Patients With Fabry Disease: A Cross-Sectional Multicentre Study

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting multiple organs, including the musculoskeletal system. The physical status of FD patients remains poorly characterized. This multicentre cross-sectional study aimed to evaluate physical fitness and function in FD patients and investigate associations with sex, FD phenotype and treatment status.

Adults (aged ≥ 18 years) with genetically confirmed FD were recruited. Demographic and laboratory data were collected. Physical fitness was assessed using cardiopulmonary exercise testing (VO₂ peak) and body composition parameters (fat-free mass index [FFMI], fat mass index [FM] and phase angle [PA]) via bioelectrical impedance analysis. Physical function was evaluated with performance tests (6-min walk test, handgrip strength test, 30-s chair-stand test, short physical performance battery), muscle strength tests (isometric and isokinetic knee strength) and self-report fatigue questionnaires. Statistical analyses were stratified by sex, phenotype (classic vs. late-onset/Variants of Uncertain Significance [VUS]) and treatment status (enzyme replacement therapy [ERT]/chaperone-treated versus untreated).

Forty-two FD patients (13 males; mean age 46 ± 13.9 years) were enrolled. VO₂ < 85% of predicted was more frequent in classic phenotype patients (53.8%) than in late-onset/VUS (11.5%; p < 0.01). FFMI was lower in classic than late-onset/VUS (16.8 ± 1.0 vs. 18.6 ± 2.1 kg/m²; p = 0.01). Treated males had lower PA than untreated males (4.8° ± 1.0° vs. 7.6° ± 0.9°; p = 0.04), and PA correlated with VO₂ peak (r = 0.879; p = 0.01). Among classic phenotype males, 74.3% scored below the 50th percentile in handgrip strength (26.1 ± 7.8 kg), and 60.9% performed below predicted values in the 30-s chair-stand test (12.4 ± 4.3 repetitions). Self-reported fatigue scores were higher in classic versus late-onset/VUS patients (p = 0.05) and in treated patients compared to untreated patients (p = 0.02).

Classic FD phenotype, particularly in males, was associated with reduced exercise capacity, muscle mass and physical performance. These findings support the integration of cardiopulmonary exercise testing, physical functional assessments and body composition analysis into the routine evaluation of FD patients.