Vitturi N; University Hospital of Padova, Padova, Italy.
Gugelmo G; Gasperetti A; Duregon F; Dalmonico A; Lenzini L;
Sponchiado S; Carraro G; Marchi G; Cominacini M; Momente C; Baciga F;
Baschirotto C; Caccia F; Girelli D; Ermolao A; Fadini GP; Battaglia Y

Journal of Cachexia, Sarcopenia and Muscle. 17(1):e70233, 2026 Feb.

BACKGROUND: 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.

METHODS: 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).

RESULTS: 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
(4.8degree +/- 1.0degree vs. 7.6degree +/- 0.9degree; 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).

CONCLUSIONS: 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.