Mitochondrial stress markers associate with phenotypic variability in Fabry disease

BACKGROUND: Fabry disease (FD) exhibits marked clinical heterogeneity that cannot be fully explained by residual α-galactosidase A activity. Mitochondrial dysfunction has been reported in FD, but the role of mitochondrial stress remains unexplored. OBJECTIVE: To investigate whether mitochondrial unfolded protein response (mtUPR) related markers associate with phenotypic variability and correlates with disease severity. METHODS: We measured intracellular heat-shock protein 60 (Hsp60) expression by western blotting in fibroblasts and peripheral blood mononuclear cells (PBMCs). In the clinical cohort, intracellular Hsp60 was measured in PBMC whole-cell lysates from 27 FD patients (14 males, 13 females). Serum fibroblast growth-factor-21 and growth differentiation-factor-15 were measured in 35 patients. Clinical outcomes included Mainz Severity Score Index, Age-Adjusting Severity Score, estimated glomerular filtration rate, and left-ventricular mass index (LVMI). RESULTS: = 0.66, p = 0.045) and greater clinical severity. Male patients had elevated growth differentiation-factor-15 vs controls (935 vs 559 pg/ml, p = 0.002). Both mitokines correlated with age and disease severity. CONCLUSIONS: mtUPR related markers exhibit sex- and genotype-specific patterns associated with disease severity, suggesting that mitochondrial stress contributes to phenotypic heterogeneity and support further longitudinal evaluation of Hsp60, FGF-21 and GDF-15 as candidate biomarkers of disease burden and treatment response.