Orphanet journal of rare diseases · 2026
Mitochondrial stress markers associate with phenotypic variability in Fabry disease.
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Lavalle Lucia, Kurdi Hibba, Martinez David Moreno, Muczynski Vincent, Heales Simon, Hughes Derralynn
Аннотация
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: Hsp60 showed variability, with sex-specific associations. In males, higher Hsp60 correlated with lower LVMI (r2 = -0.82, p = 0.01) and preserved renal function in late-onset patients (r2 = 0.89, p = 0.006). In females, higher Hsp60 associated with higher LVMI (r2 = 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.
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: Hsp60 showed variability, with sex-specific associations. In males, higher Hsp60 correlated with lower LVMI (r2 = -0.82, p = 0.01) and preserved renal function in late-onset patients (r2 = 0.89, p = 0.006). In females, higher Hsp60 associated with higher LVMI (r2 = 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.