Mitochondrial stress markers associate with phenotypic variability in Fabry disease
Lucia Lavalle1,2, Hibba Kurdi2,3, David Moreno Martinez1,2
1Cancer Institute, University College London, London, UK.
Orphanet Journal of Rare Diseases
|July 1, 2026
Summary
Mitochondrial stress markers like Hsp60 are linked to Fabry disease (FD) severity, showing sex-specific patterns. These findings suggest mitochondrial stress contributes to FD
Area of Science:
- Biochemistry
- Genetics
- Medical Research
Background:
- Fabry disease (FD) presents significant clinical variability not fully explained by residual alpha-galactosidase A activity.
- Mitochondrial dysfunction is implicated in FD, but the role of mitochondrial stress remains unclear.
Purpose of the Study:
- To investigate associations between mitochondrial unfolded protein response (mtUPR) markers and FD phenotypic variability.
- To determine if mtUPR markers correlate with Fabry disease severity.
Main Methods:
- Intracellular heat-shock protein 60 (Hsp60) was measured using western blotting in fibroblasts and PBMCs.
- Serum levels of fibroblast growth-factor-21 (FGF-21) and growth differentiation-factor-15 (GDF-15) were analyzed in FD patients.
- Clinical outcomes, including severity scores, renal function (eGFR), and left-ventricular mass index (LVMI), were assessed.
Main Results:
- Hsp60 expression showed sex-specific correlations with clinical outcomes.
- In males, higher Hsp60 associated with lower LVMI and better renal function.
- In females, higher Hsp60 correlated with higher LVMI and increased disease severity. Elevated GDF-15 was observed in male patients compared to controls.
Conclusions:
- mtUPR markers display sex- and genotype-specific patterns related to FD disease severity.
- Mitochondrial stress appears to contribute to the phenotypic heterogeneity observed in Fabry disease.
- Hsp60, FGF-21, and GDF-15 warrant further evaluation as potential biomarkers for disease burden and treatment response in FD.
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