Lavalle, Lucia; (2024) Heterogeneity in Fabry disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Fabry disease (FD) is clinically heterogeneous, with different variants of the α-galactosidase A (GLA) gene leading to distinct phenotypes. To understand factors impacting on this phenotypic diversity, medical histories of 25 individuals with GLA variants of unknown significance (GVUS: A143T, R118C, and D313Y) were compared to those with known pathogenic mutations defined as either classical or late onset in phenotype, R227X and N215S. Clinical outcomes explored included the Mainz Severity Score Index (MSSI), the Age-Adjusting Severity Scores (AASS), glomerular filtration rate (GFR), and left ventricular mass index (LVMI). Despite similar GLA activity levels, GVUS carriers had less clinical severity. Substrate accumulation was higher only in the group with nonsense mutations, suggesting additional factors influencing disease expression. To study the impact of GLA mutant protein processing on clinical manifestations, 26 individuals with FD (14 males) were assessed for GLA activity and GLA protein. Endoplasmic reticulum (ER) stress marker calnexin was measured in a subset of patients. As mitochondrial dysfunction has been reported in FD, the induction of the mitochondrial unfolded protein response was investigated by measuring intracellular heat-shock protein 60 (Hsp60) and serum mitokines Fibroblast Growth Factor-21 (FGF-21) and Growth Differentiation Factor-15 (GDF-15). Fabry participants exhibited more of the immature form of GLA protein, which was significantly associated with LVMI in females. Calnexin levels weakly associated with Hsp60 and clinical outcomes in males. Hsp60 levels correlated significantly with GDF-15 in females and with FGF-21 in males. Age was the only significant predictor for GDF-15 levels in both groups. In males, both mitokines correlated with clinical severity and GFR, but only FGF-21 correlated with LVMI. Age at therapy initiation showed some correlation with mitokine levels. These results suggest that mutant GLA protein may have an impact on ER and mitochondrial stress, and these might be possible therapeutic targets in subjects with FD.

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