Abstract
Background: Fabry disease (FD) is an X-linked progressive lysosomal disease (LD) due to glycosphingolipid metabolism impairment. Currently, plasmatic globotriaosylsphingosine (LysoGb3) is used for disease diagnosis and monitoring. However, this biomarker is inconstantly increased in mild forms and in some female patients. Materials and Methods: We applied a targeted proteomic approach to explore disease-related biological patterns that might explain the disease pathophysiology. Forty proteins, involved mainly in inflammatory and angiogenesis processes, were assessed in 69 plasma samples retrieved from the French Fabry cohort (FFABRY) and from 83 healthy subjects. For predictive performance assessment, we also included other LD samples (Gaucher, Pompe and Niemann Pick C). Results: The study yielded four discriminant proteins that include three angiogenesis proteins (fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor C (VEGFC)) and one cytokine interleukin 7 (IL-7). A clear elevation of FGF2 and IL-7 concentrations was observed in FD compared to other LD samples. No correlation was observed between these proteins and globotriaosylsphingosine (LysoGb3). A significant correlation exists between IL-7 and residual enzyme activity in a non-classical phenotype. This highlights the orthogonal biological information yielded by these proteins that might help in stratifying Fabry patients. Conclusion: This work highlights the potential of using proteomics approaches in exploring FD and enhancing FD diagnosis and therapeutic monitoring performances.
Highlights
Fabry disease (FD, OMIM #301500) is an X-linked and progressive inherited metabolic disease characterized by cellular dysfunction and microvascular pathology related to lysosomal glycosphingolipid metabolism impairment [1]
This confirms the proteins yielded by the differential analysis that showed fibroblast growth factor 2 (FGF2) as the main driver of this separation among the other cytokines and angiogenesis factors (IL-7 and VEGF family)
We observed a clear elevation of FGF2 and interleukin 7 (IL-7) in Fabry samples compared to all other lysosomal disease (LD) samples
Summary
Fabry disease (FD, OMIM #301500) is an X-linked and progressive inherited metabolic disease characterized by cellular dysfunction and microvascular pathology related to lysosomal glycosphingolipid metabolism impairment [1]. FD is due to an absence or a decrease of the lysosomal α-galactosidase A activity (GalA; EC 3.2.1.22) This leads to a progressive lysosomal accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids such as galabiosylceramide in different cell types, including endothelial and vascular cells, renal cells (podocytes, tubular cells, glomerular endothelial, mesangial, and interstitial cells), cardiac cells, and nerve cells (neurons, Schwann cells). Monitoring the effects of specific treatments in a clinical setting is still challenging due the lack of robust surrogate markers of treatment response and the large phenotype and genotype variability in FD [27,28] All these therapeutic strategies significantly improved the course of the disease and the quality of life of the patients, but they do not completely stop the course of the disease. Conclusion: This work highlights the potential of using proteomics approaches in exploring FD and enhancing FD diagnosis and therapeutic monitoring performances
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