Parsing Fabry Disease Metabolic Plasticity Using Metabolomics

Abstract

Background: Fabry disease (FD) is an X-linked lysosomal disease due to a deficiency in the activity of the lysosomal α-galactosidase A (GalA), a key enzyme in the glycosphingolipid degradation pathway. FD is a complex disease with a poor genotype–phenotype correlation. FD could involve kidney, heart or central nervous system impairment that significantly decreases life expectancy. The advent of omics technologies offers the possibility of a global, integrated and systemic approach well-suited for the exploration of this complex disease. Materials and Methods: Sixty-six plasmas of FD patients from the French Fabry cohort (FFABRY) and 60 control plasmas were analyzed using liquid chromatography and mass spectrometry-based targeted metabolomics (188 metabolites) along with the determination of LysoGb3 concentration and GalA enzymatic activity. Conventional univariate analyses as well as systems biology and machine learning methods were used. Results: The analysis allowed for the identification of discriminating metabolic profiles that unambiguously separate FD patients from control subjects. The analysis identified 86 metabolites that are differentially expressed, including 62 Glycerophospholipids, 8 Acylcarnitines, 6 Sphingomyelins, 5 Aminoacids and 5 Biogenic Amines. Thirteen consensus metabolites were identified through network-based analysis, including 1 biogenic amine, 2 lysophosphatidylcholines and 10 glycerophospholipids. A predictive model using these metabolites showed an AUC-ROC of 0.992 (CI: 0.965–1.000). Conclusion: These results highlight deep metabolic remodeling in FD and confirm the potential of omics-based approaches in lysosomal diseases to reveal clinical and biological associations to generate pathophysiological hypotheses.

Genome-wide expression analysis in a Fabry disease human podocyte cell line

“…In accordance to our previous work investigating proteome profiles of Fabry patients and healthy controls [ 93 ], SMAD5 and KITLG were found to be down-regulated while MAGED1, FXYD5, SERPINB6, MVK, UBAC1, GPKOW, PPIB, MESD, TACC3 were up-regulated in plasma Fabry samples compared to controls. Furthermore, our metabolomics investigation on plasma Fabry patients and controls also exhibited the augmentation of oxidative stress as a consequence of Gb3 accumulation [ 94 ]. Particularly, methionine level was decreased while its oxidized form, methionine sulfoxide level increased in Fabry individuals compared to control.…”

Fatigue as hallmark of Fabry disease: role of bioenergetic alterations

“…The partial or total inactivity of this enzyme, essential to metabolize glycosphingolipids (GB3), induces the deposition of GB3 in lysosomes of cells in several organs and tissues evolving progressively toward multiorgan dysfunction ( 1 , 2 ). The molecular pathogenesis of FD encompasses several pathologic mechanisms involving mitochondrial dysfunction, lysosomal dysfunction, GB3 accumulation, endothelial dysfunction, and autophagy abnormalities ( 3 , 4 ). Today, more than 1,000 GLA gene variants have been identified in the chromosomal region Xq22.1, including splicing alterations, deletions, translocations, complex gene rearrangement, and point missense variants ( 5 , 6 ), but an exact genotype-phenotype correlation in FD cannot be established.…”