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.
Highlights
The principal component analysis score plot revealed a clear separation between Fabry and control samples (Figure 2A)
Treatment or disease phenotype separation were observed on the PCA
We performed a differential analysis between the two groups Fabry versus control samples
Summary
The incidence ranges from 1 in 40,000 to 1 in 117,000 births in the general population [2]. This might be underestimated as some screening studies (Japan [3], Austria [4], northwestern Italy [5], United States (Missouri) [6] and Taiwan [7]). The impairment of GalA generates a progressive accumulation of glycosphingolipid derivatives such as globotriaosylceramide (Gb3) and galabiosylceramide in the lysosome. This may occur in various cell types such as vascular, endothelial, renal, cardiac and nerve cells (neurons, Schwann cells) where the continuous deposition leads to serious cellular damage and organ failure [8]. Damage to the kidney, heart and central nervous system will significantly decrease life expectancy [9]
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