Fabry disease is an X-linked, multisystemic lysosomal storage disorder due to alpha-galactosidase A deficiency. It is characterized by the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in biological fluids, vascular endothelium, heart, and kidneys. Treatment
by enzyme replacement therapy has been shown to be beneficial in both males and females affected with the disease. In addition to Gb3, increased concentrations of globotriaosylsphingosine (lyso-Gb3) have recently been reported in urine and plasma of Fabry patients. The overall objective of
this metabolomic study was to identify and characterize new potential plasma biomarkers in treated and untreated males and females affected with Fabry disease which might better reflect disease severity and progression. We employed a time-of-flight mass spectrometry metabolomic approach using
plasma samples of Fabry patients compared to age-matched controls. We found three new lyso-Gb3 analogs in Fabry patients presenting m/z ratios at 802, 804, and 820. As previously detected by our group, we also found a m/z ratio of 784 corresponding to the lyso-Gb3 molecule minus two hydrogen
atoms. Using exact mass measurements and tandem mass spectrometry, we confirmed that these analogs result from modifications of the lyso-Gb3 sphingosine moiety. We evaluated the relative plasma concentration by measuring area counts for each lyso-Gb3 analog. None of these analogs was detected
in the majority of healthy controls. The relative concentration of each analog was higher in males compared to female Fabry patients. We demonstrated that mass spectrometry combined to a metabolomic approach is a powerful tool to detect and identify new potential biomarkers.
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