C. Auray-Blais and M. Boutin Pages 3241 - 3252 ( 12 )
Fabry disease is characterized by the accumulation of globotriaosylsphingosine (lyso-Gb3) and globotriaosylceramide (Gb3) in biological fluids and tissues. Metabolomic studies recently undertaken by our group, showed the presence of novel plasma and urine lyso-Gb3-related analogs in male and female Fabry patients. These analogs are distinguished by differences in structure of the sphingosine moiety. The principal aim of this study was to evaluate the possibility of detecting other Fabry disease biomarkers structurally related to Gb3. A time-of-flight mass spectrometry metabolomic approach, focusing on mass-to-charge (m/z) ratios from 1000 to 1200 Da, was devised. This m/z window corresponds to the isoforms and potential analogs of Gb3. Five different categories of Gb3- related isoforms/analogs were detected: Gb3-related isoforms with saturated fatty acids, methylated Gb3-related isoforms, Gb3-related isoforms/analogs with one double bond, Gb3 analogs with hydrated sphingosine, and Gb3-related isoforms/analogs with two double bonds. A secondary objective was to elucidate the relationship between Gb3 and lyso-Gb3. The methylation observed on Gb3-related analogs was not detected on lyso-Gb3. We speculate that the methylated Gb3 may be an intermediate compound in the deacylation of Gb3 to generate the lyso-Gb3 molecule. We are in the process of devising a quantification methodology for these methylated Gb3-related analogs in Fabry patients to try to understand the underlying biochemical mechanisms involved in this complex disease.
Biomarkers, Fabry disease, globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), lysosomal storage disorders, metabolomics, multivariate data analysis, Qtof mass spectrometry, urine, biological fluids
Service of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, 3001, 12th Avenue North, Sherbrooke (Quebec), J1H 5N4, Canada.