Fabry disease is characterized by the accumulation of globotriaosylsphingosine (lyso-Gb(3)) and
globotriaosylceramide (Gb(3)) in
biological fluids and tissues. Metabolomic studies recently undertaken by our group, showed the presence of novel plasma and urine lyso-Gb(3)-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 Gb(3). 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 Gb(3). Five different categories of Gb(3)- related
isoforms/analogs were detected: Gb(3)-related
isoforms with
saturated fatty acids, methylated Gb(3)-related
isoforms, Gb(3)-related
isoforms/analogs with one double bond, Gb(3) analogs with hydrated
sphingosine, and Gb(3)-related
isoforms/analogs with two double bonds. A secondary objective was to elucidate the relationship between Gb(3) and lyso-Gb(3). The methylation observed on Gb(3)-related analogs was not detected on lyso-Gb(3). We speculate that the methylated Gb(3) may be an intermediate compound in the deacylation of Gb(3) to generate the lyso-Gb(3) molecule. We are in the process of devising a quantification methodology for these methylated Gb(3)-related analogs in Fabry patients to try to understand the underlying biochemical mechanisms involved in this complex disease.