Metabolomic discovery of novel urinary galabiosylceramide analogs as Fabry disease biomarkers

J Am Soc Mass Spectrom. 2015 Mar;26(3):499-510. doi: 10.1007/s13361-014-1060-3. Epub 2015 Jan 13.


Fabry disease is an X-linked, complex, multisystemic lysosomal storage disorder presenting marked phenotypic and genotypic variability among affected male and female patients. Glycosphingolipids, mainly globotriaosylceramide (Gb(3)) isoforms/analogs, globotriaosylsphingosine (lyso-Gb(3)) and analogs, as well as galabiosylceramide (Ga(2)) isoforms/analogs accumulate in the vascular endothelium, nerves, cardiomyocytes, renal glomerular and tubular epithelial cells, and biological fluids. The search for biomarkers reflecting disease severity and progression is still on-going. A metabolomic study using quadrupole time-of-flight mass spectrometry has revealed 22 galabiosylceramide isoforms/analogs in urine of untreated Fabry patients classified in seven groups according to their chemical structure: (1) Saturated fatty acid; (2) one extra double bond; (3) two extra double bonds; (4) hydroxylated saturated fatty acid; (5) hydroxylated fatty acid and one extra double bond; (6) hydrated sphingosine and hydroxylated fatty acid; (7) methylated amide linkage. Relative quantification of both Ga(2) and Gb(3) isoforms/analogs was performed. All these biomarkers are significantly more abundant in urine samples from untreated Fabry males compared with healthy male controls. A significant amount of Ga(2) isoforms/analogs, accounting for 18% of all glycosphingolipids analyzed (Ga(2) + Gb(3) and respective isoforms/analogs), were present in urine of Fabry patients. Gb(3) isoforms containing saturated fatty acids are the most abundant (60.9%) compared with 26.3% for Ga(2). A comparison between Ga(2) isoforms/analogs and their Gb(3) counterparts also showed that the proportion of analogs with hydroxylated fatty acids is significantly greater for Ga(2) (35.8%) compared with Gb(3) (1.9%). These results suggest different biological pathways involved in the synthesis and/or degradation of Gb(3) and Ga(2) metabolites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers / urine*
  • Child
  • Child, Preschool
  • Fabry Disease / urine*
  • Gangliosides / urine*
  • Humans
  • Infant
  • Least-Squares Analysis
  • Male
  • Mass Spectrometry / methods*
  • Metabolomics / methods*
  • Middle Aged
  • Young Adult


  • Biomarkers
  • Gangliosides
  • galabiosylceramide