Glycosphingolipid storage in Fabry mice extends beyond globotriaosylceramide and is affected by ABCB1 depletion.

Aim: Fabry disease is caused by alpha-galactosidase A deficiency leading to accumulation of globotriaosylceramide (Gb(3)) in tissues. Clinical manifestations do not appear to correlate with total Gb(3) levels. Studies examining tissue distribution of specific acyl chain species of Gb(3) and upstream glycosphingolipids are lacking. Material & methods/ Results: Thorough characterization of the Fabry mouse sphingolipid profile by LC-MS revealed unique Gb(3) acyl chain storage profiles. Storage extended beyond Gb(3); all Fabry tissues also accumulated monohexosylceramides. Depletion of ABCB1 had a complex effect on glycosphingolipid storage. Conclusion: These data provide insights into how specific sphingolipid species correlate with one another and how these correlations change in the alpha-galactosidase A-deficient state, potentially leading to the identification of more specific biomarkers of Fabry disease. Lay abstract: Fabry disease is caused by a shortage of the enzyme alpha-galactosidase A leading to storage of a fat called globotriaosylceramide (Gb(3)) in tissues. Disease severity does not appear to correlate directly with total Gb(3). Importantly, Gb(3) is comprised of many highly related but distinct species. We examined levels of Gb(3) species and precursor molecules in Fabry mice. Gb(3) species and storage are unique to each tissue. Furthermore, storage is not limited to Gb(3); precursor fats are also elevated. Detailed analyses of differences in storage between the normal and alpha-galactosidase A-deficient state may provide a better understanding of the causes of Fabry disease.