Elevated globotriaosylsphingosine as a hallmark of Fabry disease

Abstract

Fabry disease is an X-linked lysosomal storage disease caused bydeficiency of -galactosidase A that affects males and showsdiseaseexpressioninheterozygotes.Thecharacteristicprogressiverenal insufficiency, cardiac involvement, and neuropathology usu-ally are ascribed to globotriaosylceramide accumulation in theendothelium. However, no direct correlation exists between lipidstorageandclinicalmanifestations,andtreatmentofpatientswithrecombinant enzymes does not reverse several key signs despiteclearanceoflipidfromtheendothelium.Wethereforeinvestigatedthe possibility that globotriaosylceramide metabolites are a miss-ing link in the pathogenesis. We report that deacylated globotri-aosylceramide, globotriaosylsphingosine, and a minor additionalmetabolitearedramaticallyincreasedinplasmaofclassicallyaffectedmale Fabry patients and plasma and tissues of Fabry mice. Plasmaglobotriaosylceramide levels are reduced by therapy. We showthat globotriaosylsphingosine is an inhibitor of -galactosidase Aactivity. Furthermore, exposure of smooth muscle cells, but notfibroblasts, to globotriaosylsphingosine at concentrations ob-served in plasma of patients promotes proliferation. The increasedintima-media thickness in Fabry patients therefore may be relatedto the presence of this metabolite. Our findings suggest thatmeasurement of circulating globotriaosylsphingosine will be use-ful to monitor Fabry disease and may contribute to a betterunderstanding of the disorder.