Elevated globotriaosylsphingosine is a hallmark of Fabry disease

TLDR

Fabry disease, an X‑linked lysosomal storage disorder caused by alpha‑galactosidase A deficiency, leads to globotriaosylceramide accumulation that underlies progressive renal, cardiac, and neurological damage, yet the link between lipid storage and clinical symptoms remains unclear and enzyme replacement does not reverse all manifestations. The study aimed to determine whether globotriaosylceramide metabolites, particularly globotriaosylsphingosine, serve as a missing pathogenic link in Fabry disease. Plasma globotriaosylsphingosine was markedly elevated in affected males and mice, decreased by therapy, inhibited alpha‑galactosidase A, stimulated smooth‑muscle proliferation, and correlated with intima‑media thickening, indicating that its measurement could monitor disease and enhance understanding of Fabry pathology.

Abstract

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of alpha-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.