title: Elevated globotriaosylsphingosine is a hallmark of Fabry disease.
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.
authors.affiliation: Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.m.aerts@amc.uva.nl
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Groener
authors.forename: Sijmen
authors.initials: S
authors.lastname: Kuiper
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Donker-Koopman
authors.forename: Anneke
authors.initials: A
authors.lastname: Strijland
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.forename: Cindy
authors.initials: C
authors.lastname: van Roomen
authors.forename: Mina
authors.initials: M
authors.lastname: Mirzaian
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Gabor E
authors.initials: GE
authors.lastname: Linthorst
authors.forename: Anouk C
authors.initials: AC
authors.lastname: Vedder
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Rombach
authors.forename: Josanne
authors.initials: J
authors.lastname: Cox-Brinkman
authors.forename: Pentti
authors.initials: P
authors.lastname: Somerharju
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Carla E
authors.initials: CE
authors.lastname: Hollak
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Poorthuis
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D000795:Fabry Disease / Q000097:blood*; D006017:Glycolipids / Q000097:blood* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009426:Netherlands; D010375:Pedigree; D013107:Sphingolipids / Q000097:blood* / Q000494:pharmacology; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors
chemical_list: D006017:Glycolipids; D013107:Sphingolipids; C063288:globotriaosyl lysosphingolipid; D000519:alpha-Galactosidase