Elevated globotriaosylsphingosine is a hallmark of Fabry disease.
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.
Aerts
Johannes M
JM
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
Groener
Johanna E
JE
Kuiper
Sijmen
S
Donker-Koopman
Wilma E
WE
Strijland
Anneke
A
Ottenhoff
Roelof
R
van Roomen
Cindy
C
Mirzaian
Mina
M
Wijburg
Frits A
FA
Linthorst
Gabor E
GE
Vedder
Anouk C
AC
Rombach
Saskia M
SM
Cox-Brinkman
Josanne
J
Somerharju
Pentti
P
Boot
Rolf G
RG
Hollak
Carla E
CE
Brady
Roscoe O
RO
Poorthuis
Ben J
BJ
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
D006017:Glycolipids; D013107:Sphingolipids; C063288:globotriaosyl lysosphingolipid; D000519:alpha-Galactosidase