Elevated globotriaosylsphingosine is a hallmark of Fabry disease
- PMID: 18287059
- PMCID: PMC2268542
- DOI: 10.1073/pnas.0712309105
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.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Similar articles
-
Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease.Biochim Biophys Acta. 2010 Sep;1802(9):741-8. doi: 10.1016/j.bbadis.2010.05.003. Epub 2010 May 13. Biochim Biophys Acta. 2010. PMID: 20471476
-
Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort.Curr Issues Mol Biol. 2021 Jun 19;43(1):389-404. doi: 10.3390/cimb43010032. Curr Issues Mol Biol. 2021. PMID: 34205365 Free PMC article.
-
Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy.Biochim Biophys Acta. 2011 Jan;1812(1):70-6. doi: 10.1016/j.bbadis.2010.09.007. Epub 2010 Sep 17. Biochim Biophys Acta. 2011. PMID: 20851180 Clinical Trial.
-
Biomarkers for Diagnosing and Staging of Fabry Disease.Curr Med Chem. 2018;25(13):1530-1537. doi: 10.2174/0929867324666170616102112. Curr Med Chem. 2018. PMID: 28618999 Review.
-
Anderson-Fabry disease: a multiorgan disease.Curr Pharm Des. 2013;19(33):5974-96. doi: 10.2174/13816128113199990352. Curr Pharm Des. 2013. PMID: 23448451 Review.
Cited by
-
Analysis of lyso-globotriaosylsphingosine in dried blood spots.Ann Lab Med. 2013 Jul;33(4):274-8. doi: 10.3343/alm.2013.33.4.274. Epub 2013 Jun 24. Ann Lab Med. 2013. PMID: 23826564 Free PMC article.
-
Lyso-globotriaosylsphingosine (lyso-Gb3) levels in neonates and adults with the Fabry disease later-onset GLA IVS4+919G>A mutation.J Inherit Metab Dis. 2013 Sep;36(5):881-5. doi: 10.1007/s10545-012-9547-1. Epub 2012 Oct 30. J Inherit Metab Dis. 2013. PMID: 23109060
-
Molecular Pathogenesis of Central and Peripheral Nervous System Complications in Anderson-Fabry Disease.Int J Mol Sci. 2023 Dec 20;25(1):61. doi: 10.3390/ijms25010061. Int J Mol Sci. 2023. PMID: 38203231 Free PMC article. Review.
-
Renal complications of Fabry disease in children.Pediatr Nephrol. 2013 May;28(5):679-87. doi: 10.1007/s00467-012-2222-9. Epub 2012 Aug 17. Pediatr Nephrol. 2013. PMID: 22898981 Free PMC article. Review.
-
Synergy between the pharmacological chaperone 1-deoxygalactonojirimycin and the human recombinant alpha-galactosidase A in cultured fibroblasts from patients with Fabry disease.J Inherit Metab Dis. 2012 May;35(3):513-20. doi: 10.1007/s10545-011-9424-3. Epub 2011 Dec 21. J Inherit Metab Dis. 2012. PMID: 22187137
References
-
- Brady RO, et al. Enzymatic defect in Fabry's disease: Ceramidetrihexosidase deficiency. N Engl J Med. 1967;276:1163–1167. - PubMed
-
- Kint JA. Fabry's disease: α-Galactosidase deficiency. Science. 1970;167:1268–1269. - PubMed
-
- Desnick RJ, Ioannou YA. α-Galactosidase A deficiency: Fabry disease. In: Scriver R, et al., editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001. pp. 3733–3774.
-
- Brady RO, et al. Replacement therapy for inherited enzyme deficiency: Use of purified ceramidetrihexosidase in Fabry's disease. N Engl J Med. 1973;289:9–14. - PubMed
-
- Schiffmann R, et al. Enzyme-replacement therapy in Fabry disease: A randomized controlled trial. J Am Med Assoc. 2001;285:2743–2749. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases