A simple method for quantification of plasma globotriaosylsphingosine: Utility for Fabry disease.

Abstract

Fabry disease (FD) results from impaired globotriaosylceramide (Gb3) catabolism, due to a deficiency of the lysosomal hydrolase, α-galactosidase A (α-GalA). As a direct consequence, the deacetylated derivative, globotriaosylsphingosine (lyso-Gb3), is produced and contemporary evidence exemplifies its use as a biomarker. Here we developed a simple method to enable quantification of lyso-Gb3 in just 0.01mL of plasma and explored its concentration in a cohort of 73 Australian FD patients, as well as in individuals with other sphingolipidoses. In 2000 patients without FD, but with related metabolic conditions, lyso-Gb3 returned concentrations of <5pmol/mL. In the FD cohort, 53/60 patients with classical mutations returned lyso-Gb3 concentrations≥5pmol/mL whereas only 4/13 patients with "late-onset" mutations had lyso-Gb3≥5pmol/mL. Five females with normal α-GalA activity and genetically confirmed FD returned lyso-Gb3≥5pmol/mL. The prevalence of clinically significant disease including cardiomyopathy, nephropathy and cerebrovascular disease was congruent with higher lyso-Gb3 concentrations. Repeat testing was available for 51 patients-26 undergoing enzyme replacement therapy-and concentrations of lyso-Gb3 remained unaltered throughout 6-18 months independent of sex, mutation or treatment status. Our data suggest that the optimum use of lyso-Gb3 resides in laboratory confirmation of classical FD and for monitoring at least the initial response to therapeutic intervention. There is no evidence that lyso-Gb3 can inform on clinical events.

• Authors: Andrew Talbot, Kathy Nicholls, Janice M Fletcher, Maria Fuller
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 122 Issue 1-2 Pg. 121-125 (09 2017) ISSN: 1096-7206 [Electronic] United States
• PMID: 28847675 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Glycolipids
• Sphingolipids
• globotriaosyl lysosphingolipid
• alpha-Galactosidase

Topics

• Adult
• Australia
• Biomarkers (blood)
• Enzyme Replacement Therapy
• Fabry Disease (blood, diagnosis, genetics)
• Female
• Glycolipids (blood)
• Humans
• Male
• Middle Aged
• Mutation
• Sphingolipids (blood)
• Tandem Mass Spectrometry
• alpha-Galactosidase (genetics)