Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Abstract

Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC–MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC–MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as these from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study.

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study

“…[7][8][9] As an alternative, plasma ly-soGb3 concentrations are a valuable tool in the classification of FD. 4,24 In line with earlier findings, 4 lysoGb3 concentrations can, indeed, be used to differentiate between phenotypes in men with FD. Concentrations of .45 nmol/L are strongly indicative for a classical FD phenotype in men with FD.…”

Effectiveness of plasma lyso-Gb3 as a biomarker for selecting high-risk patients with Fabry disease from multispecialty clinics for genetic analysis

“…Of the four males who underwent ordinary gene analysis, three presented the p.E66Q class 2 mutation—a nonpathogenic, functional polymorphism that was found at an unexpectedly high frequency in the GLA analysis of Japanese patients selected through the abnormal α-Gal A activity in the FD screening. 14,27 One male with normal plasma lyso-Gb3 levels exhibited a gene promoter variant (c.−10C>T) in the 5'-untranslated region of exon 1 that was associated with decreased α-Gal A expression; 28 this is a nonpathogenic class 2 mutation (Supplementary Table S6 online). 28 Of the six females, four declined gene analysis and the two who underwent ordinary gene analysis presented the c.−10C>T mutation (Supplementary Table S6).…”

European expert consensus statement on therapeutic goals in Fabry disease

“…Urinary GL-3 levels may also be suitable for the diagnosis of Fabry nephropathy and monitoring the effect of ERT in patients with Fabry disease [22][23][24]. Further research is needed to explore the use of urinary GL-3 as an additional therapeutic goal for Fabry nephropathy and no goal has been included at this time.…”