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

作者：Talbot Andrew; Nicholls Kathy; Fletcher Janice M; Fuller Maria^*

来源：Molecular Genetics and Metabolism, 2017, 122(1-2): 121-125.

DOI：10.1016/j.ymgme.2017.08.004

• Fabry disease
• Lysosomal disease
• Enzyme replacement therapy
• Globotriaosylsphingosine
• Mass spectrometry
• Biomarker

Fabry disease (FD) results from impaired globotriaosylceramide (Gb3) catabolism, due to a deficiency of the lysosomal hydrolase, alpha-galactosidase A (alpha-GalA). As a direct consequence, the deacetylated derivative, globotriaosylsphingosine (Iyso-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 0.01 mL 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 < 5 pmol/mL. In the FD cohort, 53/60 patients with classical mutations returned lyso-Gb3 concentrations >= 5 pmol/mL whereas only 4/13 patients with "late-onset" mutations had Lyso-Gb3 >= 5 pmol/mL. Five females with normal aGalA activity and genetically confirmed FD returned lyso-Gb3 >= 5 pmol/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 Zyso-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.

• 出版日期2017-10