The use of globotriaosylsphingosine to detect and monitor Fabry Disease

[摘要] Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the α-galactosidase-A (α-gal-A) enzyme. The lack of enzymatic activity results in the accumulation of glycosphingolipids (GSLs) in the lysosomes of various tissues and organs. Globotriaosylceramide (Gb3) and Globotriaosylsphingosine (Lyso-Gb3) and their isoforms/analogues have been identified and quantified as potential biomarkers. This study aimed to develop an HPLC-MS based method for the quantitation of plasma and urinary Lyso-Gb3 and its analogues in Fabry patients to evaluate its utility in diagnosis and monitoring FD. The results showed that plasma Lyso-Gb3 as a reliable diagnostic biomarker for FD, as plasma Lyso-Gb3 levels could easily discern classical Fabry patients from controls. Moreover, plasma Lyso-Gb3 could also distinguish male cardiac variant Fabry patients from control males. Nevertheless, cardiac variant Fabry females showed an overlap of Lyso-Gb3 levels with controls, hence a positive value in this group would be considered diagnostic but a negative value could not exclude FD. In a small cohort of our patients on ERT there was a trend towards falling Lyso-Gb3 levels with time suggesting that Lyso-Gb3 has a potential value in monitoring these patients. Urinary Lyso-Gb3 levels were substantially different between classical and cardiac variant Fabry patients, and the lack of detectable urinary Lyso-Gb3 and analogues in controls allowed us to differentiate between these patients and healthy controls. The total levels of urinary Lyso-Gb3 and its analogues proved particularly useful in differentiating between classical and atypical Fabry patients of both genders.In the course of the study, a novel rapid MALDI-TOF-MS based Method for measuring urinary Gb3 in Fabry patients has been established. Collectively, the final findings demonstrate that urinary Lyso-Gb3 is superior to urinary Gb3 as a diagnostic biomarker for FD, where the later has been shown to be found in healthy subjects. Our study subsequently led to development of regional laboratory service for testing Lyso-Gb3 in Queen Elizabeth Hospital, Birmingham, UK. This service is now open to Fabry patients across England. InconclusionbothplasmaandurinaryLyso-Gb3levelsareusefuldiagnosticand monitoringbiomarkerinclassicalandcardiacvariantmalespatients,buthave questionable utility in cardiac variant females due to overlap with healthy controls. Although we studied the role of Lyso-Gb3 in diagnosing FD further studies are needed to establish its role in disease severity assessment and a larger study required to test our initial finding related to monitoring disease in patients on treatment.

[发布机构] University:University of Birmingham;Department:Institute of Cancer and Genomic Sciences

[关键词] R Medicine;RB Pathology