How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?

BackgroundFabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb3), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb3), is increased in patients with the disease. Until now, lyso-Gb3 was not detectable in urine, possibly because of the presence of interfering compounds.MethodsWe undertook to: 1) characterize lyso-Gb3 in urine; 2) develop a method to quantitate urinary lyso-Gb3 by mass spectrometry; 3) evaluate urinary lyso-Gb3 as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb3 is an inhibitor of α-galactosidase A activity. We analyzed urinary lyso-Gb3 from 83 Fabry patients and 77 healthy age-matched controls.ResultsThe intraday and interday bias and precision of the method were < 15%. Increases in lyso-Gb3/creatinine correlated with the concentrations of Gb3 (r2 = 0.43), type of mutations (p = 0.0006), gender (p < 0.0001) and enzyme replacement therapy status (p = 0.0012). Urine from healthy controls contained no detectable lyso-Gb3. Lyso-Gb3 did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb3 of Fabry patients correlated well with a number of indicators of disease severity.ConclusionLyso-Gb3 is a reliable independent biomarker for clinically important characteristics of Fabry disease.