Abstract
Background Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb 3), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb 3), is increased in patients with the disease. Until now, lyso-Gb 3 was not detectable in urine, possibly because of the presence of interfering compounds. Methods We undertook to: 1) characterize lyso-Gb 3 in urine; 2) develop a method to quantitate urinary lyso-Gb 3 by mass spectrometry; 3) evaluate urinary lyso-Gb 3 as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb 3 is an inhibitor of α-galactosidase A activity. We analyzed urinary lyso-Gb 3 from 83 Fabry patients and 77 healthy age-matched controls. Results The intraday and interday bias and precision of the method were < 15%. Increases in lyso-Gb 3/creatinine correlated with the concentrations of Gb 3 ( r 2 = 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-Gb 3. Lyso-Gb 3 did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb 3 of Fabry patients correlated well with a number of indicators of disease severity. Conclusion Lyso-Gb 3 is a reliable independent biomarker for clinically important characteristics of Fabry disease.
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