Monitoring enzyme replacement therapy in Fabry disease—Role of urine globotriaosylceramide

Abstract

Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

“…3 Right), without developing antibodies, showed a reduction of lyso-Gb3 within 1 year, although a complete normalization was not observed. Some of the male hemizygotes lacking ␣-galactosidase A develop neutralizing antibodies upon ERT (31)(32)(33). Fig.…”

A Fast Determination of Globotriaosylsphingosine in Plasma for Screening Fabry Disease Using UPLC-ESI-MS/MS

“…[3][4][5] Recently, researcher have paid attention to the excretion of plasma lyso-Gb3 level and published it's significant correlation with clinical severity of disease manifestations. 6,7,[9][10][11] Traditionally analytical method of lyso-Gb3 was based on O-phthalaldehyde derivatization of amine in the lysoglycolipid followed by HPLC-fluorescence detection.…”

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

“…Gb 3 accumulation in tissues and body fluids (urine and plasma) is one candidate biomarker that has been used for screening [9] and monitoring response to ERT [10], [11]. However, the usefulness of plasma and urinary Gb 3 levels has been questioned [12], and in particular, it was not elevated in most hemizygous female patients.…”