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

• Published in: Journal of inherited metabolic disease Vol. 28; no. 1; pp. 21 - 33
• Main Authors: Whitfield, P. D., Calvin, J., Hogg, S., O'Driscoll, E., Halsall, D., Burling, K., Maguire, G., Wright, N., Cox, T. M., Meikle, P. J., Deegan, P. B.
• Format: Journal Article
• Language: English
• Published: Dordrecht Kluwer Academic Publishers 01-01-2005; Springer; Blackwell Publishing Ltd
• Subjects: Adult; alpha-Galactosidase - chemistry; alpha-Galactosidase - therapeutic use; Biological and medical sciences; Biomarkers; DNA Mutational Analysis; Fabry Disease - enzymology; Fabry Disease - therapy; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Glycolipids - metabolism; Heterozygote; Humans; Immunoassay; Isoenzymes - therapeutic use; Kidney Transplantation; Male; Mass Spectrometry; Middle Aged; Models, Chemical; Molecular and cellular biology; Pain; Recombinant Proteins; Spectrometry, Mass, Electrospray Ionization; Surveys and Questionnaires; Time Factors; Trihexosylceramides - urine; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Urine; Nervous system diseases; Replacement therapy; Nutrition; Enzyme; Fabry disease; Cardiovascular disease; Lipids; Metabolic diseases; Enzymopathy; Genetic disease; Vascular disease; Surveillance; Genetics; Lipoidosis; Monitoring
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-005-4415-x

Summary
Anderson‐Fabry disease (referred to as Fabry disease) is an X‐linked disorder characterized by a deficiency of the lysosomal enzyme α‐galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb3), 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 α‐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 (Gb3) 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 Gb3 concentrations to baseline (pre‐ERT) levels, associated with the presence of antibodies to the recombinant α‐galactosidase A. The marked decline in urine Gb3 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.