Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide

P D Whitfield, J Calvin, S Hogg, E O'Driscoll, D Halsall, K Burling, G Maguire, N Wright, T M Cox, P J Meikle, P B Deegan

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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.
Original languageEnglish
Pages (from-to)21-33
Number of pages13
JournalJournal of Inherited Metabolic Disease
Volume28
Issue number1
DOIs
Publication statusPublished - 2005

Keywords

  • Adult
  • Biological Markers
  • DNA Mutational Analysis
  • Fabry Disease
  • Female
  • Glycolipids
  • Heterozygote
  • Humans
  • Immunoassay
  • Isoenzymes
  • Kidney Transplantation
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Models, Chemical
  • Pain
  • Questionnaires
  • Spectrometry, Mass, Electrospray Ionization
  • Time Factors
  • Trihexosylceramides
  • alpha-Galactosidase

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    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. (2005). Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide. Journal of Inherited Metabolic Disease, 28(1), 21-33. https://doi.org/10.1007/s10545-005-4415-x