title: 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.
authors.affiliation: Biochemical Genetics Unit, Addenbrooke's NHS Trust, Cambridge, UK.
authors.forename: P D
authors.initials: PD
authors.lastname: Whitfield
authors.forename: J
authors.initials: J
authors.lastname: Calvin
authors.forename: S
authors.initials: S
authors.lastname: Hogg
authors.forename: E
authors.initials: E
authors.lastname: O'Driscoll
authors.forename: D
authors.initials: D
authors.lastname: Halsall
authors.forename: K
authors.initials: K
authors.lastname: Burling
authors.forename: G
authors.initials: G
authors.lastname: Maguire
authors.forename: N
authors.initials: N
authors.lastname: Wright
authors.forename: T M
authors.initials: TM
authors.lastname: Cox
authors.forename: P J
authors.initials: PJ
authors.lastname: Meikle
authors.forename: P B
authors.initials: PB
authors.lastname: Deegan
mesh_terms: D000328:Adult; D015415:Biomarkers; D004252:DNA Mutational Analysis; D000795:Fabry Disease / Q000201:enzymology / Q000628:therapy*; D005260:Female; D006017:Glycolipids / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007118:Immunoassay; D007527:Isoenzymes / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008956:Models, Chemical; D010146:Pain; D011994:Recombinant Proteins; D021241:Spectrometry, Mass, Electrospray Ionization; D011795:Surveys and Questionnaires; D013997:Time Factors; D014281:Trihexosylceramides / Q000652:urine*; D000519:alpha-Galactosidase / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D006017:Glycolipids; D007527:Isoenzymes; D011994:Recombinant Proteins; D014281:Trihexosylceramides; C000627036:agalsidase alfa; C018549:globotriaosylceramide; D000519:alpha-Galactosidase