title: Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.
abstract: Fabry disease is a complex, multisystemic and clinically heterogeneous disease, in which the urinary excretion of globotriaosylceramide (Gb3), the principal substrate of the deficient enzyme, alpha-galactosidase A, is more prominent than the increased concentrations of the lipid in the plasma of affected hemizygotes and heterozygotes. We have developed and validated a simultaneous analysis of Gb3 and creatinine in a 2.6-min run using filter paper discs saturated with urine and analyzed by LC-MS/MS. Using this method, we studied the relationship between urinary levels of total Gb3/creatinine excretion and four types of mutations in the GLA gene (missense, nonsense, frameshift, and splice-site defects) in 32 children and 78 adult patients with Fabry disease. Forty-one patients were treated by enzyme replacement therapy and 69 were untreated. Our results show that the mean recoveries of Gb3 and creatinine from the urine filter paper standards were 91% and 97%, respectively, with precision, reproducibility, and linearity within acceptable ranges. Statistical analysis using the independent variables of sex, age, types of mutations and treatment showed that the mutation factor has a statistically significant impact on urinary Gb3 excretion (p = 0.0007). This means that the levels of urinary excretion of Gb3/creatinine in children and adults with Fabry disease are directly related to the types of mutations. The same correlation was found for the sex (p < 0.0001) and treatment (p = 0.0011). In conclusion, we studied 35 mutations in 110 children and adults with Fabry disease and found a significant correlation between the types of mutations and total Gb3 excretion in Fabry patients.
authors.affiliation: Service of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, Que., Canada J1H 5N4.
authors.forename: Christiane
authors.initials: C
authors.lastname: Auray-Blais
authors.forename: Denis
authors.initials: D
authors.lastname: Cyr
authors.forename: Aimé
authors.initials: A
authors.lastname: Ntwari
authors.forename: Michael L
authors.initials: ML
authors.lastname: West
authors.forename: Josanne
authors.initials: J
authors.lastname: Cox-Brinkman
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Germain
authors.forename: Rachel
authors.initials: R
authors.lastname: Laframboise
authors.forename: Serge B
authors.initials: SB
authors.lastname: Melançon
authors.forename: Tracy
authors.initials: T
authors.lastname: Stockley
authors.forename: Joe T R
authors.initials: JT
authors.lastname: Clarke
authors.forename: Régen
authors.initials: R
authors.lastname: Drouin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D003404:Creatinine / Q000652:urine; D000795:Fabry Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053719:Tandem Mass Spectrometry; D014281:Trihexosylceramides / Q000652:urine*; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide; D003404:Creatinine; D000519:alpha-Galactosidase