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 (Gb 3 ), the principal substrate of the deficient enzyme, α-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 Gb 3 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 Gb 3 /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 Gb 3 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 Gb 3 excretion ( p  = 0.0007). This means that the levels of urinary excretion of Gb 3 /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 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 Gb 3 excretion in Fabry patients.