Newborn screening for Fabry disease by measuring GLA activity using tandem mass spectrometry

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of alpha-galactosidase A (GLA). We evaluated a tandem mass spectrometry method to measure GLA activity. Methods: One 3.2 mm punch from a dried blood spot sample (DBS) was incubated with substrate and internal standard in the reaction buffer for 22 h. The resulting product was quantified against internal standard using MS/MS. Results: The median GLA activity of male newborn DBS (N = 5025) was 9.85 +/- 6.4 mu mol/h/l (Cl 95% is 9.67-10.02 mu mol/h/l); The median GLA activity of female newborns (N=4677) was 10.2 +/- 6.3 mu mol/h/l (Cl 95% is 10.02-10.38 mu mol/h/l). The difference between the two subgroups is within assay analytical variation. The GLA activities in the DBS samples from 9 juvenile and adult males with previously identified FD were below 1.64 mu mol/h/l. The GLA activities from 32 juvenile and adult females with confirmed FD were below 4.73 mu mol/h/l. In 5 (16%) females GLA activities were above the 0.5th percentile of lower limit of Cl 95% at 3.18 mu mol/h/l. Conclusions: The MS/MS method for Fabry disease newborn screening is robust and can be readily multiplexed with other lysosomal disorders such as Pompe, Gaucher, Niemann-Pick, and Krabbe diseases. (C) 2010 Elsevier B.V. All rights reserved.