Rapid diagnosis of homocystinuria and other hypermethioninemias from newborns' blood spots by tandem mass spectrometry

Abstract

We report a new method for the diagnosis of homocystinuria and other hypermethioninemias from dried blood spots on newborn screening cards, based on isotope-dilution tandem mass spectrometry. The mean concentration of methionine in 909 unaffected newborns was 19 μmol/L (CV 44%). The variability of results was reduced when the concentration of methionine was expressed relative to that of another amino acid in the same specimen. The mean ratio of methionine to leucine plus isoleucine for these same newborn blood spots was 0.16 (CV 25%). In newborn samples from a collection categorized by a Guthrie bacterial inhibition assay as true positive, unaffected, or falsely positive for hypermethioninemias, the ratio of methionine to leucine for each true-positive specimen was at least 2.5 times greater than for respective age-matched unaffected blood specimens. The ratio for falsely positive samples did not differ from that for unaffected blood samples. We predict that the ratio of methionine to leucine plus isoleucine determined by tandem mass spectrometry will successfully detect hypermethioninemias with very low rates for false positives and false negatives.