Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and other remethylation disorders with tandem mass spectrometry.

Objective To validate a 2-tier approach for newborn screening(NBS) of remethylation defects. Study design The original NBS dried blood spotsof 5 patients with a proven diagnosis of a remethylation disorder and 1 patient with biochemical evidence of such disorder were analyzed retrospectively to determine disease ranges for methionine (Met; 4.7-8.1 μmol/L; 1 percentileof healthy population, 11.1 μmol/L), the methionine/phenylalanine ratio (Met/Phe; 0.09-0.16; 1 percentileof healthy population, 0.22), and total homocysteine (tHcy; 42-157 μmol/L; 99 percentileof normal population, 14.7 μmol/L). These preliminary disease ranges showed a sufficient degree of segregation from healthy population data, allowing the selection of cutoff values. A simple algorithm was then developed to reflex cases to a second-tier testing for tHcy, which has been applied prospectively for 14 months. Results A total of 86 333 NBS samples were tested between January 2007 and March 2008, and 233 of them (0.27%) met the criteria for second-tier testing of tHcy. All cases revealed concentrations of tHcy Conclusions Pending more conclusive evidence from the prospective identification of additional true-positive cases, NBS for remethylation disorders appears to be feasible with existing methodologies, with only a marginal increase of the laboratory workload.