Two-Tier Approach to the Newborn Screening of Methylenetetrahydrofolate Reductase Deficiency and Other Remethylation Disorders with Tandem Mass Spectrometry

ObjectiveTo validate a 2-tier approach for newborn screening (NBS) of remethylation defects.Study designThe original NBS dried blood spots of 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 percentile of healthy population, 11.1 μmol/L), the methionine/phenylalanine ratio (Met/Phe; 0.09-0.16; 1 percentile of healthy population, 0.22), and total homocysteine (tHcy; 42-157 μmol/L; 99 percentile of 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.ResultsA 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 <15 μmol/L and were considered unaffected. No false-negative results have been reported with a state-wide system based on 2 combined metabolic clinics and laboratories that cover the entire Minnesota population and border areas of neighboring states.ConclusionsPending 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.