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

2010; Elsevier BV; Volume: 157; Issue: 2 Linguagem: Inglês

10.1016/j.jpeds.2010.02.027

1097-6833

Silvia Tortorelli, Coleman Turgeon, James Lim, Steve Baumgart, D Day-Salvatore, José E. Abdenur, Jonathan A. Bernstein, Fred Lorey, Uta Lichter‐Konecki, Devin Oglesbee, Kimiyo Raymond, Dietrich Matern, Lisa A. Schimmenti, Piero Rinaldo, Dimitar K. Gavrilov,

Mitochondrial Function and Pathology

Objective To validate a 2-tier approach for newborn screening (NBS) of remethylation defects. Study design The 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. 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 <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. 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. To validate a 2-tier approach for newborn screening (NBS) of remethylation defects. The 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. 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 <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. 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.