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J Pediatr. 2010 Aug;157(2):271-5. doi: 10.1016/j.jpeds.2010.02.027. Epub 2010 Apr 14.

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

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  • 1Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN 55905, USA.



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 micromol/L; 1 percentile of healthy population, 11.1 micromol/L), the methionine/phenylalanine ratio (Met/Phe; 0.09-0.16; 1 percentile of healthy population, 0.22), and total homocysteine (tHcy; 42-157 micromol/L; 99 percentile of normal population, 14.7 micromol/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 micromol/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.

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