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

Tortorelli, Silvia; Turgeon, Coleman T.; Lim, James S.; Baumgart, Steve; Day-Salvatore, Debra-Lynn; Abdenur, Jose; Bernstein, Jonathan A.; Lorey, Fred; Lichter-Konecki, Uta; Oglesbee, Devin; Raymond, Kimiyo; Matern, Dietrich; Schimmenti, Lisa; Rinaldo, Piero; Gavrilov, Dimitar K.

doi:10.1016/j.jpeds.2010.02.027

« Previous Next »The Journal of Pediatrics
Volume 157, Issue 2 , Pages 271-275, August 2010

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

Silvia Tortorelli, MD, PhD
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
Coleman T. Turgeon
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
James S. Lim, PhD
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
Steve Baumgart, MD
- Children's National Medical Center, Washington, DC
Debra-Lynn Day-Salvatore, MD, PhD
- Institute for Genetic Medicine, St. Peter's University Hospital, New Brunswick, NJ
Jose Abdenur, MD
- CHOC Children's, Orange County, CA
Jonathan A. Bernstein, MD, PhD
- Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA
Fred Lorey, PhD
- California Department of Public Health, Richmond, CA
Uta Lichter-Konecki, MD, PhD
- Children's National Medical Center, Washington, DC
Devin Oglesbee, PhD
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
Kimiyo Raymond, MD
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
Dietrich Matern, MD
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
Lisa Schimmenti, MD
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
Piero Rinaldo, MD, PhD
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
Dimitar K. Gavrilov, MD, PhD
- Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN
- Reprint requests: Dimitar Gavrilov, MD, PhD, Biochemical Genetics Laboratory - Hilton 330, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Received 21 August 2009; received in revised form 20 January 2010; accepted 17 February 2010. published online 15 April 2010.

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.

ACMG, American College of Medical Genetics, Cbl, Cobalamin, DBS, Dried blood spots, Hcy, Homocysteine, LC-MS/MS, Liquid chromatography–tandem mass spectrometry, Met, Methionine, MS/MS, Tandem mass spectrometry, MTHFR, 5,10-methylenetetrahydrofolate reductase, NBS, Newborn screening, Phe, Phenylalanine, tHcy, Total homocysteine, TPN, Total parenteral nutrition, Xle, Leucine-isoleucine