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.


METHODS
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.


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 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.


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.
Tortorelli
Silvia
S
Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN 55905, USA.
Turgeon
Coleman T
CT
Lim
James S
JS
Baumgart
Steve
S
Day-Salvatore
Debra-Lynn
DL
Abdenur
Jose
J
Bernstein
Jonathan A
JA
Lorey
Fred
F
Lichter-Konecki
Uta
U
Oglesbee
Devin
D
Raymond
Kimiyo
K
Matern
Dietrich
D
Schimmenti
Lisa
L
Rinaldo
Piero
P
Gavrilov
Dimitar K
DK
D000465:Algorithms; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007231:Infant, Newborn; D008661:Metabolism, Inborn Errors / Q000097:blood* / Q000175:diagnosis; D008715:Methionine / Q000097:blood; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency*; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*; D010649:Phenylalanine / Q000097:blood; D012016:Reference Values; D015203:Reproducibility of Results; D012189:Retrospective Studies; D053719:Tandem Mass Spectrometry / Q000379:methods*
D006710:Homocysteine; D010649:Phenylalanine; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)