title: Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.
abstract: BACKGROUND
  Down syndrome, or trisomy 21, is a complex genetic disease resulting from the presence of 3 copies of chromosome 21. The origin of the extra chromosome is maternal in 95% of cases and is due to the failure of normal chromosomal segregation during meiosis. Although advanced maternal age is a major risk factor for trisomy 21, most children with Down syndrome are born to mothers <30 y of age.
  
  
  OBJECTIVE
  On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, we hypothesized that the C-to-T substitution at nucleotide 677 (677C-->T) mutation of the methylenetetrahydrofolate reductase (MTHFR) gene may be a risk factor for maternal meiotic nondisjunction and Down syndrome in young mothers.
  
  
  METHODS
  The frequency of the MTHFR 677C-->T mutation was evaluated in 57 mothers of children with Down syndrome and in 50 age-matched control mothers. Ratios of plasma homocysteine to methionine and lymphocyte methotrexate cytotoxicity were measured as indicators of functional folate status.
  
  
  RESULTS
  A significant increase in plasma homocysteine concentrations and lymphocyte methotrexate cytotoxicity was observed in the mothers of children with Down syndrome, consistent with abnormal folate and methyl metabolism. Mothers with the 677C-->T mutation had a 2.6-fold higher risk of having a child with Down syndrome than did mothers without the T substitution (odds ratio: 2.6; 95% CI: 1.2, 5.8; P < 0.03).
  
  
  CONCLUSIONS
  The results of this initial study indicate that folate metabolism is abnormal in mothers of children with Down syndrome and that this may be explained, in part, by a mutation in the MTHFR gene.
authors.affiliation: Food and Drug Administration-National Center for Toxicological Research, the Division of Biochemical Toxicology, Jefferson, AR 72079,USA. jjames@nctr.fda.gov
authors.forename: S J
authors.initials: SJ
authors.lastname: James
authors.forename: M
authors.initials: M
authors.lastname: Pogribna
authors.forename: I P
authors.initials: IP
authors.lastname: Pogribny
authors.forename: S
authors.initials: S
authors.lastname: Melnyk
authors.forename: R J
authors.initials: RJ
authors.lastname: Hine
authors.forename: J B
authors.initials: JB
authors.lastname: Gibson
authors.forename: P
authors.initials: P
authors.lastname: Yi
authors.forename: D L
authors.initials: DL
authors.lastname: Tafoya
authors.forename: D H
authors.initials: DH
authors.lastname: Swenson
authors.forename: V L
authors.initials: VL
authors.lastname: Wilson
authors.forename: D W
authors.initials: DW
authors.lastname: Gaylor
mesh_terms: D000328:Adult; D000428:Alcohol Drinking / Q000009:adverse effects / Q000453:epidemiology; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D015252:Deoxyribonucleases, Type II Site-Specific / Q000737:chemistry; D004034:Diet Surveys; D004038:Diet, Reducing / Q000009:adverse effects / Q000706:statistics & numerical data; D019587:Dietary Supplements; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000378:metabolism*; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008715:Methionine / Q000097:blood; D008727:Methotrexate / Q000494:pharmacology; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D011795:Surveys and Questionnaires
chemical_list: D006710:Homocysteine; D004247:DNA; D005492:Folic Acid; D008715:Methionine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D015252:Deoxyribonucleases, Type II Site-Specific; C032229:GANTC-specific type II deoxyribonucleases; D008727:Methotrexate