Genetic determinants of folate and vitamin B12 metabolism: A common pathway in neural tube defect and Down syndrome?

Jean Louis Guéant, Rosa Maria Guéant-Rodriguez, Guido Anello, Paolo Bosco, Laurent Brunaud, Corrado Romano, Rafaele Ferri, Antonino Romano, Mirande Candito, Bernard Namour

Research output: Contribution to journalArticlepeer-review


One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C→T and 1298 A→C), of methionine synthase (MTR 2756 C→G), methionine synthase reductase (MTRR 66 A→G) and transcobalamin (TCN 776 C→G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C→T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C→T and MTRR 66 A→G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C→T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations.

Original languageEnglish
Pages (from-to)1473-1477
Number of pages5
JournalClinical Chemistry and Laboratory Medicine
Issue number11
Publication statusPublished - 2003


  • Down syndrome
  • Folate
  • Genetic polymorphism
  • Homocysteine
  • Neural tube defect
  • Vitamin B

ASJC Scopus subject areas

  • Clinical Biochemistry


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