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

Clin Chem Lab Med. 2003 Nov;41(11):1473-7. doi: 10.1515/CCLM.2003.226.


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.

Publication types

  • Review

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics
  • Down Syndrome / genetics*
  • Down Syndrome / metabolism
  • Folic Acid / metabolism*
  • Genotype
  • Homocysteine / metabolism
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Neural Tube Defects / genetics*
  • Neural Tube Defects / metabolism
  • Polymorphism, Genetic / genetics
  • Transcobalamins / genetics
  • Vitamin B 12 / metabolism*


  • Transcobalamins
  • Homocysteine
  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Vitamin B 12