Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects

Am J Clin Nutr. 2019 Mar 1;109(3):674-683. doi: 10.1093/ajcn/nqy340.


Background: The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms.

Objectives: This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk.

Methods: We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings).

Results: The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk.

Conclusions: The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.

Keywords: S-adenosylmethionine; gastric intrinsic factor; methionine synthase; methylenetetrahydrofolate reductase; neural tube defects; spina bifida; vitamin B-12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics*
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
  • Case-Control Studies
  • Female
  • Ferredoxin-NADP Reductase / genetics
  • Ferredoxin-NADP Reductase / metabolism
  • Fetal Diseases / enzymology*
  • Fetal Diseases / genetics
  • Fetal Diseases / metabolism
  • Folic Acid / analysis
  • Folic Acid / metabolism
  • Gestational Age
  • Humans
  • Liver / chemistry
  • Liver / embryology
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Neural Tube Defects / embryology
  • Neural Tube Defects / enzymology*
  • Neural Tube Defects / genetics
  • Neural Tube Defects / metabolism
  • Pregnancy
  • Vitamin B 12 / analysis
  • Vitamin B 12 / metabolism*


  • Folic Acid
  • methionine synthase reductase
  • Ferredoxin-NADP Reductase
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Vitamin B 12