Neural tube defects, folic acid and methylation

Abstract

Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.

Figure 1

Countries with mandatory folic acid food fortification, adapted from [71].

Figure 2

Reduction rate of NTDs after FA food fortification depending on baseline prevalence.

Figure 3

Simplified folate metabolism and its interrelation with the remethylation cycle, vitamin B12 and choline metabolism. Enzymes are in blue. Blue arrows indicate metabolites that can be provided by the diet. BADH, betaine aldehyde dehydrogenase; BHMT, betaine-homocysteine methyltransferase; CBS, cystathionine β-synthase; CHDH, choline dehydrogenase; DDH, dimethylglycine dehydrogenase; MAT, methionine adenosyltransferase; MT, methyltransferases; MTHFR, methylenetetrahydrofolate reductase; MTHFD, methylenetetrahydrofolate dehydrogenase/methylenetetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase; 5-MeTHF, 5-methyltetrahydrofolate; 5,10-MTHF, 5,10-methylenetetrahydrofolate; MTR, methionine synthase; MTRR, methionine synthase reductase; SAHH, S-adenosylhomocysteine hydrolase; SARDH, sarcosine dehydrogenase; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate.

Figure 4

Nutritional, biological, and genetic risk factors of folate, B12 vitamin, remethylation and choline metabolisms that have (potentially) been related with NTDs risk. MMA: Methylmalonic acid, holo-TC: holo-transcobalamin.