Folate, Homocysteine and Neural Tube Defects: An Overview

Abstract

Folate administration substantially reduces the risk on neural tube defects (NTD). The interest for studying a disturbed homocysteine (Hcy) metabolism in relation to NTD was raised by the observation of elevated blood Hcy levels in mothers of a NTD child. This observation resulted in the examination of enzymes involved in the folate-dependent Hcy metabolism. Thus far, this has led to the identification of the first and likely a second genetic risk factor for NTD. The C677T and A1298C mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with an increased risk of NTD and cause elevated Hcy concentrations. These levels can be normalized by additional folate intake. Thus, a dysfunctional MTHFR partly explains the observed elevated Hcy levels in women with NTD pregnancies and also, in part, the protective effect of folate on NTD. Although the MTHFR polymorphisms are only moderate risk factors, population-wide they may account for an important part of the observed NTD prevalence.

Neural tube defects and folate: case far from closed

“…These onecarbon units are covalently bound to folate (R′ in FIG . 2) and are present over the whole range of oxidized and reduced forms of the one-carbon moiety, including the formyl and methyl derivatives (for reviews, see REFS [42][43][44] ). These one-carbon units are donated to THF by the amino acids histidine and serine, and glycine and its derivatives dimethylglycine and methylglycine (sarcosine), or by formate, and are used in the synthesis of DNA building blocks -that is, purines (adenine and guanine) and thymine (the thymidine precursor dTMP is shown in FIG.…”

“…Elevated homocysteine concentrations have been observed in mothers who have delivered children with an NTD but who have normal folate levels, which was taken as an indicator of dysfunction of folate metabolism 30,43,45 . The strong homocysteine-lowering effect of folate supplementation 46 indicates that this form of dysfunctional folate metabolism can be overcome by additional folate intake.…”

“…Addition of a one-carbon unit and subsequent reduction steps produce 5-methyltetrahydrofolate (5-MeTHF) monoglutamate, which is taken up into the bloodstream and is the main form of folate in the circulation. From the blood, specific carriers or receptors transport 5-MeTHF into cells 42,43 (FIG. 3).…”

Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations

“…A phenotype characterized by high homocysteine and low folate may be pathogenic and has been associated with diverse conditions ranging from cardiovascular diseases 1 to birth defects including spina bifida. 2 Homocysteine concentrations are influenced by dietary factors such as folate and B vitamins, lifestyle factors such as smoking, and genetic factors such as functional polymorphisms in the enzymes of folate/ homocysteine metabolism. 3 The key enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR, EC 1.5.1.20) generates 5-methyltetrahydrofolate, the methyl donor that is used for homocysteine remethylation to methionine.…”

PCMT1 gene polymorphisms, maternal folate metabolism, and neural tube defects: a case–control study in a population with relatively low folate intake

“…Previous experimental studies on mouse NTD models and analysis of inheritance patterns in humans suggest that NTDs result from the interplay of multiple genes, as well as interactions between gene and environment, rather than being monogenic malformations (Harris and Juriloff 2007;Holmes et al 1976;Shaw et al 1994;van der Put et al 2001). Among the potential environmental factors, maternal folate status is known to be a protective factor against NTDs.…”