Neural tube defects and a disturbed folate dependent homocysteine metabolism.

Folate administration substantially reduces the risk on neural tube defects (NTD). The interest for 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. This leads 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 an 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.