Altered folate and vitamin B12 metabolism in families with spina bifida offspring

Folic acid intake reduces the risk of neural tube defects (NTDs). Althoughthe 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase(MTHFR) gene is a risk factor for NTDs, it only partly explains theelevated homocysteine levels in mothers of children with NTDs. We measuredvitamin B12, folate and homocysteine in patients with spina bifida (SB),their parents, and in controls, to investigate which other enzymes ofhomocysteine metabolism might be defective. Because homozygosity for the677C-->T mutation causes decreased plasma folate and increased red-cellfolate (RCF) and plasma homocysteine levels, we excluded individualshomozygous for that mutation. The remaining SB patients and their parentsstill had lowered plasma folate and elevated total homocysteine levels, anda small subset had decreased vitamin B12 levels. Red-cell folate was thesame in all groups, suggesting that dietary folate intake and its uptakewas normal. Risk of SB was increased at the 25th percentile of plasmafolate and at the 75th percentile of homocysteine values in SB patients andtheir parents, and at the 5th and 25th percentiles of vitamin B12 inmothers with SB- affected offspring. This underlines the functionalimportance of homocysteine remethylation to methionine. There was nocorrelation between vitamin B12 and homocysteine or RCF. In combinationwith the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our datado not support a major involvement of methionine synthase in the aetiologyof SB. Our data rather favour the involvement of genetic variation at locicoding for the formation of 5-methyltetrahydrofolate, such as MTHFR,methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.