Altered folate and vitamin B-12 metabolism in families with spina bifida offspring

Folic acid intake reduces the risk of neural tube defects (NTDs). Although the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for NTDs, it only partly explains the elevated homocysteine levels in mothers of children with NTDs. We measured vitamin B-12, folate and homocysteine in patients with spina bifida (SE), their parents, and in controls, to investigate which other enzymes of homocysteine metabolism might be defective. Because homozygosity for the 677C-->T mutation causes decreased plasma folate and increased red-cell folate (RCF) and plasma homocysteine levels, we excluded individuals homozygous for that mutation. The remaining SE patients and their parents still had lowered plasma folate and elevated total homocysteine levels, and a small subset had decreased vitamin B-12 levels. Red-cell folate was the same in all groups, suggesting that dietary folate intake and its uptake was normal. Risk of SE was increased at the 25th percentile of plasma folate and at the 75th percentile of homocysteine values in SE patients and their parents, and at the 5th and 25th percentiles of vitamin B-12 in mothers with SE-affected offspring. This underlines the functional importance of homocysteine remethylation to methionine. There was no correlation between vitamin B-12 and homocysteine or RCF. In combination with the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our data do not support. a major involvement of methionine synthase in the aetiology of SE. Our data rather favour the involvement of genetic variation at loci coding for the formation of 5-methyltetrahydrofolate, su ch as MTHFR, methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.