ALTERED FOLATE AND VITAMIN-B-12 METABOLISM IN FAMILIES WITH SPINA-BIFIDA OFFSPRING

Folic acid intake reduces the risk of neural tube defects (NTDs). Alth ough the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reduc tase (MTHFR) gene is a risk factor for NTDs, it only partly explains t he elevated homocysteine levels in mothers of children with NTDs. We m easured vitamin B-12, folate and homocysteine in patients with spina b ifida (SE), their parents, and in controls, to investigate which other enzymes of homocysteine metabolism might be defective. Because homozy gosity for the 677C-->T mutation causes decreased plasma folate and in creased red-cell folate (RCF) and plasma homocysteine levels, we exclu ded individuals homozygous for that mutation. The remaining SE patient s and their parents still had lowered plasma folate and elevated total homocysteine levels, and a small subset had decreased vitamin B-12 le vels. Red-cell folate was the same in all groups, suggesting that diet ary 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 a nd 25th percentiles of vitamin B-12 in mothers with SE-affected offspr ing. This underlines the functional importance of homocysteine remethy lation to methionine. There was no correlation between vitamin B-12 an d homocysteine or RCF. In combination with the lowered plasma folate ( 80-90% 5-methyltetrahydrofolate), our data do not support. a major inv olvement of methionine synthase in the aetiology of SE. Our data rathe r favour the involvement of genetic variation at loci coding for the f ormation of 5-methyltetrahydrofolate, su ch as MTHFR, methylenetetrahy drofolate dehydrogenase or serine hydroxymethyltransferase.