DECREASED METHYLENE TETRAHYDROFOLATE REDUCTASE-ACTIVITY DUE TO THE 677C-]T MUTATION IN FAMILIES WITH SPINA-BIFIDA OFFSPRING

Periconceptional folate intake reduces both the occurrence and recurre nce risk of neural tube defects. Plasma homocysteine levels can be ele vated in mothers of a child with a neural tube defect, suggesting a dy sfunctional folate metabolism. Very recently we showed that a common 6 77C-->T mutation in the 5,10-methylene tetrahydrofolate reductase gene , causing thermolability of the enzyme, is a risk factor for spina bif ida offspring. Restriction enzyme analysis of the genomic 5,10-methyle ne tetrahydrofolate reductase polymerase chain reaction fragment revea led a significantly higher prevalence of a +/+ genotype among spina bi fida patients and their mothers. The risk for spina bifida offspring i s the strongest if both the mother and her child have the mutation in the homozygous state. Enzymatic analysis showed that homozygosity for the 677C-->T mutation causes a decreased 5,10-methylene tetrahydrofola te reductase activity, resulting in elevated plasma homocysteine and r ed blood cell folate levels and lowered plasma folate and cysteine val ues. This extended study demonstrates that a nucleotide substitution i n the coding region of 5,10-methylene tetrahydrofolate reductase, resu lting in reduced activity and an impaired homocysteine and folate meta bolism, is a genetic risk factor for spina bifida.