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It is now well established that folie acid, when taken periconceptionally, can prevent many neu ral tube defects. It is also becoming clear that folie acid does not work by correcting a nutritional deficiency in pregnant women. Rather, it appears that a metabolic defect is responsible for these neural tube defects and that this defect or defects can be corrected by a sufficiently large dose of folie acid. Our recent work demon strates that homocysteine metabolism is likely to be the critical pathway affected by folie acid. We have demonstrated significantly higher homocysteine levels in women carrying affected fetuses than in control women. These findings indicate that one of the en zymes responsible for homocysteine metabolism is likely to be abnormal in affected pregnancies. Animal studies suggest that the conversion of homocysteine to methionine could be the critical step. Rat embryos in culture require methionine for neural tube closure. Methionine synthase, cystathionine synthase, and 5,10 methylene tetrahydrofolate reductase are all im portant in the metabolism of homocysteine in humans. If methionine synthase is the critical enzyme, it would raise the interesting public health issue that vitamin B-12 might be able to stimulate the abnormal enzyme as folie acid does. Adding vitamin B-12 might make it possible to reduce the dose of folie acid required in fortified food, thus allaying concerns about overexposure to folie acid. J. Nutr. 126: 756S-760S, 1996. [ABSTRACT FROM AUTHOR]