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Anomalies in homocysteine (HCY) and folate metabolism are associated with common birth defects and adult diseases, several of which can be suppressed with dietary folate supplementation. Although supplementation reduces the occurrence and severity of neural tube defects (NTDs), many cases are resistant to these beneficial effects. The basis for variable response and biomarkers that predict responsiveness are unknown. Crooked-tail (Cd) mutant mice are an important model of folate-responsive NTDs. To identify features that are diagnostic for responsiveness versus resistance to dietary folate supplementation, we surveyed metabolite and expression levels in liver samples from folate-supplemented, folate-reduced and control diets in Cd mutant and wild-type adult females. Cd homozygotes had normal total homocysteine (tHcy) levels suggesting that folate suppresses NTDs through a mechanism that does not involve modulating serum tHcy levels. Instead, parallel changes in metabolite and expression profiles in folate-supplemented Cd/Cd homozygotes and folate-reduced+/+and Cd/+mice suggest that Crooked-tail homozygotes have a defect in the utilization of intracellular folate. Then, by combining these expression and metabolite profile results with published results for other models and their controls, two clusters were found, one of which included several folate-responsive NTD models and the other previously untested and presumably folate-resistant models. The predictive value of these profiles was verified by demonstrating that NTDs of Ski-/-mutant mice, whose profile suggested resistance to folate supplementation, were not suppressed with dietary folate supplementation. These results raise the possibility of using metabolite and expression profiles to distinguish folate-responsive and resistance adult females who are at risk for bearing fetuses with an NTD.

Parallel changes in metabolite and expression profiles in crooked-tail mutant and folate-reduced wild-type mice