Abnormal folate metabolism in foetuses affected by neural tube defects
1Neural Development Unit and 2Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, 3Fetal Medicine Unit, Elizabeth Garrett Anderson and Obstetric Hospital, University College London Hospital and 4Department of Histopathology, University College London Hospital, London, UK
Correspondence to: Nicholas D. E. Greene, Neural Development Unit, Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK E-mail: n.greene{at}ich.ucl.ac.uk
Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs.
Key Words: neural tube defects; anencephaly; spina bifida; folate; s-adenosylhomocysteine; s-adenosylmethionine
Abbreviations: dTMP, deoxythymidine monophosphate; dU, deoxyuridine; MTHFR, 5,10-methylenetetrahydrofolate reductase; MTRR, methionine synthase reductase; NTDs, neural tube defects; SAH, s-adenosylhomocysteine; SAM, s-adenosylmethionine
Received December 7, 2006. Revised January 30, 2007. Accepted February 1, 2007.
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