Impaired regeneration of monoglutamyl tetrahydrofolate leads to cellular folate depletion in mothers affected by a spina bifida pregnancy

Periconceptional folate prevents neural tube defects (NTD) by a mechanism which is unclear. The present study found significant changes in the equilibrium of the homocysteine remethylation cycle in NTD affected mothers, possibly involving B-12-dependent methionine synthase or 5,10-methylenetetrahydrofolate reductase, Data were consistent with impaired Hey remethylation leading to poor regeneration of H(4)PteGlu(1), the main intracellular precursor of all folates. This lesion leads to cellular folate deficiency indicated by a significantly lower radioassay RBC folate and 5CH(3)H(4)PteGlu(4) in affected mothers. The drop in this tetraglutamate is associated with an increase in the abundance of longer chain oligo-gamma-glutamyl folate, again reflecting the underlying folate deficiency. This effect may compromise purine, DNA-thymine, and methionine production, particularly during embryogenesis when folate demand is high. At this time serine hydroxymethyltransferase may play a critical role in conserving H(4)PteGlu(1) for purine synthesis. Many of these depletion effects were corrected with folate supplementation for 1 month, (C) 1998 Academic Press.