Population-based studies of human pregnancies show that periconceptional fo
late supplementation has a significant protective effect for embryos during
early development, resulting in a significant reduction in developmental d
efects of the face, the neural tube, and the cono-truncal region of the hea
rt. These results have been supported by experiments with animal models. An
obvious quality held in common by these three anatomical regions is that t
he normal development of each region depends on a set of multi-potent cells
that originate in the mid-dorsal region of the neural epithelium. However,
the reason for the sensitive dependence of these particular cells on folic
acid for normal development has not been obvious, and there is no consensu
s about the biological basis of the dramatic rescue with periconceptional f
olate supplementation. There are two principal hypotheses for the impact of
folate insufficiency on development; each of these hypotheses has a micron
utrient component and a genetic component. In the first hypothesis the effe
ct of low folate is direct, limiting the availability of folic acid to cell
s within the embryo itself; thus compromising normal function and limiting
proliferation. The second hypothetical effect is indirect: low folate disru
pts methionine metabolism; homocysteine increases in the maternal serum; ho
mocysteine induces abnormal development by inhibiting the function of N-met
hyl-D-aspartate (NMDA) receptors in the neural epithelium. There are three
general families of genes whose level of expression may need to be consider
ed in the context of these two related hypotheses: folate-receptor genes; g
enes that regulate methionine-homocysteine metabolism; NMDA-receptor genes.