Folate, homocysteine and the cardiac neural crest.

Congenital heart defects (CHD) are the most common congenital defects worldwide, and perigestational folate supplementation (PFS) is the most effective large-scale intervention to date for reducing CHD. This review is based upon the following premises: that the majority of CHD result from disruption of development of the cardiac neural crest (CNC); and that the CNC is highly responsive to folate and homocysteine. The following roles of folate are discussed in relation to CNC development: one-carbon metabolism in support of mitosis and gene methylation; and gene regulation via direct activity of the folate receptor. The following roles of hyperhomocysteinemia are discussed in the same context: increased oxidative stress; disruption of gene methylation; homocysteinylation of key proteins; and NMDA receptor binding. It is proposed that well-focused advances in folate-CNC research could lead to development of strategies, in addition to PFS, to facilitate normal CNC and heart development, and thereby further reduce CHD.