Critical Reviews in Oral Biology & Medicine, Vol 9, 38-53, Copyright © 1998 by International & American Associations for Dental Research
Neural tube and craniofacial defects with special emphasis on folate pathway genes
R. H. Finnell, K. A. Greer, R. C. Barber and J. A. Piedrahita
Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station 77843-4458, USA.
Neural tube and orofacial defects are common congenital malformations in
humans. While etiologically heterogeneous, they are for the most part
multifactorial in their pathogenesis, having both genetic and environmental
components in their development. In recent years, there has been a great
deal of epidemiologic evidence demonstrating that women who received
multivitamins containing folic acid periconceptionally had significantly
reduced occurrence and recurrence risks for producing infants with such
malformations. This risk reduction is not observed in all populations,
further suggestive of a genetic regulation of this phenomenon.
Unfortunately, the mechanisms underlying the beneficial effects of folic
acid are not well-understood. In this article, we review the relevant
epidemiologic data on both neural tube defects and orofacial malformations,
the fundamental embryological processes involved in closing the neural
tube, and the development of the craniofacies, and propose a working
hypothesis for susceptibility to these malformations. This hypothesis is
based on the interworkings of cellular folate transport, focusing on the
key elements involved in potocytosis. We propose that infants with
mutations in the folate receptor alpha gene might be at increased risk for
congenital anomalies due to a reduced binding affinity for
5-methyltetrahydrofolate, the physiologic form of folic acid. Various
experimental approaches to test the working hypothesis are considered.
