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 wellunderstood. 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.Key words. Folic acid, birth defects, genetic susceptibility.
Clinical DescriptionNeural tube defects (NTDs) are common congenital malformations that occur when the embryonic neural tube, which ultimately forms the brain and spinal cord, fails to close properly during the first few weeks of development. Anencephaly, which is invariably fatal, is characterized by the nearly complete degeneration of exposed anterior neural tube tissue (Hunter, 1993). The superficially "brain-like" mass of exposed tissue typically consists of collagen and connective and vascular tissue covered by an epithelial membrane (Hunter, 1993). When the brain is completely absent, the defect is referred to as holo-anencephaly, which occurs in approximately 65% of failed anterior neural tube closure (Myrianthopoulos and Melnick, 1987). A more mild malformation, meroanencephaly, involves the protrusion of the cerebrovasculosa through a partially formed skull (Myrianthopoulos and Melnick, 1987). According to Hunter (1993), approximately half of anencephalic infants are stillbirths, while the remainder live for variable periods of up to 48 hours.The other major NTD is spina bifida, which involves the protrusion of neural tissue through an opening in the vertebral arches and may occur anywhere along the length of the spinal cord. The severity of the defect can range from craniorachischisis, where the entire anterior and posterior neural tube is open, to a lesion limited to a single vertebral level. The vast majority of spina bifida lesions are found in the lumbar (42.2%) or lumbos...