Neural Tube and Craniofacial Defects With Special Emphasis On Folate Pathway Genes

Abstract

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...

Chemical exposure during pregnancy and oral clefts in newborns

“…However, this phenomenon has not been observed in all populations, suggesting the existence of genetic regulation in this phenomenon (Finnell et al, 1998). Various lines of experimental research demonstrate the biological plausibility of the use of folic acid in reducing the occurrence of orofacial clefts.…”

“…The second relates to women with apoplectic disorders using anticonvulsivant medication, known antagonists of folic acid, who are at increased risk of bearing children with this birth defect (Dansky & Finnell, 1991;Shaw et al, 1995). Given the possibility that fetal deficiency in both the transport and metabolism of folic acid places the fetus at increased risk for this malformation, and that maternal folic acid supplementation is not effective in all individuals, it is important to identify potential candidate genes for regulating this process (Finnell et al, 1998). Werler et al (1999) highlight that it is not clear which combination of nutrients or which specific nutrient is related to risk reduction for other malformations, since many vitamin supplements include 7 out of 8 water-soluble vitamins and 3 fat-soluble vitamins, in addition to at least 4 minerals or trace elements.…”

“…Although they are etiologically distinct, both involve genetic and environmental components in their development (Finnell et al, 1998). Although facial clefts have been reported for centuries, their etiology has not been clearly established (Gordon & Shy, 1981).…”

Mortalidad por defectos del tubo neural en México, 1980-1997

“…10,12,13 Los datos de la Encuesta Mexicana de Nutrición de 1999 mostraron que el consumo de folatos estimado en la mujer mexicana entre 12 y 49 años de edad fue inferior a lo recomendado (304 mcg/ día versus 400 mcg/día), con cifras similares, tanto en mujeres embarazadas, como no embarazadas (330 mcg/día y 304 mcg/día, respectivamente) y muy pa- rrero mostraron significación estadística en la razón observado/esperado (p<0.10).…”

“…También la carencia de algunos micronutrientes en la dieta materna, como el ácido fólico, se asocia con MC como DTN, malformaciones cardiovasculares, anomalías craneofaciales, etcétera. [10][11][12][13] Asimismo, se ha señalado que ciertas exposiciones ambientales y laborales a diversas sustancias químicas, como los plaguicidas y algunos disolventes, pueden incrementar el riesgo de MC. [14][15][16][17] Entre las MC, los DTN ocupan un capítulo especial por el daño implícito a diversas estructuras del sistema nervioso, que los hace comúnmente incompatibles con la vida.…”