New Insights into Neural Tube Closure: Folic Acid Non-Responsive Neural Tube Defects.

Neural tube defects (NTDs) are common, severe, and complicated congenital malformations that are the result of the interaction and interplay of genetic, nutritional, and environmental factors. Maternal periconceptional folic acid (FA) supplementation is a significantly effective strategy for primary prevention of a proportion of NTDs. However, there still exists a portion of NTD cases that are intrinsically resistant to FA therapies, which are widely referred to as “FA-non-responsive NTDs” or “FA-resistant NTDs” . These diseases have a complex etiology, involving genetic, nutritional, environmental and maternal factors. This review integrates the genetic, nutritional, environmental and maternal risk factors associated with FA non-responsive NTDs and reveals the progress of research on their pathogenic mechanisms. Among them, the genetic factors cover three aspects: mouse mutants and strains, FA one-carbon metabolism genes, and key apoptosis genes, which provide possible genetic testing loci for prenatal diagnosis of these children. Nutritional factors concentrate on the roles of inositol and methionine, delineating their possible mechanisms of action and suggesting new directions for early nutritional interventions in NTDs management. In addition, this paper explores the possible mechanisms by which vitamin B12, a cofactor in the FA one-carbon metabolism, in FA-non-responsive NTDs development. We posit that a combination of FA and other vitamins may enhance treatment strategies for these malformations. At last, this paper also reviews the influence of environmental and maternal factors on FA non-responsive NTDs, aiming to provide health recommendations for early pregnancy for at-risk populations. In summary, this article reviews and evaluates research advancement concerning FA non-responsive NTD risk factors and pathogenesis, providing novel insights into the current prevention and treatment of this disease and related birth defects. [ABSTRACT FROM AUTHOR]