Fundamental origins of neural tube defects with a basis in genetics and nutrition.

Neural tube defects (NTDs) are leading congenital malformations. Its global prevalence is one in 1000 pregnancies and it has high morbidity and mortality. It has multiple risk factors like genetic errors and environmental stressors like maternal malnutrition and in utero exposure to pollutants like chemicals. The genetic program determines neural tube development based on timely expression of many genes involved in developmental signaling pathways like BMP, PCP and SHH. BMP expression defines ectoderm. SOX represses BMP in ectoderm and convertes to the neuroectoderm. Subsequently, PCP molecules define the tissue patterning for convergent-extension, a critical step in neural tube genesis. Further, SHH sets spatial patterning of the neural tube. Nutrients are the essential major environmental input for embryogenesis. But it may also carry risk factors. Malnutrition, especially folate deficiency, during embryogenesis is a major cause for NTDs. Folate is integral in the One Carbon metabolic pathway. Its deficiency and error in the pathway are implicated in NTDs. Folate supplementation alone is insufficient to prevent NTDs. Thus, a comprehensive understanding of the various risk factors is necessary to strategize reduction of NTDs. We review the current knowledge of various risk factors, like genetic, metabolic, nutritional, and drugs causing NTDs and discuss the steps required to identify them in the early embryogenesis to avoid NTDs.