Intervention Strategies for Non-Folate Responsive Neural Tube Defects

摘要 先天缺陷是新生儿死亡的主要原因，导致的婴儿死亡人数超过了 老年痴呆症、中风、糖尿病和流感的成人死亡人数。神经管缺陷（NTDs），第二个 最常见的人类出生缺陷，当神经管在发育过程中未能正确闭合时， 神经形成在全球范围内，这些缺陷估计影响每10，000例活产约18.6例， 在美国大部分地区，NTD的患病率为每1,000名新生儿1-2例。大约有2,300新台币- 在美国，每年有1000名孕妇受到影响，每个孩子一生的医疗费用估计为56万美元。 或者说全国每年16.8亿美元。尽管几十年来进行了深入的研究，但对 潜在的NTD风险因素。人们普遍认为，NTD是多因素引起的， 导致畸形的环境和遗传因素。虽然已经确定， 围怀孕期使用叶酸（FA）可以预防NTD的人口负担的显着百分比， FA降低NTD风险的机制尚不清楚。重要的是 大量的NTD不能通过FA补充预防，这些FA耐药NTD 发生率明显基线为每10，000名活产5人。因此，NTD仍然是一个重要的公共卫生问题， 问题，并且迫切需要了解FA耐药NTD的机制， 针对这一人群制定新的干预战略 为了扩大在最初的资助期间所做的工作，我们提出的研究路线探讨了机制 线粒体一碳代谢受损导致NTD的机制，以及我们提出的干预措施 成功还原正确NTC。与此同时，我们正在通过以下方法测试疗效并研究机制： 补充甘氨酸可以挽救这些FA抗性缺陷。建立这些机制并 他们对实际的人类NTD变异可能最终使我们能够利用我们提出的干预策略， 通过宣传公共卫生政策或精准医疗战略，预防以前无法预防的出生缺陷， 从而减少这些使人衰弱的缺陷对受影响的家庭和 公众

ABSTRACT Congenital defects are the leading cause of neonatal mortality, resulting in more infant deaths than the combined adult death tolls of Alzheimer’s disease, strokes, diabetes, and influenza. Neural tube defects (NTDs), the second most common category of human birth defects, arise when the neural tube fails to close properly during neurulation. Globally, these defects are estimated to affect approximately 18.6 per 10,000 live births and the prevalence of NTDs is 1–2 per 1,000 births in most regions of the US. There are approximately 2,300 NTD- affected pregnancies in the US each year, whose lifetime medical costs are estimated to be $560,000 per child or $1.68 billion per year nationwide. Despite intensive investigation for decades, relatively little is known about the underlying NTD risk factors. It is generally accepted that NTDs are of a multi-factorial origin, having both environmental and genetic factors that contribute to the malformation. Although it is established that periconceptional use of folic acid (FA) prevents a significant percentage of the population burden of NTDs, the mechanisms underlying those processes by which FA reduces NTD risk remains unknown. Importantly, there are significant numbers of NTDs that are not preventable by FA supplementation, with these FA-resistant NTDs occurring at an apparent baseline rate of 5 per 10,000 live births. Thus, NTDs remain a substantial public health problem, and there is a critical need to understand the mechanisms underlying FA-resistant NTDs and to develop novel intervention strategies targeting this population To expand upon work performed in the initial funding period, our proposed line of study explores mechanisms by which impairment of mitochondrial one carbon metabolism causes NTDs and how our proposed interventions successfully restore proper NTC. Simultaneously, we are testing the efficacy and investigating mechanisms by which glycine supplementation rescues these FA-resistant defects. Establishing these mechanisms and relating them to actual human NTD variants may eventually allow us to utilize our proposed intervention strategies to prevent previously unpreventable birth defects by informing public health policy or precision medicine strategies, thus reducing the significant negative health burden of these debilitating defects on affected families and the public.