Folate metabolism and development of Neural Tube Defects

在怀孕早期，胚胎发育中的一个关键事件是形成一种称为神经管的结构，这种结构后来将发育成大脑和脊髓。神经管未能正确形成导致一组称为神经管缺陷（NTD）的出生缺陷，其中胎儿的大脑和/或脊髓受到不可逆的损伤，导致出生前或出生后不久死亡，或存活婴儿的长期残疾。脊柱裂是NTD最常见的类型。总体而言，NTD发生率约为1/1，000，尽管发生率各不相同，并且在某些地区（例如北方爱尔兰和苏格兰）明显更高。全世界每年约有13万例NTD，其发病风险取决于遗传因素和饮食等非遗传因素，但确切原因尚不清楚。然而，如果母亲在怀孕前和怀孕早期服用叶酸补充剂，受影响怀孕的风险可以大大降低。不幸的是，并非所有NTD病例都可以通过叶酸预防，因此需要额外的治疗。为了在预防所有NTD方面取得进一步进展，我们需要更好地了解其原因。目前，NTD的遗传原因在大多数患者中无法解释，但在解开这些疾病的复杂性方面正在取得相当大的进展。我们的长期目标是确定NTD的预防性治疗方法，可以单独使用或联合使用。在已经确定遗传风险因素的家庭中，这也意味着可以提供针对家庭的治疗。在所有细胞中，有效处理称为叶酸的小分子，这与叶酸有关，需要许多不同的功能，包括为细胞分裂制造DNA。一个重要的问题是，一些NTD是否是由发育中的婴儿细胞处理叶酸的先天异常引起的。我们最近研究了一组参与叶酸处理的蛋白质，发现一些NTD患者在这些蛋白质中存在缺陷，而未受影响的人则没有。这一发现表明，这些问题的问题可能直接导致NTD。为了支持这一观点，在同一组蛋白质中存在缺陷的小鼠胚胎也会产生NTD。这些小鼠模型为研究这些叶酸处理蛋白在胚胎中的作用以及如何预防相关的NTD提供了机会。

During early pregnancy, a crucial event in the developing embryo is the formation of a structure called the neural tube, which will later develop into the brain and spinal cord. Failure of the neural tube to form correctly leads to a group of birth defects called neural tube defects (NTDs), in which the brain and/or spinal cord of the fetus become irreversibly damaged, resulting in death before or shortly after birth, or long term disability in surviving babies. Spina bifida is the best known type of NTD. Overall, NTDs occur in around 1 per 1,000 pregnancies although the rate varies and is significantly higher in some regions (e.g. Northern Ireland and Scotland). Worldwide, approximately 130,000 cases occur every year.The risk of NTDs depends on both inherited genetic factors and non-genetic factors such as diet, but the exact causes are not well understood. However, the risk of an affected pregnancy can be substantially reduced if the mother takes folic acid supplements before and during early pregnancy. Unfortunately, not all cases of NTDs are preventable by folic acid, so additional therapies are needed. In order to make further progress towards prevention of all NTDs we need a better understanding of their causes. At the present time the genetic cause of an NTD cannot be explained in most patients, but considerable progress is being made towards unravelling the complexity of these diseases. Our long-term goal is to identify preventive therapies for NTDs which may be used individually or in combination. In families where genetic risk factors have been identified this also means that family-specific therapies may be offered.In all cells, efficient handling of small molecules called folates, which are related to folic acid, is needed for a number of different functions including making DNA for cells to divide. An important question is whether some NTDs are caused by an inborn abnormality in the way that the cells in the developing baby handle folate. We recently studied a group of proteins that are involved in folate handling and found that some patients with NTDs have defects in these proteins, whereas unaffected people did not. This finding suggests that problems with these problems may directly cause NTDs. In support of this idea, mouse embryos that have defects in the same group of proteins also develop NTDs. These mouse models provide an opportunity to study what job these folate handling proteins are doing in the embryo and how the associated NTDs may be prevented.