Inositol-preventable neural tube defects: understanding the molecular causes and mechanisms of prevention

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During early pregnancy, a crucial event in the developing embryo is the formation of 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 handicap in surviving babies. 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 and for this reason, we are seeking additional protective approaches. Using a mouse model that naturally develops folate-resistant NTDs we found that another vitamin, inositol, can prevent NTDs, and we are now carrying out a clinical trial to test whether inositol prevents NTDs in humans. There are two main aims of the present research proposal. First, we will investigate the cause of the inositol-preventable NTDs in the mouse. We have used a technique that lets us separate many proteins and compare which ones are present in normal embryos and those that develop NTDs. We have detected several proteins that seem to be present at lower abundance or in abnormally modified forms in embryos developing NTDs. We will build on these studies by analysing the proteins that seem to be abnormal in the embryos that develop spina bifida. Understanding the role of specific proteins in the mouse may indicate risk factor genes in humans. The second aim of the research is to work out exactly how inositol prevents NTDs, as this may allow improvements to be made in the therapeutic approach. Knowledge of the causes of NTDs in humans may then allow more accurate counselling for affected families who are considering a further pregnancy, and may allow identification of women who will benefit from inositol supplementation.