Inositol, neural tube closure and the prevention of neural tube defects

Abstract

Susceptibility to neural tube defects (NTDs), such as anencephaly and spina bifida is influenced by genetic and environmental factors including maternal nutrition. Maternal periconceptional supplementation with folic acid significantly reduces the risk of an NTD‐affected pregnancy, but does not prevent all NTDs, and “folic acid non‐responsive” NTDs continue to occur. Similarly, among mouse models of NTDs, some are responsive to folic acid but others are not.Among nutritional factors, inositol deficiency causes cranial NTDs in mice while supplemental inositol prevents spinal and cranial NTDs in the curly tail (Grhl3 hypomorph) mouse, rodent models of hyperglycemia or induced diabetes, and in a folate‐deficiency induced NTD model. NTDs also occur in mice lacking expression of certain inositol kinases. Inositol‐containing phospholipids (phosphoinositides) and soluble inositol phosphates mediate a range of functions, including intracellular signaling, interaction with cytoskeletal proteins, and regulation of membrane identity in trafficking and cell division. Myo‐inositol has been trialed in humans for a range of conditions and appears safe for use in human pregnancy. In pilot studies in Italy and the United Kingdom, women took inositol together with folic acid preconceptionally, after one or more previous NTD‐affected pregnancies. In nonrandomized cohorts and a randomized double‐blind study in the United Kingdom, no recurrent NTDs were observed among 52 pregnancies reported to date.Larger‐scale fully powered trials are needed to determine whether supplementation with inositol and folic acid would more effectively prevent NTDs than folic acid alone. Birth Defects Research 109:68–80, 2017. © 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.

Association between biomarkers of vitamin B12 status and the risk of neural tube defects

“…Inositol is required for neural tube closure, and supplemental inositol can prevent NTD development in various experimental models. Inositol could act to overcome the underlying causative defect responsible for NTD or enhance the normal processes required for neural tube closure . A randomized controlled study is required to investigate whether inositol + folic acid has a greater protective effect against NTD than folic acid alone or not .…”

“…Inositol could act to overcome the underlying causative defect responsible for NTD or enhance the normal processes required for neural tube closure . A randomized controlled study is required to investigate whether inositol + folic acid has a greater protective effect against NTD than folic acid alone or not . It should be hypothesized that caffeine intake might result in a biological mechanism that could mimic inositol deficiency …”

Expression of 1L-myo-Inositol -1-Phosphate Synthase (EC 5.5.1.4) is Deregulated in the Cerebellum of Curly Tail Mutant Mice

“…The overall reaction mechanism consists of a tightly coupled oxidation and reduction [9,10,11]. A major nutritionally active form of inositol, myo-inositol, is vital to many neurological processes [12,13,14,15].…”

Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion

“…They arise due to failure of NT closure in the early embryo 2 . Mouse models faithfully recapitulate these conditions and have historically led to the identi cation of diagnostic and preventative strategies, as well as identifying genes and pathways required for NT closure [3][4][5] . Key genes include members of the Wnt/planar cell polarity (PCP) pathway and enzymes of folate metabolism 6 , with the latter already a clinical target for primary prevention.…”