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Genesis (New York, N.Y. : 2000) Nov 2021Neural tube defects (NTDs) are among the most common birth defects, with a prevalence of close to 19 per 10,000 births worldwide. The etiology of NTDs is complex... (Review)
Review
Neural tube defects (NTDs) are among the most common birth defects, with a prevalence of close to 19 per 10,000 births worldwide. The etiology of NTDs is complex involving the interplay of genetic and environmental factors. Since nutrient deficiency is a risk factor and dietary changes are the major preventative measure to reduce the risk of NTDs, a more detailed understanding of how common micronutrient imbalances contribute to NTDs is crucial. While folic acid has been the most discussed environmental factor due to the success that population-wide fortification has had on prevention of NTDs, folic acid supplementation does not prevent all NTDs. The imbalance of several other micronutrients has been implicated as risks for NTDs by epidemiological studies and in vivo studies in animal models. In this review, we highlight recent literature deciphering the multifactorial mechanisms underlying NTDs with an emphasis on mouse and human data. Specifically, we focus on advances in our understanding of how too much or too little retinoic acid, zinc, and iron alter gene expression and cellular processes contributing to the pathobiology of NTDs. Synthesis of the discussed literature reveals common cellular phenotypes found in embryos with NTDs resulting from several micronutrient imbalances. The goal is to combine knowledge of these common cellular phenotypes with mechanisms underlying micronutrient imbalances to provide insights into possible new targets for preventative measures against NTDs.
Topics: Animals; Gene-Environment Interaction; Humans; Micronutrients; Neural Tube Defects
PubMed: 34665506
DOI: 10.1002/dvg.23455 -
Journal of Molecular Medicine (Berlin,... Sep 2022No highly specific and sensitive biomarkers have been identified for early diagnosis of neural tube defects (NTDs). In this study, we used proteomics to identify novel...
No highly specific and sensitive biomarkers have been identified for early diagnosis of neural tube defects (NTDs). In this study, we used proteomics to identify novel proteins specific for NTDs. Our findings revealed three proteins showing differential expression during fetal development. In a rat model of NTDs, we used western blotting to quantify proteins in maternal serum exosomes on gestational days E18, E16, E14, and E12, in serum on E18 and E12, in neural tubes on E18 and E12, and in fetal neural exosomes on E18. The expression of coronin 1A and dynamin 2 was exosome-specific and associated with spina bifida aperta embryogenesis. Furthermore, coronin 1A and dynamin 2 were significantly downregulated in maternal serum exosomes (E12-E18), neural tubes, and fetal neural exosomes. Although downregulation was also observed in serum, the difference was not significant. Differentially expressed proteins were further analyzed in the serum exosomes of pregnant women during gestational weeks 12-40 using enzyme-linked immunosorbent assays. The findings revealed that coronin 1A and dynamin 2 showed potential diagnostic efficacy during gestational weeks 12-40, particularly during early gestation (12-18 weeks). Therefore, these two targets are used as candidate NTD screening and diagnostic biomarkers during early gestation. KEY MESSAGES: We used proteomics to identify novel proteins specific for NTDs. CORO1A and DNM2 showed exosome-specific expression and were associated with SBA. CORO1A and DNM2 were downregulated in maternal serum exosomes and FNEs. CORO1A and DNM2 showed good diagnostic efficacy for NTDs during early gestation. These two targets may have applications as NTD screening and diagnostic biomarkers.
Topics: Animals; Biomarkers; Dynamin II; Female; Fetus; Humans; Microfilament Proteins; Neural Tube Defects; Pregnancy; Rats
PubMed: 35915349
DOI: 10.1007/s00109-022-02236-w -
Birth Defects Research Jan 2017Disruption of the normal mechanisms that mediate neural tube closure can result in neural tube defects (NTDs) with devastating consequences in affected patients. With... (Review)
Review
Disruption of the normal mechanisms that mediate neural tube closure can result in neural tube defects (NTDs) with devastating consequences in affected patients. With the advent of next-generation sequencing, we are increasingly detecting mutations in multiple genes in NTD cases. However, our ability to determine which of these genes contribute to the malformation is limited by our understanding of the pathways controlling neural tube closure. G-protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors in humans and have been historically favored as drug targets. Recent studies implicate several GPCRs and downstream signaling pathways in neural tube development and closure. In this review, we will discuss our current understanding of GPCR signaling pathways in pathogenesis of NTDs. Notable examples include the orphan primary cilia-localized GPCR, Gpr161 that regulates the basal suppression machinery of sonic hedgehog pathway by means of activation of cAMP-protein kinase A signaling in the neural tube, and protease-activated receptors that are activated by a local network of membrane-tethered proteases during neural tube closure involving the surface ectoderm. Understanding the role of these GPCR-regulated pathways in neural tube development and closure is essential toward identification of underlying genetic causes to prevent NTDs. Birth Defects Research 109:129-139, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Embryonic Development; Gene Expression Regulation, Developmental; Hedgehog Proteins; High-Throughput Nucleotide Sequencing; Humans; Mutation; Neural Tube; Neural Tube Defects; Neurulation; Organogenesis; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 27731925
DOI: 10.1002/bdra.23567 -
Birth Defects Research Jan 2017Susceptibility to neural tube defects (NTDs), such as anencephaly and spina bifida is influenced by genetic and environmental factors including maternal nutrition.... (Review)
Review
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.
Topics: Animals; Clinical Trials as Topic; Dietary Supplements; Disease Models, Animal; Female; Folic Acid; Folic Acid Deficiency; Humans; Inositol; Inositol Phosphates; Maternal Nutritional Physiological Phenomena; Mice; Neural Tube; Neural Tube Defects; Phosphatidylinositols; Pregnancy
PubMed: 27324558
DOI: 10.1002/bdra.23533 -
Frontiers in Immunology 2022The fortification of flour with folic acid for the prevention of neural tube defects (NTD) is currently mandated in over eighty countries worldwide, hence compelling its...
The fortification of flour with folic acid for the prevention of neural tube defects (NTD) is currently mandated in over eighty countries worldwide, hence compelling its consumption by the greater part of the world's population. Notwithstanding its beneficial impact on rates of NTD, pervasive folic acid supplementation has invariably led to additive daily intakes reaching well beyond their original target, resulting in the circulation of unmetabolized folic acid. Associated idiopathic side-effects ranging from allergies to cancer have been suggested, albeit inconclusively. Herein, we hypothesize that their inconsistent detection and elusive etiology are linked to the generation of the immunosuppressive folic acid metabolite 6-formylpterin, which interferes with the still emerging and varied functions of Major Histocompatibility Complex-related molecule 1 (MR1)-restricted T cells. Accordingly, we predict that fortification-related adverse health outcomes can be eliminated by substituting folic acid with the bioequivalent folate vitamer 5-methyltetrahydrofolate, which does not break down into 6-formylpterin.
Topics: Drug-Related Side Effects and Adverse Reactions; Flour; Folic Acid; Food, Fortified; Histocompatibility Antigens Class I; Humans; Minor Histocompatibility Antigens; Neural Tube Defects
PubMed: 36016938
DOI: 10.3389/fimmu.2022.946713 -
Current Opinion in Pediatrics Dec 2019An update is presented regarding neural tube defects (NTDs) including spina bifida and anencephaly, which are among the most common serious birth defects world-wide.... (Review)
Review
PURPOSE OF REVIEW
An update is presented regarding neural tube defects (NTDs) including spina bifida and anencephaly, which are among the most common serious birth defects world-wide. Decades of research suggest that no single factor is responsible for neurulation failure, but rather NTDs arise from a complex interplay of disrupted gene regulatory networks, environmental influences and epigenetic regulation. A comprehensive understanding of these dynamics is critical to advance NTD research and prevention.
RECENT FINDINGS
Next-generation sequencing has ushered in a new era of genomic insight toward NTD pathophysiology, implicating novel gene associations with human NTD risk. Ongoing research is moving from a candidate gene approach toward genome-wide, systems-based investigations that are starting to uncover genetic and epigenetic complexities that underlie NTD manifestation.
SUMMARY
Neural tube closure is critical for the formation of the human brain and spinal cord. Broader, more all-inclusive perspectives are emerging to identify the genetic determinants of human NTDs.
Topics: Epigenesis, Genetic; Female; Humans; Mutation; Neural Tube Defects; Pregnancy; Spinal Dysraphism
PubMed: 31693581
DOI: 10.1097/MOP.0000000000000817 -
Nutrients Apr 2023Folate supplementation in the periconceptual period is the standard of care for the prevention of neural tube defects. To support dietary folate intake, some countries... (Review)
Review
Folate supplementation in the periconceptual period is the standard of care for the prevention of neural tube defects. To support dietary folate intake, some countries have introduced mandatory folic acid fortification of food products. Robust evidence supports the additional use of a low-dose folic acid supplement (0.4 mg/day) in all women from 2-3 months preconception until the end of the 12th week of gestation. For women with pre-existing diabetes, high-dose folic acid supplementation (5 mg/day) is recommended in some, but not all international guidelines. The recommendation is made based on consensus opinion and reflects the increased risk of neural tube defects in pregnant women with pre-existing diabetes. However, there is limited evidence to clarify the high-risk groups that benefit from high-dose folic acid versus those that do not. There are also some data to suggest that high-dose folic acid may be harmful to mothers and offspring, although this issue remains controversial. This narrative review explores the evidence that supports the recommendation for women with pre-existing diabetes to take high-dose folic acid in the periconceptual period. It explores the potential benefits of high-dose supplemental folate beyond the prevention of neural tube defects, and also the potential adverse impacts of high-dose folate use. These topics are considered with a specific focus on the issues that are pertinent to women with pre-existing diabetes. Based on the available evidence, a pragmatic approach to the use of folic acid supplements in women with pre-existing diabetes during the periconception period is suggested. The need for comprehensive preconception care that optimises glycaemic control and addresses other modifiable risk factors before pregnancy is emphasized.
Topics: Female; Pregnancy; Humans; Folic Acid; Dietary Supplements; Neural Tube Defects; Risk Factors; Diabetes Mellitus
PubMed: 37111098
DOI: 10.3390/nu15081879 -
Revista Medica Del Instituto Mexicano... Feb 2022Neural tube defects are a heterogeneous group of alterations of the central nervous system with multifactorial origin, mainly caused by a failure in the mechanisms of...
BACKGROUND
Neural tube defects are a heterogeneous group of alterations of the central nervous system with multifactorial origin, mainly caused by a failure in the mechanisms of closure of the neural tube which involves skin, paravertebral muscles, connective tissue, bone and spinal cord.
CLINICAL CASE
36-year-old woman with a pregnancy of 25.3 weeks, corroborated by second trimester ultrasound. She had a previous pregnancy with anencephaly and a poor prenatal care in the actual pregnancy. An obstetric ultrasound was performed with the diagnosis of craniorachischisis, which is why the delivery was performed by vaginal birth with labor induction with prostaglandins.
CONCLUSIONS
The craniorachischisis is a rare defect of the neural tube that must be diagnosed early because it is a pathology incompatible with life.
Topics: Adult; Anencephaly; Central Nervous System; Female; Humans; Neural Tube Defects; Pregnancy; Ultrasonography, Prenatal
PubMed: 35274915
DOI: No ID Found -
The Lancet. Global Health Oct 2022
Topics: Folic Acid; Food, Fortified; Humans; Neural Tube Defects
PubMed: 36113522
DOI: 10.1016/S2214-109X(22)00378-3 -
The Lancet. Global Health Oct 2022
Topics: Folic Acid; Food, Fortified; Humans; Neural Tube Defects
PubMed: 36113523
DOI: 10.1016/S2214-109X(22)00377-1