Review

Authors: Nicholas D E Greene, Andrew J Copp

Neural tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying neural tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies.

Topics: Animals; Folic Acid; Genetic Predisposition to Disease; Humans; Neural Tube Defects; Neurulation; Risk Factors

PubMed: 25032496
DOI: 10.1146/annurev-neuro-062012-170354

Review

Authors: Laura Avagliano, Valentina Massa, Timothy M George...

Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD pathogenesis has not yet been fully elucidated, many risk factors, both genetic and environmental, have been extensively reported. Classically divided in two main sub-groups (open and closed defects) NTDs present extremely variable prognosis mainly depending on the site of the lesion. Herein, we review the literature on the histological and pathological features, epidemiology, prenatal diagnosis, and prognosis, based on the type of defect, with the aim of providing important information based on NTDs classification for clinicians and scientists.

Topics: Anencephaly; Female; Humans; Neural Tube Defects; Pregnancy; Prenatal Diagnosis; Risk Factors

PubMed: 30421543
DOI: 10.1002/bdr2.1380

Review

Authors: Andrew J Copp, Philip Stanier, Nicholas D E Greene...

Neural tube defects are severe congenital malformations affecting around one in every 1000 pregnancies. An innovation in clinical management has come from the finding that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention with folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in the UK. Genetic predisposition accounts for most of the risk of neural tube defects, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human neural tube closure events remains controversial, but studies of mouse models of neural tube defects show that anencephaly, open spina bifida, and craniorachischisis result from failure of primary neurulation, whereas skin-covered spinal dysraphism results from defective secondary neurulation. Other malformations, such as encephalocele, are likely to be postneurulation disorders.

Topics: Animals; Databases, Factual; Disease Models, Animal; Folic Acid; Genetic Predisposition to Disease; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Mutation; Neural Tube Defects

PubMed: 23790957
DOI: 10.1016/S1474-4422(13)70110-8

Review

Authors: Sangmoon Lee, Joseph G Gleeson

Neural tube defects (NTDs) represent a failure of the neural plate to complete the developmental transition to a neural tube. NTDs are the most common birth anomaly of the CNS. Following mandatory folic acid fortification of dietary grains, a dramatic reduction in the incidence of NTDs was observed in areas where the policy was implemented, yet the genetic drivers of NTDs in humans, and the mechanisms by which folic acid prevents disease, remain disputed. Here, we discuss current understanding of human NTD genetics, recent advances regarding potential mechanisms by which folic acid might modify risk through effects on the epigenome and transcriptome, and new approaches to study refined phenotypes for a greater appreciation of the developmental and genetic causes of NTDs.

Topics: Folic Acid; Humans; Neural Tube Defects

PubMed: 32423763
DOI: 10.1016/j.tins.2020.04.009

Authors: Jinglei Zhai, Yanhong Xu, Haifeng Wan...

Neural tube (NT) defects arise from abnormal neurulation and result in the most common birth defects worldwide. Yet, mechanisms of primate neurulation remain largely unknown due to prohibitions on human embryo research and limitations of available model systems. Here, we establish a three-dimensional (3D) prolonged in vitro culture (pIVC) system supporting cynomolgus monkey embryo development from 7 to 25 days post-fertilization. Through single-cell multi-omics analyses, we demonstrate that pIVC embryos form three germ layers, including primordial germ cells, and establish proper DNA methylation and chromatin accessibility through advanced gastrulation stages. In addition, pIVC embryo immunofluorescence confirms neural crest formation, NT closure, and neural progenitor regionalization. Finally, we demonstrate that the transcriptional profiles and morphogenetics of pIVC embryos resemble key features of similarly staged in vivo cynomolgus and human embryos. This work therefore describes a system to study non-human primate embryogenesis through advanced gastrulation and early neurulation.

Topics: Animals; Humans; Blastocyst; Embryo, Mammalian; Embryonic Development; Macaca fascicularis; Neural Tube Defects; Neurulation; Tissue Culture Techniques

PubMed: 37172562
DOI: 10.1016/j.cell.2023.04.019

Authors: Suyash Yashwant Ambatkar, Megha Dipak Rudey

Topics: Humans; Neural Tube Defects

PubMed: 37013212
DOI: 10.11604/pamj.2023.44.24.35962

Review

Authors: Chih-Ping Chen, Yu-Peng Liu, Fuu-Jen Tsai...

OBJECTIVE

To present the prenatal magnetic resonance imaging (MRI) findings of concomitant craniorachischisis and omphalocele, review the literature, and discuss the pathogenesis.

CASE REPORT

A 20-year-old, gravida 2, para 0, woman was referred to genetic counseling at 17 weeks of gestation because of multiple congenital malformations in the fetus. Level II ultrasound revealed acrania, a ventricular septal defect, an upward-turned face, and omphalocele containing the intestines. MRI revealed normal extremities, exencephaly, hyperextension of the fetal head, significant shortening of the spinal column, marked lordosis and hyperextension of the malformed spine, an upward-turned face, and absence of a neck. A diagnosis of iniencephaly associated with anencephaly, rachischisis and omphalocele was made. Amniocentesis revealed a karyotype of 46,XY. Postnatal X-ray showed anencephaly with total spina bifida of the cervical and thoracic spine.

CONCLUSION

Prenatal MRI is able to provide a clear whole-body image of the fetus and its relationship with the placenta. Prenatal MRI is very useful in the differential diagnosis of concomitant craniorachischisis and omphalocele from amniotic band sequence, limb body-wall complex with craniofacial defect and Disorganization human homologue.

Topics: Female; Hernia, Umbilical; Humans; Magnetic Resonance Imaging; Male; Neural Tube Defects; Pregnancy; Prenatal Diagnosis; Young Adult

PubMed: 19797022
DOI: 10.1016/S1028-4559(09)60306-5

Review

Authors: Rachel A Keuls, Richard H Finnell, Ronald J Parchem...

Changes in maternal nutrient availability due to diet or disease significantly increase the risk of neural tube defects (NTDs). Because the incidence of metabolic disease continues to rise, it is urgent that we better understand how altered maternal nutrient levels can influence embryonic neural tube development. Furthermore, primary neurulation occurs before placental function during a period of histiotrophic nutrient exchange. In this review we detail how maternal metabolites are transported by the yolk sac to the developing embryo. We discuss recent advances in understanding how altered maternal levels of essential nutrients disrupt development of the neuroepithelium, and identify points of intersection between metabolic pathways that are crucial for NTD prevention.

Topics: Humans; Female; Pregnancy; Folic Acid; Neural Tube; Neurulation; Placenta; Neural Tube Defects

PubMed: 37468429
DOI: 10.1016/j.tem.2023.06.005

Review

Authors: Chih-Ping Chen

Iniencephaly is characterized by a variable deficit of the occipital bones, resulting in an enlarged foramen magnum; partial or total absence of cervical and thoracic vertebrae with an irregular fusion of those present, accompanied by incomplete closure of the vertebral arches and/or bodies; significant shortening of the spinal column due to marked lordosis and hyperextension of the malformed cervicothoracic spine; and an upward-turned face and mandibular skin directly continuous with that of the chest due to the lack of neck. This article provides a comprehensive review of the reported cases of prenatally detected iniencephaly, including prenatal diagnosis, associated malformations, associated chromosomal abnormalities, and differential diagnosis. Prenatal diagnosis of a neural tube defect involving a body defect in the occiput and rachischisis of the cervical and thoracic spine with retroflexion of the head should raise the suspicion of iniencephaly. Iniencephaly may be associated with craniorachischisis and other structural anomalies. Prenatal diagnosis of non-isolated iniencephaly and craniorachischisis should alert one to the possibility of chromosomal abnormalities and prompt a cytogenetic investigation.

Topics: Diagnosis, Differential; Female; Fetal Diseases; Humans; Neural Tube Defects; Pregnancy; Prenatal Diagnosis

PubMed: 17962097
DOI: 10.1016/S1028-4559(08)60021-2

Authors: Lei Lu, Meizhu Bai, Yufang Zheng...

Heparan sulfate proteoglycan 2 (HSPG2) gene encodes the matrix protein Perlecan, and genetic inactivation of this gene creates mice that are embryonic lethal with severe neural tube defects (NTDs). We discovered rare genetic variants of HSPG2 in 10% cases compared to only 4% in controls among a cohort of 369 NTDs. Endorepellin, a peptide cleaved from the domain V of Perlecan, is known to promote angiogenesis and autophagy in endothelial cells. The roles of enderepellin in neurodevelopment remain unclear so far. Our study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the neuroepithelia receptor neurexin in vivo. Through the endocytic pathway, the interaction of endorepellin and neurexin physiologically triggers autophagy and appropriately modulates the differentiation of neural stem cells into neurons as a blocker, which is necessary for normal neural tube closure. We created knock-in (KI) mouse models with human-derived HSPG2 variants, using sperm-like stem cells that had been genetically edited by CRISPR/Cas9. We realized that any HSPG2 variants that affected the function of endorepellin were considered pathogenic causal variants for human NTDs given that the severe NTD phenotypes exhibited by these KI embryos occurred in a significantly higher response frequency compared to wildtype embryos. Our study provides a paradigm for effectively confirming pathogenic mutations in other genetic diseases. Furthermore, we demonstrated that using autophagy inhibitors at a cellular level can repress neuronal differentiation. Therefore, autophagy agonists may prevent NTDs resulting from failed autophagy maintenance and neuronal over-differentiation caused by deleterious endorepellin variants.

Topics: Animals; Autophagy; Mice; Heparan Sulfate Proteoglycans; Humans; Neural Tube Defects; Neural Tube; Neural Stem Cells; Neuroepithelial Cells; Female; Male; Disease Models, Animal

PubMed: 38702277
DOI: 10.1016/j.scib.2024.03.026