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Table of Contents    
Year : 2020  |  Volume : 68  |  Issue : 5  |  Page : 1144-1150

Molecular Genetics involved in Neural Tube Defects: Recent Advances and Future Prospective for Molecular Medicine

1 Department of Anatomy, AIIMS, Bhubaneswar, Odisha, India
2 Additional Professor in Department of Anatomy, AIIMS, Bhubaneswar, Dumuduma, Odisha, India

Date of Web Publication27-Oct-2020

Correspondence Address:
Dr. Mayadhar Barik
Head of the Department (HOD) in Paramedical Science and Chief in Research, Mewar University, Gangrar, Chittorgarh, Rajasthan - 312 901
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.299136

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 » Abstract 

Background: Folic acid and multivitamin supplements ((FAMVS) and genetics involvement is one of the major roles in the development of neural tube defects (NTDs).
Objective: Our prior aim and objective is to establish an unique guideline and helps the policy decision making for our country India and the World.
Materials and Methods: We have collected the data through the literature from the World for their necessary action, rehabilitation part all objectively in PubMed/Medline, Scopous, Embase, Cochrane Review, Hinari, and Google scholar.
Statistical Analysis: Statistical analysis was performed with very simple and logistic statistics, percentage, mean, total as collection through the available software SPSS with new version 17.0.
Results: The overall (70-95%) we find out those infants with neural tube defects (NTDs) associated with genes involvement and maternal vitamin intake (MVI). Before pregnancy relative risk (PRR) prior to non intake noted as 90% significantly reduced their risk of the NTDs. Now (40-60%) of the women of child-bearing age (CBA) don't use the folic acid intake and supplements (FAISs) in proper way in villages, urban, industrial and sewage areas. We find out that the genetic variants of the fourteen special reported genes, had the major risk factor (MRF) for the (NTDs) and associated abnormalities rate (AAR) within the developmental process in the human brain.
Conclusions: The (45-55%) people still having at ignorant zone, due to lack of education, genetic counseling, and awareness till date.

Keywords: Decision making, genetic counseling, government action, guidelines, medical education, molecular genetics, neural tube defects, policy, prevention, protocol development and management
Key Message: Early genetic screening, folic acid supplements (FASs), multivitamin supplements (MVSs), medical education and awareness programmers (MEAPs) will help them to guide the neural tube defects (NTDs) progression, prevention and treatment part of NTDs for common public.

How to cite this article:
Mishra PR, Barik M, Mahapatra A K. Molecular Genetics involved in Neural Tube Defects: Recent Advances and Future Prospective for Molecular Medicine. Neurol India 2020;68:1144-50

How to cite this URL:
Mishra PR, Barik M, Mahapatra A K. Molecular Genetics involved in Neural Tube Defects: Recent Advances and Future Prospective for Molecular Medicine. Neurol India [serial online] 2020 [cited 2020 Nov 29];68:1144-50. Available from:

Neural tube defects (NTDs) are the common congenital malformations interactions between several genes, epigenetic, and environmental factors.[1] Researchers identified that folate supplementation intake (FSI) with genetics assimilation including with responsible factors for the development of NTDs.[2] The exact etiopathogenesis of this type of diseases is still not clear. Serum folate, vitamin B12, homocysteine levels, thrombophilia-related genetic variations and including factor V Leiden, factor II g.20210G>A is also responsible for NTDs with associated diseases.[3] Methylene tetra hydropholate reductase (MTHFR) gene is one of the mild risk factor for pregnant women with fetal NTDs.[4] Vitamin B12 supplementation along with folate may help in lowering the frequency of NTDs and provides an evidence that possibly increases the NTD risk of neonates.[5] NTDs researchers reported that cliopathies, genetic disorders due to the dysfunction of microtubule-based cellular appendages (MBCAs) called as cilia.[6] Cilias have the critical sensory and have signaling centers responsible for the growth and development of the human brain.[7]

NTDs including with an abnormal neural tube and limb patterning phenotypes are due to perturbations in the hedgehog (Hh) signaling pathway.[8] Chlamydomonas Nexin-Dynein Regulatory Complex (CNDRC) protein4 (DRC4) responsible for the development of ciliary motility.[9] GAS8 protein implicated within the Hh signaling pathway as a regulator and smoothed easily for trafficking into the cilium.[10] Additionally, Hh pathway phenotypes patients with NTDs located on missense mutation in GAS8 gene.[11] CRISPR/Cas9 homology had driven out to repair and generated the missense variants among both the human and mice model experiments.[12] GAS8 gene with Shh/Gli 3 signaling also responsible for the components and NTDs and Splitcord malformation (SCM).[13] TP53BP2gene encodes apoptosis protein of p53 2(ASPP2) is characteristics with dysmorphic features, intellectual disability, and brain morphological abnormalities.[14] ZIKV-genome and retinoic acid (RA) is now working as the best developmental biomarker responsible for NTDs.[15]

Smoking is one causal factor of birth defects, oral clefts, neural tube defects (NTDs) and neural tube closure (NTC).[16] Periconceptional second hand smoke exposure-encompassing with a period of (one month prior to conception through the first trimester) is responsible for the birth defects unlike craniosynostosis (CS), nonsyndromic craniosynostosis (NSC), hydrocephalus and NTDs.[17] Second and third trimesters are due to the potential sensitivity of the teratogens are causing for this defect through the pregnancy.[18] The second hand smokers are leading to NTDs.[19] Women were advised to use folic acid supplements (FASs) before and early during pregnancy as a compulsory in all countries for reducing their risk of NTDs. Therefore early infants and several regions are indicating that preconception folic acid supplements (FASs) is necessary.[20] Women who do not have plan for their pregnancy or do not request a preconception health visit (PCHV) to their doctor had the lowest prevalence of preconception folic acid (PCFA) use to improve their folate supplementation status (FSS) and other supplementations in non-users are also help to prevent NTDs.[21]

 » Materials and Methods Top

Study design

It is an analytical study through the World literature including with medical evidence and clinical relevance/significance in favoring to the (neural tube defects (NTDs).

Data collection

We used data bases used by the word “folic acid (FA) and multivitamin supplements (MVSs) in genetics involvement with neural tube defects (NTDs)'' unlike in PubMed/Medline, Scopous, Embase, Cochrane Review, Hinari, and Google scholar from the recent medical literature”.

Inclusion criteria

The women, who had the (live-and stillborn infants), neural tube defects (NTDs) emphasized with five unique patterns of genes responsibility and its variants were observed through the molecular genetics variation involvement (MGVI) including with both the (Mendelian and non-mendelian fashion (MNMF)) affected with the NTDs children.

Exclusion criteria

The women, who had not the (live-and stillborn infants), neural tube defects (NTDs) emphasized with no specific clinical history or records are available or not reported in the study or any clinical sign and symptoms were clearly excluded from this study.

Material and methods

We want to justify their clinical relationship with folic acid and multivitamin supplements (FAMVS) and major genes are responsible for the neural tube defects (NTDs) guidelines in the medical fraternity, researchers and the government to help policy/guideline and decision making for the neural tube defects (NTDs). NTDs prevention programs, implementation of laws in our country India including with others country in the World for their necessary action in rehabilitation would be benefitted through this policy. We have collected all the data through the literature from (1990-2020). The new guideline and new health policy for appropriate decision making is mandatory for common public in India and World. The recently updated molecules are trying to analyze to stop NTDs and prevent these diseases globally.

Statistical analysis

Statistical analysis was performed simple statistics, percentage, mean, total as a collection through the qualified inclusion criteria (QIC) from the original contribution of neural tube defects (NTDs) from (the available software SPSS with version 17.0).

 » Results Top

The overall (70-95%) we find out that adjusted relative risk (ARR) among infants with neural tube defects (NTDs) associated with genes involvement and maternal vitamin intake (MVI). Before pregnancy relative risk (PRR) prior to non intake noted as 90% significantly reduced their risk of the NTDs. (40-60%) of the women of child-bearing age (CBA) don't use the folic acid intake and supplements (FAISs) in a proper way in villages, urban, industrial and sewage areas. In fact in villages to metropolitan cities are still needed medical education, counseling and awareness. The (50%) older married or cohabiting women are frequently faced this problem with their kids. The (30%-40%) women, who had with lower parity, did not smoke during pregnancy also getting their NTDs baby still a research questions. We find out that (70-95%) of NTDs cases are mainly affected with the molecular disruption. Molecular genetics have major role to reproduce the NTDs and significantly associated with associated abnormalities rate (AAR) at the developmental process in the human brain. We find out that the genetic variants of the fourteen special reported genes, had the major risk factor (MRF) for the (NTDs) and associated abnormalities rate (AAR) within the developmental process in the human brain (attached [Figure 1] and [Figure 2]).
Figure 1: { The (NTDs) and associated abnormalities (AAs) with the development in brain (attached fig: 1 an interesting collection of closed menengocele/ menengoencephale )

Click here to view
Figure 2: { The (NTDs) and associated abnormalities (AAs) with the development in brain (attached fig: 2 as an interesting collection of open lepomylocele/ lepomylomengocele)

Click here to view

 » Discussion Top

Neural tube defects (NTDs) and neurocristopathies (NCPs) both are spectrum of diverse disorders (DDs).[22] Defective growth differentiation (DGD), migration of NC cells mechanisms with homocysteine (Hcys) and/or folate deficiencies disrupt NC development.[23] Hcys and folic acid supplementation (HFAS) helps morphogenetic processes of murine NC cellsin vitro outgrowth and proliferation of NTDs.[24] Impairment on differentiation into smooth muscle cells (SMCs) and FAS alone does not directly affected the developmental dynamics process as well.[25] The Chilean Society of Pediatrics' drafted a law governing by the decriminalization of abortion on three grounds, based on second ground observations.[26] They considers as an embryo or foetus suffering from a congenital structural anomaly (CSA) related with genetic disorder incompatible (GDI) and the life outside their wombs.[27]

Congenital anomalies (CA) a new concept in term of incompatible with life outside the womb, as an exception for longer period of survivals.[28] We should need to address the congenital anomaly (CA) had very poor prognosis among Indian patients.[29] Anencephaly, iniencephaly and craniorachischisis, pulmonary hypoplasia, acardiac foetus, ectopia cordis, non-mosaic triploidy (NMT), limb body wall complex (LBWC), body stalk anomaly (BSA), trisomy 13, trisomy 18, bilateral renal agenesis (BRA), NTDS, NTC are now associated with nonsyndromic fashion diseases (NSFDs).[30] Clinical history, prenatal records, ultrasound (USG), CT, MRI, and cytogenetic and molecular testing is required for the pregnant women to access the assessments of foetal anatomy tested (FAT) helps them to keep there in electronic health record (HER) for further use of treatment and research study.[31],[32]

Vitamin D deficiency among the pregnant woman associated with a risk factor for NTDs.[33] ADP ribosylation factor-like GTPase activating proteins (GAPs) ARL13B gene encodes a small GTPase is essential for cilia biogenesis and helps in NTDs.[34] ARL13B gene in Zebra fish is misleading to a number of phenotypes abnormalities.[35] Cilia includes cystic kidneys had (Null mutation in ARL13B gene) associated with neuraltube degects (NTDs).[36],[37] Hedgehog signaling (Hhs), Valproic acid (VA), histone deacetylase inhibitor (HDI) lowered the cyst progression in cystic kidney model (CKM) with neonatal inactivation (NI) of the Pkd1.[38] Arl13b gene identified as a potential biomarker for cystic kidney phenotype (CKP) in patients with hypomorphic in nature and these mutations are responsible for both the (NTDs and NTC).[39] Joubert's Syndrome (JS) is genetically heterozygous conditions, cliopathy characteristic with episodic hyperpnea, apnea, hypotonia, ataxia, cognitive impairment (CI), ocular motor apraxia (OMA) and molar tooth sign (MTS) are associated with MKS1 gene (C240G>T) mutation in Meckel-Gurber syndrome (MGS).[40] MKS1-variants are in JS patients and its agenesis of corpus collosum (ACC) related with the genotype and phenotype in both these clinical conditions.[41] Enlarged parietal foramina (EPF) are a very rare congenital skull defects (CSDs) due to mutation in MSX2 and ALX4 gene during development and responsible for (NTDs & NTC).[42] The prenatal sonographic feature (PSGF) of spina bifida (SB) in consecutive pregnancies are associated with the partial trisomy 3q (3q26.1-qter) and partial monosomy. 5p (5p13.33-pter) located in the molecular cytogenetic study (MCGS) with array CGH and FISH study give an idea of the unbalanced chromosome rearrangement (UCR) is one new possibility for NTDs.[43] Methylene tetra hydropholate reductase (MTHFR) gene having one major risk for NTDs reported in [Table 1].[44] The levels of serum homocysteine, Vitamin B12, Vitamin D and folate played as potential role for the (NTDs and NTCs).[45][70-84]
Table 1: Major special genes involved in NTDs, NTC, others in molecular medicine

Click here to view

Surveillance of congenital anomalies

The morphological changes are made during the neuroepithelium (NE), neural tube closure (NTC), neural crest formation (NCF), paraxial mesoderm somites (PMSs) are segmenting with the pre somatic mesoderm (PSM).[46] BMP4 inhibition regulates the morphogenesis and helps in the neural crest migration (NCM) in the development process of the human brain.[47] Fgf3 null homozygote's promote PSM-derived FGF3 regulates the BMP signals in the adjacent of neuroepithelium.[48] The Ruysch's legacy inspires and guides the young scientists, doctors and lay men for NTDs and their associated anomalies.[49] The Meckel-Gruber syndrome (MGS) is located among the consanguinity marriages and mortality occurs in more than 90% of cases. Molecular genetic counselor/researcher and doctor should discuss and address for the parents to explain the best maternal prognosis and their complications.MGS including with abortion in the early stages and subsequent genetic counseling, medical education need for all these cases of the rural to metropolitan cities.[50]

CpG-rich promoters in the mammalian genome

FBXL10 protein (KDM2B, JHDM1B, CXXC2, Xist gene and NDY1) are responsible for the histone demethylase activity (HAD) protein promotes NTDs.[51] Birth defect prevention program (BDPP) to reduce their NTDs, pregnancy planning (PP), medical health education (MHE), genetic counseling (GC), antenatal ultrasonography (ANSG), and serological screening test (SST) are helping the World.[52]

Canine Chiari-like malformation

Griffon Bruxellois (GB) stated that CM is a global problem with malformation of the cranium and craniocervical junction with a shortened skull base. It increases the proximity of the cervical vertebrae to the skull. CM is indicating that mixed breed traits posed a lesser risk for CM and SM. GB distinguish the phenotypes variants through MR images.[53] CM is additive towards the severity of the conditions of phenotypes are crossing breed types and with careful selection of appropriate conformation characteristics for craniocervical traits (CCTs) useful for quantifying CM and assessing the new possibility of SM.[54]

Recent advances and future prospective

The wild-type 3H1colony disrupts the midline craniofacial malformations (MCFMs) with or without in the anterior cephalocele (ACC) affected by their embryos are represented as neural tube closure defects (NTCDs).[55] Demethylation of cytosine (DMC) detected as a significant loss of TET enzyme activity in the heads of tuft within embryos responsible in anterior neuropore and exencephaly.[56] Washington State (WS) had detected cluster of babies born with anencephaly-a fatal condition reported that folic acid deficit (FAD) with genetic variants are in the folate pathway, exposure with a variety of environmental and occupational toxins responsible for progression of the (NTDs).[57]

Presently, whole genome sequence analysis (WGSA), NGS and microarray technology (MAT) helps to address their new findings regarding NTDs and NTC. PUSH is now leading a wider range of disabilities or death and their daily folic acid supplementation (DFAS) in the periconceptional period (PCP) to prevent neural tube defects (NTDS) actively.[58] Women Folic acid supplementation (FAS) provides by who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg (400-800 μg) of folic acid supplementation (FAS) is highly recommended.[59]

Women among the reproductive age group (RAG) should intake supplements before their conception with 0.4-1.0 mg of folic acid supplements (FAS) daily. Multivitamins enriched rice is also fortified with folic acid at 0.7 mg per pound of raw rice estimated that (1% of industrially milled rice) is fortified with folic acid (FA). Rice, the main staple food does not allow for effective folate fortification (EFF) incidence of NTDs is around 1/1000.[52] Medications with antifolate effects, smokers, diabetics, obese women may benefit from higher doses of folic acid (HDFA) daily during their first trimester had pregnancies are affected with NTDs.[60]

Those are planning for their pregnancy are recommended 0.4 mg of FA daily from at least one month before planned conception and continuing throughout the first 12 weeks of their pregnancy is a better dose[61] Nutrition interventions played all different confounding factors may guide women better doses for their of FAS.[62] Folate fortification supplementation (FFS) before initial of pregnancy risk of fetus developing a neural tube defect (NTD).[63]

Policy making in relation to food fortification (FF) should take into account in all possible health effects evidences are not stronger till date[64] Vitamin E, folate, Fe and Mg, both help in the preconceptional period (PCP) and during pregnancy helping in preventing NTDs.[65] In ventricular size (VS) after myelomeningocele closure (MMC) reduced rate of shunt placement rate (SRR) is comparable to that in utero closure of myelomeningocele.[66]

Very poor glycemic control (VPGC), preeclampsia, gestational disorder (GD), obese women have subclinical inflammatory findings (SCIFs) frequently reported.[67] National nutrition surveys are required to complement the national policy guidelines (NPGs) as an urgent home work for the WHO and government of all countries.[68] The periconceptional folic-acid supplementation (PCFAS) in Europe implementing public health policies to raise periconceptional folate status (PCFS) data on (1980- 2020) to reduce the prevalence rate of the neural-tube defects (NTDs).[69]

 » Recommendations and Validation Top

The minimum dosage of folic acid supplementation (FAS) of 0.8 mg/d, not to exceed 5.0 mg/d, is recommended.[70]


Folic acid supplementation (FAS) responsible for NTDs among infants in India and ancillary savings in medical costs but not well plan in India.

 » Conclusions Top

Women should take appropriate doses for FAS according to their age, clinical conditions, before conception and after pregnant. One should not be used to with unnecessary more doses of (FAS and FAMVSs) which may affect your molecular disruption and misleading to NTDs in your future pregnancy and your immunity. Government should make an informative guideline and policymakers should take appropriate decision for the doses for women/girls, (FAS and FAMVSs), molecular screening and research for funding.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

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