Form Of Neural Tube Defect Research Articles

Exencephaly – A Fatal Form of Neural Tube Defects in Fetus

Exencephaly is a type of cephalic disorder, wherein the brain is located outside of the skull. This condition is usually found in embryos as an early stage of exencephaly. As an exencephalic pregnancy progresses, the neural tissue gradually degenerates. The prognosis for infants born with exencephaly is extremely poor. It is rare to find an infant born with exencephaly, as most cases that are not early stages of anencephaly are usually stillborn. Those infants who are born with the condition usually die within hours or minutes. This case report concerns a multigravida woman (G2) who was 19+4 weeks±2 weeks pregnant and she came to Hakeem Abdul Hameed Centenary Hospital (HAHC) Hospital for medical termination of pregnancy as it was diagnosed with exencephaly one of a neural tube defect in growing fetus. She had been married for 6 years and this was her second pregnancy. She had not taken any folic acid supplementation and came to Hakeem Abdul Hameed Centenary Hospital (HAHC), New Delhi on October 3, 2017 for medical termination of pregnancy as it was diagnosed in level-II USG done elsewhere, neural tube defects (exencephaly) in fetus. She was unable to remember her LMP and it was a spontaneous conception and she did not come to know about her pregnancy even after 1½ months of amenorrhea since she had irregular menstruation. She had her first ultrasound on 28.06.2017 which showed a hematoma measuring 15m×6.0 mm near to the gestation sac. Again ultrasound was advised on 3.10.17, in which the fetus showed absence of calvarial bones in bilateral parietal, temporal and occipital region with presence of calvarium in frontal region. The fetal brain showed enlarged cerebral hemisphere and herniating posteriorly and directly exposed to the CSF. The cerebellum and brainstem were poorly formed. Her first child also was a case of tuberous sclerosis with symptomatic epilepsy.

Basal Encephalocele-an Uncommon Cause of Respiratory Distress in Newborn

Basal encephalocele is one of the important causes of respiratory distress in newborn, although uncommon and hence under emphasized. It is a form of neural tube defect that usually presents with symptoms of nasal obstruction. Delayed presentation with variable symptoms have been noted. Collaborative surgical intervention is the treatment modality with different approaches. However, intervention early in neonatal period is a challenge in our region with resource limitations. Prognosis is worse with associated malformations and chromosomal anomalies. We report two cases of newborn with basal encephalocele presenting as respiratory distress at birth.Nepalese Journal of ENT Head and Neck Surgery, Vol. 5, No. 2, 2014, Page: 18-20

First Trimester Diagnosis of Iniencephaly Confirmed by Postnatal Autopsy

AbstractIniencephaly (Greek: “inoin” meaning nape of neck) is an extremely rare and uniformly lethal form of neural tube defect. We report a case diagnosed in the first trimester using two-dimensional and three-dimensional ultrasound. The diagnosis was confirmed on postnatal autopsy. This case highlights the importance of diagnosing structural abnormalities in the first trimester itself.

Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization.

Scribble1 (Scrib1) is a tumor suppressor gene that has long been established as an essential component of apicobasal polarity (ABP). In mouse models, mutations in Scrib1 cause a severe form of neural tube defects (NTDs) as a result of a defective planar cell polarity (PCP) signaling. In this study, we dissected the role of Scrib1 in the pathogenesis of NTDs in its mouse mutant Circletail (Crc), in cell lines and in a human NTD cohort. While there were no obvious defects in ABP in the Scrib1Crc/Crc neuroepihelial cells, we identified an abnormal localization of the apical protein Par-3 and of the PCP protein Vangl2. These results were concordant with those obtained following a partial knockdown of Scrib1 in MDCK II cells. Par-3 was able to rescue the localization defect of Vangl1 (paralog of Vangl2) caused by partial knockdown of Scrib1 suggesting that Scrib1 exerts its effect on Vangl1 localization indirectly through Par-3. This conclusion is supported by our findings of an apical enrichment of Vangl1 following a partial knockdown of Par-3. Re-sequencing analysis of SCRIB1 in 473 NTD patients led to the identification of 5 rare heterozygous missense mutations that were predicted to be pathogenic. Two of these mutations, p.Gly263Ser and p.Gln808His, and 2 mouse NTD mutations, p.Ile285Lys and p.Glu814Gly, affected Scrib1 membrane localization and its modulating role of Par-3 and Vangl1 localization. Our study demonstrates an important role of Scrib1 in the pathogenesis of NTDs through its mediating effect of Par-3 and Vangl1/2 localization and most likely independently of ABP.

An Application of Keystone Perforator Island Flap for Closure of Lumbosacral Myelomeningocele Defects.

Myelomeningocele, also known as spina bifida, is the commonest form of neural tube defect in which both meninges and spinal cord herniate through a large vertebral defect. It may be located at any spinal level; however; lumbosacral involvement is most common. After birth, the closure of spinal lesion is preferably undertaken in the first 48 hours to minimize the risk of injury and central nervous system infection. Relatively small skin defects overlying the dural repair may be directly closed. However, larger defects require reconstructive closure. Numerous methods of reconstruction have been described, such as split skin graft, local flaps or lumbosacral fasciocutaneous flaps, muscle flaps using latissimus dorsi, gluteal or paraspinous muscles, and perforator flaps namely superior gluteal artery perforators, and dorsal intercostal artery perforator flaps. At Monash Health, Victoria, we have used the keystone perforator island flaps to reconstruct lumbosacral myelomeningocele defects on 5 newborns between January 2008 and January 2014. This article evaluates the short-term and long-term outcomes of these patients who were followed up for 10 to 66 months.

Development of brain and spinal cord in anencephalic human fetuses

Objectives: Anencephaly is the severest form of neural tube defects. The present study was undertaken to evaluate the development of brain and spinal cord in anencephalic human fetuses (specimens). Methods: 43 specimens with anencephaly were collected after obtaining written consent from parents and clearance from ethics committee of the institute as per declaration of Helsinki guidelines. All the specimens were fixed in buffered formalin. Gross examination and histological studies of the brain and spinal cord were performed in each specimen. Results: Gestational age of fetuses varied from 18 to 40 weeks, the majority being female fetuses. 31 (72%) fetuses had only anencephaly while 9 (21%) fetuses had additional spina bifida and 3 (7%) had meningomyelocele. The brain was observed as a dark brown undifferentiated mass with complete absence of the cerebellum, pons, medulla and midbrain. In 31 fetuses (72%), the spinal cord continued rostrally into an open neural tube that connected to the undifferentiated brown mass while in 12 fetuses (28%), it merged directly into the undifferentiated brown mass. Spinal cord was normal in appearance in all fetuses with anencephaly. Spinal cord was deformed in 3 fetuses (7%) having meningomyelocele. Histological examination of brain showed venous vessels of varying caliber interspersed with connective tissue, similar to an angioma along with islets of nervous tissue which mainly comprised of scattered nerve cells, astroglial cells and cavities lined by ependyma. Conclusion: Our findings indicate that there is no functional organization of brain in anencephalic fetuses, and the survival of such fetuses is not possible. The spinal cord is normal in fetuses with anencephaly only while it is deformed in anencephalic fetuses with meningomyelocele Keywords: anencephaly; brain development; spina bifida; spinal cord development; meningomyelocele

Heme oxygenase-1 promoter polymorphisms and risk of spina bifida.

Spina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)n dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs. This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 non-malformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared. For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D': 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity. Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study.

Development of Brain and Spinal Cord in Anencephaly

Anencephaly is the severest form of neural tube defect. The present study was undertaken to evaluate the development of brain and spinal cord in anencephaly foetuses (specimens). 43 specimens with anencephaly were collected after obtaining written consent from parents and clearance from Ethic committee of the Institute as per declaration of Helsinki guidelines. All the specimens were fixed in buffered formalin. Gestational age of foetuses varied from 18 to 40 weeks. There was preponderance of female foetuses. 31 (72%) foetuses had only anencephaly while 9 (21%) foetuses had additional spina bifida and 3 (7%) had meningomyelocele. On internal examination of 43 fetuses with anencephaly, the brain was seen as a dark brown undifferentiated mass with complete absence of the cerebellum, pons, medulla and midbrain. In 34 fetuses (79%), spinal cord was normal in appearance and structure and was seen to be directly merging into the undifferentiated dark brown mass. In 6 fetuses (13.9%), spinal cord continued into a small part of open neural tube, at its cranial end corresponding to the position of medulla and pons. Spinal cord was normal in appearance. Spinal cord was seen deformed in 3 foetuses (7%) having meningomyelocele. Microscopic appearance of brain in the 43 foetuses with anencephaly was reminiscent of an angioma, consisting of venous vessels of varying calibre interspersed with connective tissue and islets of nervous tissue which mainly comprised of scattered nerve cells, astroglial cells and cavities lined by ependyma. Hence, in foetuses with anencephaly, brain was replaced by an undifferentiated mass of connective tissue and vessels. Spinal cord was normal in all anencephaly foetuses.

Impact of MTHFR and RFC-1 gene in the development of neural tube defect

Neural tube defects (NTDs) are complex problem of central nervous system including brain and spinal cord. Anencephaly and myelomeningocele are the two most common forms of NTDs. Epidemiological studies reveal that genetic and environmental factors are responsible for the development of NTDs. During embryogenesis large numbers of extrinsic and intrinsic factors are responsible for the closer of neural tube which is responsible to maintain the three germ layers including neural ectoderm. The role of MTHFR & RFC-1 gene in etiopathology of NTDs has not been clearly defined in Indian population. Hence, the curiosity has been developed with the aim to evaluate folate metabolism and folate regulatory gene in clinically diagnosed NTDs by using PCR based DNA analysis with selected specific forward/reverse primers. Interestingly, the highest frequency (12.5%) of CT has been appeared of MTHFR C677T gene noticed in NTDs mother. We also observed the similar frequency of heterozygous AG genotype in NTDs of A80G RFC-1 gene. Therefore, C and A allele have high prevalence among than other genotype. However, the mutation in MTHFR partially have protective effect of embryo and these selected candidate folate markers are responsible to influence the cells of neural crest confirming the folding of neural tube associated with severity of disease in NTDs.

MicroRNAs function primarily in the pathogenesis of human anencephaly via the mitogen-activated protein kinase signaling pathway

Anencephaly is one of the most serious forms of neural tube defects (NTDs), a group of congenital central nervous system (CNS) malformations. MicroRNAs (miRNAs) are involved in diverse biological processes via the post-transcriptional regulation of target mRNAs. Although miRNAs play important roles in the development of mammalian CNS, their function in human NTDs remains unknown. Using a miRNA microarray, we identified a unique expression profile in fetal anencephalic brain tissues, characterized by 70 upregulated miRNAs (ratio ≥ 2) and 7 downregulated miRNAs (ratio ≤ 0.5) compared with healthy human samples. Ten miRNAs with altered expression were selected from the microarray findings for validation with real-time quantitative reverse transcription-polymerase chain reaction. We found that in anencephalic tissues, miR-22, miR-23a, miR-34a, miR-103, miR-125a, miR-132, miR-134, miR-138, and miR-185 were significantly upregulated, while miR-149 was significantly downregulated. Furthermore, 459 potential target genes within the validated miRNAs were revealed using combined four target prediction algorithms in the human genome, and subsequently analyzed with the Molecule Annotation System 3.0. A total of 119 target genes were ultimately identified, including those involved in 22 singular annotations (i.e., transcription, signal transduction, and cell cycle) and 55 functional pathways [i.e., mitogen-activated protein kinase (MAPK) signaling pathway, and actin cytoskeleton regulation]. Six target genes (HNRPU, JAG1, FMR1, EGR3, RUNX1T1, and NDEL1) were chosen as candidate genes and associated with congenital birth abnormalities of the brain structure. Our results, therefore, suggest that miRNA maladjustment mainly contributes to the etiopathogenesis of anencephaly via the MAPK signaling pathway.

Frontoethmoidal encephalocele: Case report and review on management

Encephaloceles, especially in the frontoethmoidal region, are a form of neural tube defect affecting patients in Southeast Asia more commonly than those in western countries, where they are more common in the occipital regions. All patients with classical frontoethmoidal encephalocele had swelling over the bridge of nose or inner canthus of eye since birth, with varying degrees of hypertelorism. This paper emphasizes on the clinical features of this pathology and its surgical management, along with, reviewing the evolution of single-stage correction and fine refinements.

Rare Case Series of Double Myelomeningocoele (MMC) Supporting Multiple Site Closure of Neural Tube

Rare Case Series of Double Myelomeningocoele (MMC) Supporting Multiple Site Closure of Neural Tube Double neural tube defect is very rare, with only a few cases published in the world’s literature. The embryogenesis of this form of neural tube defects constitutes a complex closure mechanism. The authors here present an unusual case series of 5 cases of double neural tube defects presenting at various levels. The authors emphasizes the need to better understand the molecular basis for neural tube defects .This is probably the third largest series in world literature reported so far. The normal development and rationale preceding such defects are also discussed.

Resultados del Programa de Prevención de Defectos de Tubo Neural en Chile mediante la fortificación de la harina con ácido fólico: Período 2001-2010

Congenital malformations (CMF) have an important role in infant mortality. Neural tube defects (NTD) have great relevance from both social and public health points of view. The ECLAMC (Collaborative Latin American Study of Congenital Malformations) maintains in Chile an epidemiological surveillance of CMF prevalence rate at birth since 1969. To assess the effect of wheat flour folic acid fortification on the prevalence of NTD. Only Anencephaly, Spina bifida and Cephalocele were considered as NTD. All children born in the maternities incorporated to ECLAMC between 1969 and 1999 were considered as belonging to the pre folic acid fortification period and those who were born from 2001 to 2010 were considered as belonging to the post fortification period. The NTD prevalence rate at birth in the pre fortification period was 17.03/10,000. In the second period, there were 291,996 births and among them, 280 newborns were affected by a form of NTD (9.59 in 10,000 births). This represents a 44% decrease (p < 0.01). Anencephaly rate fell from 7.16/10,000 to 3.67/10,000, representing a 49% lower rate (p < 0.01). Spina bifida rate decreased from 8.61/10,000 to 4.49/10,000, representing a 48% lower rate (p < 0.01). Cephalocele had a 20% non-significant reduction. Wheat flour fortification with folic acid reduced by 44% the prevalence rate of NTD at birth. This means that NTDs were prevented in 185 Chilean newborns each year.

Current status of potential organ donation in cases of lethal fetal anomaly

Key content Anencephaly is the most severe form of neural tube defect with most pregnancies terminated following antenatal diagnosis and those carrying to term often stillborn. Organ donation following anencephalic live birth has been undertaken worldwide, especially in the early years of infant transplantation. In the USA and Canada this ceased towards the end of the last century. Although few UK transplants occurred, and the practice has ceased, national guidelines still support organ retrieval from anencephalic babies once certified dead. With the current organ donation task‐force linked drive, obstetricians are increasingly confronted with women carrying anencephalic fetuses who decline termination, perhaps for religious reasons, who would like to consider donation. Anencephalic donation does not occur in the UK, or indeed worldwide at present. Learning objectives This paper seeks to review the current UK position and possible developments, and to provide guidance for obstetricians to reply to such requests. Ethical issues Can a pregnant women elect for her anencephalic infant to be managed in such a manner – with organ support at delivery – that eventual donation after circulatory death can provide organs for others on the subsequent death of the baby?

Genetic diversity of stem cells and their functional impact on the development of neural tube defects in Eastern population of India

Anencephaly and myelomeningocele are the 2 most common forms of neural tube defects (NTDs). During embryogenesis large numbers of extrinsic and intrinsic factors are responsible for the closing of the neural tube. "Stem cells" maintain the pluripotency during differentiation of 3 germ layers, including the neural ectoderm. We examined the role of Oct4, Nanog3, and Sox2 genes in the etiopathology of NTDs in an eastern Indian population using PCR-based DNA analysis. The highest frequency (16%) of complete loss of the Sox2 gene was found in NTDs. The highest frequency (48%) of overexpression (upregulation) was found for Nanog3, while 40% was observed for Oct4 and Sox2. The odds ratio for cases versus controls was from 0.132 at 95% confidence interval = 0.005-1.298 for Nanog3 to 2.316 (0.424-13.812) for Oct4. The highest frequency (77%) of overexpression for Nanog3 and Sox2 was observed in encephalocele and anencephalic patients, while in the comparison of regional variation, i.e., cephalic to caudal regions of NTDs, the highest frequency of downregulation (regression) of Nanog3 and Sox2 was found in lumbosacral myelomeningocele patients. However, cervical myelomeningocele patients had the highest frequency of overexpression in all 3 genes, suggesting that the mutational spectra of stem cells influence the cells of the neural crest in NTDs.

Fetal surgery for neural tube defects

The New England Journal of Medicine recently reported on a large clinical trial describing subjects with meningomyelocele (MMC) that were randomised to surgical repair either in the fetal period or...

Molecular and morphological characterization of neural tube defects in embryos of diabetic Swiss Albino mice.

Embryos from diabetic mice exhibit several forms of neural tube defects, including non-closure of the neural tube. In the present study, embryos collected at embryonic day 11.5 from diabetic pregnancies displayed open neural tube with architectural disruption of the surrounding tissues. The percentage of proliferating cells was found to be increased in the dorsal and ventral domains of the spinal neural tube of embryos from diabetic mice, indicating a defect in the proliferation index. We have analyzed the development of various cell types, including motoneurons, interneurons, oligodendrocytes and migrating neurons, as well as radial glial cells in the open neural tube using specific molecular markers. Immunofluorescence results revealed a significantly reduced number of Pax2+ interneurons and increased number of Isl-1+ motoneurons, as well as Olig2+ oligodendrocytes in the neural tube of embryos from diabetic mice as compared to controls. In addition, these embryos exhibited a decreased number of doublecortin positive migrating neurons and Glast/Blbp positive radial glial cells with shortened processes in the neural tube. Expression levels of several developmental control genes involved in the generation of different neuronal cell types (such as Shh, Ngn, Ngn2, Ascl1) were also found to be altered in the neural tube of embryos from diabetic mice. Overall, the open neural tube in embryos of diabetic mice exhibits defects in the specification of different cell types, including motoneurons and interneurons, as well as glial cells along the dorsoventral axis of the developing spinal cord. Although these defects are associated with altered expression of several development control genes, the exact mechanisms by which maternal diabetes contributes to these changes remain to be investigated.

Cdx mediates neural tube closure through transcriptional regulation of the planar cell polarity gene Ptk7

The vertebrate Cdx genes (Cdx1, Cdx2 and Cdx4) encode homeodomain transcription factors with well-established roles in anteroposterior patterning. To circumvent the peri-implantation lethality inherent to Cdx2 loss of function, we previously used the Cre-loxP system to ablate Cdx2 at post-implantation stages and confirmed a crucial role for Cdx2 function in events related to axial extension. As considerable data suggest that the Cdx family members functionally overlap, we extended this analysis to assess the consequence of concomitant loss of both Cdx1 and Cdx2. Here, we report that Cdx1-Cdx2 double mutants exhibit a severely truncated anteroposterior axis. In addition, these double mutants exhibit fused somites, a widened mediolateral axis and craniorachischisis, a severe form of neural tube defect in which early neurulation fails and the neural tube remains open. These defects are typically associated with deficits in planar cell polarity (PCP) signaling in vertebrates. Consistent with this, we found that expression of Ptk7, which encodes a gene involved in PCP, is markedly reduced in Cdx1-Cdx2 double mutants, and is a candidate Cdx target. Genetic interaction between Cdx mutants and a mutant allele of Scrib, a gene involved in PCP signaling, is suggestive of a role for Cdx signaling in the PCP pathway. These findings illustrate a novel and pivotal role for Cdx function upstream of Ptk7 and neural tube closure in vertebrates.

Molecular Genetics and Pathogenic Mechanisms for the Severe Ciliopathies: Insights into Neurodevelopment and Pathogenesis of Neural Tube Defects

Meckel-Gruber syndrome (MKS) is a severe autosomal recessively inherited disorder characterized by developmental defects of the central nervous system that comprise neural tube defects that most commonly present as occipital encephalocele. MKS is considered to be the most common syndromic form of neural tube defect. MKS is genetically heterogeneous with six known disease genes: MKS1, MKS2/TMEM216, MKS3/TMEM67, RPGRIP1L, CEP290, and CC2D2A with the encoded proteins all implicated in the correct function of primary cilia. Primary cilia are microtubule-based organelles that project from the apical surface of most epithelial cell types. Recent progress has implicated the involvement of cilia in the Wnt and Shh signaling pathways and has led to an understanding of their role in normal mammalian neurodevelopment. The aim of this review is to provide an overview of the molecular genetics of the human disorder, and to assess recent insights into the etiology and molecular cell biology of severe ciliopathies from mammalian animal models of MKS.

Polycomb group proteins are essential for spinal cord development

Birth defects are the leading cause of infantile mortality, followed by neural tube defects (NTD) and congenital heart defects. Spina bifida and anencephaly are among the most common forms of NTD. NTD etiologies are complex, and are associated with both genetic and environmental factors. Polycomb group proteins are essential for vertebrate development; therefore, the purpose of this study was to determine the role of PcGs in spinal cord morphogenesis in normal and all-trans-retinoic acid (RA)-treated fetal rat models of spina bifida. Pregnant rats were gavage-fed RA, resulting in fetal NTD, and embryos were obtained on day 15.5, 17.5, and 19.5. Western blot and immunohistochemistry were used to reveal PcGs expression in the normal and RA-treated E15.5-19.5 rat sacral cords. Western blot and immunohistochemistry revealed decreased EED, RNF2, SUZ12, and H3K27me3 expression in the normal, E15.5-19.5, rat sacral cords. In addition, the spinal cord of RA-treated rats during embryonic development exhibited altered PcGs protein expression. Administration of excess RA results in NTD. Our results suggest that the Polycomb proteins may be involved in spinal cord development.