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Epigenetics & Chromatin Dec 2023Neural tube defects (NTDs) are one of the most severe congenital abnormalities characterized by failures of the neural tube to close during early embryogenesis. Maternal...
BACKGROUND
Neural tube defects (NTDs) are one of the most severe congenital abnormalities characterized by failures of the neural tube to close during early embryogenesis. Maternal folate deficiency could impact the occurrence of NTDs, however, the mechanisms involved in the cause of NTDs are poorly defined.
RESULTS
Here, we report that histone H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) expression was significantly downregulated, and low levels of H3K79me2 were found in the corresponding NTDs samples with their maternal serum folate under low levels. Using ChIP-seq assays, we found that a decrease of H3K79me2 downregulates the expression of Shh and Sufu in mouse embryonic stem cells (mESC) under folate deficiency. Interestingly, folate antagonist methotrexate treatment led to attenuation of H3K79me2 due to Dot1l, affecting Shh and Sufu genes regulation. Upon further analysis, we find that the genes Shh and Sufu are both downregulated in the brain tissues of mice and humans with NTDs. There was a positive correlation between the transcription levels of Shh, Sufu and the protein levels of DOT1L by Pearson correlation analysis.
CONCLUSION
Our results indicate that abnormal Shh and Sufu genes expression reduced by aberrant Dot1l-mediated H3K79me2 levels could be the cause of NTDs occurrence.
Topics: Mice; Humans; Animals; Histones; Neural Tube Defects; Methylation; Folic Acid; Gene Expression; Hedgehog Proteins; Histone-Lysine N-Methyltransferase
PubMed: 38093377
DOI: 10.1186/s13072-023-00517-3 -
Child's Nervous System : ChNS :... Jul 2023Neural tube defects continue to be one of the main congenital malformations affecting the development of the nervous system and a significant cause of disability and... (Review)
Review
BACKGROUND
Neural tube defects continue to be one of the main congenital malformations affecting the development of the nervous system and a significant cause of disability and disease burden to individuals living with these conditions. Mandatory food fortification with folic acid is, by far, one of the most efficacious, safe, and cost-effective interventions to prevent neural tube defects. However, most countries fail to effectively fortify staple foods with folic acid, impacting public health and healthcare systems and generating dismal disparities.
AIM
This article discusses the main barriers and facilitators for implementing mandatory food fortification as an evidence-based policy to prevent neural tube defects worldwide.
METHODS
A comprehensive review of the scientific literature allowed the identification of the determinant factors acting as barriers or facilitators for the reach, adoption, implementation, and scaling up of mandatory food fortification with folic acid as an evidence-based policy.
RESULTS
We identified eight barriers and seven facilitators as determinant factors for food fortification policies. The identified factors were classified as individual, contextual, and external, inspired by the Consolidated Framework for Implementation of Research (CFIR). We discuss mechanisms to overcome obstacles and seize the opportunities to approach this public health intervention safely and effectively.
CONCLUSIONS
Several determinant factors acting as barriers or facilitators influence the implementation of mandatory food fortification as an evidence-based policy worldwide. Notoriously, policymakers in many countries may lack knowledge of the benefits of scaling up their policies to prevent folic acid-sensitive neural tube defects, improve the health status of their communities, and promote the protection of many children from these disabling but preventable conditions. Not addressing this problem negatively affects four levels: public health, society, family, and individuals. Science-driven advocacy and partnerships with essential stakeholders can help overcome the barriers and leverage the facilitators for safe and effective food fortification.
Topics: Child; Humans; Folic Acid; Food, Fortified; Neural Tube Defects; Public Health; Policy
PubMed: 37209199
DOI: 10.1007/s00381-023-05944-x -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Aug 2023To summarize the clinical manifestation, classification, and experience of surgical treatment of primary tethered cord syndrome (TCS) in adults.
OBJECTIVE
To summarize the clinical manifestation, classification, and experience of surgical treatment of primary tethered cord syndrome (TCS) in adults.
METHODS
The authors retrospectively analyzed a series of 171 adult patients with primary TCS who were surgically treated under microscope from March 2007 to October 2019. There were 61 males and 110 females whose ages were 18-65 years, with an average age of (39.02±11.81) years. Clinically, the patients presented with various neurological symptoms and signs including lower back and legs pain, reflex changes, sensory disturbances, muscle weakness, and sphincter problems. They were divided into 5 types by clinical manifestations and neuro-imaging features: (1) filum terminale traction in 69 cases, (2) split cord malformation in 21 cases, (3) myelomeningocele in 20 cases, (4) lipomyelomeningocele in 36 cases, and (5) dermal sinus traction in 25 cases. All the patients underwent microsurgery to untether the spinal cord. The patients kept prone position 7 days postoperatively. The Kirollos grading was used to evaluate the outcome of intraoperative untethering. The visual analogue scale (VAS) was used to evaluate the pain, the score of critical muscle strength was used to evaluate the lower extremity motor function, and the Japanese Orthopaedic Association (JOA) sphincter function score was used to evaluate the bladder function.
RESULTS
All of the 171 patients were treated with microsurgery to release the adhesion and cut off the filum terminalis. 61 cases of them received resection of the lesions according to the etiology. All the tethered spinal cord reached Kirollos grade Ⅰ untethering and the dural sac was reconstructed. Other than 5 patients had cerebrospinal fluid leakage and incision laceration and underwent re-suture, there was no surgical complication. The local pain was relieved, the lower limbs weakness or bowel and bladder dysfunction gradually recovered postoperatively. The period of follow-up ranged from 6 months to 12.5 years with an average of (5.62±2.31) years. The neurological function was improved in 153 cases and stable in 18 cases. There was no recurrence of tethered cord be found during the follow-up period.
CONCLUSION
The primary TCS in adulthood could be classified into 5 types by clinical manifestations and neuro-imaging features and surgical treatment should be undertaken in regard to the classifications including dissection and resection of the lesion detethering the spinal cord and reconstruction of the dura sac under microscope. The outcome of surgical treatment is satisfactory.
Topics: Male; Female; Humans; Adult; Middle Aged; Retrospective Studies; Treatment Outcome; Meningomyelocele; Neural Tube Defects; Pain
PubMed: 37534645
DOI: 10.19723/j.issn.1671-167X.2023.04.012 -
Advances in Nutrition (Bethesda, Md.) Mar 2021Weekly iron and folic acid supplementation (WIFAS) is among the 8 key effective actions for improving adolescent nutrition included by the WHO in the 2018 guidelines.... (Review)
Review
Perspective: Weekly Iron and Folic Acid Supplementation (WIFAS): A Critical Review and Rationale for Inclusion in the Essential Medicines List to Accelerate Anemia and Neural Tube Defects Reduction.
Weekly iron and folic acid supplementation (WIFAS) is among the 8 key effective actions for improving adolescent nutrition included by the WHO in the 2018 guidelines. However, at present WIFAS in the WHO-recommended formulation is not included in the Model Essential Medicines List (MEML), limiting the potential for countries to import, produce, and prioritize this formulation as part of their national supply management and procurement plans for medicines. The WHO WIFAS guideline presents evidence that the formulation reduces anemia, but not that folic acid reduces neural tube defects (NTDs), because sufficient evidence was unavailable at the time of the last review. Recently, a 3-arm, parallel-group, randomized, double-blind, placebo-controlled folic acid efficacy trial on WIFAS was conducted to address this evidence gap. The study population included 331 women (18-45 y old), randomly assigned to 3 treatment groups, including a supplement with 60 mg Fe as ferrous fumarate and either 0 mg, 0.4 mg, or 2.8 mg of folic acid, to be consumed once weekly for 16 wk, followed by a 4-wk washout period. In this article we critically review how the outcomes of this folic acid efficacy trial, and how the evidence generated, could potentially be used to inform WHO WIFAS guidelines for the potential inclusion of this formulation on the MEML, and how this, in turn, may affect product availability. If the new evidence on weekly folic acid is assessed as adequately reducing the risk of NTDs, a guideline revision could be warranted and WIFAS could be presented to the MEML for the dual benefits of anemia reduction and NTD prevention. This inclusion could enable acceleration of implementing policies and programs to contribute to global anemia and NTD reduction efforts.
Topics: Adolescent; Anemia; Dietary Supplements; Female; Folic Acid; Humans; Iron; Neural Tube Defects; Randomized Controlled Trials as Topic
PubMed: 33439978
DOI: 10.1093/advances/nmaa169 -
BMJ Open Nov 2023This study aims to estimate the prevalence of neural tube defects (NTDs) and to identify potential risk factors in the Ethiopian context. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study aims to estimate the prevalence of neural tube defects (NTDs) and to identify potential risk factors in the Ethiopian context.
STUDY DESIGN
Systematic review and meta-analysis.
STUDY PARTICIPANTS
A total of 611 064 participants were included in the review obtained from 42 studies.
METHODS
PubMed (Medline), Embase and Cochrane Library databases in combination with other potential sources of literature were systematically searched, whereby studies conducted between January 2010 and December 2022 were targeted in the review process. All observational studies were included and heterogeneity between studies was verified using Cochrane Q test statistics and I test statistics. Small study effects were checked using Egger's statistical test at a 5% significance level.
RESULT
The pooled prevalence of all NTDs per 10 000 births in Ethiopia was 71.48 (95% CI 57.80 to 86.58). The between-study heterogeneity was high (I= 97.49%, p<0.0001). Birth prevalence of spina bifida (33.99 per 10 000) was higher than anencephaly (23.70 per 10 000), and encephalocele (4.22 per 10 000). Unbooked antenatal care (AOR 2.26, 95% CI (1.30 to 3.94)), preconception intake of folic acid (AOR 0.41, 95% CI (0.26 to 0.66)), having chronic medical illness (AOR 2.06, 95% CI (1.42 to 2.99)), drinking alcohol (AOR 2.70, 95% CI (1.89 to 3.85)), smoking cigarette (AOR 2.49, 95% CI (1.51 to 4.11)), chewing khat (AOR 3.30, 95% CI (1.88 to 5.80)), exposure to pesticides (AOR 3.87, 95% CI (2.63 to 5.71)), maternal age ≥35 (AOR 1.90, 95% CI (1.13 to 3.25)), maternal low educational status (AOR 1.60, 95% CI (1.13 to 2.24)), residing in urban areas (AOR 0.75, 95% CI (0.58 to 0.97))and family history of NTDs (AOR 2.51, 95% CI (1.36 to 4.62)) were associated with NTD cases.
CONCLUSION
The prevalence of NTDs in Ethiopia is seven times as high as in other Western countries where prevention measures are put in place. Heredity, maternal and environmental factors are associated with a high prevalence of NTDs. Mandatory fortification of staple food with folic acid should be taken as a priority intervention to curb the burden of NTDs. To smoothen and overlook the pace of implementation of mass fortification, screening, and monitoring surveillance systems should be in place along with awareness-raising measures.
PROSPERO REGISTRATION NUMBER
CRD42023413490.
Topics: Female; Pregnancy; Humans; Prevalence; Ethiopia; Neural Tube Defects; Folic Acid; Risk Factors; Food, Fortified
PubMed: 37940152
DOI: 10.1136/bmjopen-2023-077685 -
Cellular and Molecular Life Sciences :... Jun 2022The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a...
The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a paucity of animal models. Here, we generated homozygous (Slc25a32 and Slc25a32) and compound heterozygous (Slc25a32) knock-in mice by mimicking the missense mutations identified from our patient. A homozygous knock-out (Slc25a32) mouse was also generated. The Slc25a32 and Slc25a32 mice presented with mild motor impairment and recapitulated the biochemical disturbances of the patient. While Slc25a32 mice die in utero with NTDs. None of the Slc25a32 mutations hindered the mitochondrial uptake of folate. Instead, the mitochondrial uptake of flavin adenine dinucleotide (FAD) was specifically blocked by Slc25a32, Slc25a32, and Slc25a32 mutations. A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency was observed. Besides the flavoenzymes involved in fatty acid β-oxidation and amino acid metabolism being impaired, Slc25a32 embryos also had a subunit of glycine cleavage system-dihydrolipoamide dehydrogenase damaged, resulting in glycine accumulation and glycine derived-formate reduction, which further disturbed folate-mediated one-carbon metabolism, leading to 5-methyltetrahydrofolate shortage and other folate intermediates accumulation. Maternal formate supplementation increased the 5-methyltetrahydrofolate levels and ameliorated the NTDs in Slc25a32 embryos. The Slc25a32 and Slc25a32 mice had no glycine accumulation, but had another formate donor-dimethylglycine accumulated and formate deficiency. Meanwhile, they suffered from the absence of all folate intermediates in mitochondria. Formate supplementation increased the folate amounts, but this effect was not restricted to the Slc25a32 mutant mice only. In summary, we established novel animal models, which enabled us to understand the function of SLC25A32 better and to elucidate the role of SLC25A32 dysfunction in human disease development and progression.
Topics: Animals; Humans; Mice; Carbon; Flavin-Adenine Dinucleotide; Folic Acid; Formates; Glycine; Mitochondria; Neural Tube Defects
PubMed: 35727412
DOI: 10.1007/s00018-022-04404-0 -
Birth Defects Research Jan 2018Several studies have assessed potential associations between use of weight loss products in the periconceptional period and neural tube defects (NTDs). However, the... (Review)
Review
BACKGROUND
Several studies have assessed potential associations between use of weight loss products in the periconceptional period and neural tube defects (NTDs). However, the individual studies are inconclusive and there has not been a systematic review of this literature.
METHODS
We conducted a systematic search, using Ovid MEDLINE and PubMed, to identify studies that evaluated the association between products used for weight loss and the risk of NTDs. Because many studies of birth defects only evaluate a composite birth defect outcome, we evaluated studies that defined the outcome as "any major birth defect" or as NTDs. We abstracted data on study design, exposure definition, outcome definition, covariates and effect size estimates from each article that met our inclusion criteria. For studies that evaluated a composite birth defect outcome, we also abstracted the number of NTD cases included in the composite outcome. We used a modified version of the Newcastle-Ottawa Scale to assess the quality of each article.
RESULTS
We screened 865 citations and identified nine articles that met our inclusion criteria. The majority of studies reported positive associations between maternal use of weight loss products and birth defects (overall and NTDs). However, there were few significant associations and there was considerable heterogeneity in the specific exposures assessed across the nine studies.
CONCLUSION
Our systematic review of weight loss products and NTDs indicates that the literature on this topic is sparse. Because several studies reported modest, positive associations between risk and use of weight loss products, additional studies are warranted. Birth Defects Research 110:48-55, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Anti-Obesity Agents; Female; Humans; Neural Tube Defects; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors; Weight Loss
PubMed: 29024488
DOI: 10.1002/bdr2.1116 -
Pediatric Neurosurgery 2023Myelomeningocele (MMC) is a malformation resulting from the neural tube's failure to close during embryonic development, and the majority of the cases of neural tube...
INTRODUCTION
Myelomeningocele (MMC) is a malformation resulting from the neural tube's failure to close during embryonic development, and the majority of the cases of neural tube defects (NTDs) were prevalent as single location lesions along the spine; however, multiple NTDs (MNTDs) are a very rare condition. Only a few cases of MNTDs were found in the literature.
CASE PRESENTATION
We report the case of a 2-month-old male infant prenatally diagnosed with MMC, presented with two unconnected lumbar and lumbosacral epidermal, soft, dome-shaped swellings located on both sides of the midline (paravertebral) covered by intact skin. MRI revealed double MMC at the level of L4-L5, with spinal nerve roots. The patient underwent surgical repair of the defects by replacing the spinal cord and its nerve roots inside the thecal sac and recreating a covering layer around the neural structures to resemble thecal sac. The outcome was favorable, and postoperative head CT scan did not show any complication.
CONCLUSION
Our case report is considered the first from Algeria to report the condition and the first to report the occurrence of double lesions in the same spine region. MMC can be associated with neurological deficits or other congenital anomalies, thus it is necessary to thoroughly examine such patients. However, there was no antenatal folic acid deficiency in our case. We recommend antenatal care with adequate folic acid supplementation given that its deficiency during pregnancy is considered a ubiquitous risk factor for the condition. The optimal timing for surgery of MMC cases is 8 ± 5 days. Prenatal intrauterine repair of the condition provides favorable outcomes but carries high fetal and maternal risks. Surgical repair should include the sac removal, the reconstruction of the placode, and the closure of the overlying meninges. With early diagnosis and proper repair of such cases, MMC has good prognosis and favorable outcomes.
Topics: Infant; Pregnancy; Female; Humans; Male; Meningomyelocele; Neural Tube Defects; Spine; Spinal Cord; Fetus
PubMed: 37075706
DOI: 10.1159/000530726 -
PloS One 2016We conducted this systematic review and meta-analysis to address the open question of a possible association between the socioeconomic level of the neighborhoods in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We conducted this systematic review and meta-analysis to address the open question of a possible association between the socioeconomic level of the neighborhoods in which pregnant women live and the risk of Congenital Heart Defects (CHDs), Neural Tube Defects (NTDs) and OroFacial Clefts (OFCs).
METHODS
We searched MEDLINE from its inception to December 20th, 2015 for case-control, cohort and ecological studies assessing the association between neighborhood socioeconomic level and the risk of CHDs, NTDs and the specific phenotypes Cleft Lip with or without Cleft Palate (CLP) and Cleft Palate (CP). Study-specific risk estimates were pooled according to random-effect and fixed-effect models.
RESULTS
Out of 245 references, a total of seven case-control studies, two cohort studies and two ecological studies were assessed in the systematic review; all studies were enrolled in the meta-analysis with the exception of the two cohort studies. No significant association has been revealed between CHDs or NTDs and neighborhood deprivation index. For CLP phenotype subgroups, we found a significantly higher rate in deprived neighborhoods (Odds Ratios (OR) = 1.22, 95% CI: 1.10, 1.36) whereas this was not significant for CP phenotype subgroups (OR = 1.20, 95%CI: 0.89, 1.61).
CONCLUSION
In spite of the small number of epidemiological studies included in the present literature review, our findings suggest that neighborhood socioeconomic level where mothers live is associated only with an increased risk of CLP phenotype subgroups. This finding has methodological limitations that impede the formulation of firm conclusions, and further investigations should confirm this association.
Topics: Databases, Factual; Female; Heart Defects, Congenital; Humans; Mouth Abnormalities; Neural Tube Defects; Odds Ratio; Pregnancy; Residence Characteristics; Risk Factors; Socioeconomic Factors
PubMed: 27783616
DOI: 10.1371/journal.pone.0159039 -
The American Journal of Clinical... May 2023RBC folate concentrations are monitored at the population level, with a recommended threshold for optimal neural tube defect (NTD) prevention. A corresponding threshold...
Estimating the serum folate concentration that corresponds to the red blood cell folate concentration threshold associated with optimal neural tube defects prevention: A population-based biomarker survey in Southern India.
BACKGROUND
RBC folate concentrations are monitored at the population level, with a recommended threshold for optimal neural tube defect (NTD) prevention. A corresponding threshold for serum folate has not been established.
OBJECTIVES
This study aimed to estimate the serum folate insufficiency threshold corresponding to the RBC folate threshold for NTD prevention and examine how this threshold is modified by vitamin B status.
METHODS
Participants were women (15-40 y; not pregnant or lactating; n = 977) from a population-based biomarker survey in Southern India. RBC folate and serum folate were measured via microbiologic assay. RBC folate deficiency (<305 nmol/L) and insufficiency (<748 nmol/L), serum vitamin B deficiency (<148 pmol/L) and vitamin B insufficiency (<221 pmol/L), elevated plasma MMA (>0.26 μmol/L), elevated plasma homocysteine (>10.0 μmol/L), and elevated HbA1c (≥6.5%) were evaluated. Bayesian linear models were used to estimate unadjusted and adjusted thresholds.
RESULTS
Compared with adequate vitamin B status, the estimated serum folate threshold was higher in participants with serum vitamin B deficiency (72.5 vs. 28.1 nmol/L) or vitamin B insufficiency (48.7 vs. 24.3 nmol/L) and elevated MMA (55.6 vs. 25.9 nmol/L). The threshold was lower in participants with elevated HbA1c (HbA1c ≥6.5% vs. <6.5%; 21.0 vs. 40.5 nmol/L).
CONCLUSIONS
The estimated serum folate threshold for optimal NTD prevention was similar to previous reports (24.3 vs. 25.6 nmol/L) among participants with sufficient vitamin B status. However, this threshold was more than 2-fold higher in participants with vitamin B deficiency and substantially higher across all indicators of insufficient vitamin B status (<221 pmol/L, elevated MMA, combined B, impaired vitamin B status), and lower in participants with elevated HbA1c. Findings suggest a serum folate threshold for NTD prevention may be possible in some settings; however, it may not be appropriate in populations with high prevalence of vitamin B insufficiency. Am J Clin Nutr 2023;xx:xx-xx. This trial was registered at https://clinicaltrials.gov as NCT04048330.
Topics: Humans; Female; Pregnancy; Male; Folic Acid; Bayes Theorem; Glycated Hemoglobin; Lactation; Neural Tube Defects; Vitamin B 12; Vitamin B 12 Deficiency; Biomarkers; Erythrocytes; Vitamins; Homocysteine
PubMed: 37137617
DOI: 10.1016/j.ajcnut.2023.01.016