The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects
01 Mar 2013-Science (American Association for the Advancement of Science)-Vol. 339, Iss: 6123, pp 1222002-1222002
TL;DR: The process of neural tube development and how defects in this process lead to NTDs are reviewed and it is suggested that discovering the genetic risk factors for these serious birth defects could provide ways to prevent and treat neural tube defects.
Abstract: Human birth defects are a major public health burden: The Center for Disease Control estimates that 1 of every 33 United States newborns presents with a birth defect, and worldwide the estimate approaches 6% of all births. Among the most common and debilitating of human birth defects are those affecting the formation of the neural tube, the precursor to the central nervous system. Neural tube defects (NTDs) arise from a complex combination of genetic and environmental interactions. Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, and we are only now beginning to understand their etiology. Here, we review the process of neural tube development and how defects in this process lead to NTDs, both in humans and in the animal models that serve to inform our understanding of these processes. The insights we are gaining will help generate new intervention strategies to tackle the clinical challenges and to alleviate the personal and societal burdens that accompany these defects.
Citations
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TL;DR: Genetic and functional evidence suggests that hyperactivation of this pathway is a driver of oncogenesis and establishes a link to cellular epigenetic status, which could present opportunities for translation into precision cancer medicine.
Abstract: One-carbon metabolism involving the folate and methionine cycles integrates nutritional status from amino acids, glucose and vitamins, and generates diverse outputs, such as the biosynthesis of lipids, nucleotides and proteins, the maintenance of redox status and the substrates for methylation reactions. Long considered a 'housekeeping' process, this pathway has recently been shown to have additional complexity. Genetic and functional evidence suggests that hyperactivation of this pathway is a driver of oncogenesis and establishes a link to cellular epigenetic status. Given the wealth of clinically available agents that target one-carbon metabolism, these new findings could present opportunities for translation into precision cancer medicine.
1,190 citations
TL;DR: Understanding both the common themes and the variations in apical constriction mechanisms promises to provide insight into the mechanics that underlie tissue morphogenesis.
Abstract: Apical constriction is a cell shape change that promotes tissue remodeling in a variety of homeostatic and developmental contexts, including gastrulation in many organisms and neural tube formation in vertebrates In recent years, progress has been made towards understanding how the distinct cell biological processes that together drive apical constriction are coordinated These processes include the contraction of actin-myosin networks, which generates force, and the attachment of actin networks to cell-cell junctions, which allows forces to be transmitted between cells Different cell types regulate contractility and adhesion in unique ways, resulting in apical constriction with varying dynamics and subcellular organizations, as well as a variety of resulting tissue shape changes Understanding both the common themes and the variations in apical constriction mechanisms promises to provide insight into the mechanics that underlie tissue morphogenesis
408 citations
Cites background from "The Continuing Challenge of Underst..."
...Apical constriction of populations of cells that maintain cell-cell adhesion can bend and fold epithelial tissues, in some cases transforming flat epithelial sheets into threedimensional structures, such as tubes (Lewis, 1947; Hardin and Keller, 1988; Alvarez and Navascués, 1990; Kam et al., 1991; Sweeton et al., 1991; Wallingford et al., 2013)....
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...…maintain cell-cell adhesion can bend and fold epithelial tissues, in some cases transforming flat epithelial sheets into threedimensional structures, such as tubes (Lewis, 1947; Hardin and Keller, 1988; Alvarez and Navascués, 1990; Kam et al., 1991; Sweeton et al., 1991; Wallingford et al., 2013)....
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TL;DR: Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.
Abstract: Planar cell polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted WNT ligands and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.
404 citations
TL;DR: Information is provided on the pre- and post-conception use of oral folic acid with or without a multivitamin/micronutrient supplement for the prevention of neural tube defects and other congenital anomalies to help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic Acid/multivitamin supplementation before and during pregnancy.
Abstract: Objective To provide updated information on the pre- and post-conception use of oral folic acid with or without a multivitamin/micronutrient supplement for the prevention of neural tube defects and other congenital anomalies This will help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic acid/multivitamin supplementation before and during pregnancy. Evidence Published literature was retrieved through searches of PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., folic acid, prenatal multivitamins, folate sensitive birth defects, congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies Costs, risks, and benefits The financial costs are those of daily vitamin supplementation and eating a healthy folate-enriched diet. The risks are of a reported association of dietary folic acid supplementation with fetal epigenetic modifications and with an increased likelihood of a twin pregnancy These associations may require consideration before initiating folic acid supplementation The benefit of folic acid oral supplementation or dietary folate intake combined with a multivitamin/micronutrient supplement is an associated decrease in neural tube defects and perhaps in other specific birth defects and obstetrical complications. Values The quality of evidence in the document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1).
201 citations
TL;DR: Tight metabolic control, surveillance, and labor management remain the cornerstone of care for pregnant women with diabetes, but advances in the field indicate that new treatments to protect the mother and baby are not far from becoming clinical realities.
Abstract: Introduction
Pregestational and gestational diabetes mellitus (PGDM; GDM) are significant health concerns because they are associated with an increased rate of malformations and maternal health complications.
Methods
We reviewed the data that help us to understand the effects of diabetes in pregnancy.
Results
Diabetic embryopathy can affect any developing organ system, but cardiovascular and neural tube defects are among the most frequent anomalies. Other complications include preeclampsia, preterm delivery, fetal growth abnormalities, and perinatal mortality. Neurodevelopmental studies on offspring of mothers with diabetes demonstrated increased rate of Gross and Fine motor abnormalities, of Attention Deficit Hyperactivity Disorder, learning difficulties, and possibly also Autism Spectrum Disorder. The mechanisms underlying the effects of maternal hyperglycemia on the developing fetus may involve increased oxidative stress, hypoxia, apoptosis, and epigenetic changes. Evidence for epigenetic changes are the following: not all progeny are affected and not to the same extent; maternal diet may influence pregnancy outcomes; and maternal diabetes alters embryonic transcriptional profiles and increases the variation between transcriptomic profiles as a result of altered gene regulation. Research in animal models has revealed that maternal hyperglycemia is a teratogen, and has helped uncover potential therapeutic targets which, when blocked, can mitigate or ameliorate the negative effects of diabetes on the developing fetus.
Conclusions
Tight metabolic control, surveillance, and labor management remain the cornerstone of care for pregnant women with diabetes, but advances in the field indicate that new treatments to protect the mother and baby are not far from becoming clinical realities. Birth Defects Research (Part C) 105:53–72, 2015. © 2015 Wiley Periodicals, Inc.
193 citations
References
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TL;DR: The four articles in this special section onMeta-analysis illustrate some of the complexities entailed in meta-analysis methods and contributes both to advancing this methodology and to the increasing complexities that can befuddle researchers.
Abstract: During the past 30 years, meta-analysis has been an indispensable tool for revealing the hidden meaning of our research literatures. The four articles in this special section on meta-analysis illus...
20,272 citations
"The Continuing Challenge of Underst..." refers background in this paper
...ciated with the risk of NTDs in the offspring of diabetic women (23, 24)....
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TL;DR: An unexplained elevated level of maternal serum alpha-fetoprotein in the second trimester of pregnancy is associated with an increased risk of subsequent fetal death, up to four to five months after alphafetoprotein screening.
2,832 citations
Journal Article•
TL;DR: Current methods to detect FBDOs are improving, and several changes to improve the ease and timeliness of reporting FBDO data are occurring (e.g., a revised form to simplify FBDO reporting by state health departments and electronic reporting methods).
Abstract: Problem/condition Since 1973, CDC has maintained a collaborative surveillance program for collection and periodic reporting of data on the occurrence and causes of foodborne-disease outbreaks (FBDOs) in the United States. Reporting period covered This summary reviews data from January 1993 through December 1997. Description of system The Foodborne-Disease Outbreak Surveillance System reviews data concerning FBDOs, defined as the occurrence of two or more cases of a similar illness resulting from the ingestion of a common food. State and local public health departments have primary responsibility for identifying and investigating FBDOs. State, local, and territorial health departments use a standard form to report these outbreaks to CDC. Results During 1993-1997, a total of 2,751 outbreaks of foodborne disease were reported (489 in 1993, 653 in 1994, 628 in 1995, 477 in 1996, and 504 in 1997). These outbreaks caused a reported 86,058 persons to become ill. Among outbreaks for which the etiology was determined, bacterial pathogens caused the largest percentage of outbreaks (75%) and the largest percentage of cases (86%). Salmonella serotype Enteritidis accounted for the largest number of outbreaks, cases, and deaths; most of these outbreaks were attributed to eating eggs. Chemical agents caused 17% of outbreaks and 1% of cases; viruses, 6% of outbreaks and 8% of cases; and parasites, 2% of outbreaks and 5% of cases. Interpretation The annual number of FBDOs reported to CDC did not change substantially during this period or from previous years. During this reporting period, S. Enteritidis continued to be a major cause of illness and death. In addition, multistate outbreaks caused by contaminated produce and outbreaks caused by Escherichia coli O157:H7 remained prominent. Actions taken Current methods to detect FBDOs are improving, and several changes to improve the ease and timeliness of reporting FBDO data are occurring (e.g., a revised form to simplify FBDO reporting by state health departments and electronic reporting methods). State and local health departments continue to investigate and report FBDOs as part of efforts to better understand and define the epidemiology of foodborne disease in the United States. At the regional and national levels, surveillance data provide an indication of the etiologic agents, vehicles of transmission, and contributing factors associated with FBDOs and help direct public health actions to reduce illness and death caused by FBDOs.
1,810 citations
TL;DR: It is proposed that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproIC acid in the treatment of bipolar disorder.
1,672 citations
"The Continuing Challenge of Underst..." refers background in this paper
...mised by VPA exposure, which inhibits HDACs and limits the availability of folate molecules (34),...
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TL;DR: The connections between cilia and developmental signalling have begun to clarify the basis of human diseases associated with ciliary dysfunction, and the cilium represents a nexus for signalling pathways during development.
Abstract: The primary cilium has recently stepped into the spotlight, as a flood of data show that this organelle has crucial roles in vertebrate development and human genetic diseases. Cilia are required for the response to developmental signals, and evidence is accumulating that the primary cilium is specialized for hedgehog signal transduction. The formation of cilia, in turn, is regulated by other signalling pathways, possibly including the planar cell polarity pathway. The cilium therefore represents a nexus for signalling pathways during development. The connections between cilia and developmental signalling have begun to clarify the basis of human diseases associated with ciliary dysfunction.
1,669 citations
"The Continuing Challenge of Underst..." refers background in this paper
...Second, cilia are crucial organelles for Hedgehog signal transduction (76), and Hedgehog signals have been linked directly to neural patterning and to neural epithelium bending, a process facilitated by apical constriction (79)....
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...Cilia are small microtubule-based cellular protrusions that are essential for cell-cell signaling (76), a discovery first made in the course ofmouse genetic screens focused on neural tube morphogenesis (77, 78)....
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