The Continuing Challenge of Understanding, Preventing, and Treating Neural Tube Defects

Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX 78712, USA.
Science (Impact Factor: 33.61). 03/2013; 339(6123):1222002. DOI: 10.1126/science.1222002
Source: PubMed


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.

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Available from: Richard H Finnell, Oct 07, 2015
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    • "NTDs such as spina bifida and anencephaly are structural malformations of the central nervous system caused by delayed closure of the neural tube in the first few weeks after conception [10]. NTD births constitute considerable social and economic burden for the affected families and the health system [11]. "
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    ABSTRACT: Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (>18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia.
    Journal of Perinatal Medicine 03/2015; DOI:10.1515/jpm-2014-0346 · 1.36 Impact Factor
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    • "Additionally, in vertebrates, the PCP pathway has been adapted to morphogenetic processes such as neural tube closure [75] [79] [80] [83] [84], development of the cardiac outflow tract [83, 85–87], face and palate structure [88], somite organization [89], lung branching morphogenesis [90], cochlear development [81] [91] [92], and other morphogenetic processes. The prototypic feature of many mouse PCP gene mutants is a severe neural tube defect, craniorachischisis, which represents complete failure of neural tube closure (extensively reviewed in [93] [94]). Neural tube formation is a complex process which begins with flattening of the neural plate. "
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    ABSTRACT: The evolutionarily conserved planar cell polarity (PCP) signaling pathway controls tissue polarity within the plane orthogonal to the apical-basal axis. PCP was originally discovered in Drosophila melanogaster where it is required for the establishment of a uniform pattern of cell structures and appendages. In vertebrates, including mammals, the PCP pathway has been adapted to control various morphogenetic processes that are critical for tissue and organ development. These include convergent extension (crucial for neural tube closure and cochlear duct development) and oriented cell division (needed for tubular elongation), ciliary tilting that enables directional fluid flow, and other processes. Recently, strong evidence has emerged to implicate the PCP pathway in vertebrate kidney development. In this review, we will describe the experimental data revealing the role of PCP signaling in nephrogenesis and kidney disease.
    01/2015; 2015:1-15. DOI:10.1155/2015/764682
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    • "It has been estimated that more than 320,000 infants are born with an NTD each year worldwide [1]. The etiology of NTDs is complex, with contributions from both genetic and environmental factors [2] [3]. Studies have shown that maternal exposure to environmental chemicals, such as polycyclic aromatic hydrocarbons [4] [5] [6], pesticides [6] [7], antiepileptic drugs [8], and heavy metals [9] [10], is associated with an increased risk of NTDs. "
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    ABSTRACT: Neural tube defects (NTDs) are among the most common and severe congenital malformations. To examine the association between markers of macromolecular oxidative damage and risk of NTDs, we measured levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), protein carbonyl (PC), and 8-iso-prostaglandin F2α (8-iso-PGF2α) in maternal serum samples of 117 women with NTD-affected pregnancies and 121 women with healthy term newborns. We found higher levels of 8-OHdG and PC in the NTD group than in the control group; however, we did not observe a statistically significant difference in 8-iso-PGF2α levels between the NTD and control groups. NTD risk increased with increasing quartiles of 8-OHdG [odds ratio (OR)=1.17; 95% confidence interval (CI) 0.39-3.51; OR=2.19; 95% CI, 0.68-7.01; OR=3.70; 95% CI, 1.30-10.51, for the 2(nd), 3(rd), 4(th) quartile relative to the lowest quartile, respectively; p=0.009], and with increasing quartiles of PC (OR=2.26; 95% CI, 0.66-7.69; OR=3.86; 95% CI, 1.17-12.80; OR=5.98; 95% CI, 1.82-19.66, for the 2(nd), 3(rd), 4(th) quartile relative to the lowest quartile, respectively; p=0.002]. Serum levels of 8-OHdG were higher in women who did not take folic acid supplements during the periconceptional period. These results suggest that oxidative stress is present in women carrying pregnancies affected by NTDs. Copyright © 2014. Published by Elsevier Inc.
    Free Radical Biology and Medicine 12/2014; 80. DOI:10.1016/j.freeradbiomed.2014.12.014 · 5.74 Impact Factor
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