Investigations into the etiology of neural tube defects

Cabrera, Robert M.; Hill, Denise S.; Etheredge, Analee J.; Finnell, Richard H.

doi:10.1002/bdrc.20025

Cited by 70 publications

(47 citation statements)

References 195 publications

(167 reference statements)

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“…This country not only fortifies wheat flour but also maize flour, cow's milk and rice (28) . Other countries showed NTD reductions of about 50 % (16,20,21,57) and similar reductions in spina bifida (21,25,38) and anencephaly (16,35,39) . The results varied by country and depended on the integrity and quality of the country's surveillance system.…”

Section: References Identified Medline Viamentioning

confidence: 88%

Impact of folic acid fortification of flour on neural tube defects: a systematic review

Castillo-Lancellotti

Tur

Uauy

2012

Public Health Nutr.

163

136

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Objective: To review the impact of folic acid fortification of flour on the prevalence of neural tube defects (NTD). Design: Systematic review of the literature on MEDLINE via PubMed, Scopus, OvidSP and LILACS (Latin American and Caribbean Health Sciences Literature) reporting the impact of folic acid fortification of flour on the prevalence of NTD in 2000-2011. Focusing on Santiago of Chile's birth defects registry (1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009) and the monitoring of flour fortification, we analysed the prevalence (NTD cases/ 10 000 births) pre and post flour fortification and the percentile distribution of folic acid content in flour (2005)(2006)(2007)(2008)(2009). We explored the potential association between median folic acid in flour (mg/kg) and the prevalence of NTD. Setting: Chile, Argentina, Brazil, Canada, Costa Rica, Iran, Jordan, South Africa and the USA. Subjects: Live births and stillbirths. Results: Twenty-seven studies that met inclusion criteria were evaluated. Costa Rica showed a significant reduction in NTD ( , 60 %). Prevalence in Chile decreased from 18?6 to 7?3/10 000 births from 1999 to 2007 and showed a slight increase to 8?5 in 2008-2009, possibly due to changes in fortification limits. When we related the prevalence of NTD with levels of flour fortification, the lowest prevalence was observed at a folic acid level of 1?5 mg/kg. Conclusions: Fortification of flour with folic acid has had a major impact on NTD in all countries where this has been reported. Chile showed a 55 % reduction in NTD prevalence between 1999 and 2009. There is a need to constantly monitor the levels of flour fortification to maximize benefits and prevent the potential risk of folic acid excess, moreover to be vigilant for any new adverse effects associated with excess. Keywords Folic acid Neural tube defects Spinal dysraphism Food fortification Systematic reviewThe importance of nutrition in the aetiology of neural tube defects (NTD) was suggested by Hibbard and Smithells, who found that women deficient in folate had an increased number of abortions, placental abruptions and fetal malformations and intra-uterine growth retardation (1) . The first reports on folate deficiency and NTD, published by Smithells et al. (2,3) , showed the protective effect of folic acid on the recurrence of NTD. A randomised study by Czeizel and Dudas (4) showed a decrease in first NTD occurrence in women supplemented with twelve vitamins containing 0?8 mg of folic acid, but not in women supplemented with trace elements and a very low dose of vitamin C. A rigorous double-blind randomised controlled trial supported by the UK Medical Research Council showed that supplementing women who had a history of children with NTD with 4 mg of folic acid daily decreased recurrence by 72 % (5) . Although some studies were retrospective, their results revealed an inverse relationship between NTD and folic acid consumption of 100-400 mg/d (6,7) . Based on this information, in 1992 the US Public Health Service r...

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Section: References Identified Medline Viamentioning

confidence: 88%

Impact of folic acid fortification of flour on neural tube defects: a systematic review

Castillo-Lancellotti

Tur

Uauy

2012

Public Health Nutr.

163

136

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“…Folic acid (vitamin B 9 ) is known to reduce the risk of human NTDs, and mouse models with loss-of-function mutations affecting the Folr1 or Slc19a1 genes show NTDs and embryonic lethality (Blom et al, 2006;Cabrera et al, 2004;Gelineau-van Waes et al, 2008a;Piedrahita et al, 1999;Zhao et al, 2001). LRP2 has been shown to mediate the uptake of many hormones and vitamins bound to their respective carrier proteins, including vitamin D-binding protein (DBP), retinol-binding protein (RBP) and sex hormone-binding globulins (SHBG).…”

Section: Discussionmentioning

confidence: 99%

LRP2 mediates folate uptake in the developing neural tube

Kur

Mecklenburg

Cabrera

et al. 2014

Journal of Cell Science

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The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell-surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for the delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole-embryo cultures showed that LRP2-deficient neuroepithelial cells are unable to mediate the uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2 2/2 embryos compared with control littermates. Moreover, the folic-aciddependent gene Alx3 is significantly downregulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure.

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“…It uses one-carbon units for the synthesis of purines and pyrimidines and sends one-carbon units to the methionine cycle for use in methylation reactions. Folate is a B vitamin and deficiency is known to be associated with neural tube defects [42], a decrease in DNA methylation [43], and the higher homocysteine levels that are biomarkers for cardio-vascular disease [44]. Folate deficiency and folate excess are associated with a variety of cancers [45,46].…”

Section: The Folate Cyclementioning

confidence: 99%

The biological significance of substrate inhibition: A mechanism with diverse functions

2010

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Many enzymes are inhibited by their own substrates, leading to velocity curves that rise to a maximum and then descend as the substrate concentration increases. Substrate inhibition is often regarded as a biochemical oddity and experimental annoyance. We show, using several case studies, that substrate inhibition often has important biological functions. In each case we discuss, the biological significance is different. Substrate inhibition of tyrosine hydroxylase results in a steady synthesis of dopamine despite large fluctuations in tyrosine due to meals. Substrate inhibition of acetylcholinesterase enhances the neural signal and allows rapid signal termination. Substrate inhibition of phosphofructokinase ensures that resources are not devoted to manufacturing ATP when it is plentiful. In folate metabolism, substrate inhibition maintains reactions rates in the face of substantial folate deprivation. Substrate inhibition of DNA methyltransferase serves to faithfully copy DNA methylation patterns when cells divide while preventing de novo methylation of methyl-free promoter regions. Keywords:.b iological function; enzyme kinetics; substrate inhibitionThe kinetics of an enzymatic reaction are typically studied by varying the concentration of substrate and plotting the rate of product formation as a function of substrate concentration. In the conventional case this yields a typical hyperbolic Michaelis-Menten curve, and a linear reciprocal LineweaverBurk plot, from which the kinetic constants of the enzyme can be calculated. A surprisingly large number of enzymes do not behave in this conventional way. Instead, their velocity curves rise to a maximum and then decline as the substrate concentration goes up. This phenomenon is referred to as substrate inhibition, and it is estimated that it occurs in some 20% of enzymes [1]. A partial list of enzymes that show substrate inhibition appears in Box 1.Substrate inhibition is often interpreted as an abnormality that comes from using artificially high substrate concentration in a laboratory setting. In a review article on the mechanisms of substrate inhibition in 1994, Kuehl [2] commented that ''although recognized early on as an almost universal phenomenon, it has nevertheless met an almost universal disinterest. Probably the main reason for this neglect is that the majority of enzymologists and many authorities in the field regard substrate inhibition as being almost always a nonphysiological phenomenon.'' There are several reasons for suspecting that substrate inhibition is not a pathological phenomenon, but a biologically relevant regulatory mechanism. First, in many cases normal substrate concentrations are to the right of the velocity maximum, which indicates that these enzymes typically operate under substrate inhibition. Second, many enzymes have specialized sites where a second substrate molecule can bind and act as an allosteric inhibitor. For those enzymes, substrate inhibition is clearly a specially evolved property. Third, evidence is accumulating that substr...

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Investigations into the etiology of neural tube defects

Cited by 70 publications

References 195 publications

Impact of folic acid fortification of flour on neural tube defects: a systematic review

Impact of folic acid fortification of flour on neural tube defects: a systematic review

LRP2 mediates folate uptake in the developing neural tube

The biological significance of substrate inhibition: A mechanism with diverse functions

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