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PubMed2002

Presence of the 5,10-methylenetetrahydrofolate reductase C677T mutation in Puerto Rican patients with neural tube defects.

Folic acid supplementation can reduce the incidence of neural tube defects. The first reported genetic risk factor for neural tube defects is a C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme. We examined the enzyme mutation role of methylenetetrahydrofolate reductase in the etiology of neural tube defects in our population. The study group consisted of 204 Puerto Rican individuals including 37 pregnant females with a prenatal diagnosis of neural tube defects in their fetuses, 31 newborns, 36 fathers, and 100 healthy adults. The prevalence of the C677T mutation was examined. Homozygosity for the alanine to valine substitution (TT) was observed in 9% of the controls and 19% of the mothers with children with neural tube defects. Our results indicate that the presence of the T allele at the methylenetetrahydrofolate reductase 677 position may increase the risk of giving birth to an infant with a neural tube defect.

Adult↗
PubMed2005

Neural tube closure and neural tube defects: studies in animal models reveal known knowns and known unknowns.

The vertebrate central nervous system is a hollow structure that develops first as a flat sheet of cells and subsequently rolls into a tube during embryogenesis. Failure of this rolling process, called neural tube closure, results in a class of common human birth defects called neural tube defects. The cellular and molecular mechanisms governing neural tube closure have been studied extensively in animal models, but much remains to be elucidated. In this review, I will highlight recent progress in understanding neural tube closure mechanisms and how these studies can inform our search for the genes that underlie human neural tube defects. Supplementary material for this article can be found on the American Journal of Medical Genetics (Part C) website (http://www.mrw.interscience.wiley.com/suppmat/1552-4868/suppmat/2005/135/v135.1.wallingford.html)

Animals↗
PubMed1982

Prenatal serum alpha-fetoprotein screening for neural tube defects.

Twenty-two cases of open neural tube defect were found in a population of 17,703 unselected pregnancies (1.2 per 1000) within the Long Island, New York, region. Voluntary screening of maternal serum alpha-fetoprotein levels identified 20 of the 22 cases (91%). Six hundred ninety-two participants demonstrated serial elevations in maternal serum alpha-fetoprotein. Of this group, which was designated at increased risk for open neural tube defect, 24% had underestimated gestational age, 13% had multiple gestations, and 53% were candidates for amniocentesis. In the amniocentesis group, the detection yield of neural tube defect was 20 per 365 (5.5%). Neither false-negative amniotic fluid evaluations nor termination of normal pregnancy due to false-positive amniotic fluid levels occurred. Perinatal outcome data, including pregnancy complications, date, mode of delivery, sex, birth weight, Apgar score, and congenital malformations of the neonate other than neural tube defect, are reported for the first 9300 consecutive participants of the 17,703 population study. These data identify a correlation between rate of perinatal loss and maternal serum alpha-fetoprotein levels.

Amniocentesis↗
PubMed1986

Neural tube defects: issues in prenatal diagnosis and counselling.

Neural tube defects are a heterogeneous group of malformations resulting from failure of neural tube closure during early embryogenesis. They range widely in severity from the lethal condition of anencephaly, to severely disabling meningomyeloceles, to completely surgically correctable meningoceles. Occurring in 1.4 to 1.6 per 1000 live births, neural tube defects rank second only to cardiac abnormalities as a cause of major congenital malformations in the United States. Technical developments over the past decade have enabled better detection of these conditions prenatally. Understanding of the etiology, neonatal treatment, and potential prevention of neural tube defects is increasing. Further, the ethical issues of treatment and screening are being widely discussed in both news magazines and the Congressional Record. Thus, it is timely to review this important area of prenatal counselling, diagnosis, and management.

Acetylcholinesterase↗
PubMed1983

Chromosome translocation (T(2;4)1 Sn)-induced neural tube defects in the mouse embryo.

Neural tube closure was studied in embryos obtained from matings of male mice heterozygous for a reciprocal chromosome translocation (T(2;4)1 Sn) with normal female (CFLP) mice. When litters were examined on the 9th to 12th days of gestation, there was a high incidence of resorption, developmental delay and neural tube closure defects in these embryos. SEM observations indicated that the neural tube closure defects ranged in severity from a side-to-side flattening of the midbrain to extensive anomalies in which the entire cephalic neural tube had failed to close. In addition to cephalic defects, a number of embryos exhibited open defects or abnormal subectodermal blebbing in the future lumbosacral region. In spinal regions, even in areas in which the neural tube had previously closed, it often was irregular and folded. These observations are discussed in relation to studies of gene-related defects of neural tube closure.

Animals↗
PubMed1993

Trends in neural tube defects 1980-1989.

OBJECTIVES: To determine trends in prevalence of neural tube defects in Australia over the past decade; to investigate the impact of terminations of pregnancy on the birth prevalence of neural tube defects; and to provide a baseline against which to evaluate the potential effects of preventive public health measures. DATA SOURCES: Two population-based registries in Victoria and Western Australia and a statewide survey from Tasmania. DESIGN AND METHOD: A cohort study. Data on the numbers and the prevalence proportions of neural tube defects from three States--Western Australia, Victoria and Tasmania--were compared by Poisson regression. RESULTS: The prevalence proportions for all neural tube defects for all three States remained level over the study period 1980-1989. Terminations of pregnancy for all neural tube defects increased significantly over the decade in all three States. By 1989, 39.9% of all neural tube defects were ascertained as terminations before 20 weeks' gestation, while 10 years previously only 2.9% were. The percentage of cases of anencephaly ascertained as terminations of pregnancy increased from 4.8% in 1980 to 58.6% in 1989. Corresponding figures for spina bifida were 1.4% (1980) and 26.9% (1989), and for encephalocele 0% (1980) and 12.5% (1989). This increase in terminations was associated with a decrease per year in the birth prevalence proportion for anencephaly of 7.0%, for spina bifida of 4%, and for encephalocele of 11.0%, and a reduction in the risk of a birth with a neural tube defect in 1989 of 47% compared with the risk in 1980. CONCLUSION: Complete ascertainment of all terminations for neural tube defects as well as births with neural tube defects is necessary to provide reliable baseline data on the prevalence of neural tube defects. Such data are essential in evaluating primary preventive measures such as the effect of an increase in folic acid intake by women of child-bearing age.

Abortion, Induced↗
PubMed2002

Trends in neural tube defects in Western Australia.

OBJECTIVE: To report on trends in neural tube defects in Western Australia, in relation to folate promotion, periconceptional use of folic acid supplements and food fortification with folate. METHODS: Data on neural tube defects from the Western Australian Birth Defects Registry. RESULTS: A 30% fall in neural tube defects was documented from 1996 to 2000. CONCLUSIONS AND IMPLICATIONS: The sustained fall in neural tube defects is thought to be due to increased periconceptional folate intake in response to health promotion campaigns and fortification of selected foods. There is room for further improvement.

Anencephaly↗
PubMedDate not supplied

[Primary prevention program for neural tube defects in Poland].

The National Neural Tube Defect Primary Prevention Programme is presented. The programme is based on an information and education campaign aimed at showing health benefits derived from appropriate level of consumption of folic acid by women of reproductive age.

Adult↗
PubMed2005

Neural tube defects: pathogenesis and folate metabolism.

Neural tube defects (NTDs) are a group of congenital malformations with worldwide distribution and complex aetio-pathogenesis. Animal studies indicate that there may be four sites of initiation of neural tube closure (NTC). Selective involvement of these sites may lead to defects varying from anencephaly to spina bifida. The NTC involves formation of medial and dorsolateral hinge points, convergent extension and a zipper release process. Proliferation and migration of neuroectodermal cells and its morphological changes brought about by microfilaments and other cytoskeletal proteins mediate NTC. Genetic, nutritional and teratogenic mechanisms have been implicated in the pathogenesis of NTDs. Folate is an important component in one carbon metabolism that provides active moieties for synthesis of nucleic acids and proteins. Several gene defects affecting enzymes and proteins involved in transport and metabolism of folate have been associated with NTDs. It may be possible in future, to identify individuals at higher risk of NTDs by genetic studies. Epidemiological and clinical studies have shown that dietary supplementation or food fortification with folic acid would reduce the incidence of NTDs. The protective effect of folic acid may be by overcoming these metabolic blocks through unidentified mechanisms. Genetic and biochemical studies on foetal cells may supplement currently available prenatal tests to diagnose NTDs. Antiepileptic drugs (AEDs), particularly valproate and carbamazepine have been shown to increase the risk of NTDs by possibly increasing the oxidative stress and deranging the folate metabolism. Accordingly, it is recommended that all women taking AEDs may use 1-5 mg folic acid daily in the pre conception period and through pregnancy.

Dietary Supplements↗
PubMed2000

Neural tube closure in humans initiates at multiple sites: evidence from human embryos and implications for the pathogenesis of neural tube defects.

The closure of the neural tube (NT) in the human embryo has generally been described as a continuous process that begins at the level of the future cervical region and proceeds both rostrally and caudally. On the other hand, multiple initiation sites of NT closure have been demonstrated in mice and other animals. In humans, based on the study of neural tube defects (NTD) in clinical cases, van Allen et al. (1993) proposed a multisite NT closure model in which five closure sites exist in the NT of human embryos. In the present study, we examined human embryos in which the NT was closing (Congenital Anomaly Research Center, Kyoto University) grossly and histologically, and found that NT closure in human embryos initiates at multiple sites but that the mode of NT closure in humans is different from that in many other animal species. In addition to the future cervical region that is widely accepted as an initiation site of NT closure (Site A), the mesencephalic-rhombencephalic boundary was found to be another initiation site (Site B). The second closure initiating at Site B proceeds bidirectionally and its caudal extension meets the first closure from Site A over the rhombencephalon, and the rostral extension of the second closure meets another closure extending from the rostral end of the neural groove (Site C) over the prosencephalon, where the anterior neuropore closes. The caudal extension of the first closure initiating at Site A was found to proceed all the way down to the caudal end of the neural groove where the posterior neuropore is formed, indicating that in humans, NT closure does not initiate at the caudal end of the neural groove to proceed rostrally. Since there is a considerable species difference in the mode of NT closure, we should be careful when extrapolating the data from other animals to the human. It seems that the type of NTD affects the intrauterine survival of abnormal embryos. Almost all the embryos with total dysraphism appear to die by 5 weeks of gestation, those with an opening over the rhombencephalon by 6.5 weeks, and those with a defect at the frontal and parietal regions survive beyond 7 weeks.

Age Factors↗
PubMed1999

Crooked tail (Cd) models human folate-responsive neural tube defects.

Genetic correlation of human neural tube defects (NTDs) with NTD genes identified in mouse may unravel predisposing complex traits for assessment of individual risk and treatment in clinical settings. Folic acid (FA) can reduce the recurrence of NTDs in human populations by as much as 50-70%, though the mechanism of this rescue is unknown. We examined whether Crooked tail ( Cd ), a mouse strain prone to exencephaly, could provide a genetic animal model for folate-responsive NTDs. The Cd locus was localized to a 0.2 cM interval of the Mouse Genome Database genetic map, identifying tightly linked markers for genotyping prior to phenotypic expression. In a controlled diet study, Cd was found to mimic closely the clinical response to FA. FA supplementation reduced the recurrence risk of Cd exencephaly by as much as 55%. This rescue was dose dependent and did not require subjects to be inherently folate deficient. Like the female predominance of NTDs in humans, female Cd embryos were most likely to display exencephaly and were more responsive than males to the FA rescue. Importantly, FA supplementation shifted the severity of Cd phenotypic expression from early embryonic lethality to longer survival, and reduced the incidence of NTDs. The Cd locus is distinct from the known genes associated with neurulation defects, and isolation of this gene will assist identification of biochemical, genetic and gender-dependent factors contributing to folate-responsive NTDs.

Animals↗
PubMed1998

Reduced glucose consumption in the curly tail mouse does not initiate the pathogenesis leading to spinal neural tube defects.

At embryonic stages of neural tube closure, the mouse embryo exhibits a high rate of glycolysis with glucose as the main energy source. In the curly tail mouse, often used as model system for study of human neural tube defects, a delay in closure of the posterior neuropore (PNP) is proposed to be indirectly caused by a proliferation defect in the caudal region. Because glucose is important for proliferation, we tested glucose uptake in curly tail and control embryos, and in a BALB/c-curly tail recombinant strain. The structure and expression of Glut-1, a glucose transporter molecule that is abundantly present during those embryonic stages and that has been mapped in the region of the major curly tail gene, were also studied; however, no strain differences could be demonstrated. Glucose uptake was determined by measuring glucose depletion from the medium in long-term embryo cultures that encompassed the stages of PNP closure and by measuring accumulation of 3H-deoxyglucose in short-term cultures at the stages of early and final PNP closure. Both approaches indicated a reduced glucose uptake by curly tail and recombinant embryos. Surprisingly, the uptake per cell appeared normal, accompanied by a significantly lower DNA content of the mutant embryos. Therefore, it is unlikely that reduced cell proliferation is caused by a reduction in glucose supply during the pathogenesis of the defects in curly tail embryos. The reduced DNA content as well as the reduced glucose uptake per embryo are likely downstream effects of the aberrant proliferation pattern.

Animals↗
PubMed2002

Surveillance of neural tube defects in Israel.

BACKGROUND: Open neural tube defects are among the most common malformations of the fetus. Secondary prevention by early diagnosis during pregnancy and abortion of affected fetuses result in a marked reduction of NTD incidence at birth. The dramatic effect of folic acid for primary prevention of these defects led to recommendations for folic acid supplementation in women of reproductive age. OBJECTIVE: To describe the epidemiologic features of NTD in Israel in 1999-2000. METHODS: A national registry of NTD was begun in 1999. During the years 1999-2000, a non-syndromic NTD was diagnosed in at least 394 pregnancies (166 anencephaly, 166 spina bifida, 43 encephalocele, and 19 with other types of NTD). The religious-ethnic affiliation was known in 392 cases (209 Jews and 183 non-Jews). RESULTS: Despite a marked decline in the rate of NTD at birth in the last few decades, the total rates during pregnancy did not change significantly, demonstrating that the changes were secondary to termination of affected pregnancies. At birth, NTD were almost four times more frequent among non-Jews (3.6 per 10,000 live births for anencephaly and 5.9 for spina bifida) than among Jews (anencephaly 1/10,000 live births, spina bifida 1.4/10,000 live births). The complete data of the registry showed an approximately twofold difference in the overall rates during pregnancy between Jews (anencephaly 5.3, spina bifida 4.6, total 11/10,000 live births) and non-Jews (anencephaly 8.8, spina bifida 10.3, total 22.3/10,000 live births). The registry demonstrated that the significant differences in NTD incidence observed at birth between Jews and non-Jews are secondary to a combined effect of a higher frequency of the malformations among non-Jews and a lower proportion of termination of affected pregnancies among non-Jews. CONCLUSIONS: The data presented here will serve as a basis for evaluating the impact of the Ministry of Health recommendations for folic acid supplementation on the incidence of NTD.

Abortion, Therapeutic↗
PubMedDate not supplied

Folic acid and neural tube defects in pregnancy: a review.

Neural tube defects (NTDs) are common fetal malformations. They are multifactorial in origin, with folic acid as the primary known environmental factor. It is recommended that all women consume 0.4 mg of synthetic folic acid daily if there is any possibility of becoming pregnant. Women who have had a previous pregnancy affected by NTD should increase their folic acid intake to 4.0 mg daily periconceptually. The purpose of this article is to review the relationship between folic acid and NTDs. It also discusses how the knowledge and use of folic acid has affected the incidence of NTDs, and ways in which the knowledge and use of folic acid before pregnancy can be increased.

Female↗
PubMed1988

Immunobiological methods in the prenatal diagnosis and evaluation of foetal neural tube defects.

In cases of foetal neural tube defects (NTDs) macrophages are present in the amniotic fluid. These mononuclear cells were analysed with immunobiological methods: functional markers as Fc and C3b receptor-mediated phagocytosis and chemoluminescence have been studied. It was found that most of these pathognomic cells ingest haemolysin sensitized sheep red blood cells (sSRBCs) and zymosan (Mannozym) particles opsonized with fresh human serum. Amniotic fluid cell suspensions from pregnancies with and without foetal NTDs were stimulated by opsonized Mannozym; consistently higher chemoluminescence activities were found when open lesion was present. The evaluation of multiple functional markers is likely to provide a better basis for understanding the characteristics of amniotic fluid macrophages and may contribute to the prenatal diagnosis of NTDs.

Amniocentesis↗
PubMed1994

Screening for neural tube defects.

The birth prevalence of neural tube defects fell by 95% in England and Wales between 1970 and 1990 largely as a result of antenatal screening, subsequent diagnosis and selective abortion of affected pregnancies. Anencephaly can be diagnosed using ultrasound, whereas both amniotic fluid biochemistry and ultrasound are required for the diagnosis of spina bifida. Both methods have a false-positive rate of about two per 1000 when carried out in high-risk pregnancies. The diagnostic results are likely to be better if the two methods are used in parallel. Maternal serum alpha-fetoprotein screening at 16-18 weeks gestation can detect about 75% of pregnancies affected by spina bifida. Routine ultrasound anomaly screening, usually performed at 18-20 weeks gestation, can detect a similar proportion. New developments indicate that earlier, more accurate detection may be possible but more research will be needed before this can be established.

Biochemistry↗
PubMed1995

Prevention program for reducing risk for neural tube defects--South Carolina, 1992-1994.

Neural tube defects (NTDs) are common and serious malformations that originate early in pregnancy. In the United States, approximately 4000 pregnancies each year are affected by the two most common NTDs (spina bifida and anencephaly), and an estimated 2500 infants are born with NTDs. Based on a Public Health Service (PHS) recommendation published in September 1992, at least one half of NTDs could be prevented if all women capable of becoming pregnant consumed 0.4 mg of folic acid daily during the periconceptional period (1). Women who have previously had an NTD-affected pregnancy would especially benefit from folic acid supplements (2). In 1992, with support from a CDC cooperative agreement, the South Carolina Department of Disabilities and Special Needs implemented a prevention program to reduce the incidence of folic acid-preventable NTDs in the pregnancies of women with prior NTD-affected pregnancies. This report describes surveillance findings resulting from this program during 1992-1994.

Female↗
PubMed1999

Folate status, homocysteine metabolism, and methylene tetrahydrofolate reductase genotype in rural South African blacks with a history of pregnancy complicated by neural tube defects.

The birth incidence of neural tube defects (NTDs) in South Africa is threefold to sixfold higher in rural compared with urban blacks. We investigated whether folate deficiency and aberrant homocysteine metabolism could explain the high NTD incidence in rural black populations. Plasma folate and total homocyst(e)ine (tHcy) concentrations were determined in apparently healthy rural black women (n = 107), rural black women with a history of pregnancy complicated by NTDs (n = 54), and urban blacks (n = 101). Methionine load tests were performed on the 54 women with a history of NTD-affected pregnancy and 54 controls matched for age and body mass. The presence of the 677C --> T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene was investigated in both groups by a polymerase chain reaction (PCR) of genomic DNA and HinfI digestion of the PCR product. Apparently healthy urban black women (n = 101) had a lower (P < .001) plasma folate concentration compared with rural black women (n = 107). Women with a history of NTD-affected pregnancy did not differ significantly from controls with respect to plasma folate, fasting homocyst(e)ine, methionine, and the post-methionine load increase in plasma homocyst(e)ine. More than 50% of both of the latter groups had a post-methionine load increase in plasma tHcy less than the fifth percentile as observed in a healthy white control group. No homozygotes for the 677C --> T mutation in the MTHFR gene were found in black mothers with NTD-affected offspring or controls. It is concluded that black urbanization is characterized by a diminished folate status that is paradoxically associated with a lower NTD birth incidence. Homozygosity for the 677C --> T mutation in the gene coding for MTHFR does not constitute a genetic risk factor for NTDs in blacks. No aberrant homocysteine metabolism could be demonstrated in black women with NTD-affected pregnancies.

Adult↗