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PubMed1999

Risk of neural tube defects in the offspring of thalassaemia carriers in Hong Kong Chinese.

The risk of having an offspring with neural tube defect is negatively correlated with early pregnancy maternal folate levels. Thalassaemia carriers often have subnormal folate levels. We postulate that their offspring may be at increased risk of having neural tube defect. We retrospectively reviewed the records of 1961 Chinese women referred to a tertiary centre for prenatal diagnosis between January 1997 and August 1998. Women with a mean corpuscular volume greater than 80 fl were assumed not to be alpha-thalassaemia-1 or beta-thalassaemia heterozygotes. alpha- and beta-thalassaemia heterozygotes were diagnosed by haemoglobin studies. Of the 1961 women studied, pregnancy outcome was not available in 20 and thalassaemia screening was not available in 109 and these were excluded from the final analysis. Two-hundred-and-six women were alpha-thalassaemia-1 heterozygotes, 102 women were beta-thalassaemia heterozygotes and one woman had HbE disease. Three alpha-thalassaemia carriers and one beta-thalassaemia carrier had a pregnancy affected by anencephaly (odds=1:76). In the 1523 non-carriers, five pregnancies were affected by spina bifida (odds=1:304). The odds ratio (95 per cent confidence interval) for neural tube defects in the alpha- and beta-thalassaemia carriers was 3.99 (1.07 to 14.94; p<0.05, Chi-square test). Because of the small number of affected pregnancies studied, the finding needs to be substantiated by a larger series. If the increased risk is genuine, women need to be screened for thalassaemia before conception and the thalassaemia carriers should be given periconceptional folate supplement to reduce the occurrence of neural tube defects.

Asian People↗
PubMed2003

Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse.

We identified two novel mouse mutants with abnormal head-shaking behavior and neural tube defects during the course of independent ENU mutagenesis experiments. The heterozygous and homozygous mutants exhibit defects in the orientation of sensory hair cells in the organ of Corti, indicating a defect in planar cell polarity. The homozygous mutants exhibit severe neural tube defects as a result of failure to initiate neural tube closure. We show that these mutants, spin cycle and crash, carry independent missense mutations within the coding region of Celsr1, encoding a large protocadherin molecule [1]. Celsr1 is one of three mammalian homologs of Drosophila flamingo/starry night, which is essential for the planar cell polarity pathway in Drosophila together with frizzled, dishevelled, prickle, strabismus/van gogh, and rhoA. The identification of mouse mutants of Celsr1 provides the first evidence for the function of the Celsr family in planar cell polarity in mammals and further supports the involvement of a planar cell polarity pathway in vertebrate neurulation.

Animals↗
PubMed2006

A hypothesis linking low folate intake to neural tube defects due to failure of post-translation methylations of the cytoskeleton.

Neural tube defects are serious congenital malformations which can be prevented by periconceptional folic acid supplementation. We hypothesize that folic acid provides the methyl group used for post-translational methylation of arginine and histidine in the highly conserved regulatory domains of the cytoskeleton and that these are required for neural tissue differentiation. Presumptive neural tissue has an unusually high need for folates due to the activity of phosphoethanolamine methyl transferase in producing neural tissue specific lipids at a time when the cytoskeleton is also competing for methylation. According to the cell state splitter hypothesis, the cytoskeleton is required to coordinate the spatial and temporal component of differentiation. When folate supply is low and the cytoskeleton is not methylated properly, the result is a neural tube defect due to failure of this coordination.

Animals↗
PubMed1998

Alternative methods of maternal weight adjustment in maternal serum screening for Down syndrome and neural tube defects.

Serum markers used in screening for Down syndrome and neural tube defects are often adjusted to take account of the effect of maternal weight on the marker levels. The standard adjustment procedure is based on a linear relationship between the marker concentration, expressed as the log of the multiple of the median (MOM), and maternal weight on a linear scale. It has been proposed that maternal weight adjustment may be better performed using a linear relationship between marker concentration expressed in MOM and the reciprocal of maternal weight. In a dataset of 8905 singleton pregnancies in white women without Down syndrome or neural tube defects we compared the two methods of weight adjustment and found that both were satisfactory and neither had an obvious advantage over the other. In the analysis it was noticed that hCG levels in very heavy women (> 120 kg) were higher than expected from the decreasing linear trend with maternal weight--a result that was statistically highly significant (p < 0.01) but for which we have no explanation. In screening it will have virtually no effect because the finding was restricted to only the 0.3 per cent of the heaviest women.

Biomarkers↗
PubMed1981

Demonstration of astrocytes in cultured amniotic fluid cells of three cases with neural-tube defect.

We have investigated the origin of rapidly adhering (RA) cells in three cases of neural tube defects (two anencephali, one encephalocele). We were able to demonstrate the presence of glial fibrillary acidic (GFA) protein in variable percentages (4--80%) of RA cells cultured for 4--6 days by use of indirect immunofluorescence with GFA antiserum. Cells cultured from amniotic fluids of normal pregnancies and fetal fibroblasts were completely GFA protein negative. GFA protein is well established as a highly specific marker for astrocytes. Demonstration of astrocytes may prove to be a criterion of high diagnostic value for neural tube defects. The percentage of astrocytes decreased with increasing culture time, while the percentage of fibronectin positive cells increased both in amniotic fluid cell cultures from neural tube defects and normal pregnancies.

Amniocentesis↗
PubMed1999

A possible link between neural tube defects and ultraviolet light exposure.

The protective role of folate in preventing neural tube defects is now well established. The hypothesis is advanced here that photolysis of folate by ultraviolet (UV) light may, in some women, precipitate a folate deficiency sufficient to cause a neural tube defect (NTD) during the first few weeks of pregnancy. This hypothesis is supported by the demonstration of in vitro photolysis of folate by simulated strong sunlight (1), a decline in folate levels in light-skinned subjects exposed to UV light for dermatological conditions (1), and the occurrence of NTDs in the offspring of women who exposed themselves to high levels of UV light on the sunbeds of tanning salons (2). If established, a connection between in vivo folate photolysis by UV light, clinical folate deficiency and NTDs would suggest that intense or prolonged periconceptual exposure of women to UV light for recreational or therapeutic reasons should be avoided.

Female↗
PubMed1995

Immunochemical determination of amniotic fluid acetylcholinesterase in the antenatal diagnosis of open neural tube defects.

The aims of the studies reviewed were 1) to identify the molecular forms of acetylcholinesterase encountered in amniotic fluid from pregnancies with a normal fetus and those with a fetal open neural tube defect or other fetal malformation and, 2) to raise and characterize antibodies against human acetylcholinesterase and to identify those useful for immunochemical determination of amniotic fluid acetylcholinesterase where there is a fetal open neural tube defect. Eleven monoclonal antibodies and one polyclonal rabbit antibody were evaluated with regard to their clinical usefulness in the antenatal diagnosis of open neural tube defects. One of these, the monoclonal antibody 4F19, preferentially bound acetylcholinesterase from human brain and identified better than the others amniotic fluid samples from pregnancies with a fetal open neural tube defect (I, II). The monoclonal antibody 4F19 was used in an enzyme antigen immunoassay whose performance was found to be similar to that of the polyacrylamide electrophoretic gel test for acetylcholinesterase determination (III). However, the 4F19 enzyme antigen immunoassay is simpler, more rapid and less technically demanding than the gel test, and furthermore, it gives a quantitative result. The 4F19 enzyme antigen immunoassay was also compared with the alpha-fetoprotein test, normally used as the primary test for the antenatal diagnosis of open neural tube defects. The 4F19 enzyme antigen immunoassay performed better than the alpha-fetoprotein test, but the best performance was found for a combination of the two tests (VI). A positive result can be found using the combined tests for conditions other than open neural tube defects, e.g. abdominal wall defects, intrauterine fetal death and other fetal malformations. These conditions can often be discerned by ultrasound examination. However, combining the result of the 4F19 enzyme antigen immunoassay with the result of an enzyme antigen immunoassay for butyrylcholinesterase makes a discrimination between these conditions possible (V). The diagnostic implications of the above procedures are evaluated and specific recommendations concerning their use are given.

Acetylcholinesterase↗
PubMed1982

Gel electrophoresis of maternal and fetal serum cholinesterases from normal pregnancies and of those affected by neural tube defects.

The cholinesterase isozymes of maternal and fetal sera from normal pregnancies and those in which the fetus had a neural tube defect were studied using flat-bed vertical polyacrylamide gel electrophoresis. Normal maternal and fetal sera had multiple bands of cholinesterase activity, including the two bands in the position of those found in amniotic fluid from NTD pregnancies. The one difference between maternal and fetal sera was that the faster of these two "amniotic fluid bands" was acetylcholinesterase in fetal serum, as in the neural tube defect amniotic fluids, but non-specific cholinesterase in maternal serum. In artificial mixtures this difference could be used to differentiate between maternal and fetal blood-contamination of amniotic fluids, but in samples naturally contaminated at amniocentesis this test did not always agree with the Kleihauer findings. Both maternal and fetal sera had additional weak acetylcholinesterase activity in the most anodally migrating enzyme bands, but all other enzyme activity was non-specific cholinesterase. No difference was observed in the isozymes of fetal serum from normal fetuses and those with neural tube defects, or of maternal serum from normal and neural tube defect pregnancies.

Amniotic Fluid↗
PubMed1983

Prevention of neural tube defects in an urban health district.

An evaluation of voluntary prenatal screening for neural tube defects with serum alphafetoprotein (s-AFP) is presented. During a three year period, there were 52 fetuses with neural lesions. Of 46 mothers who bore a fetus with an open neural lesion, 25 were detected, of whom 23 agreed to the termination of their pregnancies. An unscreened group of 2331 mothers (17% of all deliveries) produced 14 fetuses with neural tube defects, an incidence of 6.0 per 1000, 1.8 times the incidence (3.3 per 1000) in the screened group. Pitfalls occurring in the assessment of hyper-alphafetoproteinemia included inaccurate gestational dating and allowance for excessive body weight. The results of a robust AFP-NTD screening programme supported in selected cases by ultrasonar visualisation of the spine argue for its continuance in this district.

Child, Preschool↗
PubMed2003

[Influence of folic acid in primary prevention of neural tube defects].

OBJECTIVE: The aim of the study was to analyze the incidence of neural tube defects in Lublin Province between 1990 and 2000 after application of primary prevention with folic acid. MATERIAL AND METHODS: A total of 293,039 newborns were analyzed. RESULTS: Neural tube defects were diagnosed in 53 newborns. CONCLUSION: Reduction of frequency of meningocele was shown after application of primary prevention with folic acid in 1998. Meningoceles were most frequent in 1992 (1.32/1000) and in 1998 frequency of these defects was reduced and in 2000 was down to 0.62/1000 births.

Female↗
PubMed1993

Interaction between splotch (Sp) and curly tail (ct) mouse mutants in the embryonic development of neural tube defects.

The mouse mutations splotch (Sp) and curly tail (ct) both produce spinal neural tube defects with closely similar morphology, but achieve this by different embryonic mechanisms. To determine whether the mutants may interact during development, we constructed mice carrying both mutations. Double heterozygotes exhibited tail defects in 10% of cases, although the single heterozygotes do not express this phenotype. Backcrosses of double heterozygotes to ct/ct produced offspring with an elevated incidence of neural tube defects, both spina bifida and tail defects, compared with a control backcross in which Sp was not involved. Use of the deletion allele Sp2H permitted embryos carrying a splotch mutation to be recognised by polymerase chain reaction assay. This experiment showed that only embryos carrying Sp2H develop spina bifida in the backcross with ct/ct, suggesting that the genotype Sp2H/+, ct/ct is usually lethal around the time of birth as a result of severe disturbance of neurulation. The interaction between Sp and ct was investigated further by examining embryos in the backcross for developmental markers of the Sp/Sp and ct/ct genotypes. Sp/Sp embryos characteristically lack neural crest derivatives, such as dorsal root ganglia, and die on day 13 of gestation. Double mutant embryos from the backcross did not exhibit either of these characteristics suggesting that homozygosity for ct does not cause Sp/+ embryos to develop as if they were of genotype Sp/Sp. The angle of ventral curvature of the posterior neuropore region is enhanced in affected ct/ct embryos whereas it was found to be reduced in Sp/Sp embryos compared with their normal littermates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Neural tube defects in Western Australia 1966-81 and a review of Australian data 1942-81.

Cases of neural tube defects born in Western Australia during the years 1966-81 were identified from hospital records and death certificates. The overall rate for the 16 year period was 1.81 cases of neural tube defects per 1000 births. The rate rose and then fell over the 16 years. The initial lower rate may have been due to underascertainment, but the recent dramatic fall is statistically significant and has been observed in other Australian states and other parts of the world. This fall was not accounted for by termination of affected pregnancies before 20 weeks' gestation nor by demographic changes in birth order, father's occupation, or parental country of birth. The birth prevalence of neural tube defects determined in previous Australian studies is reviewed in relation to the recent decline in these disorders.

Australia↗
PubMed1999

Neural tube defects and drinking water disinfection by-products.

We conducted a population-based case control study of neural tube defects and drinking water contaminants, specifically, disinfection by-products. We used public monitoring records concurrent with the first month of gestation to assess exposure. The prevalence odds ratios (PORs) for the highest tertile of total trihalomethanes compared with the lowest was 1.6 (95% confidence interval [CI] = 0.9-2.70). Surface water source was also associated with neural tube defects (POR = 1.5; 95% CI = 0.9-2.5). Sensitivity analyses restricted to isolated neural tube defect cases and mothers with known residence at conception yielded stronger associations [total trihalomethanes, POR = 2.1 (95% CI = 1.1-4.0); surface water, POR = 1.7 (95% CI = 0.9-3.2)]. Other major groups of disinfection by-products (haloacetic acids and haloacetonitriles) showed little relation to these defects.

Anencephaly↗
PubMed2000

Evaluation of the prenatal diagnosis of neural tube defects by fetal ultrasonographic examination in different centres across Europe.

OBJECTIVE: Evaluation of prenatal diagnosis of neural tube defects by ultrasound examination in unselected populations across Europe. SETTING: Prenatal ultrasound units in areas that report to contributing congenital malformation registers. METHODS: All cases with a suspected or confirmed neural tube defect and delivered within the 30 month study period were identified from 18 Congenital Malformation Registers from 11 European countries. Data on the pregnancy, prenatal scans, outcome of pregnancy, and information on different screening policies for each country were analysed. RESULTS: 670766 deliveries occurred in the area covered by the registers during the study period. A neural tube defect was diagnosed at delivery in 542 cases. In 84% of these, the lesion was isolated (166 anencephaly, 252 spina bifida, 35 encephalocele). Of the 166 isolated cases with anencephaly, 96% were correctly identified prenatally; one was missed on scan, two were wrongly diagnosed, and four were not scanned (sensitivity 98%). 84% of the prenatal diagnoses were made before 24 weeks' gestation; 86% of isolated anencephalic pregnancies were terminated. Of the 252 cases of isolated spina bifida, 171 (68%) were correctly identified prenatally; 66% of these before 24 weeks' gestation. The diagnosis was missed on scan in 60 cases and 21 were not scanned (sensitivity 75%). The mean reduction in birth prevalence because of termination of pregnancy for spina bifida was 49% (range 6-100%). There was a wide variation between centres in prenatal detection rate (33-100%), termination of pregnancy of prenatally diagnosed cases (17-100%), and gestation both at diagnosis and termination of pregnancy. CONCLUSION: A high prenatal detection rate for anencephaly was reported by all registers. There is a large variation in prenatal detection and termination rates for spina bifida between centres, reflecting differences both in policy and culture.

Europe↗
PubMed1981

Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects.

A randomized controlled double-blind trial was undertaken in south Wales to prevent the recurrence of neural-tube defects in women who had had one child with a neural-tube defect. Sixty women were allocated before conception to take 4 mg of folic acid a day before and during early pregnancy and 44 complied with these instructions. Fifty-one women were allocated to placebo treatment. There were no recurrences among the compliant mothers but two among the non-compliers and four among the women in the placebo group. Thus there were no recurrences among those who received supplementation and six among those who did not; this difference is significant (p = 0.04). It is concluded that folic acid supplementation might be a cheap, safe, and effective method of primary prevention of neural-tube defects but that this must be confirmed in a large, multicentre trial.

Clinical Trials as Topic↗
PubMed1999

Methionine synthase: high-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects.

Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tube defects. Methionine synthase catalyzes the vitamin B(12)-dependent conversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. The observation that homocysteine and vitamin B(12) levels are independent predictors of NTD risk suggested that methionine synthase could be a candidate gene for NTDs. To assess the role of the MS gene in NTDs, we performed high-resolution physical mapping of the MS locus, isolated highly polymorphic markers linked to the MS gene, and tested for an association between specific MS alleles and NTDs. We mapped the MS gene to a position between 909 and 913 cR(10000) on chromosome 1 by radiation hybrid mapping. Polymorphic markers D1S1567 and D1S1568 map to locations no more than 900 and 194 kb from the MS gene, respectively. The segregation of these polymorphic markers was measured in 85 Irish NTD families. No allele of either marker showed a significant association with NTDs using the transmission disequilibrium test. A lack of association was also observed for the D1919G missense mutation within the gene. Our results suggest that inherited variation in the MS gene does not contribute to NTD risk in this population.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2004

Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect.

BACKGROUND: In the absence of clinical folate deficiency, periconceptional supplementation with folic acid reduces a woman's risk of having an infant with a neural-tube defect. Since antiserum to folate receptors induces embryo resorption and malformations in rats, we hypothesized that autoantibodies against folate receptors in women may be associated with pregnancy complicated by a neural-tube defect. METHODS: Serum from 12 women who were or had been pregnant with a fetus with a neural-tube defect and from 24 control women (20 with current or prior normal pregnancies and 4 who were nulligravid) was analyzed for autoantibodies by incubation with human placental folate receptors radiolabeled with [3H]folic acid. The properties of these autoantibodies were characterized by incubating serum and the autoantibodies isolated from serum with placental membranes, ED27 cells, and KB cells, which express the folate receptors. RESULTS: Serum from 9 of 12 women with a current or previous affected pregnancy (index subjects) and 2 of 20 control subjects contained autoantibodies against folate receptors (P<0.001). The autoantibodies blocked the binding of [3H]folic acid to folate receptors on placental membranes and on ED27 and KB cells incubated at 4 degrees C and blocked the uptake of [3H]folic acid by KB cells when incubated at 37 degrees C. CONCLUSIONS: Serum from women with a pregnancy complicated by a neural-tube defect contains autoantibodies that bind to folate receptors and can block the cellular uptake of folate. Further study is warranted to assess whether the observed association between maternal autoantibodies against folate receptors and neural-tube defects reflects a causal relation.

Adult↗