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PubMed2001

Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population.

Neural tube defects (NTD) are likely to result from an interaction of several genes and environmental factors. Because periconceptional folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine levels, gene polymorphisms of the folate and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T, MTHFR 1298A-->C and cystathionine beta-synthase (CBS) 844ins68, have been implicated in the etiology of NTD. Several studies have demonstrated that these polymorphisms may indeed be associated with NTD in some populations. In order to evaluate the role of these polymorphisms and their interaction in NTD, we genotyped 417 individuals for case-control studies and 129 families for transmission disequilibrium tests. We are the first to present detailed data on MTHFR haploid genotypes in combination with CBS 844ins68. The MTHFR risk genotype 677CT/1298AC, known to be associated with decreased enzyme activity and increased homocysteine, was found significantly more often in patients than in controls (P = 0.02). A CBS insertion allele in addition to MTHFR 677CT/ 1298AC heterozygosity or MTHFR 677TT/1298AA homozygosity did not result in an increased risk for NTD. This is in agreement with the recently reported homocysteine-lowering effect of the CBS 844ins68 allele in carriers of MTHFR variants.

Alleles↗

PubMed1981

Prenatal screening for neural tube defects in South Africa. An assessment.

Neural tube defects (NTDs) occur in at least 1 in every 1000 babies born in South Africa. The incidence is uncertain but appears to be highest in Whites and Coloureds and lowest in Blacks. Spina bifida is a particularly serious problem because many affected babies survive and require extensive, costly treatment and care. A high maternal serum alpha-fetoprotein (AFP) level may indicate that the fetus has an NTD. Enzyme-linked immunosorbent assay is well suited to mass screening of maternal sera. The Natal population is used as a model here, and it is calculated that of some 122000 pregnancies annually 38725 might be screened. Of 98 expected fetuses with an NTD, 32 (16 with anencephaly and 16 with spina bifida) should be detected. If the 16 fetuses with spina bifida were not detected and those pregnancies terminated, the cost of caring for the affected children through their first decade is conservatively estimated at R145660, an average of R9 100 per patient; 92% of this would be incurred in the first 3 years. The cost of screening, at R2,27 per subject, is calculated to be R87 825, equivalent to R2 744 per fetus with an NTD detected or R5 489 per fetus with spina bifida detected. Financially the introduction of mass screening of maternal serum AFP is justified, but before this can be done adequate ultrasound facilities must be provided and a permanent health visitor must be available to trace women at risk and arrange their further investigations. A public education campaign should also be introduced. Some ethical and legal implications of mass screening for NTDs are discussed briefly.

Child↗

PubMed2000

Investigation of folate pathway gene polymorphisms and the incidence of neural tube defects in a Texas hispanic population.

Neural tube defects (NTDs) are multifactorial in their etiology, having both genetic and environmental factors contributing to their development. Recent evidence demonstrates that periconceptional supplementation of the maternal diet with a multivitamin containing folic acid significantly reduces the occurrence and recurrence risk for having a pregnancy complicated by NTDs. Unfortunately, the mechanism underlying the beneficial effects of folic acid remains unknown. NTD surveillance data from the Texas-Mexico border show that the high NTD rate (28/10,000 live births) noted during the 1990-1991 Cameron county NTD cluster was superimposed on a background Cameron county NTD rate (16/10,000 live births) which is considerably higher than that generally noted in the United States (8-10/10,000 live births). These data suggest that genetic factors as well as transient environmental factors may contribute to the etiology of the NTDs. Furthermore, clinical and experimental evidence imply that allelic forms of genes involved with folate metabolism and/or transport may explain some of the observed variation in the NTD rates found across different populations. Two folate pathway genes were selected for evaluation in this study. The loci investigated included two known alleles of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, as well as the promoter region of the folate receptor-alpha (FR-alpha) gene. Odds ratios (ORs) for the C677T polymorphism in the MTHFR gene were 1.8 (CI 0.47-6.8) for heterozygosity and 1.8 (CI 0.35-9.4) for homozygosity for the mutant 677T allele, relative to wildtype homozygotes. The odds ratio for the heterozygosity for the A1298C polymorphism in the same gene was 1.1 (CI 0.09-14). No individuals homozygous for the 1298C allele were observed. The OR for heterozygosity of FR-alpha gene polymorphisms detected at nucleotide 762 and at nucleotides 610/631 was 1.4 and 0.7, respectively. Neither of the FR-alpha polymorphisms was observed in the homozygous condition. No statistically significant associations were observed for any of the polymorphisms examined, as the 95% confidence intervals for all of the ORs included one. However, the frequency of the MTHFR 677T allele in the largely Hispanic control group from Texas was significantly different from other populations (P < 0.005), and among the highest reported for any control populations examined.

Adult↗

PubMed1997

Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis.

Neural tube defects are among the most common of the malformations associated with diabetic embryopathy. To study the molecular mechanisms by which neural tube defects occur during diabetic pregnancy, we have developed a new experimental system using pregnant diabetic mice. In this system, the rate of neural tube defects is about three times higher in embryos of diabetic mice than in embryos of nondiabetic mice. Most of the defects affected presumptive midbrain and hindbrain structures and included open defects (i.e., exencephaly) and gross maldevelopment. By semiquantitative reverse transcription-polymerase chain reaction and in situ hybridization, we found that expression of Pax-3, a gene required for neural tube closure in the area of the midbrain and hindbrain, is significantly reduced in the embryos of diabetic mice. The same regions of the neural tube where Pax-3 had been underexpressed were found subsequently to contain high concentrations of cells undergoing apoptosis. Reduced expression of Pax-3 appears to be responsible for this apoptosis because apoptotic cells were also found at sites of neural tube defects in embryos carrying null mutation of the Pax-3 gene. Finally, mouse strains that carry null mutations in Pax-3 develop neural tube defects that resemble the malformations that occur in embryos of diabetic mice. These results suggest that Pax-3 is an important developmental control gene, expression of which is disturbed in embryos of diabetic mice, and that as a consequence, apoptosis of the neural tube occurs. This pathway may be responsible for many of the neural tube defects resulting from diabetic pregnancy.

Animals↗

PubMed1993

Clinical teratology counseling and consultation case report: two distinct anterior neural tube defects in a human fetus: evidence for an intermittent pattern of neural tube closure.

Human neural tube closure is believed to be a continuous process that begins in the cervical region and progresses both rostrally and caudally. In contrast, an intermittent pattern of anterior neural tube closure has been demonstrated in rodents. Based on individual case photographs, a similar pattern of anterior neural tube closure, with multiple sites of closure, may also exist in humans. We report a human fetus with two distinct anterior neural tube defects separated by a cutaneous and mesenchymal bridge. The two defects occurred within distinct closure sites predicted by the murine model, one falling within closure II and the second within closure IV. Although one defect had adherent amniotic bands, evidence is presented to support a primary dysraphy rather than disruption from an amniotic band. This case provides further evidence supporting an intermittent pattern of anterior neural tube closure in human embryogenesis.

Abortion, Therapeutic↗

PubMed2000

Lead levels in domestic water supplies and neural tube defects in Glasgow.

OBJECTIVE: To study the association between "pregnancy" prevalence (affected births and terminations) of neural tube defects in postcode districts of Glasgow and lead concentrations in domestic water. SETTING: Postcode districts of Glasgow supplied by water from the Loch Katrine reservoir. DESIGN: An ecological study. Lead concentrations from 1911 randomly selected domestic water samples were obtained from the Glasgow 93 lead study. Neural tube defects (affected births and terminations) were identified from the Glasgow register of congenital anomalies for the period 1983-95 for each postcode district in the study population. Correlations were sought between lead concentrations and pregnancy prevalence of neural tube defects/1000 live births in postcode districts. RESULTS: No correlation was found between domestic water lead concentrations > 10 microg/litre and pregnancy prevalence of neural tube defects within postcode districts. Areas of Glasgow previously with high domestic water lead concentrations did not have a higher prevalence of neural tube defects. Houses with the lowest domestic water lead concentrations were in Carstairs deprivation categories 1 (least deprived), 6, and 7 (most deprived). The highest pregnancy prevalence of neural tube defects was found in the most deprived areas. CONCLUSION: Deprivation is a risk factor for neural tube defects and might have been a confounding factor in previous studies looking at the association between such defects and domestic water lead concentrations. This study does not support the hypothesis that levels of lead > 10 microg/litre in domestic water supplies are associated with a higher pregnancy prevalence of neural tube defects. The reasons behind the decline in pregnancy prevalence of neural tube defects seen in the past two decades remain unexplained.

Female↗

PubMed1997

Neural tube defects in chromosomally normal and abnormal human embryos.

Neural tube defects (NTDs) were recognized in eight out of 91 intact embryos from spontaneous abortions and in one case of an induced abortion following prenatal diagnosis of a chromosomal disorder. Five of the nine cases showed chromosomal abnormalities. Trisomy 18 and triploidy were associated with spina bifida in three cases, trisomy 7 with parieto-occipital encephalocele and monosomy X with spina bifida and iniencephaly in one case. A sixth anencephalic embryo in which chromosomal analysis was not performed showed a malformation pattern highly suggestive for trisomy 18. Discussion focuses on the high rate and the type of chromosomal abnormalities among spontaneously aborted NTD embryos, on the contrasting phenotype of 45,X conceptions and on the morphogenesis of the different neural tube defects in early development. In view of future early endovaginal ultrasound diagnosis, the changing morphological pattern is exemplified, and ranges from apparently hyperplastic to degenerative alterations of the exposed neural tissue.

Chorionic Villi Sampling↗

PubMed1987

Valproic acid-induced neural tube defects: reduction by folinic acid in the mouse.

Neural tube defects were induced dose-dependently by single injections of the anticonvulsant drug valproic acid (VPA) as sodium salt in mice on gestational day 8. Folinic acid (5-CHO-THF) coadministration by i.p. injection or by a constant rate infusion via osmotic minipumps, implanted s.c., significantly reduced the exencephaly rates using a randomized double-blind experimental procedure. 5-CHO-THF supplementation cut the exencephaly rates into half even at high maternal plasma levels of VPA (p less than 0.005, chi 2-test); resorption rates were not affected. The VPA plasma kinetics were not changed by any of the application regimens of 5-CHO-THF. The investigation of the folate metabolite pattern (determined by HPLC) showed that 5-CHO-THF and 5-methyl-tetrahydrofolic acid (5-CH3-THF) were the main metabolites in untreated mice. After supplementation with 5-CHO-THF, only the concentrations of this folate vitamer were increased in the plasma from 0.3 microgram/ml (normal) to 0.6 or 1.9 micrograms/ml (after injection of 3 x 1 mg/kg or 3 X 4 mg/kg) and to 4.2 micrograms/ml (after infusion via osmotic minipumps). Our results indicate that VPA-induced exencephaly in mice combined with the investigation of the plasma levels of VPA and the different folate metabolites could be an appropriate animal model to study protective effects of folates on the occurrence of neural tube defects.

Animals↗

PubMed1987

Epidemiological studies of neural tube defects in Newfoundland.

A 9-year survey of neural tube defects in Newfoundland showed (1) evidence for secular variation, with a peak in 1980, but no general downward trend as seen in some other populations; (2) significant geographic variation which did not correlate with hardness or nitrate content of the lake water; (3) a tendency for the proportion of females among anencephalic births to increase with increasing frequency of anencephaly among geographic regions. This supports previous evidence for a female-specific contribution to the causes of increased liability to neural tube defect.

Abortion, Spontaneous↗

PubMed1992

Periconceptional vitamin supplementation and neural tube defects; evidence from a case-control study in Western Australia and a review of recent publications.

STUDY OBJECTIVE: The aim was to assess the association of neural tube defects with periconceptional vitamin supplementation. DESIGN: This was a matched, population based case-control study. SETTING: Western Australia, 1982-1984. PARTICIPANTS: Mothers of 77 cases (93% of those eligible) with isolated neural tube defects, mothers of 77 matched control infants with defects other than neural tube defects (control group I), and mothers of 154 liveborn, matched, control infants with no birth defects (control group II) participated in the study. MEASUREMENTS AND MAIN RESULTS: Information was collected by interview and self administered questionnaire. Crude and adjusted odds ratios (and their 95% confidence intervals) showed a small but non-significant protective effect of folate supplementation in comparisons with both control groups. The adjusted ratios for the three months before pregnancy were 0.69 (0.06, 8.53) with control group I, and 0.11 (0.01, 1.33) with control group II. In the first six weeks of pregnancy, the adjusted odds ratios were 0.70 (0.32, 1.52) with control group I and 0.74 (0.29, 1.88) with control group II. The odds ratios for vitamin supplementation of any kind were all very close to or greater than one, and all confidence intervals embraced unity. CONCLUSIONS: These data do not provide evidence of an association between periconceptional vitamin supplementation and neural tube defects, although a protective effect of folate supplementation cannot be excluded with confidence, due to the low power of the study. Of three other observational studies of vitamins and neural tube defects, two have shown an association. While further studies of this kind may be of value, evidence must now be sought from randomised controlled trials.

Case-Control Studies↗

PubMed1991

Congenital urinary abnormalities and neural tube defects.

The records of 178 children with a neural tube defect were reviewed to determine the pattern of associated congenital urinary malformation. Ten (6%) of the children had a significant congenital urinary malformation. Although unilateral renal agenesis was the most common single congenital urinary abnormality, as a group, abnormalities in fusion or migration were equally common in this study and more common in several previously reported studies. Lower congenital urinary tract abnormalities were also identified but were less common. No correlation was found between the level of the neural tube defect and the specific congenital urinary abnormality.

Child↗

PubMed1995

A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects.

It is now well-established that folic acid, taken peri-conceptionally, can reduce the risk of neural tube defects (NTDs). Recent work has demonstrated that an abnormality of homocysteine metabolism is a critical factor. The gene for 5,10 methylenetetrahydrofolate reductase, an enzyme important in homocysteine metabolism, was studied in relation to NTDs. To determine the frequency of the allele for the thermolabile form of the reductase, DNA samples were collected from people with NTDs, parents of people with NTDs, and normal controls. Of 82 people with NTDs, 15 (18.3%) were homozygous for the abnormal, thermolabile allele. This was significantly higher (p = 0.01) than the rate of 6.1% in the control population (odds ratio 3.47, 95% CI 1.28-9.41). This is the first specific genetic abnormality to be identified in NTDs. It explains the association between some NTDs and elevated homocysteine, given that the reductase is important in homocysteine metabolism. It also explains how folic acid supplementation prevents some NTDs, by overcoming a partial block in the conversion of 5,10 methylenetetrahydrofolate to 5 methyltetrahydrofolate. Genetic screening could identify women who will require folic acid supplements to reduce their risk of having a child with an NTD.

Case-Control Studies↗

PubMed1983

Early morphological abnormalities in splotch mouse embryos and predisposition to gene- and retinoic acid-induced neural tube defects.

Genetic and environmental factors contribute to an individual's neural tube defect liability. In the mouse, the gene mutation Splotch (Sp) causes a pigmentation defect in heterozygotes while homozygotes have spina bifida +/- exencephaly. Splotch homozygotes, heterozygotes, and wild-type embryos were examined for somite number, anterior neuropore closure, and posterior neuropore length. The aim was to distinguish potentially affected homozygotes early in pathogenesis and find a morphological basis for increased teratogen susceptibility in heterozygotes. Posterior neuropore closure as well as anterior neuropore closure was significantly delayed in potentially affected Sp as compared to wild-type litter embryos exceeding the incidence found in day-10-diagnosed homozygotes. Part of this excess was attributed to a transient delay in heterozygotes which in turn might predispose to retinoic acid-induced neural tube defects. This idea was supported by an outcross of Sp heterozygote males by inbred SWV females and wild-type males by SWV where a significant increase in retinoic acid-induced neural tube defects was found in Sp carrier litters.

Animals↗

PubMed1993

Changing trend of neural tube defects in eastern Turkey.

STUDY OBJECTIVE: The aim was to study the relationship between birth prevalence of neural tube defect (including anencephaly) in Eastern Turkey before and after the Chernobyl disaster. DESIGN: This was a prospective study of time trends in live births and stillbirths over the years 1985-1990. Medical and sociodemographic data were recorded for the mothers. SETTING: Elazig, Eastern Turkey. SUBJECTS: There were 5240 live births and stillbirths during the study period, 24 of whom had neural tube defect and of these 20 had anencephaly. MAIN RESULTS: Of the 5240 newborns, 24 had a neural tube defect, giving a birth prevalence of 4.5 per 1000 total births. Of these, 20 were anencephalic (3.8 per 1000). In all, of the 2355 conceptions estimated to have occurred prior to the Chernobyl disaster in May 1986, the birth prevalences of total neural tube defect and anencephaly were the same (1.7 per 1000). This contrasts with the years following after Chernobyl, when the birth prevalence of total neural tube defect was 6.9 per 1000 (5.5 per 1000 for anencephaly). The differences were statistically significant (p < 0.001). These two increased rates reached a peak of 12.4 (for total neural tube defects) and 8.9 (for anencephaly) in 1988. In 1989 the rate of total neural tube defects decreased to 10.0 and that of anencephaly to 8.6 per 1000. In 1990 the rate of total neural tube defects fell to 5.6 and that of anencephaly fell to 4.2. CONCLUSIONS: The changes in birth prevalence of neural tube defects might be due to the Chernobyl disaster. However, the increases observed occurred mainly in infants conceived well over a year after the Chernobyl disaster, suggesting that other factors may be responsible.

Air Pollution, Radioactive↗

PubMed1992

Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs.

We analyzed the spectrum of neural-tube defects associated with maternal exposure to antiepileptic drugs (AEDs) and the possible contribution of familial and genetic factors to epilepsy or neural-tube defects. No specific association with maternal family history of neural-tube defects or epilepsy was seen. The ratio of spina bifida to anencephaly (33:1) suggested a specific association with caudal defects. Hydrocephaly was documented in at least 21 cases. Other midline defects, all associated with valproate (VPA), were hypospadias (two), hypertelorism (two), partial agenesis of corpus callosum, agenesis of septum pellucidum with lissencephaly of medial sides of occipital lobes, Dandy-Walker anomaly, and ventricular septal defect. This study shows that most neural-tube defects following maternal VPA use are severe open defects. They are frequently complicated by hydrocephaly and other midline defects. Prenatal diagnosis is possible.

Anticonvulsants↗

PubMed1993

Prevalence of neural tube defects in South Australia, 1966-91: effectiveness and impact of prenatal diagnosis.

OBJECTIVE: To determine trends in total prevalence of neural tube defects in South Australia during 1966-91, the impact of prenatal diagnosis on birth prevalence, and the effectiveness of prenatal screening for neural tube defects in 1986-91. DESIGN: All births and terminations of pregnancy affected by neural tube defects and information on prenatal screening were ascertained from multiple sources including the South Australian perinatal and abortion statistics collections, birth defects register, and state maternal serum alpha fetoprotein screening programme. SETTING: Southern Australia. SUBJECTS: All 1058 births and terminations of pregnancy affected by neural tube defects in 1966-91. MAIN OUTCOME MEASURES: Total prevalence and birth prevalence of individual and all neural tube defects. The proportion of screened cases detected prenatally. RESULTS: Total prevalence of neural tube defects during 1966-91 was 2.01/1000 births with no upward or downward trend. However, birth prevalence fell significantly (by 5.1% a year), with an 84% reduction from 2.29/1000 births in 1966 to 0.35/1000 in 1991 (relative risk = 0.16, 95% confidence interval 0.07 to 0.34). The fall was 96% for anencephaly and 82% for spina bifida. 85% of defects, both open and closed, were detected before 28 weeks' gestation in women screened by serum alpha fetoprotein or mid-trimester ultrasonography, or both, in 1986-91 (99.0% for anencephaly and 75.7% for spina bifida). CONCLUSIONS: While the total prevalence of neural tube defects in South Australia remained stable, prenatal diagnosis and termination of pregnancy resulted in an 84% fall in birth prevalence during 1966-91. Screening detected over four fifths of cases in 1986-91.

Confidence Intervals↗

PubMed1992

An epidemiologic study of neural tube defects: Delta County, Michigan, 1969-1988.

We determined the incidence of neural tube defects (anencephaly, spina bifida, hydrocephalus) in a rural county in the Upper Peninsula of Michigan because several local physicians perceived that the incidence in this area might be high. To assure that all neural tube defects that occurred were noted, data for the study were collected from hospital birth-log books, patient records of all neural tube defect births, all stillbirth records, and from records of babies transferred to other regional hospitals. A reference group consisting of 10% of all nonneural tube defect births during the 20 years of the study was selected at random and used to make comparisons to the case group. During the twenty-year period 1969-1988, the incidence of neural tube defects (NTDs) was found to be 2.09 per 1000 total births. The incidence of anencephaly was 1.05/1000; of spina bifida, 0.56/1000; and for hydrocephalus, 0.48/1000. Seasonal variations by month of conception were noted for anencephaly and spina bifida, confirming previous findings in the literature. Study results showed that between 1972 and 1976 there was a cluster of NTDs, but the NTD incidence was not statistically different from what might be expected over a twenty-year period. The incidence of NTDs in Delta County was found to be normal for this part of North America. The results of this study indicate that physicians should be cautious when attempting to interpret rare events, which often occur in clusters, leaving the impression that their incidence is excessive.

Adult↗

PubMed1976

Amniotic fluid alpha-fetoprotein as a marker in prenatal diagnosis of neural tube defects.

The prenatal diagnosis of anencephaly and spina bifida (neural tube defect, NTD) through amniotic fluid analysis for alpha-fetoprotein (AFP) is gradually gaining clinical recognition. AFP concentrations were determined in 237 amniotic fluids from normal pregnancies ranging between 7 and 42 weeks of gestation. A steady decline in AFP from 26 mug/ml at 7-9 weeks to 155 ng/ml at term is observed. AFP concentration was determined in 35 amniotic fluids from 33 confirmed neural tube defective pregnancies. In 14 cases where amniotic fluid was examined prior to the 26th week of gestation. AFP was markedly elevated when compared with the normal range of the same gestational period. In 21 amniotic fluids past the 26th week, 17 cases (85-) had markedly elevated AFP levels; however, 2 cases of anencephaly, 1 of spina bifida, and 1 of hydrocephaly gave levels within the normal range. It is concluded that elevated AFP in the amniotic fluid is a reliable but nonspecific marker for open neural tube defects prior to the 26th week of pregnancy, but may become normal after the 26th week in a small percentage of patients.

Amniotic Fluid↗