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PubMed1997

Genetic epidemiology of birth defects: nonsyndromic cleft lip and neural tube defects.

This review has focused on only two common structural malformations. However, the difficulties and successes encountered while attempting to elucidate the genetic contribution to these two conditions are likely to be echoed in studies of other complex congenital anomalies. As our understanding of the mechanisms which give rise to a particular malformation gradually unfolds, the importance of a multidisciplinary approach to understanding the genetic contribution to these conditions becomes increasingly apparent. Experience indicates that both traditional and genetic epidemiologic approaches will be integral components of any such efforts, since the identification of environmental risk factors (e.g., folic acid) may provide clues regarding the nature of disease susceptibility loci, and the identification of susceptibility loci will provide new opportunities to explore potential environmental covariates of disease risk (e.g., maternal cigarette smoke). Although we are not yet in a position to completely describe the genetic contribution to any single structural malformation, advances over the past decade have led to a rapid increase in our ability to elucidate the relevant genetic factors. Given the complex nature of the nonsyndromic structural malformations, there is undoubtedly much work to be done before we fully understand the genetic contribution to even a single malformation. However, for the first time, such an understanding and the accompanying potential for prevention seem within our reach.

Abnormalities, Multiple↗
PubMed2000

Assay precision of serum alpha fetoprotein in antenatal screening for neural tube defects and Down's syndrome.

OBJECTIVES: To assess the impact of current serum alpha fetoprotein (AFP) assays on the performance of screening for open neural tube defects and Down's syndrome. METHODS: Maternal serum samples, collected between weeks 15 and 22 from 470 singleton pregnancies without neural tube defects or Down's syndrome, were assayed for AFP using an automated fluorometric immunoassay. The samples had been assayed for AFP using an in house radioimmunoassay with a lower precision ten years before. The variance of AFP using the radioimmunoassay was compared with that using the current fluorometric assay and then used to estimate the detection rates and false positive rates for neural tube defect and Down's syndrome screening. RESULTS: Current serum AFP assays are more precise. Using a cut off level of 2.5 multiples of the median, the false positive rate in screening for anencephaly and open spina bifida was 0.8% with the new assay compared with 2% using the previous assay. When screening for Down's syndrome, the false positive rate is reduced by about one percentage point without loss of detection. CONCLUSION: Improvements in the precision of maternal serum AFP measurement have led to small but useful improvements in screening for open neural tube defects and Down's syndrome. Published estimates of screening performance using such modern assays can be revised accordingly.

Anencephaly↗
PubMed2004

[MAP kinase signal pathway in hyperglycemia-induced congenital neural tube defects].

The aim of the present study was to determine molecular mechanism in hyperglycemia-induced congenital neural tube defects and the its potential pharmacologic rescuing agents. In order to explore these questions, six study groups of Sprague-Dawley rats were employed: Group 1 was normal control rats with normal diet; group 2 represented streptozotocin (STZ) -induced diabetic rats with congenital neural tube defects in offspring; group 3 included STZ-induced diabetic rats with normal offspring; groups 4,5 and 6 included rats exposed to the same STZ-induced diabetic condition, but receiving daily oral supplementation of 80 microg/mL of the sodium salt of arachidonic acid (AA), 400mg of vitamin E and a cocktail of a polyunsaturated fatty acid (safflower oil) plus an antioxidant ( vitamin E) respectively. Yolk sac cells were harvested at gestational day 12 from each rat group. Changes in MAPK signaling pathways were detected by western blot analysis using special antibodies directed against phosphorylated forms of extracellular signal regulated kinase (ERK), Jun N-terminal/stress-activated protein kinase (JNK/SAPK). Furthermore, activity of RAF-1, an upstream kinase in ERK1/2 signaling cascade, was evaluated by immunoprecipitation assay. The results showed that in yolk sac cells in embryopathic offspring from experimentally-induced diabetic rats, activities of ERK1/2 were dramatically decreased (group 2). Consisted with these observation, reduction in RAF-1 kinase activity could be discerned in these diabetic yolk sac cells. In contrast, activities of JNK1/2 were significantly increased in yolk sac cells of group 2. Under rescuing circumstance,activations of ERK1/2 and RAF-1 were increased, and JNK1/2 were decreased. MAP kinase signal pathway plays a very important role in hyperglycemia induced neural tube defects. The supplementation of polyunsaturated fatty acid arachidonic acid, and antioxidant vitamin E rescued conceptuses from diabetic embryopathy by triggering a restoration of normal membrane signaling pathways.

Animals↗
PubMed2001

Repeated neural tube defects and valproate monotherapy suggest a pharmacogenetic abnormality.

Valproate (VPA) is an effective, widely used antiepileptic drug. Unfortunately its use in pregnant women is associated with neural tube defects in the offspring. Although the etiology of neural tube defects is multifactorial, there is evidence that underlying genetic susceptibility plays a part. We describe two women taking moderate doses of VPA who repeatedly bore children with neural tube defects, despite folate supplementation. This suggests a pharmacogenetic susceptibility to the teratogenic effects of VPA.

Adult↗
PubMed1993

Methionine but not folinic acid or vitamin B-12 alters the frequency of neural tube defects in Axd mutant mice.

The Axd (axial defects) mutation, which causes open neural tube defects (NTD) in 25-30% of d 14 mouse embryos of heterozygous (Axd/+) matings and curly tails (CT) in 31%, can be useful in studying neurovertebral morphogenesis. Current interest focuses on the role of methionine in neurulation, because supplementation of dams with this essential amino acid (70 mg/kg body wt) has been shown to reduce by 41% the incidence of NTD among embryos of Axd/+ x Axd/+ crosses when administered on d 8 and 9 of pregnancy. The present experiments were undertaken to determine whether supplementation of dams with a higher dose of methionine could effect a greater level of remediation. At a dose of 180 mg/kg body wt, the amino acid produced a reduction in NTD of 47%, similar to that produced at 70 mg/kg body wt. Supplementation of dams of reciprocal matings of Axd/+ x BALB/cByJ or CF-1 mice allowed assessment of the effects of methionine in heterozygous embryos, which exhibit CT. The amino acid had no effect on Axd/+ embryos from the BALB crosses, but the frequency of CT declined significantly among embryos of the CF-1 outcrosses. Maternal supplements of folinic acid (33 mg/kg) or vitamin B-12 (330 mg/kg) did not alter the incidence of NTD or CT among Axd embryos. No difference in methionine concentration was detected in the serum of Axd/+ and +/+ dams.

Amino Acids↗
PubMed2004

Recommendations for accelerating global action to prevent folic acid-preventable birth defects and other folate-deficiency diseases: meeting of experts on preventing folic acid-preventable neural tube defects.

BACKGROUND: In April of 2003, The Micronutrient Initiative, in collaboration with several other organizations, convened a group of knowledgeable scientists and policy experts to discuss ways to accelerate the global pace at which countries implement effective and sustainable programs to prevent folic acid-preventable birth defects and other folate-deficiency diseases. Programs implemented to date by fewer than 40 countries have prevented only 10% of the estimated 240,000 annual cases of folic acid-preventable spina bifida and anencephaly. METHODS: Participants in this meeting summarized and presented scientific evidence showing that increased consumption of synthetic folic acid prevents a large proportion of spina bifida and anencephaly cases. They also reviewed related guidance and endorsement issued by national professional societies and advisory bodies as well as policies and programs implemented by some countries that have already demonstrated successful results in terms of reduced rates of neural tube defects and improved folate nutrition. CONCLUSIONS: The group formulated and discussed recommendations and strategies for increasing the pace of neural tube defect prevention globally. The recommendations and strategies are published here.

Dietary Supplements↗
PubMed2005

Valproic acid increases conservative homologous recombination frequency and reactive oxygen species formation: a potential mechanism for valproic acid-induced neural tube defects.

Valproic acid, a commonly used antiepileptic agent, is associated with a 1 to 2% incidence of neural tube defects when taken during pregnancy; however, the molecular mechanism by which this occurs has not been elucidated. Previous research suggests that valproic acid exposure leads to an increase in reactive oxygen species (ROS). DNA damage due to ROS can result in DNA double-strand breaks, which can be repaired through homologous recombination (HR), a process that is not error-free and can result in detrimental genetic changes. Because the developing embryo requires tight regulation of gene expression to develop properly, we propose that the loss or dysfunction of genes involved in embryonic development through aberrant HR may ultimately cause neural tube defects. To determine whether valproic acid induces HR, Chinese hamster ovary 3-6 cells, containing a neomycin direct repeat recombination substrate, were exposed to valproic acid for 4 or 24 h. A significant increase in HR after exposure to valproic acid (5 and 10 mM) for 24 h was observed, which seems to occur through a conservative HR mechanism. We also demonstrated that exposure to valproic acid (5 and 10 mM) significantly increased intracellular ROS levels, which were attenuated by preincubation with polyethylene glycol-conjugated (PEG)-catalase. A significant change in the ratio of 8-hydroxy-2'-deoxyguanosine/2'-de-oxyguanosine, a measure of DNA oxidation, was not observed after valproic acid exposure; however, preincubation with PEG-catalase significantly blocked the increase in HR. These data demonstrate that valproic acid increases HR frequency and provides a possible mechanism for valproic acid-induced neural tube defects.

Animals↗
PubMed2004

Oxidative stress in mothers who have conceived fetus with neural tube defects: the role of aminothiols and selenium.

BACKGROUND & AIMS: Methionine metabolic impairment and selenium deficit have been associated to neural tube defects. The relationship between thiol metabolism and selenium is not well known. We assessed the status of aminothiols and selenium, as well as thiolic status and the amino acids involved in arginine synthesis in the case of selenium depletion and repletion, studying their relationship to neural tube defects. METHODS: We studied 44 women of 37 +/- 8 years (mean +/- SD) who had conceived fetuses with neural tube defects as cases; and 181 women of 39 +/- 7 years (mean +/- SD) with healthy children as controls. We determined selenium, vitamin B12, serum folates, plasma thiol compounds and amino acids. Homocysteine transsulfuration was assessed using total cysteine/total homocysteine ratio (tCys/tHcy), and selenium repletion cut-off value was 1.06 micromol/l (84 microg/l). RESULTS: Cases showed significantly lower levels (median) than controls of total homocysteine (P = 0.001), total cysteinylglycine (P < 0.001), selenium (P < 0.001) and tryptophane (P = 0.002); and higher tCys/tHcy levels (P < 0.001), glutathione (P = 0.008) and L-arginine (P = 0.001). Cases with selenium depletion (selenium < or = 1.06 micromol/l) had significantly higher levels than controls of cysteine (P = 0.010), glutathione (P = 0.005), tCys/tHcy (P < 0.001), and arginine (P = 0.004), but significantly lower levels than controls of tryptophane (P = 0.027), cysteinylglycine (P < 0.001) and folates (P < 0.001). Only cysteinylglycine was lower than controls (P < 0.001) when selenium > 1.06 micromol/l. Methionine levels were higher in cases with selenium depletion than in repletion (P = 0.029). CONCLUSIONS: According to our data, a diet deficient in selenium and folates or their absorption impairment, and/or other mechanisms related to polyamines and nitric oxide can lead to oxidant/antioxidant imbalance and to a higher occurrence of these malformations.

Adult↗
PubMedDate not supplied

Arsenic-induced neural tube defects in mice: alterations in cell cycle gene expression.

The potential of arsenic to cause neural tube defects (NTD) in the human population remains a topic of controversy. While clearly toxic, the lack of well-defined human epidemiologic studies on this subject has made it difficult to fully understand the effects arsenic may have on the developing human neural tube. In the absence of good clinical data, we have tried to develop a murine model where hypotheses about the reproductive toxicity of arsenate can be tested. For these studies a murine strain (LM/Bc) that has proven to be susceptible to arsenic-induced NTD was use. Because cellular proliferation is vital for normal neural tube closure (NTC) to occur, in the present study we investigated whether an acute arsenate treatment could alter the expression of several cell cycle genes during murine neurulation. Pregnant LM/Bc dams were injected intraperitoneally on gestation day (GD) 7:12 (day:hour) and 8:12 with 40 mg/kg of arsenate, a treatment that causes exencephaly in 90 to 100% of the exposed fetuses. Neural tubes were then isolated from both control and arsenic treated embryos at GD 9:00, 9:12, 10:00, and 10:12, which encompasses all the stages of neurulation for this murine strain. Using the molecular techniques of in situ transcription and antisense RNA amplification (RT/aRNA) the expression pattern for bc1-2, p53, wee-1, and wnt-1 was analyzed at each of these time points. In the neural tubes isolated from control embryos, the expression of all four genes was significantly altered as neurulation progressed, demonstrating their developmental regulation. Following arsenate treatment, however, there was a significant upregulation in the expression of bc1-2 and p53 at gestational day 9:0, compared to their control values. The heightened expression of both of these genes suggests that arsenic inhibits cell proliferation, rather than inducing apoptosis, which delayed NTC and ultimately led to the neural tube defects observed in exposed embryos.

Abnormalities, Drug-Induced↗
PubMed1986

Spinal cord tumors presenting with neural tube defects.

Two primary lumbosacral tumors arising at the site of neural tube defects are presented. One was a teratoma diagnosed in an infant with myelomeningocele. The other was an ependymoma that developed in an adult with meningocele. It is postulated that these cases represent a neoplastic transformation of heterotopic primordial elements that have been incorporated within the defect, supporting the view that overgrowth of neural tissue may be the result rather than the cause of neural tube deformity. Such rare occurrences may be due to interaction between intrauterine teratogenic factors and familial predisposition in affected patients.

Adult↗
PubMed1999

Mini-review: toward understanding mechanisms of genetic neural tube defects in mice.

We review the data from studies of mouse mutants that lend insight to the mechanisms that lead to neural tube defects (NTDs). Most of the 50 single-gene mutations that cause neural tube defects (NTDs) in mice also cause severe embryonic-lethal syndromes, in which exencephaly is a nonspecific feature. In a few mutants (e.g., Trp53, Macs, Mlp or Sp), other defects may be present, but affected fetuses can survive to birth. Multifactorial genetic causes, as are present in the curly tail stock (15-20% spina bifida), or the SELH/Bc strain (15-20% exencephaly), lead to nonsyndromic NTDs. The mutations indicate that "spina bifida occulta," a dorsal gap in the vertebral arches over an intact neural tube, is usually genetically and developmentally unrelated to exencephaly or "spina bifida" (aperta). Almost all exencephaly or spina bifida aperta of genetic origin is caused by failure of neural fold elevation. The developmental mechanisms in genetic NTDs are considered in terms of distinct rostro-caudal zones along the neural folds that likely differ in mechanism of elevation. Failure of elevation leads to: split face (zone A), exencephaly (zone B), rachischisis (all of zone D), or spina bifida (caudal zone D). The developmental mechanisms leading to these genetic NTDs are heterogeneous, even within one zone. At the tissue level, the mutants show that the mechanism of failure of elevation can involve, e.g., (1) slow growth of adjacent tethered tissue (curly tail), (2) defective forebrain mesenchyme (Cart1 or twist), (3) defective basal lamina in surface ectoderm (Lama5), (4) excessive breadth of floorplate and notochord (Lp), (5) abnormal neuroepithelium (Apob, Sp, Tcfap2a), (6) morphological deformation of neural folds (jmj), (7) abnormal neuroepithelial and neural crest cell gap-junction communication (Gja1), or (8) incomplete compensation for a defective step in the elevation sequence (SELH/Bc). At the biochemical level, mutants suggest involvement of: (1) faulty regulation of apoptosis (Trp53 or p300), (2) premature differentiation (Hes1), (3) disruption of actin function (Macs or Mlp), (4) abnormal telomerase complex (Terc), or (5) faulty pyrimidine synthesis (Sp). The NTD preventative effect of maternal dietary supplementation is also heterogeneous, as demonstrated by: (1) methionine (Axd), (2) folic acid or thymidine (Sp), or (3) inositol (curly tail). The heterogeneity of mechanism of mouse NTDs suggests that human NTDs, including the common nonsyndromic anencephaly or spina bifida, may also reflect a variety of genetically caused defects in developmental mechanisms normally responsible for elevation of the neural folds.

Animals↗
PubMed1987

Association of neural tube defects with omphalocele in chromosomally normal fetuses.

Omphalocele is frequently associated with other congenital malformations or a chromosome abnormality. Previously published series of omphalocele have emphasized the association of congenital heart defects or chromosomal abnormalities. We present five cases of omphalocele with concurrent neural tube defect from among the 15 cases of omphalocele evaluated between 1981 and 1985. Fourteen of 15 were detected prenatally. A sixth case is presented in which both a neural tube defect and an omphalocele were suspected on a prenatal ultrasound, but only the latter was found on autopsy. We recommend that a systematic evaluation be performed on every fetus with an omphalocele to include amniotic fluid alpha fetoprotein, acetylcholinesterase levels, chromosome study, and careful ultrasonography looking for evidence of other abnormalities, especially neural tube defects, before counseling the parents.

Adult↗
PubMed1985

Maternal serum folate and vitamin B12 concentrations in pregnancies associated with neural tube defects.

Serum folate and vitamin B12 concentrations in early pregnancy were compared for 32 mothers with pregnancies affected by neural tube defects and 395 randomly selected pregnant control women from the same maternity hospitals. No significant differences were found between the affected mothers and the controls in the median values and frequency distributions of either vitamin. Sixteen of the samples from mothers whose infants had neural tube defects were taken between 9 and 13 weeks' gestation and 11 of these had both serum folate and vitamin B12 concentrations within the normal ranges for our laboratory. These findings are discussed in relation to the concept of folate deficiency as a major factor in the aetiology of neural tube defects.

Female↗
PubMedDate not supplied

In utero repair of an experimental neural tube defect in a chronic sheep model using biomatrices.

OBJECTIVE: Persistent exposure of the unprotected spinal cord to amniotic fluid and the uterine wall can lead to progressive damage of neural tissue in case of a myelomeningocele (two-hit hypothesis). The aim of this study was to evaluate whether in utero repair of an experimental neural tube defect in a fetal lamb could protect neural tissue from secondary injury and save neurologic functions after birth. METHODS: In 19 fetal lambs, a neural tube defect was created at 79 days' gestation. In 12 lambs the defect was covered either with a novel, molecular defined collagen-based biocompatible and biodegradable matrix (UMC) or with a small intestinal submucosa (SIS) biomatrix (Cook) or by closing the skin over the defect. RESULTS: All lambs with the defect covered showed no or minor neurologic morbidity in contrast to the lambs with the defect uncovered in which major neurologic morbidity was seen. CONCLUSIONS: These results demonstrate that long-term exposure of the open spinal cord to the intrauterine environment can lead to damage of neural tissue and, consequently loss of neurologic functions and that coverage of the defect can lead to a better neurologic outcome. Furthermore, we could show that a UMC biomatrix and an SIS biomatrix are useful for in utero coverage of a surgically created neural tube defect in our model.

Animals↗
PubMed1975

An investigation of space and space-time clustering in a large sample of infants with neural tube defects born in Cardiff.

Altogether 406 infants with neural tube defects born in Cardiff between 1956-71 were investigated for evidence of space-time clustering and 100 similarly affected infants, together with matched controls born in Cardiff between 1964-66 were investigated for evidence of spatial clustering. No evidence of excessive prevalence in either dimension was observed.

Anencephaly↗
PubMed2006

[Uncertain effects of folic acid on disorders other than neural-tube defects].

Periconceptional supplemention with folic acid prevents neural-tube defects in infants. However, contrary to expectations, clinical trials found no beneficial effect of folic acid on the recurrence of cardiovascular disease. Trial evidence on folic acid and cognitive decline or dementia is scarce, though observational studies suggest that high folate intake may prevent these disorders. In contrast, animal studies suggest that high doses of folic acid enhance the growth of existing tumours. However, recent clinical trials failed to show significant effects of folic acid on cancer incidence and mortality. There are also speculations that folic-acid fortification may increase the number of newborns with the thermolabile variant of methylene tetrahydrofolate reductase. There appears to be little evidence that folic-acid supplementation may mask vitamin-B12 deficiency. In view of these controversies, it is unlikely that The Netherlands will mandate folic-acid fortification of staple foods in the near future. Therefore, women who are planning a pregnancy should be urged to take folic-acid supplements.

Animals↗
PubMed1993

Neural tube defects at Korle Bu Teaching Hospital, Accra, Ghana.

This study involved a retrospective analysis of 19094 delivery records of all infants born at the Korle Bu Teaching Hospital in Accra, Ghana, between January 1991 to December 1992. During this two year period, the prevalence of neural tube defects (NTDs) was 1.15/1000 births. Anterior neural tube defects (anencephaly) accounted for 73% and posterior neural tube defects (spina bifida) accounted for 27% of all cases of NTDs. We conclude that NTDs occurs commonly in our subregion. Current available data strongly indicate that periconception folic acid supplementation significantly reduces the prevalence of NTDs. Some of this data is discussed. We strongly recommend preconception folate supplementation in our sub-region.

Female↗
PubMedDate not supplied

Cholinesterase evaluation in the prenatal diagnosis of open neural tube defects.

Alpha-fetoprotein (AFP) and cholinesterase levels in amniotic fluid were determined and the efficiency of these laboratory tests in the prenatal diagnosis of neural tube defects was examined. Using the AFP test with cut-off levels correlated to gestational age, we have detected 8 cases of neural tube defects and one case of abdominal wall defect in about 1,200 pregnancies; false-negative values were absent. Acetylcholinesterase (AChE) and butyrylcholinesterase activities were measured and the electrophoretic pattern of AChE was examined in 100 amniotic fluid samples. The diagnosis of neural tube defects was always confirmed. There were no diagnostic problems due to blood-contaminated amniotic fluid samples. The results obtained using different quantitative methods for the determination of cholinesterase activity, as well as the potential use of these tests in routine examinations, are discussed.

Acetylcholinesterase↗