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PubMed2000

Genetic studies in neural tube defects. NTD Collaborative Group.

Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families. Advances in genetic laboratory and statistical techniques have made this a prime opportunity for investigation into the causes of complex disorders, such as NTD. However, traditional approaches may prove to be challenging due to the difficulty of ascertaining samplable multiplex families.

Animals↗
PubMed2005

Mouse models of neural tube defects: investigating preventive mechanisms.

Neural tube defects (NTD), including anencephaly and spina bifida, are a group of severe congenital abnormalities in which the future brain and/or spinal cord fail to close. In mice, NTD may result from genetic mutations or knockouts, or from exposure to teratogenic agents, several of which are known risk factors in humans. Among the many mouse NTD models that have been identified to date, a number have been tested for possible primary prevention of NTD by exogenous agents, such as folic acid. In genetic NTD models such as Cart1, splotch, Cited2, and crooked tail, and NTD induced by teratogens including valproic acid and fumonisins, the incidence of defects is reduced by maternal folic acid supplementation. These folate-responsive models provide an opportunity to investigate the possible mechanisms underlying prevention of NTD by folic acid in humans. In another group of mouse models, that includes curly tail, axial defects, and the Ephrin-A5 knockout, NTD are not preventable by folic acid, reflecting the situation in humans in which a subset of NTD appear resistant to folic acid therapy. In this group of mutants alternative preventive agents, including inositol and methionine, have been shown to be effective. Overall, the data from mouse models suggests that a broad-based in utero therapy may offer scope for prevention of a greater proportion of NTD than is currently possible.

Animals↗
PubMed1995

Absence of linkage between familial neural tube defects and PAX3 gene.

Neural tube defects (NTD) are among the most common and disabling birth defects. The aetiology of NTD is unknown and their genetics are complex. The majority of NTD cases are sporadic, isolated, nonsyndromic, and generally considered to be multifactorial in origin. Recently, PAX3 (formerly HuP2, the human homologue of mouse Pax-3), on chromosome 2q35-37, was suggested as a candidate gene for NTD because mutations of Pax-3 cause the mouse mutant Splotch (Sp), an animal model for human NTD. Mutations in PAX3 were also identified in patients with Waardenburg syndrome type 1 (WS1). At least eight patients with both WS1 and NTD have been described suggesting pleiotropy or a contiguous gene syndrome. Seventeen US families and 14 Dutch families with more than one affected person with NTD were collected and 194 people (50 affected) from both data sets were genotyped using the PAX3 polymorphic marker. The data were analysed using affecteds only linkage analysis. The lod scores were -7.30 (US), -3.74 (Dutch), and -11.04 (combined) at theta = 0.0, under the assumption of the autosomal dominant model. For the recessive model, the lod scores were -3.30 (US), -1.46 (Dutch), and -4.76 (combined) at theta = 0.0. Linkage between PAX3 and familial NTD was excluded to 9.9 cM on either side of the gene for the dominant model and to 3.63 cM on either side of the gene for the recessive model in the families studied. No evidence of heterogeneity was detected using the HOMOG program. Our data indicate that PAX3 is not a major gene for NTD.

Base Sequence↗
PubMed1999

Possible interaction of genotypes at cystathionine beta-synthase and methylenetetrahydrofolate reductase (MTHFR) in neural tube defects. NTD Collaborative Group.

Neural tube defects are a common, complex disorder with genetic and environmental components to risk. We investigated the previously reported interaction between homozygosity for the thermolabile variant at the methylenetetrahydrofolate reductase and heterozygosity for the 844ins68 allele at the cystathionine beta-synthase loci in cases with lumbosacral myelomeningocele and their parents. Using control allele frequencies from our sample pooled with those published in the literature, we confirm a marginally significant interaction at these two loci. This finding suggests that additional, larger studies are warranted to investigate this possible interaction in more detail.

Alleles↗
PubMed2000

[Basic principles of evaluation of neural tube defects primary prevention programme].

Neural Tube Defects (NTD) Primary Prevention Programme has been developed in Poland since 1997. The Programme directed by Professor Z. J. Brzezinski is based on an information and education campaign directed at health professionals, women in childbearing age and high school students. The Central Programme Office has been directing the development and implementation of the Programme through a network of provincial programmes. In the present paper the main principles of NTD primary prevention were presented as well as some principles of Programme building and evaluation. Due to the relatively short period of Programme implementation, it is too early to perform the full evaluation. However, some examples were presented including process evaluation and testing the main tools (questionnaires, school programme project). It was assumed that the effectiveness of NTD Primary Prevention Programme in Poland will be assessed by: 1) changes in women's knowledge, attitude and behaviour concerning folic acid supplementation, 2) changes in NTD mortality and morbidity rates, 3) changes in the amount of sold tablets containing 0.4 mg of folic acid. For each of these indicators some international results and Polish baseline results were discussed.

Adolescent↗
PubMed2003

Method of weighted proportion of reproductive-aged women taking folic acid supplements to predict a neural tube defect rate decline.

BACKGROUND: Neural tube defect (NTD) rates can be lowered by increased consumption of folic acid (FA) by women before and during early pregnancy. The crude proportion of reproductive-aged women taking FA supplements has been used to predict a decline of the NTD rate in the general population. In this study we examine the potential error in using the crude proportion to predict NTD risk reduction, and offer an alternative method. METHODS: The crude proportion measures the number of women taking FA. It ignores the substantial variability by maternal age in the probability of giving birth. Age-specific fertility rates (ASFRs) reflect the probability that a woman in a specific age group will give birth in a given year. In this study, we show how to calculate a proportion weighted by ASFRs to predict a decline in the NTD rate, and to assess the effectiveness of FA consumption in preventing NTDs. RESULTS: Our results show that a crude proportion of 50% of women (15-49 years old) taking FA is associated with a range of 24-77% in weighted proportions. Assuming a 40% risk reduction from taking 400 microg of FA daily, the expected NTD rate decline could vary from 9.6% to 30.6%, depending on the age distribution of women taking FA. CONCLUSIONS: The ASFR-weighted proportion estimates the proportion of babies born to women taking FA, as opposed to the crude proportion of women taking FA. We recommend using the ASFR-weighted proportion to predict an NTD rate decline and measure the success of FA education campaigns. We found that when women in high-fertility age groups increased their FA consumption, the decline in the NTD rate was greater than when women in low-fertility age groups did so. Our findings suggest that the more efficient approach to NTD prevention is to focus on women with a higher probability of giving birth. For example, by focusing on <50% of women of childbearing age (20-34 years), as much as 76% of the maximum NTD rate reduction can be achieved.

Adolescent↗
PubMed1995

Sex, neural tube defects, and multisite closure of the human neural tube.

While neural tube defects (NTD) overall have a female sex bias, this does not apply to all sites along the neuraxis. The findings regarding sex and NTD in a series of midtrimester fetuses are reviewed, and then analysed in terms of the recent hypothesis that during embryogenesis of the human neural tube there are multiple closure sites, rather than a single zipping up process. Females more often than males tend to have craniorachischisis, spina bifida involving the thorax, the holoacrania form of anencephaly, anencephaly and cervical spina bifida and encephalocoeles, while males more often than females have spina bifida affecting the lower spine. Meroacrania occurs equally in both sexes. Other sources indicate that there is a male bias in frontoethmoidal encephalocoeles. Since sex seems to be a factor that is differentially associated with lack of closure of specific areas of the neural tube, it would seem to support the notion that there are multiple closure sites in the human neural tube. However, no association was found between a particular sex and either the type of NTD which have an isolated abnormality or those NTD associated with developmental abnormalities of other body systems.

Anencephaly↗
PubMed2000

Mouse models for neural tube closure defects.

Neural tube closure defects (NTDs), in particular anencephaly and spina bifida, are common human birth defects (1 in 1000), their genetics is complex and their risk is reduced by periconceptional maternal folic acid supplementation. There are > 60 mouse mutants and strains with NTDs, many reported within the past 2 years. Not only are NTD mutations at loci widely heterogeneous in function, but also most of the mutants demonstrate variable low penetrance and some show complex inheritance patterns (e.g. SELH/Bc, Abl / Arg, Mena / Profilin1 ). In most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly) or spina bifida or both, reflecting failure of neural fold elevation in well defined, mechanistically distinct elevation zones. NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid ( Pax3, Cart1, Cd mutants), inositol ( ct ) and methionine ( Axd ). Lack of de novo methylation in embryos ( Dnmt3b -null) leads to NTD risk, and we suggest a potential link between methylation and the observed female excess among cranial NTDs in several models. Some surprising NTD mutants ( Gadd45a, Terc, Trp53 ) suggest that genes with a basic mitotic function also have a function specific to neural fold elevation. The genes mutated in several mouse NTD models involve actin regulation ( Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl ), support the postulated key role of actin in neural fold elevation, and may be a good candidate pathway to search for human NTD genes.

Actins↗
PubMed1987

Vascular basis for neural tube defects: a hypothesis.

A hypothesis is set forth that neural tube defects are produced by inadequate nutrient supply to the rapidly growing neural folds. According to this hypothesis, a delay in establishing blood flow or an aberration of blood supply to neural tissue may interfere with nutrition and prevent neural tube closure. The hypothesis was tested by examining the vasculature of fetuses with spinal neural tube defects. In each case, the arterial supply to the region of the neural tube defect was disturbed. Because development of arterial supply to the neural folds predates neural tube closure, these vascular abnormalities are considered to be primary malformations that lead to neural tube defects rather than secondary morphologic disturbances resulting from neural tube defects.

Blood Vessels↗
PubMed1996

Concanavalin-A-induced open neural tube defects in chick embryos.

Open neural tube defects developed in 12 of 122 alive chick embryos treated with exogenous lectin (concanavalin-A) at stages between 10 or 14 as defined by Hamburger and Hamilton. Embryos treated at stage 10, the time of anterior neuropore closure, developed exencephaly or extensive neural openings from the level of rhombencephalon to the thoracic spinal cord, while embryos treated at stages between 11 and 14, at posterior neuropore closure, developed only small myeloschisis in the thoracolumbar region. The failure of neural tube closure at a critical time is a major cause of neural tube defects.

Animals↗
PubMed2002

Effects of folate supplementation on the risk of spontaneous and induced neural tube defects in Splotch mice.

BACKGROUND: Neural tube defects (NTDs) are among the most common human congenital malformations. Although clinical investigations have reported that periconceptional folic acid supplementation can reduce the occurrence of these defects, its mechanism remains unknown. Therefore, the murine mutant Splotch, which has a high incidence of spontaneous NTDs, along with the inbred strains SWV and LM/Bc, were used to investigate the relationship between folate and NTDs. METHODS: To investigate whether folates could reduce spontaneous NTDs, heterozygous Splotch dams (+/Sp) were treated with either folate or folinic acid throughout neurulation, gestational day (GD) 6.5 to 10.5. On GD 18.5 the dams were sacrificed and the fetuses examined for any neural tube defects. Subsequently, Sp/+ dams were treated with arsenic while receiving either a folate or folinic acid supplementation. Similar experiments were performed in the LM/Bc and SWV strains. RESULTS: Neither folate nor folinic acid supplements reduced the frequency of spontaneous NTDs in the embryos from Splotch heterozygote crosses. Arsenic increased the frequency of NTDs and embryonic death in the Splotch, LM/Bc and SWV litters and folinic acid failed to ameliorate the teratogenic effect of this metal. A folate supplement given to arsenic-treated dams proved to be maternally lethal in all three strains. CONCLUSIONS: Splotch embryos were not protected from either spontaneous or arsenic-induced NTDs by folinic or folic acid supplementation. Furthermore, folinic acid supplements did not reduce the incidence of arsenic-induced NTDs in either the LM/Bc or SWV litters.

Animals↗
PubMed1997

Genetic disorders among Palestinian Arabs. 2. Hydrocephalus and neural tube defects.

Congenital hydrocephalus and/or open neural tube defect was present in at least one individual of 98 families out of the 2,000 Palestinian Arabic families who have visited the Genetic clinic at the Hadassah Medical Center. In 22 families the brain malformation was part of a syndrome: Meckel syndrome in 10, Warburg syndrome in another 5, Carpenter in one, and undiagnosed in 6 families. In 76 of the families the neural tube defect and/or the hydrocephalus were non-syndromal. It seems that most of the cases of isolated non-syndromal hydrocephalus represented autosomal recessive traits and that an abnormal allele is common among Palestinian Muslim Arabs.

Abnormalities, Multiple↗
PubMed2000

Epidemiology of neural tube defects, Hawaii, 1986-1997.

Neural tube defects (NTDs) in Hawaii between 1986 and 1997 were examined using data from a statewide birth defects surveillance system. The prevalence increased significantly over the twelve-year period. NTD prevalence did not appear to vary by place of residence. The relationship of type of defect, maternal age, and infant/fetus sex was similar to that reported in the literature.

Adolescent↗
PubMed1992

Effects of H-2 on neural tube defects in congenic mice.

Pregnant mice congenic with C57BL/10 (B10.A, B10.BR, B10.D2, B10.A[2R], B10.A[5R], B10.A[15Rd, B10.A[1R], B10.A[18R], and B10.0L) were fed Purina Mouse Chow or the same diet plus 200 IU of vitamin A daily. The pregnant dams were sacrificed on the eighteenth day of gestation, and the fetuses were sexed and examined for defects in neural tube development. The frequency of neural tube defects was low (mean frequency of all strains, 0.36%) and was not affected by the addition of vitamin A (200 IU/day) to the diet. Twenty-seven of the 29 defects observed occurred in the anterior tube (exencephaly); fourteen were identified in female fetuses, but the sex could not be determined in the other 15 cases because of fetal death and early autolysis. Variations in frequency among the strains suggest that a locus between E beta and H-2D has a moderate influence on the occurrence of neural tube defects. Strains that had H-2d alleles in this segment of the H-2 complex had relatively high frequencies, and those with H-2b or H-2k alleles had significantly lower frequencies.

Animals↗
PubMed2000

Karyotyping for isolated neural tube defects. A report of two cases.

BACKGROUND: Neural tube defects occur in approximately 1 in every 1,000 live births. In the United States, chromosomal abnormalities have been noted in 2-10% of fetuses with neural tube defects; however, there is no consensus on whether to offer karyotype analysis to patients with isolated neural tube defects found on ultrasound. CASE: We reviewed the prenatal diagnosis database for the University of Washington between 1985 and 1997. We report on two fetuses who, on ultrasound, were found to have "isolated" neural tube defects. Karyotype analysis revealed trisomy 18 in both fetuses. The pregnancies were subsequently terminated, and autopsy revealed subtle syndromic findings that were not identified on ultrasound. CONCLUSION: Fetuses with isolated neural tube defects also appear to have a high risk of chromosomal abnormalities, so patients should be offered fetal karyotyping to define recurrence risks for future pregnancies.

Abortion, Therapeutic↗
PubMed1998

Associated malformations in infants and fetuses with upper or lower neural tube defects.

The paper describes associated malformations in infants born with neural tube defects (N = 3,809) from three large malformation registers and in fetuses aborted because of a diagnosed neural tube defect (N = 748) from two of the registers. In infants, upper spina bifida and encephalocele are more often associated with non-neural malformations than anencephaly or lower spina bifida. Aborted fetuses with spina bifida or encephalocele have associated malformations registered more often than infants with those neural tube defects, but the opposite is true for anencephaly. The degree of detail of the investigation of an aborted specimen or a perinatally dead infant will contribute to such differences but they can also depend on the fact that prenatal detection may be facilitated by the simultaneous presence of other malformations like body wall defects. Also, fetuses with many malformations may be more prone to abort spontaneously late in pregnancy. Variable prenatal diagnosis may, therefore, explain population differences in the pattern of associated malformations. The type of associated malformation differs with the level of the neural tube defect: this could be due to different causal mechanisms or be a question of cranio-caudal level and/or timing. For limb reduction defects, however, we did not find any association between upper limb and upper neural tube defects or lower limb and lower neural tube defects. These findings together with other epidemiological data support the idea that upper and lower neural tube defects may have different significance in epidemiological studies and should be treated separately.

Abnormalities, Multiple↗
PubMed1996

Understanding How Neural Tube Defects Occur--And Can Be Prevented.

Neural tube defects occur in 1.3 to 2.0 fetuses per 1000 live births, and are second only to cardiac malformations as the most frequent congenital anomaly in the US. The genetic and environmental influences on neural tube defect formation are currently being investigated. It is now thought that neural tube closure occurs in 5 separate sites, with each site possibly controlled by separate genes and subject to different external influences. Evidence suggests that one basic genetic defect involves homocysteine metabolism. Folic acid supplements before conception reduce both occurrence and recurrence risks. Prenatal screening and diagnosis are available, although management options after diagnosis are limited. Dietary alterations and adjustment of medical therapy prior to conception will reduce neural tube defect occurrence.

Journal Article↗