Cause Of Neural Tube Defects Research Articles

Delayed neural crest cell emigration from Sp and Spd mouse neural tube explants

Splotch (Sp) and splotch-delayed (Spd) are allelic mutations on chromosome 1 of the mouse. Embryos homozygous for either allele have neural tube defects (NTDs) and deficiencies in neural crest cell (NCC) derived structures. The fact that Spd mouse mutants sometimes have deficiencies in NCC derivatives in the absence of an NTD led to the hypothesis that neurulation and the release of NCCs may depend on a regulatory event that is common to both processes. Therefore, it may be possible to understand the cause of NTDs in these mutants by examining the basis of aberrant NCC derivatives. Caudal neural tubes were excised from day 9 Sp and Spd embryos and placed into gelatin-coated tissue culture dishes, or 3-dimensional basement membrane matrigel, and cultured for 72 hours. A cytogenetic marker was used to genotype the embryos. In planar cultures, no morphological differences were observed between NCCs from neural tube explants of Spd mutants compared to those from heterozygous or wild-type embryos. However, there appeared to be a delay in the release of NCCs from the neural tube in both Sp and Spd mutants, which was particularly evident in Sp. After 24 hours in culture, the extent of NCC outgrowth, as well as the number of NCCs emigrating from explanted neural tubes, was significantly lower in Sp and Spd mutant cultures than in controls. No differences were observed in the mitotic indices among cells which had emigrated. By 72 hours, mutant cultures and their non-mutant counterparts were similar in terms of outgrowth, cell number, and migratory capability. After 24 hours in 3-dimensional basement membrane matrigel, cell outgrowth from Sp explants was also significantly less than controls. The pattern of NCC outgrowth in both types of culture conditions indicates a 24 hour delay in mutant cultures compared to controls. This stems from a delay in the release of NCCs from the neural tube, suggesting that the defect lies within the neuroepithelium with respect to the release of NCCs.

The cause of neural tube defects: some experiments and a hypothesis.

The mouse mutant curly-tail is an animal model for human neural tube defects (NTD). Around 60% spontaneously have NTD. It has been found that maternal administration of hydroxyurea, mitomycin C, or 5-fluorouracil on day 9 of pregnancy, that is, when the fetal neural tube is in the final stages of closure, leads to a significant reduction in the proportion of NTD (to 15 to 20%) in the offspring, while total litter size is unaffected. All these substances are inhibitors of DNA synthesis, yet are apparently beneficial to subjects predisposed to NTD. As a consequence, it is suggested that the underlying mechanism causing NTD in the mice, and also in man, is a basic metabolic defect in DNA synthesis which affects cell replication and results in abnormal morphogenesis of the neuraxis.

Evidence against oral contraceptives as a cause of neural-tube defects.

Information on oral contraceptive (OC) use, collected at the first antenatal visit, was abstracted from the medical notes in respect of 107 index pregnancies resulting in the delivery of an infant with a neural-tube defect (NTD) and 214 unaffected controls. The relative risk of having an NTD infant for women who had at any time used OCs was 0.82 (95% confidence interval 0.52, 1.32) compared with that in women who had never used OCs. For women who stopped OC use less than 3 months before becoming pregnant or who continued in early pregnancy, the relative risk was 1.18 (95% confidence interval 0.70, 1.98) compared with women who had used OCs at any other time. An analysis restricted to those women who had at any time used OCs did not suggest an association between NTD risk and the interval between stopping OC use and becoming pregnant. None of our analyses therefore provided any evidence that OCs cause NTDs and if a risk exists it can only be small.

The Puzzling Epidemiology of Neural Tube Defects

Elucidating the cause of disease is often not easy and may require answers to many questions. Perhaps the most important questions have been rather simply stated in verse by Rudyard Kipling.1 I keep six honest serving men; (They taught me all I knew) Their names are What and Why and When and How and Where and Who. In terms of neural tube defects, many of these servants of Mr Kipling have provided valuable epidemiologic clues as to the cause of neural tube defects (NTDs),2 but the specific mechanism responsible for this disabling birth defect has so far escaped definition.

Neural tube malformations: complex segregation analysis and recurrence risk.

A sample of 223 families with at least one child with anencephaly and/or spina bifida was ascertained in Southern Poland, where the incidence of neural tube malformations is 0.92/1,000. The recurrence risk in proband's sibs was 3.4%. The calculated heritability (h2) was 76%, implying a substantial contribution of genetic factors to the cause of neural tube defects. Complex segregation analysis was applied in an attempt to discriminate between the hypothesis of a single locus and that of quasi-continuity under multifactorial inheritance. The results excluded the hypothesis of dominant inheritance with full penetrance. The hypothesis of the two-allele model (at a single locus) fit the data with the same degree of exactness; however, for all hypotheses the estimated penetrance was low, and the phenocopy frequency was high. Less accurate conformity was observed for the multifactorial hypothesis. In view of very low penetrance and high frequency of phenocopies in single locus hypotheses and the finding that empirical data gave better support to the multifactorial model, the differences in chi 2 values should not be viewed as sufficient to discriminate between single locus and multifactorial models. The recurrence risks, assessed in the complex segregation analysis, showed an increase together with the growing number (r) of affected children. For constant r the recurrence risks decreased in successive pregnancies. Although discrimination between the mendelian and multifactorial inheritance models was incomplete, the risk values obtained can be employed in genetic counseling.

Neural‐tube Defects and Mid‐cycle Abstinence: a Test of the ‘Over‐ripeness' Hypothesis in Man

The prevalence of mid-cycle abstinence at the time of conception of infants born with neural-tube defects was found to be only 6-7 per cent (8/119) compared with that of 9-8 per cent (32/325) at the time of conception of non-affected siblings. This is suggestive evidence against mid-cycle abstinence--and, by inference, over-ripeness--as an important possible cause of neural-tube defects.