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1.
It has been suggested that neural tube defects (NTDs) of the upper type (anencephaly, encephalocele, and thoracic spina bifida) may have a pathogenesis different from those of the lower type (lumbosacral spina bifida), since recurrent cases within a sibship were said always to be concordant with respect to NTD type. Also, spontaneous abortion, additional malformation, and recurrence rate were observed to be higher in the upper group, and there was an excess of females in upper NTD probands. To test this hypothesis, we measured the above variables in upper and lower NTDs in a sample from Quebec. We found less than full concordance (50%) of NTD type in 18 sib pairs. Recurrence rate was not significantly lower in the lower NTD group (5.6 v 5.8%). The other variables were in general agreement with previous studies, inconsistent findings possibly attributable to different NTD population incidences. These findings can be accounted for if upper and lower NTDs share a similar pathogenesis and the embryo is more susceptible during early than late neural tube formation. 相似文献
2.
Adverse pregnancy outcomes may be more frequent among sibs of individuals with neural tube defects (NTDs), and transmission of risk in families with an NTD may be more frequent among maternal relatives. In a study designed to evaluate matrilineal risk for NTDs, we compared adverse pregnancy outcomes among maternal and paternal first cousin pregnancies. Pregnancy histories were obtained by interview with 288 uncles and aunts (parents of the first cousin pregnancies) in 48 Irish NTD families. We analyzed pregnancy outcomes (preterm deliveries, stillbirths, and miscarriages) among 1,033 singleton first cousin pregnancies and compared risk among maternal versus paternal relatives. Maternal first cousin pregnancies were more likely to end adversely when compared to paternal first cousin pregnancies (17.4% vs. 11.7%, P = 0.01). In a logistic regression analysis of pregnancies unaffected by birth defects, maternal line remained independently associated with adverse outcomes (odds ratio (OR) = 1.55, 95% confidence interval (CI) 1.06, 2.27) after controlling for NTD type, maternal age, maternal smoking during pregnancy, first cousin pregnancy's year of birth. The excess risk with maternal line related mainly to spina bifida occulta families (OR = 42.4; CI 2.64, 681; P = 0.008); risk in open spina bifida families was 1.24 (CI 0.82, 1.87; P = 0.3). These results support the hypothesis of excess risk for adverse pregnancy outcomes among maternal relatives in NTD families. Further work is needed, epidemiological as well as clinical and molecular, not only to confirm these findings, but also to define the underlying biological mechanisms linking adverse reproductive outcomes, excess maternal risk and occurrence of NTDs. 相似文献
3.
Greene ND Copp AJ 《American journal of medical genetics. Part C, Seminars in medical genetics》2005,(1):31-41
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. 相似文献
4.
F. Vogel John M. Opitz James F. Reynolds 《American journal of medical genetics. Part A》1985,20(4):695-697
We present data from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) on prevalence rates and etiologic factor associations in neural tube defects. Two series of data are analyzed: the A series, including 740, 139 consecutive infants born in the 1967–1979 period suitable for secular trend analysis and case-control study of risk factors; and the B series, including 255, 834 consecutive stillborn and liveborn infants of the 1980–1982 period suitable for prevalence rate analysis. Anencephaly was registered in 6.0/10,000 births, spina bifida aperta in 6.2/10,000 births, and cephalocele in 2.4/10,000 births. A stable secular trend was observed for the frequency of all three neural tube defect types. Spina bifida was more frequent in Chile than in the rest of South America. No differences in prevalence rates were seen between tropical and non tropical areas. Parental consanguinity and environmental prenatal factors including maternal illnesses, drug intake, and radiation exposure were found in association with anencephaly and spina bifida. 相似文献
5.
Epidemiology of neural tube defects 总被引:3,自引:0,他引:3
Mitchell LE 《American journal of medical genetics. Part C, Seminars in medical genetics》2005,(1):88-94
The epidemiological investigation of the common open neural tube defects (NTDs), anencephaly, and spina bifida, has a long history. The most significant finding from these past studies of NTDs was the identification of the protective effect of maternal, periconceptional supplementation with folic acid. Fortuitously, the association between folic acid and NTDs became widely accepted in the early 1990s, at a time when genetic association studies of complex traits were becoming increasingly feasible. The confluence of these events has had a major impact on the direction of epidemiological, NTD research. Association studies to evaluate genes that may influence the risk of NTDs through their role in folate-related processes, or through other metabolic or developmental pathways are now commonplace. Moreover, the study of genetic as well as non-genetic, factors that may influence NTD risk through effects on the nutrient status of the mother or embryo has emerged as a major research focus. Research efforts over the past decade indicate that gene-gene, gene-environment, and higher-order interactions, as well as maternal genetic effects influence NTD risk, highlighting the complexity of the factors that underlie these conditions. The challenge for the future is to design studies that address these complexities, and are adequately powered to detect the factors or combination of factors that influence the development of NTDs. 相似文献
6.
Michael K. McCormack Nancy Breslin Patricia J. Coppola-McCormack 《Clinical genetics》1980,17(6):394-402
Spina bifida represents a broad category of neural tube defects (NTD) which affects approximately 1–4/1,000 live births. Since effective prenatal diagnostic testing for 90 % of NTD is available through measurement of alpha-fetoprotein (AFP) in amniotic fluid, ascertainment of high risk factors associated with the occurrence of NTD would be both desirable and important. At the present time, generally, the major indication for prenatal testing for NTD is the presence of a first-degree relative with some form of NTD. To date, few other factors have been utilized to identify a family as "at risk".
We have studied a group of 19 families of 10 female and 9 male index cases with NTD. The parents of each index case were interviewed and pedigrees were prepared on each family. Conditions screened for in these families included spina bifida and other NTD, pilonidal cysts, scoliosis, kyphosis and other vertebral disorders which were hypothesized to be possibly related to NTD. There were 58 first-, 171 second-, and 802 third-degree relatives screened in this study. This sample population was similarly characteristic with regard to sex, maternal age and birth order distributions as compared to previous populations of NTD described and was therefore considered to be representative. Our results indicate that: (1) pilonidal cysts are 6 times more frequent in the fathers and twice as frequent in the mothers of children with spina bifida than in the general population;
These preliminary studies suggest that several minor clinical conditions in parents may be important to consider as possible risk signs suggesting couples be considered for prenatal evaluation for the prevention of NTD. 相似文献
We have studied a group of 19 families of 10 female and 9 male index cases with NTD. The parents of each index case were interviewed and pedigrees were prepared on each family. Conditions screened for in these families included spina bifida and other NTD, pilonidal cysts, scoliosis, kyphosis and other vertebral disorders which were hypothesized to be possibly related to NTD. There were 58 first-, 171 second-, and 802 third-degree relatives screened in this study. This sample population was similarly characteristic with regard to sex, maternal age and birth order distributions as compared to previous populations of NTD described and was therefore considered to be representative. Our results indicate that: (1) pilonidal cysts are 6 times more frequent in the fathers and twice as frequent in the mothers of children with spina bifida than in the general population;
These preliminary studies suggest that several minor clinical conditions in parents may be important to consider as possible risk signs suggesting couples be considered for prenatal evaluation for the prevention of NTD. 相似文献
7.
Neural tube defects (NTDs) have a well-established genetic basis, although no single genetic factor has been identified as a major risk factor in NTD susceptibility. A large number of association studies have been conducted to investigate the possibility that NTD susceptibility is linked to polymorphic variation in genes involved in early embryonic development or in the absorption or metabolism of folate, a nutrient that has been clearly associated with a reduction in the risk of NTD pregnancy. A study of three candidate gene polymorphisms at loci implicated in folate absorption and metabolism has been conducted on a population of 211 mothers of a heterogeneous mix of NTD phenotypes: 59% spina bifida aperta (SBA), 20.3% spina bifida occulta (SBO), 17% anencephaly, and 3.7% other NTD. Allele and genotype frequencies were stratified according to offspring NTD phenotype, and variation in the level of NTD risk was associated with different phenotypes. All the three variants (MTHFR 677C > T, GCPII 1561C > T, and RFC-1 80G > A) were shown to significantly influence the risk of anencephalic pregnancy. In addition, the MTHFR 677C > T variant conferred a modest protective effect in SBO mothers and the total NTD mother group, but not in SBA mothers. The RFC-1 80G > A variant elevated the risk of SBO and anencephalic pregnancy. The findings of this study suggest that NTD phenotypic heterogeneity may help explain the mixed findings of previous association studies and that different polymorphisms may hold differing degrees of significance for the various NTD phenotypes. 相似文献
8.
Mary J. Seller 《American journal of medical genetics. Part A》1995,58(4):332-336
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. © 1995 Wiley-Liss, Inc. 相似文献
9.
10.
McKernon WL Holmbeck GN Colder CR Hommeyer JS Shapera W Westhoven V 《Journal of pediatric psychology》2001,26(1):41-54
OBJECTIVE: To study coping socialization longitudinally by examining reported and observed family environment and parenting variables in relation to children's problem-focused coping in a sample of 68 families of preadolescents with spina bifida and 68 matched able-bodied comparison families. METHODS: Family environment and parenting variables were assessed with mother and father reports and observational measures. Children's problem-focused coping was self-reported. RESULTS: Prospective analyses revealed that maternal responsiveness, paternal responsiveness, and family cohesion predicted an increase in children's use of problem-focused coping strategies, while change in paternal responsiveness and maternal responsiveness and demandingness was related concurrently to change in coping. Few group (spina bifida vs. able-bodied) or gender differences with respect to parenting and family influences on children's coping behaviors were found. CONCLUSIONS: Multimethod findings suggest that the quality of parenting and family environment is associated with children's problem-focused coping behaviors. We discuss clinical implications. 相似文献
11.
S. Cowchock E. Ainbender G. Prescott B. Crandall L. Lau R. Heller W. A. Muir E. Kloza M. Feigelson M. Mennuti L. Cederquist Laurence E. Karp 《American journal of medical genetics. Part A》1980,5(3):309-314
To determine the recurrence risk for patients with one prior pregnancy affected with neural tube defects (NTD), the authors have pooled date from eight testing centers. In 831 pregnancies studies because one sib was affected with an NTD, the recurrence rate was 3.0%, with 95% confidence limits of 2.0–4.3%, and 99% confidence limits of 1.8–4.8%. The recurrent lesion, whether spina bifida or anencephaly, tended to be concordant with the first to a significant degree. Only 12.2% or recurrent NTD were different from the first, with 95% confidence limits of 4.1–26.2%, and 99% confidence limits of 1.7–30.9%. Both an accurate recurrence risk and the information that a recurrent NTD lesion tends to be concordant with that in the first asffected child are useful in the genetic counseling of patients in the United States and in the selecton of appropriate prenatal diagnostic studies. 相似文献
12.
K. MORRISON C. PAPAPETROU F. A. HOL E. C. M. MARIMAN S. A. LYNCH J. BURN Y. H. EDWARDS 《Annals of human genetics》1998,62(5):379-396
Clues regarding candidate genes which influence susceptibility to spina bifida and anencephaly come from the identification of folate-associated risk factors and from studies of mouse mutants showing neural tube anomalies. On this basis we selected five candidate genes; CBS , MS , MTHFR , T ( Brachyury ) and BRCA1 for genetic analysis in 31 Dutch and 48 British NTD families. Ten polymorphisms, two for each gene, were used in transmission tests for disequilibrium (TDT). In six instances more than 50 transmissions from heterozygous parents could be examined. Using TDT we find evidence for an association between an allele at the T gene and liability to NTD in the embryo. Data from British and Dutch populations showed the same trend and in combination gave a χ2 TDT =4.89, P =0.03 (OR 2.39, CI 95% 1.02–5.61). No association, in either population group, was found for CBS , MS and MTHFR , the enzymes most directly associated with the known risk factors in folate metabolism. The possibility of complex genetic interactions was explored; the data show that a Gly919 MS variant occurs more frequently in combination with the MTHFR thermolabile variant in mothers of NTD offspring (OR 3.94, CI 95% 1.0–16.3). 相似文献
13.
A targeted sequencing panel identifies rare damaging variants in multiple genes in the cranial neural tube defect,anencephaly
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M. Ishida T. Cullup C. Boustred C. James J. Docker C. English GOSgene N. Lench A.J. Copp G.E. Moore N.D.E. Greene P. Stanier 《Clinical genetics》2018,93(4):870-879
Neural tube defects (NTDs) affecting the brain (anencephaly) are lethal before or at birth, whereas lower spinal defects (spina bifida) may lead to lifelong neurological handicap. Collectively, NTDs rank among the most common birth defects worldwide. This study focuses on anencephaly, which despite having a similar frequency to spina bifida and being the most common type of NTD observed in mouse models, has had more limited inclusion in genetic studies. A genetic influence is strongly implicated in determining risk of NTDs and a molecular diagnosis is of fundamental importance to families both in terms of understanding the origin of the condition and for managing future pregnancies. Here we used a custom panel of 191 NTD candidate genes to screen 90 patients with cranial NTDs (n = 85 anencephaly and n = 5 craniorachischisis) with a targeted exome sequencing platform. After filtering and comparing to our in‐house control exome database (N = 509), we identified 397 rare variants (minor allele frequency, MAF < 1%), 21 of which were previously unreported and predicted damaging. This included 1 frameshift (PDGFRA), 2 stop‐gained (MAT1A; NOS2) and 18 missense variations. Together with evidence for oligogenic inheritance, this study provides new information on the possible genetic causation of anencephaly. 相似文献
14.
Neural tube defects and sex ratios 总被引:15,自引:0,他引:15
M J Seller 《American journal of medical genetics》1987,26(3):699-707
The sex ratio of 147 fetuses with presumed multifactorial neural tube defect (NTD) was studied. Overall, the ratio (males:females) was 0.73 with expected female excess. However, when the NTDs were subdivided according to the site of the lesion, the sex ratios varied. Total craniorachischisis, anencephaly with cervical spina bifida, holoacrania, and thoracic spina bifida showed a greater female excess than that overall; the sex ratio for meroacrania was close to unity, while that for low spinal lesions, particularly those involving the sacrum, showed an extreme bias towards males. These findings are related to the mode of formation of the neural tube. Females seem prone to defects of neurulation and males to defects in canalization. An explanation for these findings is suggested in possible sex differences in rate of early embryonic development. 相似文献
15.
Date of conception and prevention of neural tube defects 总被引:1,自引:0,他引:1
Louis Dallaire Serge B. Melancon Michel Potier Jean-P. Mathieu Gilles Ducharme 《Clinical genetics》1984,26(4):304-307
The authors studied the time of conception of 280 fetuses and liveborns with anencephaly or spina bifida seen in a French Canadian population during a period of six years. There is an evident seasonal variation in the conception of NTD fetuses. Using a wave statistical model applied to data recorded over a six year period the authors have rejected the "no variation between the six two-month intervals" hypothesis at a P less than or equal to 0.005 level. It is postulated that, in any vitamin intake or environmental program to prevent NTD in families at risk, one must take into account the annual and seasonal variations, ethnic groups identity and the date of conception in the choice of control mothers. 相似文献
16.
17.
Morin I Devlin AM Leclerc D Sabbaghian N Halsted CH Finnell R Rozen R 《Molecular genetics and metabolism》2003,79(3):197-200
Genetic variants in folate metabolism have been reported to increase risk for neural tube defects (NTD). The first such sequence change was the 677C-->T substitution in methylenetetrahydrofolate reductase (MTHFR), but additional sequence changes have been identified in enzymes or transporters for folates. Two recently identified variants are the 1561C-->T (H475Y) mutation in glutamate carboxypeptidase II (GCPII) and the 80A-->G (H27R) change in the reduced folate carrier RFC-1. We examined a group of mothers of spina bifida offspring, and a group of control women, for the above polymorphisms to assess their impact on NTD risk as well as on homocysteine and nutrient (RBC folate, serum folate, and serum cobalamin) levels. The GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels; homozygous mutant (YY) women were not observed in our study group. The homozygous mutant (RR) genotype for the RFC-1 gene was not associated with a significant difference in NTD risk (OR=1.39, 95% CI=0.55-3.54), but there was a borderline significant (p=0.065) decrease in RBC folate levels, compared with the HH genotype. However, the combination of the RR genotype for RFC-1 and low RBC folate was associated with a significant 4.6-fold increase in NTD risk (OR=4.6, 95% CI=1.47-14.37). Since this small study is the first to demonstrate increased risk for women with the RFC-1 variant for having a child with a NTD, additional larger studies are required to confirm this change as another potential genetic modifier for spina bifida risk. 相似文献
18.
Parle-McDermott A Pangilinan F Mills JL Kirke PN Gibney ER Troendle J O'Leary VB Molloy AM Conley M Scott JM Brody LC 《American journal of medical genetics. Part A》2007,(11):1174-1180
Periconceptional maternal folic acid supplementation can prevent up to 70% of pregnancies affected with neural tube defects (NTDs), including spina bifida. This has focused attention on folate-related genes such as dihydrofolate reductase (DHFR) in a bid to identify the genetic factors that influence NTD risk through either the fetal or maternal genotype. We considered a novel intronic 19-bp deletion polymorphism and two polymorphisms within the 3' untranslated region (721A>T and 829C>T) of the DHFR gene as candidates for NTD risk. We studied NTD cases (n=283), mothers of cases (n=280), fathers of cases (n=279), and controls (n=256). We did not find the DHFR 829C>T polymorphism to be variable within the Irish population. The 19-bp intron deletion and the 721A>T polymorphisms were found to be in linkage disequilibrium. In contrast to a previous study, the 19-bp intron deletion allele did show a significant protective effect in mothers of NTD cases when present in one (relative risk 0.59 [95%CI: 0.39-0.89], P=0.01) or two copies (relative risk 0.52 [95%CI: 0.32-0.86], P=0.01). Analysis of mRNA levels revealed a small increase in expression ( approximately 1.5-fold) associated with the 19-bp intron deletion polymorphism, but this was not significant. In conclusion, the DHFR intron 19-bp deletion allele may be a protective NTD genetic factor by increasing DHFR mRNA levels in pregnant women. 相似文献
19.
Barbara Field 《Journal of medical genetics》1978,15(5):329-338
Cases of spina bifida cystica, encephalocele, and anencephaly occurring over a 9-year period, 1965 to 1973, in New South Wales, Australia, were identified. A low frequency of 1·1 for spina bifida and encephalocele (SB) and 0·9 for anencephaly (A) was found. 相似文献
20.
Frans A Hol Nathalie MJ van der Put Monique PA Geurds Sandra G Heil Frans JM Trijbels Ben CJ Hamel Edwin CM Mariman Henk J Blom 《Clinical genetics》1998,53(2):119-125
It is now well recognized that periconceptional folic acid or folic acid containing multivitamin supplementation reduces the risk of neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the enzyme methylenetetrahydrofolate reductase is associated with an increased risk for spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all folic acid preventable NTDs. In an attempt to identify additional folate related enzymes that contribute to NTD etiology we now studied the methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single protein with three catalytic properties important in the folate metabolism. The cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying spina bifida occulta and the other being unaffected. The second change turned out to be an amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the methylenetetrahydrofolate-dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD. 相似文献