Sib risks of anencephaly and spina bifida in British Columbia

The prevalence at birth of anencephaly or spina bifida cystica among sibs of individuals born in British Columbia with these defects was studied using routinely collected records of morbidity and mortality within the province. The population prevalence of these neural-tube defects in British Columbia is approximately 1.55 per thousand births, lower than in other areas where family studies have been carried out. A total of 1,028 affected individuals born in British Columbia during the period 1952–1970 was ascertained from health and vital documents collected on an ongoing basis by the Division of Vital Statistics of the British Columbia Ministry of Health. Information on the families of these cases was acquired using computer-linked groupings of British Columbia marriage, birth, and stillbirth records. The risk of affected individuals among the sibs was 2.4%, about 15 times the population prevalence at birth. The prevalence among subsequent sibs of the first affected individual in a family was 2.1%. There was no difference in risk when various factors that influence the population incidence of these conditions were considered. The risk of recurrence of either of these anomalies after two previously affected sibs was 4.8%, or double the risk after one affected sib. From these results and those of a recent New York survey of sib risks of neural-tube anomalies it would seem that the risk of anencephaly and spina bifida cystica to sibs of affected cases in North America is approximately half the risk in Great Britain, and it is this lower risk of 2% that should be used for genetic counseling in North America.     

Spinal dysraphism: genetic relation to neural tube malformations.

The families of 207 index patients treated for spinal dysraphism at The Hospital for Sick Children were studied to discover whether the condition was aetiologically related to the classical neural tube malformation--spina bifida cystica and anencephaly. The index patients had all had a tethered conus medullaris and one or more of a variety of anomalies of the spinal cord, vertebrae, or skin overlying the vertebral column. Of 364 sibs of index patients, 9 had an encephaly and 6 spina bifida cystica, a pro-proportion of 4.12%. This approximates to the proportion of sibs affected by neural tube malformations in the London region when the index patients themselves have spina bifida or anencephaly. It is, therefore, appropriate that the mothers of children with spinal dysraphism should be offered prenatal screening for neural tube malformations.     

Are congenital vertebral anomalies and spina bifida cystica aetiologically related?

Radiological records of 104 patients with multiple vertebral anomalies without apparent spina bifida and 112 infants with spina bifida cystica were surveyed and the incidences of hemivertebrae and of rib, vertebral body, and vertebral arch fusions were recorded. The distributions of these four anomalies along the vertebral axis were found not to be statistically different between the two age groups. This is additional evidence to support the hypothesis that multiple vertebral anomalies and anencephaly-spina bifida cystica are aetiologically related.     

Spinal dysraphia as an autosomal dominant defect in four families

Four families were selected randomly on the basis of the occurrence of spina bifida cystica and/or spina bifida occulta in one or more family members. Sixty-three relatives were studied clinically and roentgenologically; their roentgenograms were evaluated blindly. Twenty-eight were clinically and roentgenologically normal; 35 were diagnosed as having spina bifida occulta (SBO), spina bifida cystica (SBC), vertebral anomalies, and/or external defects usually interpreted as evidence for SBO. Excluding one proband we found the frequency of SBO to be 19/51 (37%) and the frequency of all types of spinal/vertebral defects (excluding five probands) to be 30/58 (52%). The distribution of these defects in the four families was analyzed using likelihood methods corrected for random ascertainment. The log likelihood values for sporadic, recessive, and dominant models were ?26.69, ?20.95, and ?18.90, respectively, indicating a higher likelihood of autosomal dominant inheritance than sporadic occurrence or recessive inheritance. The penetrance probability in this dominant model, estimated by maximum likelihood, is 0.749 ± 0.100. Further examination of these data suggests that SBO and SBC represent different expressions of the same dominant gene in these kindreds.     

Risk of recurrence after two children with central nervous system malformations in an area of high incidence.

This study was undertaken to provide an estimate of the recurrence risk of central nervous system (CNS) malformation in families with two or more affected children. The hospital records and the records of the Genetic Counseling Clinics were examined for instances where a child born between 1962 to 1973 had spina bifida and anencephalus and was documented as having an affected elder sib; such children were taken as index patients. Parents of 76 families with 89 index patients were interviewed. Fifty-one index patients had younger sibs; of 85 younger sibs, 12 had spina bifida and six anencephalus (1 in 4.7). Little variation was observed in the proportion of subsequent children affected with the type of lesion in the index patient and the affected older sib. Ten index patients with two older affected sibs had 14 subsequent sibs of whom four had a CNS malformation (1 in 3.5). For the purpose of genetic counselling it was suggested that the risk after two and three children with CNS malformations in Northern Ireland was 1 in 5 and 1 in 4, respectively.     

Sib risk of neural tube defect: is prenatal diagnosis indicated in pregnancies following the birth of a hydrocephalic child?

Recurrence frequencies of central nervous system malformations in sibs of probands with anencephalus or spina bifida range between 1% and 7%. The frequency of hydrocephalus among sibs of such probands is low (0.21%) but, nevertheless, is increased 2 to 5-fold when compared to general population frequencies. Anencephalus and spina bifida cystica were observed in 1.65% of sibs of children with hydrocephalus, a 2- to 8-fold increased over the population frequencies. These data indicate that some aetiological factors may be common to all three malformations. The risk figure of 1.65% for anencephalus and spina bifida in sibs born after the birth of a hydrocephalic proband constitutes sufficient indication for prenatal diagnosis by alphafetoprotein determination of the amniotic fluid.     

A family study of spina bifida and anencephalus in Belfast, Northern Ireland (1964 to 1968).

The parents of 226 of the 360 patients with anencephalus or spinal bifida or both, born in Belfast 1964 to 1968, were visited to document the occurrence of these malformations among other relatives. The proportions of sibs with anencephalus and spina bifida were 10.41% for spina bifida index patients and 6.4% for anencephalus. For patients born after the index patients, the proportions were 12.19% and 6.35%, respectively. The overall incidence of either malformation among sibs was 8.87%. This estimate is higher than the 4 to 5% commonly reported and is probably related to the specific background of the Northern Ireland population, which is known to have the highest incidence of CNS malformations in the United Kingdom. The substantial size of this risk indicates the importance of amniocentesis for monitoring subsequent pregnancies of women who have had one child with a CNS malformation.     

Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts?

Abnormalities in folate and/or homocysteine metabolism may adversely influence embryonic development, leading to the birth of infants with a variety of congenital malformations, including neural tube defects (NTDs) and craniofacial abnormalities. Based upon suggestive evidence that periconceptional folic acid supplementation is effective in preventing a significant proportion of the aforementioned birth defects, genetic variation in the folate biosynthetic pathways may influence the infant's susceptibility to these birth defects. The goal of our study was to investigate sequence variations in the betaine-homocysteine methyltransferase (BHMT) and betaine-homocysteine methyltransferase (BHMT2) genes as modifiers of risk of spina bifida, cleft palate, and cleft lip and palate. The results of this study indicated that individuals homozygous for the single nucleotide polymorphism R239Q in BHMT did not have elevated risks for spina bifida. Genotype frequencies for the BHMT2 rs626105 polymorphism also did not reveal any elevated risks for spina bifida, and only a modest, imprecise elevation of risk for orofacial clefts. The results of these experiments suggest that variants of the BHMT/BHMT2 genes in infants do not substantially contribute to the risk of spina bifida or orofacial clefts in our study population.     

Possible causal heterogeneity in spina bifida cystica

A study was performed to determine whether causal heterogeneity can be demonstrated among the nonsyndromal spina bifida cysticas based on the vertebral level of the defect. Two groups were compared, probands with defects at or above T 11, likely representing defects of neuralization, and probands with defects at or below T 12, likely defects of canalization. Differences between the two groups were found with respect to reproductive history and occurrence of other malformations. A high degree of concordance for the type of defect among affected sib pairs was also observed. These findings indicate that there is probably heterogeneity within the spina bifida cysticas based on the level of the defect.     

The Neu-Laxova syndrome

A study was performed to determine whether causal heterogeneity can be demonstrated among the nonsyndromal spina bifida cysticas based on the vertebral level of the defect. Two groups were compared, probands with defects at or above T 11, likely representing defects of neuralization, and probands with defects at or below T 12, likely defects of canalization. Differences between the two groups were found with respect to reproductive history and occurrence of other malformations. A high degree of concordance for the type of defect among affected sib pairs was also observed. These findings indicate that there is probably heterogeneity within the spina bifida cysticas based on the level of the defect.     

A family showing apparent X linked inheritance of both anencephaly and spina bifida.

A family is reported which includes five males, two with spina bifida, two sibs with anencephaly, and one with both high and low spinal lesions. The affected subjects came from four sibships in three generations. The mode of inheritance of these neural tube defects is consistent with X linkage.     

Adverse reproductive outcomes among pregnancies of aunts and (spouses of) uncles in Irish families with neural tube defects

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.     

Morphology of experimental spina bifida in the chick embryo.

Open malformations of the central nervous system may involve the brain or spinal cord, or both. Preliminary experiments in which a window was cut in the shell overlying early chick embryos (with removal of 2 ml of albumen) produced a range of neural and non-neural malformations. Exposure of Stage 5--10 embryos at 26 hours of incubation produced open brain and cord defects. Embryos were recovered at 11--12 days for gross examination. Open cord defects in 12 day experimental embryos could be divided morphologically into 2 types. One group showed an everted symmetrical plaque of neural tissue. In the other group the cord defect was more irregular, partly covered by skin, and often combined with rump and trunk defects. Skeletal staining showed that vertebral lesions increased in severity in a cranio-caudal sequence. Spina bifida occulta was found in the cervical and upper thoracic regions; spina bifida manifesta, associated with open cord defects, occurred from the lower thoracic to the sacral regions; vertebral deletions were almost confined to the caudal region. Spina bifida manifesta at the site of open cord defects also showed 2 distinct patterns. Regular cord defects were associated with regular spinal defects, showing loss of spinous processes, reduction of laminae and eversion of the pedicles. Irregular cord defects were associated with more irregular spinal defects showing vertebral deletions or fusions, rumplessness, and pelvic reduction. Neither group, however, showed local kyphosis or scoliosis. Early neurogenesis in the avian and human embryos is very similar with development of the spinal cord from neural plate and tail bud materials which fuse in an overlap zone. These experimental defects in the chick embryo, separable into regular and irregular types thus provide a useful model for investigation of the embryogenesis of spina bifida.     

Non-multifactorial neural tube defects

Although most neural tube defects (anencephaly, spina bifida) occur as isolated malformations, a substantial proportion are attributable to chromosome anomalies, known teratogens, or component manifestations of multiple anomaly syndromes. This review describes known chromosome alterations and the candidate genes residing in the altered region, as well as syndromes associated with neural tube defects and causative genes, if known.     

A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida

Folate binding protein 1 (Folr1) knockout mice with low maternal folate concentrations have been shown to be excellent animal models for human folate-responsive neural tube defects (NTDs). Previous studies using the Folr1 knockout mice revealed that maternal folate supplementation up-regulates the expression of the PCMT1 gene in Folr1 nullizygous neural tube tissue during neural tube closure. PCMT1 encodes the protein repair enzyme l-isoaspartate (d-aspartate) O-methyltransferase (PIMT) that converts abnormal d-aspartyl and l-isoaspartyl residues to the normal l-aspartyl form. PIMT is known to protect certain neural cells from Bax-induced apoptosis. Pcmt1-deficient mice present with abnormal AdoMet/AdoHcy homeostasis. We hypothesized that a known functional polymorphism (Ile120Val) in the human PCMT1 gene is associated with an increased risk of folate-responsive human NTDs. A case-control study was conducted to investigate a possible association between this polymorphism and risk of spina bifida. Compared to the Ile/Ile and Ile/Val genotypes, the homozygous Val/Val genotype showed decreased risk for spina bifida (adjusted odds ratio=0.6, 95% confidence interval: 0.4-0.9). Our results showed that the Ile120Val polymorphism of PCMT1 gene is a genetic modifier for the risk of spina bifida. Val/Val genotype was associated with a reduction in risk for spina bifida.     

Influencing clinical practice regarding the use of antiepileptic medications during pregnancy: Modeling the potential impact on the prevalences of spina bifida and cleft palate in the United States

Selected antiepileptic drugs (AEDs) increase the risk of birth defects. To assess the impact of influencing AED prescribing practices on spina bifida and cleft palate we searched the literature for estimates of the association between valproic acid or carbamazepine use during pregnancy and these defects and summarized the associations using meta-analyses. We estimated distributions of the prevalence of valproic acid and carbamazepine use among women of childbearing age based on analyses of four data sets. We estimated the attributable fractions and the number of children born with each defect that could be prevented annually in the United States if valproic acid and carbamazepine were not used during pregnancy. The summary odds ratio estimate for the association between valproic acid and spina bifida was 11.9 (95% uncertainty interval (UI): 4.0–21.2); for valproic acid and cleft palate 5.8 (95% UI: 3.3–9.5); for carbamazepine and spina bifida 3.6 (95% UI: 1.3–7.8); and for carbamazepine and cleft palate 2.4 (95% UI: 1.1–4.5) in the United States. Approximately 40 infants (95% UI: 10–100) with spina bifida and 35 infants (95% UI: 10–70) with cleft palate could be born without these defects each year if valproic acid were not used during pregnancy; 5 infants (95% UI: 0–15) with spina bifida and 5 infants (95% UI: 0–15) with cleft palate could be born without these defects each year if carbamazepine were not used during pregnancy. This modeling approach could be extended to other medications to estimate the impact of translating pharmacoepidemiologic data to evidence-based prenatal care practice. Published 2011 Wiley-Liss, Inc.     

Risk factors associated with neural tube defects

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.     

Body wall defects in two sibs

We describe 2 sibs, a male fetus with an unusual lumbar hernia and spina bifida occulta, and a female fetus with a median abdominoschisis. The first fetus had some signs of lumbocostovertebral syndrome (LCVS), which consists of a congenital lumbar hernia and associated abnormalities such as absent or hypoplastic ribs, hemivertebrae, and scoliosis. Abdominoschisis has not been described in LCVS, and the given abnormalities in the 2 sibs have not been published to date. One can hypothesize that vascular disruption of a somite or a group of somites may result in the described abdominal wall defects. We conclude that these abnormalities could be coincidental in the 2 sibs or could have a related, probably multifactorial, cause. Am. J. Med. Genet. 73:15–18, 1997. © 1997 Wiley-Liss, Inc.     

HLA Gene and Haplotype Frequencies in Spina Bifida. Population and Family Studies

The search for HLA association in spina bifida is particularly interesting since this condition can be associated with the effects of the T locus in mice. Gene and haplotype frequencies in 32 unrelated patients suffering from spina bifida were studied. Gene frequency of HLA—B5 and haplotype frequency of A2, B5 were increased without reaching signification levels. Fourteen families were examined clinically and radiologically. A high frequency of spina bifida occulta and other vertebral abnormalities was found without evidence of linkage with HLA haplotypes.