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PubMed2005

Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association.

Methionine synthase reductase (MTRR) regenerates methylated cobalamin levels from the oxidised cob(II)alamin form and in so doing plays a crucial role in maintaining the active state of methionine synthase (MTR). MTR is an essential enzyme catalyzing the conversion of homocysteine to methionine. Single nucleotide polymorphisms (SNPs) within the MTRR gene may potentially compromise MTR activity leading to elevated homocysteine levels, a known risk factor for neural tube defects (NTDs). We studied the MTRR polymorphisms I22M (66A-->G), S175L (524C-->T), and K350R (1049A-->G) as potential NTD risk factors in a large homogeneous Irish NTD population. Degree of risk was assessed via case/control comparison, log-linear analysis, and transmission disequilibrium testing. No association was found between NTDs and I22M in mothers (p = 0.16, OR1.14 [0.95-1.38], n = 447) or cases (p = 0.13, OR1.15 [0.96-1.38], n = 470) compared to controls (n = 476). A dominant I22M paternal effect was found through case/control comparison and log-linear modelling (p = 0.019) (goodness-of-fit p=0.91, OR 1.46 [1.10-1.93], n = 423). No significant NTD association was found with S175L or K350R in cases or their parents and no interactions were observed between these polymorphisms and the D919G variant of MTR or the A222V variant of 5,10-methylenetetrahydrofolate reductase (MTHFR). We also compared the frequencies of I22M, S175L, and K350R in African-Americans versus American-Caucasians. The frequencies of I22M and K350R differed significantly between the two groups (p = 0.0005 and p = 0.0001, respectively). Our findings do not support an important role for these MTRR variants in NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2004

Vitamin supplements and the risk for congenital anomalies other than neural tube defects.

Randomized trials, supported by many observational studies, have shown that periconceptional use of folic acid, alone or in multivitamin supplements, is effective for the primary prevention of neural tube defects (NTDs). Whether this is true also for other congenital anomalies is a complex issue and the focus of this review. It is useful to consider the evidence not only for specific birth defects separately but, importantly, also for all birth defects combined. For the latter, the Hungarian randomized clinical trial indicated, for periconceptional multivitamin use, a reduction in the risk for all birth defects (odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.35-0.70), even after excluding NTDs (OR = 0.53, 95% CI = 0.38-0.75). The Atlanta population-based case-control study, the only large observational study to date on all major birth defects, also found a significant risk reduction for all birth defects (OR = 0.80, 95% CI = 0.69-0.93) even after excluding NTDs (OR = 0.84, 95% CI = 0.72-0.97). These and other studies also evaluated specific anomalies, including those of the heart, limb, and urinary tract, as well as orofacial clefts, omphalocele, and imperforate anus. For cardiovascular anomalies, two studies were negative, whereas three, including the randomized clinical trial, suggest a possible 25-50% overall risk reduction, more marked for some conotruncal and septal defects. For orofacial clefts, six of seven case-control studies suggest an apparent reduced risk, which could vary by cleft type and perhaps, according to some investigators, by pill dosage. For limb deficiencies, three case-control studies and the randomized trial estimated approximately a 50% reduced risk. For urinary tract defects, three case-control studies and the randomized trial reported reduced risks, as did one study of nonsyndromic omphalocele. All these studies examined multivitamin supplement use. With respect to folic acid alone, a reduced rate of imperforate anus was observed among folic acid users in China. We discuss key gaps in knowledge, possible avenues for future research, and counseling issues for families concerned about occurrence or recurrence of these birth defects.

Adult↗
PubMed1977

Prenatal diagnosis of neural tube defects. III. A reevaluation of the alpha-fetoprotein assay.

Alpha-fetoprotein was measured in 2209 amniotic fluid samples under improved assay conditions. All cases of open neural tube defects had elevated values greater than 5 SD above the mean. The false positive rate based on the 3 SD cutoff is estimated at less than 9.15%. Alpha-fetoprotein assays are recommended for all patients undergoing second trimester amniocentesis, optimally between 14 and 16 weeks' gestation.

Adult↗
PubMedDate not supplied

Neural tube defects in New South Wales: management and preventive policies, 1965-1980.

This paper reviews the results of the programme of antenatal testing and selective termination of fetuses with anencephaly and spina bifida in New South Wales over the last eight years. It discusses the problems associated with pregnancy screening, with reference to those involved in selection for treatment of newborn infants with spina bifida. The incidence of neural tube defects has been declining, and this, although possibly the result of early termination of affected fetuses, may have its basis in a worldwide trend. Preventive action based on a more precise understanding of aetiological factors will further decrease the incidence, thereby reducing the load of long-term handicapped survivors.

Abortion, Legal↗
PubMed1985

Ventricular shunt survival in children with neural tube defects.

Ventricular shunting has dramatically improved the care of children with hydrocephalus. Yet shunt malfunctions are extremely common and cause significant morbidity. To document shunt problems in children with a neural tube defect and hydrocephalus, 67 children born since 1973 were studied via life-table analysis. 28% of the shunts failed within the first 6 months after insertion, 37% failed within the first year and 50% failed by 4 1/2 years after insertion. Shunt survival was similar in children whether or not they had previous shunt failures. The brand of shunt system and pressure rating, the level of neurological function, the interval between closure of the neural tube lesion and shunt insertion, and head circumference percentile at the time of insertion were also not correlated with shunt failure. However, shunts inserted in the first year of life were much more likely to fail than those inserted after one year of age (p less than 0.05). 68% of the revisions required replacement of the ventricular catheter. Shunt failure from all causes of hydrocephalus accounted for approximately 1% of paediatric admissions to Strong Memorial Hospital in 1982 with a mean cost of $4,543 and a mean length of stay of 9 days. Thus shunt problems remain both common and serious.

Age Factors↗
PubMed1994

Split hand/split foot, syndactyly, urinary tract obstruction, radial, diaphragmatic, and neural tube defects: Czeizel-Losonci syndrome?

We report on a baby girl with absence of the left hemidiaphragm, lumbosacral myelomeningocele, syndactyly with limb deficiencies, and bilateral hydronephrosis. A similar array of malformations was described previously by Czeizel and Losonci [Hum Genet 77:203-204, 1987] in a single family which showed a transmission pattern suggesting autosomal dominant inheritance with variable expressivity. The presence of limb abnormalities and the location of the neural tube defects in these cases suggest that the underlying pathogenesis probably does not involve the same disturbances of midline field development which have been postulated to occur in the schisis association.

Abnormalities, Multiple↗
PubMed1980

Antenatal attendance and screening for neural tube defects.

An analysis of factors influencing the time of booking at seven hospital antenatal clinics in one Health Authority Area showed that only 52.5 per cent of patients booked before 16 weeks gestation and 78.9 per cent before 19 weeks gestation. The principle reasons for late booking were delay in the patient seeking medical advice and delay in referral to hospital by the general practitioner (GP) after pregnancy was confirmed. Possibilities for improving early attendance and hence implementing an effective screening programme for the detection of neural tube defects are discussed.

Appointments and Schedules↗
PubMed1981

A cost-benefit analysis of prenatal detection of Down syndrome and neural tube defects in older mothers.

Infants of older mothers have an increased risk of Down syndrome. As public awareness of this disorder increases, so does the number of women requesting prenatal diagnosis for advanced maternal age. A cost-benefit analysis was done to determine the maternal age for which screening for Down syndrome is cost-beneficial. The analysis took into account the cases of neural tube defects which would be detected "incidentally" on amniocentesis, as all amniotic fluid samples have alpha fetoprotein levels measured. British Columbia (B.C.) provides a unique opportunity for such a study: single-year maternal age risk figures for Down syndrome based on virtually complete ascertainment are available; the Department of Medical Genetics Prenatal Diagnosis Clinic is the main referral centre for the province; B.C. has a universal medicare system which facilitates the calculation of medical costs and gives all women financially equal access to prenatal diagnosis. The study concludes that prenatal screening for Down syndrome is cost beneficial for women 34 years old or older at conception. A discount rate of 14% was chosen for this analysis and the effect of such a rate on the results is discussed.

Cost-Benefit Analysis↗
PubMed1989

[The determination of acetylcholinesterase activity in amniotic fluid as a further possibility for the prenatal diagnosis of open neural tube defects].

A method for the determination of the activity of acetylcholinesterase (AChE) in amniotic fluid is developed. In connection with other AChE-determination methods for blood quinidine sulphate in a concentration of 2.10(-5) mol/l is used as an inhibitor for the serum-cholinesterase (ChE). With amniotic fluid samples of 162 gravidities are established preliminary limits of reference ranges. The hitherto existing experiences showed that values below the 90. percentile can be classified as normally, above the 99. percentile as pathological findings. This method is to consider among the ultrasonographical examination and the measurement of alpha-fetoprotein in serum and amniotic fluid as a further diagnosis confirming part on the suspicion of the presence of open neural tube defects.

Acetylcholinesterase↗
PubMed1993

Protection by acetylsalicylic acid against hyperglycemia-induced glycation and neural tube defects in cultured early somite mouse embryos.

The embryopathic effects of hyperglycemia have been established in rodent embryos maintained in whole embryo culture during neurulation. This study addressed the possibility that the hyperglycemia-mediated teratogenic effects are associated with increased concentrations of glycated embryonic protein. Early somite mouse embryos were cultured in 50 mmol/l glucose for 48 h and subsequently demonstrated growth retardation and severe neural malformations. Incubation with 0.005 mmol/l acetylsalicylic acid, an effective anti-glycation agent, was partially protective against hyperglycemia-induced growth retardation, neural tube defects as well as the deleterious effects on the morphological development of specific tissues. Furosine measurements indicated that acetylsalicylic acid reduced individual embryonic concentrations of glycated protein in both hyperglycemic and normoglycemic embryos. Also, the total morphological score, somite number, head length and the forebrain morphological rating of individual embryos were negatively correlated with their tissue furosine content. The results indicate the possibility that hyperglycemia during embryo culture causes dysmorphogenesis via enhanced production of glycated embryonic proteins and that the protective action of acetylsalicylic acid could be mediated by its anti-glycation properties.

Animals↗
PubMed1981

The use of amniotic fluid AFP action limits in diagnosing open neural tube defects.

An analysis is made of alphafetoprotein (AFP) concentrations in 3630 amniotic fluids submitted for prospective prenatal diagnoses over a 7-year period. There were 89 cases of anencephaly, 74 of open spina bifida and 3467 with normal singleton outcomes. The AFP data were expressed in both standard deviations above the mean and multiples of the normal median for individual weeks of gestation. False positive and false negative rates were comparable in the two systems at selected cut-offs. It is concluded that either system may be used in setting action limits for the primary distinction of unaffected pregnancies from those in which an open neural tube defect is present.

Amniotic Fluid↗
PubMed2005

Maternal fumonisin exposure and risk for neural tube defects: mechanisms in an in vivo mouse model.

BACKGROUND: Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, a common contaminant of corn worldwide. FB1 disrupts sphingolipid biosynthesis by inhibiting the enzyme ceramide synthase, resulting in an elevation of free sphingoid bases and depletion of downstream glycosphingolipids. A relationship between maternal ingestion of FB1-contaminated corn during early pregnancy and increased risk for neural tube defects (NTDs) has recently been proposed in human populations around the world where corn is a dietary staple. The current studies provide an in vivo mouse model of FB1 teratogenicity. METHODS: Pregnant LM/Bc mice were injected with increasing doses of FB1 on GD 7.5 and 8.5, and exposed fetuses were examined for malformations. Sphingolipid profiles and (3)H-folate concentrations were measured in maternal and fetal tissues. Immunohistochemical expression of the GPI-anchored folate receptor (Folbp1) and its association with the lipid raft component, ganglioside GM1, were characterized. Rescue experiments were performed with maternal folate supplementation or administration of gangliosides. RESULTS: Maternal FB1 administration (20 mg/kg of body weight) during early gestation resulted in 79% NTDs in exposed fetuses. Sphingolipid profiles were significantly altered in maternal and embryonic tissues following exposure, and (3)H-folate levels and immunohistochemical expression of Folbp1 were reduced. Maternal folate supplementation partially rescued the NTD phenotype, whereas GM1 significantly restored folate concentrations and afforded almost complete protection against FB1-induced NTDs. CONCLUSIONS: Maternal FB1 exposure altered sphingolipid metabolism and folate concentrations in LM/Bc mice, resulting in a dose-dependent increase in NTDs that could be prevented when adequate folate levels were maintained.

Animals↗
PubMed1997

Spinal and cranial neural tube defects.

Developmental lesions of the central nervous system with failure of normal midline fusion are often referred to as being dysraphic and vary from inapparent and insignificant to a massive deformity incompatible with survival. Several different schemata are used to classify this wide variety and often complex set of malformations; however, the nomenclature is confusing and even contradictory. As most of these congenital lesions of clinical significance involve an aberration in the formation of the neural tube, it is suggested that the term neural tube defects (NTD) be used to characterize this entire group of anomalies. From a practical clinical standpoint, NTD can be subdivided into three main groupings: open spinal NTD, closed spinal NTD, and cranial NTD. This article briefly covers the epidemiology, embryology, classification, clinical presentation, and management of this group of congenital lesions.

Case Management↗
PubMed2003

Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation.

Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifida than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.

Abnormalities, Drug-Induced↗
PubMed2003

The H475Y polymorphism in the glutamate carboxypeptidase II gene increases plasma folate without affecting the risk for neural tube defects in humans.

In the diet, folate exists predominantly in the form of polyglutamates. Before absorption, these polyglutamates must be deconjugated to monoglutamates by the enzyme folylpoly-gamma-glutamate carboxypeptidase (FGCP), which is located in the jejunum. Recently, a H475Y polymorphism in the glutamate carboxypeptidase II (GCPII) gene, encoding the FGCP enzyme, was reported to be associated with decreased plasma folate and increased plasma homocysteine (tHcy) levels. Low folate and elevated tHcy levels are risk factors for neural tube defects (NTD). Therefore, we examined whether this polymorphism is associated with NTD risk and plasma folate, erythrocyte folate and plasma tHcy levels in 96 NTD patients, 113 mothers, 97 fathers and 101 controls. This variation was associated with increased plasma folate (P < 0.04) and tended to be associated with decreased plasma tHcy (P < 0.09). It was not associated with erythrocyte folate or the risk for NTD. The H475Y polymorphism in the GCPII gene may increase the deconjugation activity of the FGCP enzyme, resulting in an increased absorption of folate in the body, as reflected by the increased plasma folate and decreased plasma homocysteine concentrations.

Adolescent↗
PubMed1988

Con A non-reactive fractions of human amniotic fluid alpha-fetoprotein in prenatal diagnosis of fetal neural tube defects and fetal abdominal wall defects. Predictive values, sensitivity, and specificity, and comparison to acetylcholinesterase and ultrasound scanning.

During a 6-year period 19,647 consecutively received amniotic fluid samples were analyzed for the alpha-fetoprotein (AFP) concentration. In samples with an AFP concentration above the 95% upper normal limit the fraction of AFP non-reactive with concanavalin A (con A) was determined by crossed affinity immunoelectrophoresis. Of 436 samples from normal pregnancies with a moderate elevation of AFP (between the 95% limit and 2.5 times the median) the con A fraction was normal in 92 to 98% of the cases, depending on the gestational age. At significantly elevated AFP concentrations (above 2.5 times the median), the fractions were normal in 78% of the 50 cases with a normal outcome. In 80 of 89 cases of fetal malformations, abnormally low fractions were found, and in all 19 cases of abdominal wall defects and congenital nephrosis the fractions were low. No significant difference was found in the sensitivity for detection of fetal malformations by con A analysis compared to quantitative analysis for acetylcholinesterase (AChE). However, significantly more false positive results were found in normal pregnancies for the con A analysis compared to the AChE analysis. Both analyses performed significantly better than ultrasound scanning in terms of sensitivity. It is concluded that AChE is the test of choice in prenatal diagnosis of fetal neural tube defects. However, a sensitivity of 1.00 and a predictive value of a negative test of 1.00 were found for the con A analysis for fetal abdominal wall defects. The AchE analysis performed less well in this context.

Abdominal Muscles↗