Modeling anterior development in mice: Diet as modulator of risk for neural tube defects.

Kappen C. (2013). Modeling anterior development in mice: Diet as modulator of risk for neural tube defects.  American Journal of Medical Genetics Part C Seminars in Medical Genetics. 163(4):333-56. doi: 10.1002/ajmg.c.31380. Epub 2013 Oct 4.

Abstract

Head morphogenesis is a complex process that is controlled by multiple signaling centers. The most common defects of cranial development are craniofacial defects, such as cleft lip and cleft palate, and neural tube defects, such as anencephaly and encephalocoele in humans. More than 400 genes that contribute to proper neural tube closure have been identified in experimental animals, but only very few causative gene mutations have been identified in humans, supporting the notion that environmental influences are critical. The intrauterine environment is influenced by maternal nutrition, and hence, maternal diet can modulate the risk for cranial and neural tube defects. This article reviews recent progress toward a better understanding of nutrients during pregnancy, with particular focus on mouse models for defective neural tube closure. At least four major patterns of nutrient responses are apparent, suggesting that multiple pathways are involved in the response, and likely in the underlying pathogenesis of the defects. Folic acid has been the most widely studied nutrient, and the diverse responses of the mouse models to folic acid supplementation indicate that folic acid is not universally beneficial, but that the effect is dependent on genetic configuration. If this is the case for other nutrients as well, efforts to prevent neural tube defects with nutritional supplementation may need to become more specifically targeted than previously appreciated. Mouse models are indispensable for a better understanding of nutrient-gene interactions in normal pregnancies, as well as in those affected by metabolic diseases, such as diabetes and obesity. © 2013 Wiley Periodicals, Inc.

 

PMID:24124024

Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their

Ratan SK, Rattan KN, Pandey RM, Singhal S, Kharab S, Bala M, Singh V, Jhanwar A. (2008) Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls. Pediatric Surgery International. Jul;24(7):803-8.

Department of Pediatric Surgery, Pandit BD Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India. drjohnsimmi@yahoo.com

The aim of this study is to evaluate the folate, vitamin B12, fluoride and homocysteine levels in newborns with neural tube defect (NTD) and their parents. The study included 35 neonates with NTD and their parents, 31 neonates with congenital anomalies other than NTD formed control 1, 24 neonates with no anomalies, with the highest birth order and normal siblings formed control 2. These groups matched for socio-economic and nutritional status. Demographic, antenatal history, parental habits, folate (RBC, whole blood and serum), serum vitamin B12 and homocysteine levels were estimated using chemiluminescence technology. Chi-square test was used to assess association between factors and the outcome. One-way ANOVA was used to compare means in the three groups. To determine the risk factors for NTD, odds ratios (95% CI) was computed using bivariate and multivariate logistic regression analysis (STATA 9.0). No difference was found between NTD group and 'control 1' group. The fathers in NTD group had significantly lower folate and vitamin B12 and a higher homocysteine, in comparison to 'control 2' group (i.e. with normal babies). The babies with NTD had higher homocysteine while their mothers had significantly low folate levels in comparison to 'control 2' mothers. Low RBC folate, low serum vitamin B12 and high plasma homocysteine in both the parents had an association with NTD. Multivariate logistic regression revealed high homocysteine of father as the only independent significant risk factor [OR(95% CI):2.6(2.6, 226)] for NTD and also for other anomalies. NTD (and other congenital anomalies) may not only be due to nutritional deficiency in the mothers but also due to more intricate gene-nutrient interaction defects in the affected families, probably some abnormal folate-homocysteine metabolism. These defects seem to be affect the fathers more severely and in all likelihood, get transmitted to the babies from either or both the parents. The emergence of father's serum homocysteine levels as an independent risk factor for NTD and also other congenital anomalies calls for further studies to evaluate if this can be taken as a marker for congenital anomalies in the fetus during antenatal screening.

PMID: 18463884

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects.

Deak KL, Siegel DG, George TM, Gregory S, Ashley-Koch A, Speer MC; NTD Collaborative Group. (2008) Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects. Birth defects research. Part A, Clinical and molecular teratology. 2008 Oct;82(10):662-9.

Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA.

BACKGROUND: Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.

METHODS: We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types.

RESULTS: Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04-0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04).

CONCLUSIONS: Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.

PMID: 18937341

High prevalence of NTDs in Shanxi Province: a combined epidemiological approach.

Gu X, Lin L, Zheng X, Zhang T, Song X, Wang J, Li X, Li P, Chen G, Wu J, Wu L, Liu J.
High prevalence of NTDs in Shanxi Province: a combined epidemiological approach. Birth Defects Research, Part A: Clinical and Molecular Teratology. 2007 Oct;79(10):702-7.

BACKGROUND: Shanxi Province has historically reported a high prevalence of NTDs. In order to establish baseline rates for NTDs and discuss the risk factors associated with sociodemographic, maternal characteristics, and geographic factors, we performed the present study using an approach combining population and hospital-based methodologies.

METHODS: We used chi(2) and Fisher's exact tests to evaluate variation in the prevalence by selected covariates and computed crude ORs and 95% CIs. Adjusted odds ratios (AORs) were performed using logistic regression with all the covariates included in the model.

RESULTS: The overall NTD prevalence during the 3 year study period was 199.38 per 10,000 births, with a higher NTD prevalence clustered in 46 villages within this geographic area. However, no statistical significance was found between NTD prevalence and the elevation of the villages or their distance from coal plants. AORs revealed women aged 20 and above had a lower risk of NTDs compared to those younger than 20 (AOR range 0.4-0.5). A higher risk of NTDs was observed among female infants (AOR 1.50; 95% CI: 1.04-2.17), women with four or more previous births (AOR 2.80; 95% CI: 1.20-6.52), and a previous history of birth defects (AOR 3.23; 95% CI: 1.46-7.12).

CONCLUSIONS: This study has documented a high prevalence of NTDs in Shanxi. Similar variations to other reports were found in the risk of NTDs by maternal demographic characteristics and a clustering of NTDs in certain villages that require further exploration.

PMID: 17729293

Risk of recurrence in major central nervous system malformations between 1976 and 2005

Joo JG, Beke A, Papp Z, Csaba A, Rab A, Papp C. Risk of recurrence in major central nervous system malformations between 1976 and 2005. Prenatal Diagnosis. 2007 Aug 13; [Epub ahead of print]

OBJECTIVE: The goal of the current publication is to review isolated central nervous system malformations (CSMs) using a database in excess of 75 000 cases, with special regard to the risk of recurrence of these malformations alone or in combination.

METHODS: In the period between 1 January 1976 and 31 December 2005, among the 75 320 documented cases, consultations were requested due to earlier isolated CSMs in the patients' histories in 3030 cases (4.2%). Processing the data we only considered disorders of genetic origin, and that was why we excluded the cases due to intrauterine infection. Monogenically inherited malformations were also excluded from the analysis. The diagnosis of the malformations was based on the prenatal diagnosis of ultrasonography as well as the findings of the foetopathological examination.

RESULTS: In 65% of the cases, the couples sought counselling because of malformation in a previous pregnancy. In these cases, the risk of recurrence was thought to be 5.2%, while in the case of two affected children this figure stood at 21.9%. Analysing the values for the risk of recurrence in 5-year periods, neural tube defects (NTDs) (particularly anencephaly and spina bifida) showed a detectable decrease, which could be attributed to a growing use of folic acid supplementation around the time of conception and during pregnancy.

CONCLUSION: There is a clear decrease of risk of recurrence of NTDs, while in the case of the other CSMs in this study, there is no noteworthy chronological change in their risk of recurrence. Copyright (c) 2007 John Wiley & Sons, Ltd.

PMID: 17694579