Association of the 677C-->T mutation on the methylenetetrahydrofolate reductase gene in Turkish patients with neural tube defects

We report the analysis of the 677C-->T mutation on the 5, 10-methylenetetrahydrofolate reductase gene in Turkish controls and cases of neural tube defects. Mutation analysis of 91 patients with neural tube defects, 72 mothers, 63 fathers, and 93 healthy controls has been made by polymerase chain reaction and allele specific restriction digestion with Hinf I. We did not find a significant difference in the 677C-->T allele and genotype distribution among the patients with neural tube defects, their parents, and the control group. This result suggests that another mutation in the folate-related enzyme genes could be responsible for neural tube defects in Turkey. None of the mothers of patients with neural tube defects was advised to use folic acid as recommended to prevent neural tube defects. An immediate attempt to establish an education program for healthcare providers and women of childbearing age is crucial in Turkey. Furthermore, fortification of foods with folate would be a better approach.     

Impaired predictability: enhanced fluctuations in the parenting behaviour of mothers of pre-school children with clinical diagnoses across three different play tasks

Fluctuations in parenting behaviour are thought to be important for the development of child psychopathology. This study focusses on fluctuations in the parenting behaviour of mothers with 3–6-year-old children with a clinical diagnosis according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) (N = 39) and compared them with a control group of mothers with children without a clinical diagnosis (N = 41). In a laboratory setting, we compared the quality of mother–child interactions between both groups using three increasingly challenging co-operation tasks. At first, the mother and child interacted via a free play task. They then co-operated within a constructional play task and finally within a challenging problem-solving task. We analysed the mothers’ parenting behaviour using the Laboratory Parenting Assessment Battery (LAB-PAB) and children’s problem behaviours by means of their mothers’ rating using the Child Behavior Checklist 1 ½–5 (CBCL). The results corroborated our hypotheses. Mothers of the group of children with clinical diagnoses had a lower parenting quality and higher fluctuations in parenting behaviour across situations compared with the non-clinical group. Further analysis revealed that specific fluctuations in maternal involvement and hostility uniquely predicted child psychopathology, measured with the CBCL, showing incremental validity of fluctuations in maternal involvement, when controlling for parenting quality and maternal difficulties in emotion regulation, measured with the Difficulties in Emotional Regulation scale. The results are discussed in terms of their implications for clinical interventions, as well as theoretical implications and future research.

     

Association of DRD4 polymorphism with severity of oppositional defiant disorder,separation anxiety disorder and repetitive behaviors in children with autism spectrum disorder

The objective was to examine whether a common polymorphism in the dopamine D4 receptor gene (DRD4) might be a potential biomarker for behavioral variation within the autism spectrum disorder clinical phenotype. Children (N = 66) were evaluated with a validated mother‐ and teacher‐completed DSM‐IV‐referenced rating scale. Partial eta‐squared (ηp²) was used to gauge the magnitude of group differences: 0.01?0.06 = small, 0.06?0.14 = moderate and > 0.14 = large. Children who were 7‐repeat allele carriers had more severe oppositional defiant disorder behaviors according to mothers’ (ηp² = 0.10) and teachers’ (ηp² = 0.06) ratings than noncarriers, but the latter was marginally significant (P = 0.07). Children who were 7‐repeat allele carriers also obtained more severe maternal ratings of tics (ηp² = 0.07) and obsessions–compulsions (ηp² = 0.08). Findings for maternal ratings of separation anxiety were marginally significant (P = 0.08, ηp² = 0.05). Analyses of combined DRD4 and dopamine transporter gene (DAT1) genotypes approached significance (P = 0.05) for teachers’ ratings of oppositional behavior and mothers’ ratings of tics. DRD4 allelic variation may be a prognostic biomarker for challenging behaviors in children with autism spectrum disorder, but these exploratory findings remain tentative pending replication with larger independent samples.     

Presence of the 5,10-methylenetetrahydrofolate reductase C677T mutation in Puerto Rican patients with neural tube defects

Folic acid supplementation can reduce the incidence of neural tube defects. The first reported genetic risk factor for neural tube defects is a C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme. We examined the enzyme mutation role of methylenetetrahydrofolate reductase in the etiology of neural tube defects in our population. The study group consisted of 204 Puerto Rican individuals including 37 pregnant females with a prenatal diagnosis of neural tube defects in their fetuses, 31 newborns, 36 fathers, and 100 healthy adults. The prevalence of the C677T mutation was examined. Homozygosity for the alanine to valine substitution (TT) was observed in 9% of the controls and 19% of the mothers with children with neural tube defects. Our results indicate that the presence of the T allele at the methylenetetrahydrofolate reductase 677 position may increase the risk of giving birth to an infant with a neural tube defect.     

Prevalence and outcome of congenital heart disease in patients with neural tube defect

A prospective clinical study was designed to establish the risk factors, the prevalence, and the progress of congenital heart defects in children with neural tube defects. Study included 90 children with a mean age of 13.5 +/- 30.4 months. There were 53 (59%) patients with spina bifida occulta and 37 (41%) patients with spina bifida aperta. The overall prevalence of congenital heart disease was 27.8% (40.5% in spina bifida aperta and 18.9% in spina bifida occulta; P = .024). There was no statistically significant difference for maternal age, usage of periconceptional folate, and maternal diabetes between the patient and control groups. The authors conclude that congenital heart defects are more common than reported in neural tube defects, and screening echocardiograms are warranted. This should be kept in mind especially in patients requiring minor or major surgical procedures. Furthermore, routine obstetric examination and therefore the use of periconceptional folic acid during pregnancy is still lacking in our country.     

解偶联蛋白2基因-866G/A,Ala55Val及Ins/Del多态性对宁夏回族人群血清抗氧化物质含量的影响分析

目的以宁夏地区回族人群为研究对象,分析UCP2基因多态性对血清抗氧化物质含量的影响。方法收集宁夏地区回族正常人群及回族脑缺血患者外周血样本,提取外周血基因组DNA,采用聚合酶链反应-限制性片断长度多态性方法检测各样本UCP2基因-866G/A、Ala55Val及Ins/Del多态性,利用试剂盒检测血清抗氧化物质SOD、TAOC、GSH含量。结果宁夏地区回族健康人群中,UCP2基因-866位点GA基因型血清GSH值(125.78±4.55)U/L低于GG野生型基因型GSH值(130.35±10.68)U/L(P0.05);脑缺血患者中Ins/Del位点组Ins/Ins基因型血清GSH值(108.71±8.30)U/L低于Del/Del基因型血清GSH值(116.43±8.24)U/L(P0.05)。结论在一定条件下,UCP2基因-866G/A,Ins/Del多态性可能影响宁夏地区回族人群血清GSH值。     

Retrospective approach to methylenetetrahydrofolate reductase mutations in children

Methylenetetrahydrofolate reductase reduces methyltetrahydrofolate, a cosubstrate in the remethylation of homocysteine, from methylenetetrahydrofolate. Congenital defects, hematologic tumors, and intrauterine growth retardation can occur during childhood. This study evaluated clinical and laboratory treatment approaches in children diagnosed with methylenetetrahydrofolate reductase mutations. Our group included 23 boys and 14 girls, aged 103.4 ± 70.8 months S.D. Clinical findings of patients and homocysteine, vitamin B12, folate, hemogram, electroencephalography, cranial magnetic resonance imaging, and echocardiography data were evaluated in terms of treatment approach. Our patients’ findings included vitamin B12 at 400.4 ± 224.6 pg/mL S.D. (normal range, 300-700 pg/mL), folate at 10.1 ± 4.5 ng/mL S.D. (normal range, 1.8-9 ng/mL), and homocysteine at 8.4 ± 4.7 μmol/L S.D. (normal range, 5.5-17 μmol/L). Eighty-eight percent of patients demonstrated clinical findings. In comparisons involving categorical variables between groups, χ² tests were used. No relationship was evident between mutation type, laboratory data, and clinical severity. All mothers who had MTHFR mutations and had babies with sacral dimples had taken folate supplements during pregnancy. To avoid the risk of neural tube defects, pregnant women with a MTHFR mutation may require higher than normally recommended doses of folic acid supplementation for optimum health.     

Maternal flu or fever,medications use in the first trimester and the risk for neural tube defects: a hospital-based case–control study in China

Purpose

This study aims to evaluate the effects of maternal flu or fever, and medications (antibiotics and antipyretics) use in the first trimester on neural tube defects (NTDs) risk in offspring.

Methods

Data came from a hospital-based case–control study conducted between 2006 and 2008 in Shandong/Shanxi provinces including 459 mothers with NTD-affected births and 459 mothers without NTD-affected births. Logistic regression models were used to evaluate the effects of maternal flu, fever, and medications use on NTD risk. The effects were evaluated by adjusted odds ratio (OR) and 95 % confidence intervals (CIs) with SAS9.1.3.software.

Results

NTDs risks were significantly associated with maternal flu or fever (OR?=?2.63, 95 % CI?=?1.64–4.23) and antipyretics use (OR?=?3.38, 95 % CI?=?1.68–6.79), but not with antibiotics use (OR?=?1.82, 95 % CI?=?0.85–3.93). The risk effect of antipyretics use on anencephaly (OR?=?7.81, 95 % CI?=?1.96–31.13) was markedly higher than on spina bifida (OR?=?3.02, 95 % CI?=?1.08–8.42). Maternal flu or fever together with antipyretics use showed a higher OR for total NTDs (3.27 vs.1.87), anencephaly (7.38 vs.2.08), and spina bifida (2.97 vs.2.07) than maternal flu or fever with no antipyretics use.

Conclusions

Maternal flu or fever and antipyretics use in the first trimester were risk for NTDs. Maternal flu or fever together with antipyretics use increased NTD risk than only maternal flu or fever.     

Brief Report: Antibodies Reacting to Brain Tissue in Basque Spanish Children with Autism Spectrum Disorder and Their Mothers

Previous investigations found that a subset of children with autism spectrum disorder (ASD) in California possessed plasma autoantibodies that reacted intensely with brain interneurons or other neural profiles. Moreover, for several cohorts of American women, maternal autoantibody reactivity to specific fetal brain proteins was highly specific to mothers of children with ASD. We sought to determine whether children and their mothers from a regionally specific cohort from the Basque Country of Spain demonstrated similar reactivity. Some children’s plasma reacted to interneurons, beaded axons or other neural profiles with no difference in the occurrence of these antibodies in children with or without ASD. Findings on the maternal antibodies confirmed previous research; plasma reactivity to fetal brain a combination of proteins at 37 and 73 kDa or 39 and 73 kDa was found exclusively in mothers of children with ASD.     

Stress trajectories in mothers of young children with Down syndrome

Background In this study, we investigated the early development of stress in mothers of children with Down syndrome, compared with mothers of children with developmental disabilities of mixed aetiologies. Growth modelling analyses were used to explore: (1) whether mothers of children with Down syndrome demonstrated distinct patterns of stress during their children’s early development, compared with mothers of children with other developmental disabilities; and (2) whether there was a relation between child behavioural characteristics and the level and rate of change in stress observed in each population. Method The stress trajectories of mothers of young children with Down syndrome (n = 25) and a mixed‐aetiology comparison group (n = 49) were estimated, using growth modelling on data collected at ages of 15, 30 and 45 months. Results On average, stress in the mixed comparison group was higher at Time 1 and remained unchanged over time, while stress in the Down syndrome group was lower at Time 1 but increased steadily. After taking diagnostic group membership into account, more advanced cognitive‐linguistic functioning and lower levels of maladaptive behaviours at all time points were associated with lower levels of maternal stress. Conclusions These findings suggest that the cognitive‐linguistic and behavioural trajectory observed in early development in Down syndrome may contribute to the changes in maternal stress levels observed throughout these early years. Implications for developing targeted and time‐ sensitive family interventions for families of children with Down syndrome are discussed.     

Sleep Problems of Children with Autism May Independently Affect Parental Quality of Life

The current study explored how and to what extent sleep problems in children with autism spectrum disorder (ASD) impacted their parents’ quality of life (QOL). A total of 440 ASD children and 344 age-matched typically developing (TD) children were included in the case–control designed study. In the TD group, a linear regression model showed that the Children’s Sleep Habits Questionnaire (CSHQ) total scores were negatively associated with maternal mental health summary (MCS) scores in the SF-36v2 (β = ? 2.831), while in the ASD group, the CSHQ total scores were negatively associated with the parental physical health summary (PCS) scores (β = ? 3.030 for mothers, β = ? 3.651 for fathers). Path analysis showed that sleep problems in ASD children had both direct and indirect effects on maternal PCS scores. The results indicated that sleep problems in children with ASD might affect parental QOL differently from TD children, and act as independent impact factors on parental physical health.

     

Resolution of the diagnosis and maternal sensitivity among mothers of children with Intellectual Disability

We examined mothers’ resolution of their children's diagnosis of Intellectual Disability (ID) and its link to maternal sensitivity, and we hypnotized that mothers’ who are “resolved” will show more sensitivity during their interactions with their children than “unresolved” mothers. We assessed maternal resolution using the Reaction to Diagnosis Interview and maternal sensitivity in three different play episodes using the Emotional Availability Scales. Our sample included 40 children between the ages of 2.5 and 5.5 with clinical diagnoses of non-syndromic ID and their mothers. Supporting our hypothesis we found that mothers who were resolved regarding the diagnosis of their children showed more maternal sensitivity to their children in two of the three play episodes. Another important finding was that resolution and sensitivity were associated even when we controlled for the child's responsiveness to and involvement with the mother, suggesting that the link between resolution and sensitivity cannot be accounted by the impact of the child's behavior on the mother.     

沉默信息调节基因2的microRNA结合位点多态性与散发帕金森病的相关性研究

目的探讨沉默信息调节基因2(Sirtuin 2)3’UTR的microRNA结合位点多态性与散发帕金森病(Parkinson’s disease,PD)的关系。方法采用病例-对照研究、聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法分析了83例PD患者(PD组)与101例健康成人(对照组)Sirtuin 2基因3’UTR G+281A位点多态性。结果 PD组Sirtuin 2基因3’UTR的miRNA-486-3p结合位点(3’UTR G+281A位点)A等位基因频率以及GA+AA基因型频率高于对照组,但两组差异无统计学意义(P>0.05);在女性PD组A等位基因携带者的频率较对照组高,经χ2检验提示有相关倾向(χ2=3.205,P=0.073);PD组出现两例AA基因型,而对照组则无此种基因型。结论 Sirtuin 2基因3’UTR G+281A多态性的纯合子AA可能是PD的遗传易感性基因型,而在女性A等位基因携带者PD患病的风险可能增加。     

Confirmation of LRRK2 S1647T variant as a risk factor for Parkinson’s disease in Southern China

Background: Leucine‐rich repeat kinase 2 (LRRK2) S1647T has been identified as a risk variant for Parkinson’s disease (PD) in Han Chinese. Methods: To replicate the association of LRRK2 S1647T with risk of PD, we conducted a case–control study of this variant involving 406 PD subjects and 412 controls from southern mainland China. Results: The results showed that the frequency of A allele was higher in patients with PD (OR = 1.238, 95% CI: 1.015–1.510, P = 0.035) compared to controls. In a multivariate logistic regression analysis with the disease group (patients with PD vs. controls) as the dependent variable and genotype as an independent factor adjusting for the effect of age and gender, the homozygous S1647T genotype (AA) was associated with an increased risk of PD (OR = 1.815, 95% CI:1.270–2.594, P = 0.001). The pooled analysis of present data and the data from the previous work demonstrated that the frequency of A allele was higher in patients with PD (OR = 1.2, 95% CI: 1.09–1.32, P < 0.0001). Conclusions: LRRK2 S1647T increases the risk of Parkinson’s disease in southern China.     

Effects of maternal oral morphine consumption on neural tube development in Wistar rats

Opiate abuse during pregnancy may result in abnormal nervous system function. In order to evaluate the effects of morphine on the development of the nervous system, the present study focused on the effects of maternal morphine consumption on neural tube development in Wistar rats. Female Wistar rats (250-300 g) were crossed with male rats and coupling time was recorded (embryonic day 0-E0). Experimental groups received 0.1, 0.05, and 0.01 mg/ml of morphine in drinking water daily (14 ml water for each rat). Control group received tap water. On embryonic day 9.5 (E9.5), the animals were anesthetized and the embryos were surgically removed. The embryos were fixed in 10% formalin for 1 week. After this time, weights and lengths (antero-posterior axis--A-P) of the embryos were determined and then tissues were processed, sectioned, and stained in hematoxylin and eosin (H&E). The sections were investigated for neural tube development by light microscope and MOTIC software. The decrease in "A-P" length and embryonic weight for the group that received 0.01 mg/ml morphine was significant. It seems that daily consumption of morphine sulfate could delay neural tube development. In addition, administration of 0.01 mg/ml of morphine led to damage to the regulated neuro-ectoderm layer and its thickness. This study showed that oral morphine consumption leads to neural tube defects, as indicated in the morphometric change and also reduction in weight and length of the embryos. These defects might affect the behavior of the animals.     

Maternal Vitamin D Levels and the Autism Phenotype Among Offspring

We tested whether maternal vitamin D insufficiency during pregnancy is related to the autism phenotype. Serum 25(OH)-vitamin D concentrations of 929 women were measured at 18 weeks’ pregnancy. The mothers of the three children with a clinical diagnosis of autism spectrum disorder had 25(OH)-vitamin D concentrations above the population mean. The offspring of 406 women completed the Autism-Spectrum Quotient in early adulthood. Maternal 25(OH)-vitamin D concentrations were unrelated to offspring scores on the majority of scales. However, offspring of mothers with low 25(OH)-vitamin D concentrations (<49 nmol/L) were at increased risk for ‘high’ scores (≥2SD above mean) on the Attention Switching subscale (odds ratio: 5.46, 95 % confidence interval: 1.29, 23.05). The involvement of maternal vitamin D during pregnancy in autism requires continued investigation.     

Maternal smoking during pregnancy and neural tube defects in offspring: a meta-analysis

Purpose

This study aims to examine the association between maternal smoking during pregnancy and neural tube defects (NTDs) in offspring.

Methods

We retrieved published studies on the association between maternal smoking during pregnancy and NTDs risk in offspring. Meta-analysis was applied to calculate the overall odds ratios (ORs) and their 95 % confidence intervals (CIs). The publication bias was assessed by the Egger’s regression asymmetry test and Begg’s rank correlation test.

Results

The overall effect of maternal smoking during pregnancy on NTDs was 1.03 (OR?=?1.03, 95 % CI?=?0.80–1.33). When subgroup analysis was conducted by geographic regions, the overall effects were 1.39 (OR?=?1.39, 95 % CI?=?1.18–1.64), 0.88 (OR?=?0.88, 95 % CI?=?0.66–1.17) in Europe and USA; when subgroup analysis was conducted by NTDs types, the overall effect was 1.55 (OR?=?1.55, 95 % CI?=?1.06–2.26) for spina bifida.

Conclusions

Women who smoked during pregnancy had mildly elevated risk of having infants with NTDs.     

Vasoactive Intestinal Peptide (VIP) Regulates Activity-Dependent Neuroprotective Protein (ADNP) Expression In Vivo

Vasoactive intestinal peptide (VIP) is an important mediator of development during the neural tube closure period of embryogenesis and may regulate, in part, the expression of activity-dependent neuroprotective protein (ADNP), which is essential for neural tube closure and embryogenesis. To evaluate the impact of VIP expression in vivo on ADNP and the related protein ADNP2 the current study examined gene expression in adult wild-type (VIP +/+) and VIP null (VIP −/−) offspring of VIP deficient mothers (VIP+/−) comparing them to wild-type offspring of wild-type mothers. Quantitative real time polymerase chain reaction (PCR), using an ABI Prisma cycler revealed regionally specific reductions of ADNP mRNA in the brains of VIP null mice compared with the brains of wild-type offspring of a wild-type mother. ADNP was significantly reduced in the cortex and hypothalamus of VIP null mice, but not in the hippocampus or thalamus. ADNP2 exhibited a similar pattern but reached a statistically significant reduction only in the hypothalamus. The mRNA for ADNP and ADNP2 also tended to be reduced in the cortex and hippocampus of the wild-type littermates of the VIP null mice, indicating that the VIP genotype of the mother may have had an impact on the ADNP expression of her offspring, regardless of their own VIP genotype. These results showed that VIP regulated brain ADNP expression in a regionally specific manner and indicated that both maternal and offspring VIP genotype may influence ADNP expression in the brain.     

Heavy maternal alcohol consumption and cerebral palsy in the offspring

Aim The aim of this study was to investigate the association between heavy maternal alcohol consumption and pre‐ peri‐ and postneonatally acquired cerebral palsy (CP). Method The records of all mothers with an International Classification of Diseases, revision 9 or 10 (ICD‐9/‐10) alcohol‐related diagnostic code, indicating heavy alcohol consumption, recorded on population‐based health, mental health, and drug and alcohol data sets from 1983 to 2007, and their children were identified through the Western Australian Data‐linkage System. This ‘exposed’ cohort was frequency matched with mothers without an alcohol‐related diagnosis and their offspring (comparison group). Cases of CP were identified through linkage with the Western Australia CP Register. Analyses were undertaken using multivariate logistic regression. Results There were 23 573 live births in the exposed group (58.6% non‐Aboriginal; 41.4% Aboriginal) and 292 cases of CP. The odds of pre/perinatally acquired CP were elevated for children of non‐Aboriginal mothers with an alcohol‐related diagnosis recorded during pregnancy (adjusted odds ratio 3.32; 95% confidence interval [CI] 1.30–8.48) and for Aboriginal children when an alcohol‐related diagnosis was recorded up to 12 months before the mother’s pregnancy (adjusted odds ratio 2.49; 95% CI 0.99–6.25). Increased odds of postneonatally acquired CP following any alcohol‐related diagnosis were found for non‐Aboriginal children (adjusted odds ratio 7.92; 95% CI 2.23–28.14). Interpretation These results suggest that heavy maternal alcohol consumption is a direct cause of pre/perinatally acquired CP, and an indirect cause of postneonatally acquired CP, in non‐Aboriginal children. The lack of an association for Aboriginal children requires further investigation but may be due to under ascertainment of alcohol use disorders during pregnancy and other aetiological pathways.     

Relationship Between Children’s Sleep and Mental Health in Mothers of Children with and Without Autism

The study employed 90 children with autism spectrum disorders (ASDs) who were matched to 90 typically developing children on age, gender, and ethnicity. Using structural equation modeling, maternal sleep and maternal stress mediated the relationship between children’s sleep and mothers’ mental health for mothers of children with and without ASDs. Mothers of children with ASDs reported more problems related to children’s sleep, their own sleep, greater stress, and poorer mental health; however, children’s sleep and maternal sleep were more closely related to maternal stress for mothers of typically developing children. Implications of these findings and future directions for research are discussed.