华中地区神经管缺陷家庭叶酸代谢相关基因的单核苷酸多态性研究

目的 通过对叶酸代谢相关基因的单核苷酸多态性(single nucleotide polymorphism,SNP)与环境危险因子交互作用的关联分析,寻找神经管缺陷(neural tube defects,NTD)致病基因及环境危险因素. 方法收集NTD流产胎儿组织标本或患儿血标本(n=278)及其正常双亲的血标本(n=478),记录母亲围孕期补充叶酸、糖尿病、服药史等情况.采用CEQ 8800系统进行多重SNP分析,对所有样本叶酸代谢相关的12个基因共28个SNP测序.通过病例-双亲对照研究及传递/不平衡检验,分析SNP与环境危险因子(孕期补充叶酸、母亲糖尿病、孕期服药史)的交互作用对NTD发病的影响. 结果 亚甲基四氢叶酸还原酶(基因为MTHFR)rs1801133与NTD的关联具有统计学意义,而且环境风险因子(未补充叶酸、母亲糖尿病)对NTD的发生起增效作用;而甜菜碱同型半胱氨酸甲基转移酶(基因为BHMT)rs3733890仅在未补充叶酸层与NTD存在连锁不平衡,基因型本身并不能单独导致疾病;而其他基因的SNP与NTD的发生没有显著关联. 结论 MTHFRrs1801133是NTD的危险因子,而BHMT rs3733890不是NTD的独立危险因子.未来尚需要对更大的样本进行基因与基因、基因与环境交互作用的研究以探讨NTD的发病原因.     

Development of neural tube defects and genetic counseling

The analysis of thirty-seven cases of neural tube defects (NTD) resulted in the following conclusions: a) At least eleven cases had the Arnold-Chiari malformation, an autosomal recessive disorder which often remains unrecognized; b) Trisomy 18 and amniotic disease associated with NTD were diagnosed in two newborns; c) In eight cases there was one or more older children with NTD; d) In two families the parents were related. A review of the literature and the exposed data indicate a heterogeneous etiology and an important role of genetic factors in the genesis of NTD.     

Prevention of neural tube defects with folic acid

Neural Tube Defects (NTD's) include a large number of congenital malformations produced when the open neural tube presents a very early stages in the development of the human embryo fails to close on or before the first month post conception. NTD's are considered to be one of the most common forms of malformations with varying degrees depending of genetic and environmental conditions. The studies prove that the additional taken of folic acid plays an important role against the NTD's. Numerous studies prove this "B" vitamin has an important protective effect not only for the recurrence of NTD's, but for new cases too. In light of these, in 1992 the US Public Health Services issued the recommendation that all women in child-bearing age should consume at least 0.4 mg (400 micrograms) of folic acid daily.     

Associated anomalies with neural tube defects in fetal autopsies

Neural tube defects (NTD), the consequences of aberrant neural tube closure during embryogenesis, have been mostly investigated in terms of their high prevalence, rate of mortalities and serious morbidities. A proper prenatal outcome counseling of couples coming across a fetal anomaly necessitates the detection and categorization of the primer abnormality, all the co-existing malformations. The aim of this work is to study the incidence and relevance of associated malformations in order to offer a complete pathology report with a true diagnosis. In this study, among 542 fetal autopsy 62 (%11.4) cases with NTD was recorded by the Akdeniz University Pathology Department between January 2006 and June 2012. Twenty (32.4%) NTD cases were associated with anomaly. Twelve cases of associated groups consisted of a congenital syndrome/association, spondylothoracic dysplasia, amniotic band syndrome, Meckel–Gruber syndrome, schisis association. The frequency of associated NTD was 32%, this result was higher than previous reports. NTDs have a significant genetic component to their etiology that interacts with environmental risk factors, which might pose Turkey to be a country with high prevalence of NTD. We want to emphasize that intensive screening, documentation of co-existent abnormalities of NTD, should be conducted in order to exhibit certain diagnosis, to perform proper prenatal genetic counseling of parents for on-going/future pregnancies.     

Pathogenesis and genetics of neural tube defects

After congenital heart defects neural tube defects (NTDs) is the second most prevalent congenital malformation among birth defects. The average rate of isolated NTDs is 1.4-2.0 per 1000 live births worldwide. The etiology of isolated (nonsyndromic) NTDs is believed to be the result of a combination of genetic predisposition and environmental factors. Over 80 genes believed to be engaged in the neurulations have been identified during the investigation and research of the mouse models. Despite exhaustive research efforts, now spanning several decades, little is known about the actual genetic mechanisms governing the primary events involved in neural tube closure (NTC).     

Reproductive history in mothers of children with neural tube defects

The reproductive history of 100 women with at least 1 child with a neural tube defect (NTD) has been studied. The data analyzed correspond to the period previous to their first visit to a genetic counseling service. A total of 204 pregnancies resulted in 205 outcomes. Of the 100 sibships, 14 (14%) had more than 1 affected member. The pregnancy was shorter than 28 weeks in 56/205 (27%) of the total outcomes. Of 104 evaluable previous outcomes, 34 corresponded to short pregnancies, positioned before an affected (23/60, 38%), a healthy (2/18, 11%), or an undiagnosed product (9/26, 35%). Short pregnancies subsequent to affected outcomes were also increased. The inter-gestational interval varied according to diagnosis: it was longer in the affected group than in the healthy one (0.1 > p > 0.05) and the subsequent intervals were shorter for the affected group (p < 0.05). An increased number of abortions adjacent to affected offspring and a changing fertility pattern, depending on the product diagnosis, point to an environmental etiological component in this high-risk NTD group of mothers.     

Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects

We analyzed the karyotype of fetuses with ultrasonographically detected neural tube defects (NTDs). In our study, we included a total of 194 fetuses with NTDs. We analyzed the type of NTD, the karyotype, maternal age, fetal gestational age at diagnosis, and fetal sex. Of the 194 fetuses with NTDs, 87 were anencephalic and 107 had other, nonanencephalic, NTDs. A total of 12 fetuses were shown to have chromosomal abnormalities. Three of 87 anencephalic fetuses (3.45%) had chromosomal abnormalities. The sex ratio for anencephalic fetuses was 65.5% : 34.5% for female and male fetuses. Nine of 107 fetuses with other NTDs (8.41%) had chromosomal abnormalities. Seven fetuses had isolated NTDs and a further seven fetuses had additional ultrasonographic anomalies. Two of the latter had abnormal karyotypes. The sex ratio of all other NTD cases was 67.3% : 32.7% for female and male fetuses. The high number of chromosomal abnormalities justifies prenatal karyotyping in all fetuses with ultrasonographically diagnosed NTDs.     

Glial fibrillary acidic protein in amniotic fluids from pregnancies with fetal neural tube defects

The glial fibrillary acidic protein (GFAP) is the subunit protein of intermediate filaments in astrocytes and closely related cell types. By means of an enzyme immunoassay we have determined the concentration of GFAP in amniotic fluids from normal pregnancies and from pregnancies complicated by various fetal malformations. The group of 20 cases of fetal anencephaly had a significantly higher mean amniotic fluid GFAP concentration (115 micrograms/l +/- 133.6 (S.D.), range 6-378 micrograms/l) than the control group of 117 normal pregnancies (13 micrograms/l +/- 5.5 (S.D.), range 0-31 micrograms/l), (P less than 0.001). Two cases of fetal encephalocele likewise had very high amniotic fluid GFAP concentrations. None of the other cases of fetal malformations investigated, including 12 cases of spina bifida, had increased amniotic fluid GFAP concentrations. We conclude that determination of the amniotic fluid GFAP concentration may give additional information in the prenatal diagnosis of fetal nervous system malformations.     

叶酸代谢相关基因与神经管畸形发生关系的研究进展

神经管畸形是在胚胎发育过程中,由于神经管闭合不全所引起的一组缺陷,包括无脑畸形、脑膨出、脊柱裂、脑脊膜膨出等.世界范围内神经管畸形发病率为0.05%～0.2%[1].我国是神经管畸形的高发国家,每年大约有8万～10万例神经管畸形患儿出生,其中山西省发生率最高可达1.02%[2].因此,神经管畸形是最常见的人类出生缺陷之一,其危害极大,严重影响患儿的生理发育和生活质量,也给家庭和社会带来沉重的精神压力和经济负担.     

Maternal obesity and risk of neural tube defects: a metaanalysis

We conducted a metaanalysis of published evidence on the relationship between maternal obesity and the risk of neural tube defects (NTDs). Eligible studies were identified from 3 sources: (1) PubMed search of articles that were published from January 1980 through January 2007, (2) reference lists of publications that were selected from the PubMed search, and (3) reference lists of review articles on obesity and maternal outcomes that were published from January 2000 through January 2007. Twelve studies met inclusion criteria. A Bayesian random effects model was used for the metaanalysis and metaregression. Unadjusted odds ratios for an NTD-affected pregnancy were 1.22 (95% CI, 0.99-1.49), 1.70 (95% CI, 1.34-2.15), and 3.11 (95% CI, 1.75-5.46) among overweight, obese, and severely obese women, respectively, compared with normal-weight women. None of the study characteristics included in the metaregression analysis affected the results significantly. Maternal obesity is associated with an increased risk of an NTD-affected pregnancy.     

综合征性神经管缺陷3 798例分析

目的：探讨综合征性神经管缺陷（neural tube defects,NTDs）的发生形式和伴发畸形谱。方法：中国出生缺陷监测网采用以医院为基础的监测方法,收集1987-1995年间,孕28周到产后7d,伴各种出生缺陷的围产儿资料,包括活产、死胎和死产。结果：3498例综合征性NTDs,无脑、脊柱裂和脑膨出分别为997例、2394例和407例。伴发肌肉、骨骼系统,面、耳、颈部和泌尿生殖系统畸形的围产儿分别为51.3％,19.6％和9.3％。前5位高发畸形分别是马蹄内翻足、唇腭裂（唇裂合并腭裂）、腹裂、足外翻、足月睾丸未降。神经管缺陷的裂联合征（schisis-association）中,NTDs合并总唇裂（唇裂 唇裂合并腭裂）占67.5％,无脑合并腭裂占8.3％,无脑合并脐膨出占6.6％。综合征性NTDs患儿低出生体重儿发生率为36.9％,围产期病死率为71.2％,产前诊断率为33.1％。结论：为1/3的NTDs可伴发其他畸形。综合征性NTDs儿病死率高,预后差。     

Diagnostic ultrasound: early detection of fetal neural tube defects

In a series of 366 patients identified as at risk for a fetal neural tube defect (NTD) before the 24th week of pregnancy, 64 had an abnormal fetus. The abnormalities included anencephaly (39), open spinal defect (17), closed spinal defect (2), encephalocele (1), and a miscellany of other abnormalities (5). An ultrasound examinaton prior to diagnostic anmiocentesis positively identified all anencephalic fetuses, the fetus with the encephalocele, and 15 of the 19 fetuses with spina bifida. The spinal defects in 3 of the remaining 4 fetuses were demonstrated at a second examination. Since both amniotic fluid alpha-fetoprotein (AFP) assays and ultrasound examination have been shown to give false results in the diagnosis of NTDs, the importance of using 2 independent diagnostic techniques is stressed. In patients with elevated levels of maternal serum AFP, a careful ultrasound examination, in addition to identifying the majority of cases associated with an abnormal fetus, provided a good explanation for the elevation in over half of the remainder. In this series more than half the patients (40/69) who underwent amniocentesis because of raised maternal serum AFP levels were shown to have an abnormal fetus.     

Elevated homocysteine levels in mothers with neural tube defects: a systematic review and meta-analysis

Purpose: To find the real relationship between maternal total homocysteine (tHcy) level and risk of neural tube defects (NTDs).

Materials and methods: A systematic review and meta-analysis were conducted. The literature search was conducted with the use of PubMed and EMBASE databases and weighted mean difference (WMD) with 95% confidence interval (CI) was applied to measure the difference in tHcy level between case and control group. Seventeen articles involving 3237 subjects were included according to the inclusion criteria.

Results: Pooled result showed that mothers with NTDs offspring demonstrated significantly a higher mean log plasma tHcy level than mothers with normal offspring (log WMD: 0.06; 95%CI: 0.02–0.09, p?=?0.001), corresponding to an increase of 6% (2–9%) in the geometric mean. Subgroup analyses also displayed this difference in subjects who were detected during pregnancy or without folate supplementation before sampling. However, in the mandatory folate fortification countries, we did not find this association.

Conclusions: A slightly higher tHcy level in mothers with NTDs was indicated, but potential confounders could not be ruled out completely. Further larger or cohort studies are needed to confirm this association.     

Primary prevention of neural tube defects with folic acid supplementation: Cuban experience

Folic acid (5 mg) was given daily, for not less than one menstrual period before conception and until the tenth week of pregnancy, to 81 women (FS) with a history of a previous neural tube defect (NTD) birth. There was no NTD recurrence among this group or among the offspring of a further 20 women (PS) whose folic acid supplementation fell short of the full regime. In another 114 women who became pregnant without folic acid supplementation (US), there were four NTD recurrences (3.5 per cent). Our results suggest that folic acid supplementation might be an effective method of primary prevention of neural tube defects.     

Inidcations for prenatal diagnosis in relatives of patients with neural tube defects

We have reviewed the family histories of children with neural tube defects to determine which relatives are at sufficient risk to be offered amniocentesis for prenatal diagnosis. The recurrence risks for sibs was 6%; therefore, women with one affected child should be made aware of the availability of this test for monitoring subsequent pregnancies. The empiric recurrence risks for various groups of second and third degree relative exceeds 1% only for mothers' sisters' children. The lower values for the other groups may reflect either true biologic differences of reporting biases. Unit the matter is clarified, all sibs of affected children and all sibs of the parents of affected children should be informed of the availability of amniocentesis for monitoring their (or their spouse's) pregnancies.     

Prenatal diagnosis of chromosomal abnormalities and neural tube defects

We have reviewed the current status of prenatal diagnosis for chromosomal indications and for neural tube defects. The number of pregnancies monitored will increase as greater resources become available and as public education about genetics increases. The methodology has proved to be a powerful means of preventing the birth of individuals with significant genetic defects, thereby sparing both parents and society from the burdens produced by such disorders. In the future, it is likely to be even more effective.