Serial 1H-MRS in GM2 gangliosidoses

GM2 gangliosidoses are a group of neuronal storage disorders caused by deficiency in the lysosomal enzyme hexosaminidase A. Clinically, the disease is marked by a relentless encephalopathy. Proton magnetic resonance spectroscopy (1H-MRS) provides in-vivo measurement of various brain metabolites including N-acetyl aspartate+N-acetyl aspartate glutamate (NAA), myo-inositol (mI), choline (Cho) and creatine (Cr). The NAA represents neuronal integrity while elevation in the mI reflects abnormal inflammation and gliosis in the brain tissue. An elevation in the Cho levels suggest cell membrane breakdown and demyelination. We report the clinical and laboratory data in two patients with GM2 gangliosidoses. Serial 1H-MRS evaluations were performed to drive metabolite ratios of NAA/Cr, mI/Cr and Cho/Cr. We acquired the data from four regions of interest (ROI) according to a standard protocol. The results documented a progressive elevation in mI/Cr in all four ROI in patient one and only one ROI (occipital gray matter) in patient 2. We also documented a decline in the NAA/Cr ratios in both cases in most ROI. These results were compared to six age-matched controls and confirmed statistically significant elevation in the mI in our cases. In conclusion, 1H-MRS alterations were suggestive of neuronal loss and inflammation in these patients. 1H-MRS may be a valuable tool in monitoring the disease progress and response to therapy in GM2 gangliosidoses. Elevation in the mI may prove to be more sensitive than the other metabolite alterations.     

A family with combined Farber and Sandhoff,isolated Sandhoff and isolated fetal Farber disease: postnatal exclusion and prenatal diagnosis of Farber disease using lipid loading tests on intact cultured cells

Abstract An earlier described patient with combined sphingolipidoses, Farber and Sandhoff disease, had two healthy older brothers and two further sibs, one with Sandhoff disease and one (a fetus) with Farber disease, showing segregation of the respective genes. The prenatal diagnosis in the latter was performed using lipid (sphingomyelin and glucosylceramide) loading tests on the cultured amniotic fluid cells. After 1–3 days of incubation the cells' lipid extract revealed radioactive ceramide to be released and highly accumulated. The deficiency in acid ceramidase was known from the patient with the combined diseases. Confirmation of the prenatal Farber diagnosis was done by similar loading tests on the fetal fibroblasts and by analysis of liver lipids of the less than 18-week-old fetus.Conclusion This is the first report on the use of lipid loading tests on intact cultured cells for prenatal diagnosis of Farber disease. The postnatal diagnosis of Farber disease can also be readily made using those tests, as was shown in four further cases.     

胎儿先天性心脏病产前诊断与生后治疗一体化模式的探讨

目的 探讨胎儿先天性心脏病产前诊断与生后治疗一体化模式.方法 2006年8月至2010 年5月共有46位孕妇在我院产前诊断出胎儿先心病并选择继续妊娠.在我院产科自然分娩或剖腹产,胎儿出生后24 h内复查心脏超声,连续监测经皮血氧饱和度,由小儿心内科、小儿心外科、新生儿科联合制定治疗和随访方案.结果 孕妇剖腹产36例,自然分娩10例;共分娩活产新生儿47例,男40例,女7例;平均胎龄(38.0±1.4)孕周,平均体重(3.00±0.44) kg;产前和生后主要心脏畸形诊断相符.10例动脉导管依赖型复杂先心病患儿新生儿期静脉滴注前列腺素E.23例接受外科手术治疗,其中15例于新生儿期手术.7例行内科介入治疗,4例经皮肺动脉瓣成形术,3例行房间隔或室间隔缺损封堵术.16例随访患儿中2例室间隔缺损自然愈合,7例房间隔缺损和5例室间隔缺损等待择期治疗,2例随访丢失.30例已治疗的患儿中21例心脏结构恢复正常,7例心脏瓣膜存在轻微改变,术后死亡2例(病死率6.7％).结论 产前诊断与生后治疗一体化模式符合先天性心脏病诊治的发展趋势,需要多科室合作,才能及早发现胎儿心脏畸形,预测胎儿出生后的变化,消除复杂先心病出生后的急危重状态,提高生后治疗的成功率.     

3 例Menkes病患儿的临床与ATP7A基因分析及1例产前诊断研究

Menkes 病是一种罕见的X 连锁隐性遗传病,由于ATP7A 基因突变导致铜吸收障碍,铜相关酶功能缺陷,引起多系统功能障碍。该文拟通过对3 例Menkes 病患儿的临床经过和ATP7A 基因突变分析对该症进行研究,并对1 例再孕母亲进行产前诊断研究。3 例男婴于8~9 个月时来院就诊,均为婴儿期起病,主要表现为抽搐和智力运动落后,抗癫癎治疗无效,面色苍白,毛发稀疏、卷曲,小头,MRI 扫描显示脑萎缩、白质异常、基底节损害和脑血管形态改变,血浆铜蓝蛋白均显著降低,分别为70.2、73.5、81.0 mg/L（参考值210~530 mg/L）,符合经典型Menkes 病临床表型。例1 和2 的ATP7A 基因存在c.3914A>G（p. D1305G）突变,例3 为c.3265G>T（p.G1089X）突变,均为新生突变。c.3914A>G（p. D1305G）为已知突变,c.3265G>T（p.G1089X）为新突变,均为我国首次报道。例1 患儿的母亲再孕,于妊娠20 周时抽取羊水细胞,通过胎儿ATP7A 基因突变分析,进行产前诊断。羊水细胞ATP7A 基因未见c.3914A>G,提示胎儿未患与先证者相同的疾病。胎儿出生后发育正常。     

儿童期脊肌萎缩症的基因诊断及产前基因诊断

为建立脊肌萎缩症（ＳＭＡ）产前诊断方法，应用３个与ＳＭＡ基因紧密连锁的ＣＡ重复序列位点ＪＫ５３ＣＡ１／２、５ＤＳ６３７、ＣＡＴＴ１，对１８个ＳＭＡ家系进行了连锁分析；应用聚合酶链反应－单链构型多态性（ＰＣＲ－ＳＳＣＰ）分析，对３７例ＳＭＡ患儿作了ＳＭＡ基因缺失的检测；并作２例ＳＭＡ产前诊断。结果：１８个家系通过ＪＫ５３ＣＡ１／２位点诊断１２个（可诊断率６６．７％），通过５ＤＳ６３７位点诊断１４个（７．８％），１０个ＳＭＡ家系通过ＣＡＴＴ１位点诊断９．５个（９５．０％）；３７例患儿中３２例（８６．５％）有端粒侧ｅｘｏｎ７的纯合性缺失；２例接受产前诊断者，１例胎儿患病，１例胎儿为正常。结论：应用ＳＭＡ基因旁侧ＣＡ重复序列联合ＰＣＲ－ＳＳＣＰ检测进行ＳＭＡ基因诊断和产前诊断简便、准确、可应用于临床。     

Abdominal wall defects in the era of prenatal diagnosis

In order to study the effects of prenatal diagnosis, we reviewed all 141 cases of abdominal wall defects (AWD) seen in our institution since 1980. In the period up to the end of 1994, 65 AWDs were diagnosed at the Department of Obstetric Ultrasound and another 76 infants were born with an AWD, 44 with omphalocele (prenatal diagnosis 29), 21 with a cord hernia (prenatal diagnosis 4), and 76 with gastroschisis (prenatal diagnosis 32). In the prenatal diagnosis group the frequency of cesarean section was 48%, in the postnatal diagnosis group 13%. In the omphalocele group, the pregnancy was terminated in 12 cases and there were 10 intrauterine deaths. A further 10 babies died in the first days of life, so that only 12 came to operation; 6 survived. At least 27 of the 44 infants had other severe anomalies. Omphalocele has a poor prognosis that is not improved by prenatal diagnosis, so that termination is a reasonable option. In the cord hernia group 1 patient died because of a cardiac anomaly; all the others had primary closure without complications. In the gastroschisis group, the pregnancy was terminated in 7 cases and there were 2 intrauterine and 2 neonatal deaths. Sixty-five infants were operated upon immediately after birth, 50 (77%) with primary closure and 15 in two stages. Four died after primary closure (8%) and 4 after a silastic silo (27%). The overall mortality was 12.3%. Postoperative intestinal morbidity was assessed by the period until total enteral nutrition could be established, which was from 8 to 185 days (median 17 days). The unfavorable prognostic factors were intestinal thickening and staged closure. Neither prenatal diagnosis nor mode of delivery could be shown to have any effect on mortality or morbidity.     

How accurate is prenatal sonography for the diagnosis of imperforate anus and Hirschsprung's disease?

Imperforate anus (IA) and Hirschsprung's disease (HD) are the commonest causes of coloanal obstruction in the neonate. We prospectively studied 15,092 pregnancies over a 4-year period to determine the accuracy of prenatal sonography (US) in diagnosing these conditions. Based on location and appearance, 13 fetuses were thought to have colonic dilatation on prenatal US. Nine of these had dilated bowel located in the pelvis. Postnatally, 7 were normal and 2 had an IA. Four fetuses were thought to have dilated proximal colon based on the peripheral location of the bowel loops in the abdomen. All 4 had normal colons, but had small-bowel obstruction postnatally (3 meconium ileus, 1 malrotation). Neonatal or fetal pathologic follow-up was obtained for all pregnancies. Twenty-three fetuses without dilated colon on US had coloanal obstruction (20 IA, 3 HD). Other anomalies had been sonographically evident in 17 of these fetuses (all with IA).Overall sensitivity and positive predictive value for sonographically dilated colon in predicting IA or HD were very low in this series (8% and 15%, respectively). No cases of HD were diagnosed prenatally. The incidence of associated anomalies was high in fetuses with IA. Dilated bowel loops outside the pelvis represented small bowel rather than colon, even if they were peripheral in location. These data suggest that prenatal US is of limited value for either diagnosing or excluding IA and HD.     

Congenital adenomatoid disease of the lung: prenatal diagnosis and perinatal management

Prenatal ultrasonographic (US) detection of congenital adenomatoid malformation (CAM) was made in 18 fetuses at 17–36 weeks' gestation and managed in our institution during a 10-year period (1985–1994). The lesion was left-sided in 13 cases, right-sided in 4, and bilateral in 1. According to Stocker's classification, 12 cases were type I, 4 type II, and 2 type III. The prenatal course was followed with serial US examinations in 13 cases; the size of the lesion was stable in 8 and decreased in 5. Mediastinal shift was usually observed, and amniotic fluid volume was increased in 4 cases. One fetus was aborted. Six infants presented with respiratory distress syndrome and required neonatal surgery; delayed surgery was performed in 9 cases. Spontaneous regression of the lesion was observed on follow-up in 2 cases. Surgery consisted in lobectomy in 8 cases and segmentectomy in 6. The presence of fetal hydrops, type III lesions, and bilateral lung involvement are prenatal factors known to be associated with a poor prognosis. However, this series and a review of the literature suggest that caution should be observed with regard to the initial impression when counseling the parents regarding prognosis.     

Non-invasive prenatal diagnosis: public and patient perceptions

The possibility of the application of reliable non-invasive prenatal diagnosis to clinical practice, and its likely availability as a tool for routine antenatal screening, is an important and exciting development that will be of interest to women and couples - especially where there is a known risk arising from family history, or some other source, of having a baby with a serious, disabling or life-limiting condition. Managing the introduction of this new technology will require attention to the understanding and perceptions of women, couples and the wider society, as well as to the clinical, scientific, technical and logistic issues that will inevitably arise.     

X连锁肾上腺脑白质营养不良的携带者筛查及产前诊断探讨

目的探讨X连锁肾上腺脑白质营养不良(X linkedadrenoleukodystrophy,X ALD)的携带者筛查及产前诊断方法。方法应用气相色谱质谱联用法对83例X ALD可疑携带者血浆、9例高危孕妇羊水细胞及其中5例胎儿出生后的血浆中极长链脂肪酸(VLCFAs)水平进行了检测。应用PCR、测序方法对31例X ALD可疑携带者及羊水细胞VLCFAs增高的男性及女性各1例进行了基因突变分析。结果83例X ALD可疑携带者中,51例血浆VLCFAs水平增高,31例ABCD1基因突变分析,29例有突变。9例胎儿中,7例羊水细胞VLCFAs水平正常,2例增高(1例男性,1例女性)。5例出生后进行了血浆VLCFAs水平检测,结果与产前诊断结果相一致。2例羊水细胞VLCFAs水平增高的胎儿,均有ABCD1基因突变,其核苷酸与氨基酸的改变分别为871G>A(E291K)和726G>A(W242X)。结论血浆及羊水细胞中VLCFAs水平检测结合基因突变分析可以准确地进行X ALD携带者筛查及产前诊断。     

Upper urinary tract dilatation: prenatal diagnosis, management and outcome

Upper urinary tract dilatation is one of the most common abnormalities detected on prenatal ultrasound scanning. It is commonly due to transient urine flow impairment (UFI) at the level of the pelvi-ureteric and vesico-ureteric junctions, which improves with time in most cases. It is usually in the neonatal period that the diagnosis is confirmed and during the first 18 months of life that the prognosis of the dilatation is defined.     

Duodenal atresia: associated anomalies,prenatal diagnosis and outcome

Background  The diagnosis of duodenal atresia is commonly made prenatally, either as an isolated lesion or due to its association with other chromosomal abnormalities (Robertson et al. in Semin Perinatol 18:182–195, 1994; Hemming and Rankin in J Prenat Diagn 27:1205–1211, 2007). The aim of this study was to describe the prevalence of associated anomalies, prenatal diagnostic accuracy and survival of cases of congenital duodenal atresia in our institution. Methods  All cases of duodenal atresia registered with our local congenital anomaly register over a 10-year period, 1995–2004 inclusive, were studied, including those resulting in termination of pregnancies, stillbirths, intrauterine deaths and neonatal deaths. To ensure high-case ascertainment, data were cross checked with prenatal ultrasound, cytogenetic laboratory, pathology department and neonatal surgical data base. Data were analysed for associated anomalies, accuracy of prenatal diagnosis and neonatal outcomes. Results  A total of 65 patients were initially diagnosed as having duodenal atresia, of these 4 were subsequently excluded (1 postnatal normal bowel and 3 high jejunal atresias). In the remaining 61 cases, 35 (57%) had an association with other congenital abnormalities and 26 (43%) were isolated anomalies. Thirty-five were male and 26 female (M:F = 1.4:1). Twenty-one out of 29 (72%) patients prenatally diagnosed, compared with 14 out of 32 (44%) patients diagnosed postnatally had associated anomalies. Duodenal atresia was suspected on routine prenatal ultrasonography at 20-week gestation in 33 cases and confirmed in 29 (48%) cases with 4 false-positive diagnoses (1 normal bowel and 3 high jejunal atresias). No prenatal diagnosis was made in 32 (52%) babies. Of the 61 cases, 53 were live births with 2 early neonatal deaths (1 cardiac and 1 VACTERL), 5 terminations, 2 intrauterine deaths and 1 stillbirth (Fig. 3). Overall neonatal survival was 96% (51 cases). Mortality in the group diagnosed prenatally was 34 % (10 cases). Conclusion  This study shows an overall increased association of duodenal atresia with Down’s syndrome. In the group diagnosed prenatally, mortality as well as the association with other congenital anomalies was found to be higher. We have demonstrated a greater prenatal diagnostic accuracy, but confirm postnatal outcomes similar to previous studies.     

肉碱棕榈酰转移酶Ⅱ缺乏症家系CPT2基因突变分析及产前诊断

分析肉碱棕榈酰转移酶Ⅱ（CPTⅡ）缺乏症患儿及其父母CPT2基因突变类型,为家系成员提供遗传咨询及产前诊断。先证者,女,于3个月时发烧8 h入院,血液酯酰肉碱谱分析显示棕榈酰肉碱显著增高,提示CPTⅡ缺乏症。收集患儿临床资料,采集患儿和父母外周血,提取基因组DNA,应用直接测序法进行CPT2基因5个外显子编码区及与外显子交界的部分内含子区域进行测序。患儿母亲于妊娠中期采取羊水,分取羊水细胞进行CPT2基因突变分析。Sanger测序发现先证者CPT2基因存在两个已知致病突变c.886C > T（p.R296X）和c.1148T > A（p.F383Y）,突变来自父母双方。母亲第二胎羊水细胞CPT2基因存在c.886C > T（p.R296X）,为致病基因携带者。胎儿出生后血液酯酰肉碱谱正常,发育正常。通过家系CPT2基因分析,证实了先证者死因为CPTⅡ缺乏症,在突变明确的前提下,成功地进行了下一胎同胞的产前诊断,为该家庭提供帮助。     

Fetal thoracic measurements in prenatal diagnosis of jeune syndrome

We describe prenatal sonographic findings in a 34-week fetus with Jeune syndrome or asphyxiating thoracic dystrophy (ATD). The long bones measured were less than third percentile; the thoracic circumference (TC) measured 216 mm (< 2.5th percentile); the abdominal circumference (AC) measured 303.5 mm (50th – 75th percentiles) and the rib cage perimeter (RCP) measured was 98 mm. The TC/AC was 0.70 (normal, 0.85) and the RCP/TC was 0.45 (normal, 0.68). Following birth diagnosis of Jeune syndrome was made based on radiographic analysis, which was subsequently confirmed by clinical and postmortem examination. This case highlights the utility of both TC/AC and RCP/TC in diagnosis of ATD and other skeletal dysplasias associated with a small thorax.     

Recent progress in non-invasive prenatal diagnosis

Although the first finding that fetal cells can enter the maternal circulation was made more than a century ago, it is still unclear if this finding will be translated into a clinically useful diagnostic tool in the foreseeable future. However, significant progress has been made via the analysis of cell-free fetal DNA in maternal plasma/serum and clinical services are now already being offered for the determination of fetal rhesus D status and sex. Currently, however, this technology is really only suited for the analysis of fetal genetic loci completely absent from the maternal genome. The detection of more subtle fetal genetic traits, such as point mutations involved in Mendelian disorders (thalassaemia, cystic fibrosis), is considerably more complex. Preliminary reports indicate that the detection of fetal aneuploidies might be possible using epigenetically modified genes, e.g. maspin on chromosome 18. Additionally, an exiting recent development is that it might be feasible to detect Down syndrome via the quantitative assessment of placentally derived cell-free mRNA of chromosome-21-specific genes such as PLAC4.     

1例Bartter综合征的家系基因突变分析和产前诊断

目的对1例Bartter综合征的家系进行相关致病基因突变分析和产前诊断。方法应用高通量捕获测序技术、PCR-Sanger测序法从基因组水平对先证者进行Bartter综合征相关致病基因的检测及家系分析;明确遗传学病因后进一步对已妊娠5个月的先证者母亲抽取羊水进行产前诊断。结果先证者编码氯通道蛋白CLC-Kb的CLCNKB基因存在c.88CT(p.Arg30*)和c.968+2TA复合杂合突变,其中c.88CT(p.Arg30*)为已报道的致病突变,c.968+2TA为新突变。家系分析显示这两个突变分别源自其母亲和父亲。产前诊断结果显示胎儿未遗传其父母的突变,为两个位点均正常的健康个体,随诊显示出生的婴儿健康,证实了基因诊断及产前诊断的准确性。结论 CLCNKB基因的复合杂合突变c.88CT(p.Arg30*)和c.968+2TA为先证者的病因,产前诊断可以预防该家系Bartter综合征的再发风险。     

4个甲基丙二酸尿症的家系基因突变分析及其胎儿产前诊断

目的 分析4 个甲基丙二酸尿症（MMA）的家系基因突变情况,阐明开展MMA 基因突变分析及产前诊断的意义。方法 对诊断为MMA 的先证者或其父母行相关基因的高通量测序,确定基因突变位点,并采用聚合酶链反应和直接测序法对家系行一代测序验证。家系1、3、4 于先证者母亲再次妊娠11~13 周时超声引导下行绒毛活检,进行早期产前诊断。结果 家系1 先证者父亲检出MUT 基因c.656A > T 杂合突变,先证者母亲检出c.729-730insTT 杂合突变;早期产前诊断发现胎儿为c.656A > T 和c.729-730insTT 双重杂合突变,终止妊娠。家系2 先证者检出MUT 基因c.1106G > A 和c.755-756insA 双重杂合突变,c.1106G > A 来自父亲,c.755-756insA 来自母亲。家系3 先证者检出MMACHC 基因c.217C > T 和c.609G > A 双重杂合突变,c.217C > T 来自父亲,c.609G > A 来自母亲;产前诊断提示胎儿携带c.609G > A 杂合突变,胎儿出生时脐血检测结果与产前诊断一致。家系4 先证者检出MMACHC 基因c.609G > A 和c.567dupT 双重杂合突变,c.609G > A 来自父亲,c.567dupT 来自母亲;产前诊断提示胎儿携带c.567dupT 杂合突变,胎儿顺利出生,脐血检测结果与产前诊断一致。结论 明确基因突变有助于MMA 家系行产前诊断,避免缺陷患儿出生。     

Cultural variation in values attached to informed choice in the context of prenatal diagnosis

One of the ethical implications of the widespread introduction of non-invasive prenatal diagnosis (NIPD) is that it might undermine the making of informed choices. There is an almost universal agreement among health professionals and policy makers that prenatal testing decisions should reflect informed choices. It is, however, unclear the extent to which this is a universally held value. We present evidence to suggest that although informed choice is highly valued in Western, individualistically orientated countries, it is less highly valued in non-Western, more collectivist countries. This raises questions as to whether it is beneficial - and indeed appropriate - to recommend facilitating informed choices in countries where this is not a dominant value.