信息动态

目的 利用MassArray基因分型技术对苯丙酮尿症(PKU)患儿家系致病基因进行检测,探讨该技术应用于孕前、产前和新生儿PKU预测与诊断的可行性.方法 采用新生儿遗传代谢病常规检测与串联质谱相结合的方式,在烟台地区筛查到2例PKU患儿,利用MassArray技术对PKU患儿及亲属苯丙氨酸羟化酶(PAH)基因突变位点进行检测,寻找可能的致病突变位点,并采用下一代测序技术对MassArray基因检测结果进行验证.结果 在2个家系样本中发现4种基因突变.突变位点是c.158G＞A,c.1197A ＞T,c.728G＞A,C.442-1G ＞A.结论 MassArray基因分型技术可快速对PKU基因突变位点进行检测,随着检测突变位点的增加,可为PKU的预测与基因确诊提供有效的临床参考依据.     

西北地区751例新生儿耳聋基因突变筛查

目的初步了解西北地区新生儿常见耳聋基因突变类型和携带率,探讨耳聋基因突变筛查对于辅助诊断和防治新生儿遗传性耳聋的临床价值。方法采集西北地区751例新生儿的足跟血,采用15项遗传性耳聋基因检测试剂盒(微阵列芯片法)对中国人群常见4种耳聋基因15个突变位点进行筛查。结果在751例新生儿中,检测到39例新生儿携带耳聋基因突变,总突变携带率为5.18%。其中GJB2基因突变19例,突变携带率为2.53%;SLC26A4基因突变16例,突变携带率为2.12%;线粒体12SrRNA 1555A>G均质突变4例,突变携带率为0.53%。新疆出生的新生儿279例中,检测到耳聋基因突变11例,突变携带率3.95%;甘肃省出生的新生儿277例中,检测到耳聋基因突变12例,突变携带率4.32%;陕西省出生的新生儿178例中,检测到耳聋基因突变12例,突变携带率6.74%;青海省出生的新生儿17例中,检测到耳聋基因突变4例,突变携带率23.52%。结论西北地区新生儿耳聋基因突变携带率偏高,但是GJB2基因235 del C位点的突变携带率偏低,可能与西北地区的地域特征和人口遗传学特点有关。新生儿耳聋基因筛查对于听力筛查具有很好的互补作用,可以从基因水平发现可能出现迟发性耳聋和药物敏感性耳聋的高危新生儿。     

有机阴离子转运体1B1基因与新生儿黄疸关系的研究进展

有机阴离子转运体2(OATP2)是一种肝细胞膜上转运胆红素等物质的转运体,影响胆红素的代谢.OATP2 由有机阴离子转运体1B1(SLCO1B1)基因编码,该基因突变可抑制OATP2 的转运功能,致胆红素清除减慢,引起高胆红素血症.近年的研究显示,SLCO1B1 基因多态性可能与新生儿黄疸发生相关.该文综述了SLCO1B1 基因结构、功能及SLCO1B1 基因突变与新生儿黄疸的关系.     

新生儿高未结合胆红素血症遗传因素的研究

目的：探讨尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）Gly71Arg、TATA盒基因突变和葡萄糖-6-磷酸脱氢酶（G6PD）基因突变与新生儿高未结合胆红素血症的关系。方法：UGT1A1 TATA盒、外显子1、外显子5和G6PD基因外显子12经PCR扩增和测序,构建突变样本的克隆,对其进行验证。分析病例组及对照组UGT1A1 Gly71Arg和TATA盒基因多态性频率的差异,应用logistic回归分析基因突变对新生儿高未结合胆红素血症发生的影响。结果：病例组UGT1A1 Gly71Arg基因多态性的基因型分布与对照组比较差异有统计学意义（P0.05）。Logistic回归分析显示UGT1A1 Gly71Arg、TATA盒基因和G6PD基因突变对新生儿高未结合胆红素血症发生的OR值（95％CI）分别为5.468（2.274,12.818）、0.688（0.266,1.778）和5.081（1.070,24.133）。结论：UGT1A1 Gly71Arg和G6PD基因突变可能是新生儿高未结合胆红素血症发生的原因。     

Research progress in neonatal hypoglycemic brain injury

<正>新生儿低血糖是早产儿、小于胎龄儿及糖尿病母亲婴儿等的常见并发症,目前对新生儿低血糖的诊断与临床干预有了较深入的认识,但是新生儿低血糖出现脑损伤的血糖阈值和时间域值并不清楚,持续或反复的低血糖可导致新生儿永久性脑损伤,遗留认知障碍、视觉障碍、枕叶癫癎、脑瘫等后遗症。部分临床医师对新生儿低血糖性脑损伤也缺乏充分的认识,诊断标准有待建立[1]。现就新生儿低血糖     

格列本脲治疗6q24暂时性新生儿糖尿病一例

新生儿糖尿病(neonatal diabetes mellitus, NDM)是一种罕见的基因异质性疾病。迄今为止, NDM至少与26个基因的遗传缺陷有关。其特点是生后6个月内起病, 持续存在严重的高血糖, 持续时间至少2周, 由于胰岛素分泌不足需要依赖外源性胰岛素治疗[1, 2]。NDM的发病率约为1/(40～50)万活产婴儿[3]。NDM诊断需注意与其他引起新生儿高血糖症的病因如肠外静脉输注葡萄糖速度过快、窒息、感染、颅脑损伤、低体温、体外膜肺氧合的应用、类固醇激素药物应用等相鉴别[1, 4, 5]。对疑似NDM患儿的初步评估应包括血糖、尿酮、C肽、胰岛素的实验室评估, 并应进行胰腺超声检查[6]。根据临床表型不同, NDM分为暂时性新生儿糖尿病(transient neonatal diabetes mellitus, TNDM)、永久性新生儿糖尿病(permanent neonatal diabetes mellitus, PNDM)、症状性糖尿病[1, 2, 7, 8]。本研究报道1例TNDM患者, 总结其临床表现、基因特点及诊疗过程, 以期增强临床医师对TNDM的认识, 及...     

新生儿难治性惊厥STXBP1基因突变的研究

目的 探讨STXBP1 基因突变与不明原因新生儿难治性惊厥的关系。方法 应用直接测序法对11 例原因不明的新生儿难治性惊厥患儿进行STXBP1 编码区的突变检测。结果 11 例患儿中,1 例检测到STXBP1 基因突变。突变类型为错义突变,突变位点c.1439C>T（p.P480L）。结论 在新生儿难治性惊厥患儿中,可检测到STXBP1 基因突变,为该类疾病的深入研究提供了新的思路。     

10例原发性肉碱缺乏症新生儿的基因诊断

目的对新生儿原发性肉碱缺乏症(PCD)基因突变谱进行分析,为PCD早期诊断和治疗以及遗传咨询和产前诊断提供理论依据。方法对进行新生儿串联质谱筛查的34 167份滤纸干血片进行血酰基肉碱谱分析,对其中游离肉碱(C0)低于10μmol/L的新生儿及父母行SLC22A5基因测序。结果酰基肉碱谱筛查C0低于10μmol/L的新生儿10例,患儿母亲游离肉碱均未见降低,10例患儿的SLC22A5基因测序检测到10种20个突变位点,其中c.976CT、c.919del G、c.517del C、c.338GA未见报道,生物信息学分析提示高致病风险。结论串联质谱技术结合SLC22A5基因测序有助于PCD早期诊断,新突变的发现丰富了SLC22A5基因突变谱。     

基因芯片技术用于广西柳州地区G-6PD缺乏症基因突变的检测

目的明确广西柳州地区葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症基因突变类型.方法聚合酶链反应扩增柳州地区籍44例G6PD缺乏症足月新生儿和30例G6PD活性对照者的DNA标本相应片断,扩增产物与G6PD缺乏症诊断芯片杂交,扫描仪检测荧光信号强度,作出基因诊断.结果44例G6PD缺乏症的DNA标本中,检出1388G→A20例(基因频率43.1%)、1376G→T9例(基因频率21.6%)、95A→G 6例(基因频率15.7%)、392G→T 5例(基因频率11.8%)、1024C→T 1例(基因频率1.9%)、未知突变3例(基因频率5.8%).结论基因芯片诊断技术是检测G6PD缺乏症基因突变的有效方法,可在临床推广应用.     

高危新生儿听力和聋病易感基因联合筛查临床研究

目的探讨高危新生儿听力和聋病易感基因联合筛查的临床意义。方法选择2012年5月至2014年2月入住南方医科大学附属佛山市妇幼保健院新生儿重症监护室的920例具有听力损失高危因素的新生儿为研究组,选取同期产后区938例健康新生儿为对照组,于生后检测GJB2基因35del G、176-191del16、235del C、299-300del AT;SLC26A4基因IVS7-2AG、2168AG;线粒体12Sr RNA基因1494CT、1555AG等3个基因8个突变位点;听力筛查复筛未通过者于3月龄行听力学诊断。结果研究组920例检出35例聋病基因携带,3个基因突变的总体携带率3.8%;检出听力障碍34例(3.7%)、其中重度以上听力障碍15例(1.6%);30例(85.7%)聋病基因携带者通过了听力筛查。对照组938例检出21例聋病基因携带,3个基因突变的总体携带率2.2%;检出听力障碍4例(0.4%)、重度以上听力障碍1例(0.1%);17例(1.8%)聋病基因携带者通过了听力筛查。研究组听力损失和重度以上听力损失检出率、聋病基因突变的总携带率及聋病基因携带者的听力筛查通过率与对照组比较差异均有显着性(均P0.05)。结论高危新生儿听力障碍的检出率和聋病基因突变携带率均高于正常新生儿;采用听力和聋病易感基因联合筛查能及时发现常规通过听力筛查但具有耳聋高危因素和迟发性聋病遗传因素的新生儿,对早期干预、定期随访、减少聋病发生具有指导意义。     

Transient neonatal diabetes with two novel mutations in the KCNJ11 gene and response to sulfonylurea treatment in a preterm infant

Neonatal diabetes mellitus (NDM) is a rare condition that can be either transient or permanent. K(ATP) channel (Kir6.2 or SUR1) mutation, chromosome 6 abnormalities, insulin, or glucokinase gene mutations can lead to isolated NDM. Cases caused by Kir6.2 mutation usually result in permanent NDM (PNDM) rather than transient NDM (TNDM). The majority of patients with the Kir6.2 or SUR1 mutation can be successfully managed with a sulfonylurea agent, without the need for insulin. We report a preterm male with NDM having two novel missense mutations, E322A and D352H, in the KCNJ11 gene. At 2 months of age, successful transition from insulin to glibenclamide (glyburide) therapy of the patient was managed. At 5 months of age, his diabetes went in to remission.     

Neonatal diabetes mellitus and KCNJ11 gene mutation: report of a family case

Neonatal diabetes mellitus (NDM) is characterized by hyperglycemia within the first month of life and insulin dependence for at least two weeks. There are two types of NDM, transient (TNDM) and permanent (PNDM), which are genetically different. We report the case of two brothers who developed hyperglycemia without ketosis on the 18th day and 2 h of life, respectively. Thyroid function tests, abdominal ultrasound and karyotype where normal and there were no pancreatic antibodies. The first one required insulin therapy for the first 92 days of life and the second for 5 months. The mother developed gestational diabetes during both pregnancies and she was later diagnosed diabetes mellitus (without antibodies). They were studied for mutations in KCNJ11 gene (principally related to the permanent form). The three of them showed the E229K mutation (frequently associated with the transient form). A genetic study is essential in NDM to achieve the most accurate prognosis possible.     

Neonatal diabetes mellitus due to L233F mutation in the KCNJ11 gene

Background

Neonatal diabetes mellitus (NDM) due to KCNJ11 gene mutation presents with diabetes in the first 3 months of life and sometimes with neurological features like developmental delay, muscle weakness and epilepsy.

Methods

A 5-week-old boy presented with diabetic ketoacidosis. Molecular genetic analysis of the patient revealed heterozygous missense mutation, L233F in the KCNJ11 gene, while his mother was mosaic for the same mutation.

Results

The treatment strategy was changed from insulin injections to oral glibenclamide and with a better glycemic control.

Conclusion

The patient with NDM due to mutation L233F (not reported till date) in the KCNJ11 gene can be successfully treated with oral glibenclamide therapy.     

Neonatal diabetes mellitus because of pancreatic agenesis with dysmorphic features and recurrent bacterial infections

Abstract:  Pancreatic agenesis is a rare cause of neonatal diabetes mellitus (NDM). It can be associated with malformations of the heart, the biliary tract, and the cerebellum. We report an infant with NDM because of pancreatic agenesis, intra-uterine growth retardation, dysmorphic features, and recurrent bacterial infections. He was born to healthy consanguineous parents. With adequate replacement of insulin and pancreatic enzymes, his blood glucose levels were controlled and his weight slowly increased. However, he continued to develop recurrent serious bacterial infections and died at the age of 11 months with sepsis and respiratory failure. Analysis of the PTF1A and PDX1 genes, which have been associated with congenital agenesis of the pancreas, did not reveal any mutation. Genetic abnormalities of chromosome 6 associated with transient neonatal diabetes as well as mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic potassium channel were also excluded as a cause of the NDM in this patient. The association of permanent neonatal diabetes because of pancreatic agenesis, dysmorphism, and non-specific immunodeficiency is previously undescribed and may represent a new possibly autosomal recessive syndrome.     

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目的观察格列本脲治疗新生儿糖尿病(NDM)的疗效。方法收集2010年4月至2011年1月于我院收治并确诊为NDM的4例患儿临床资料,对其进行用格列本脲替代胰岛素治疗的前瞻性研究,分析用格列本脲治疗NDM的方法及疗效,并进行KCNJ11基因和ABCC8基因分析。结果 4例患儿出生体重2.5~3.0kg,就诊年龄3d至2个月,来诊时血糖均明显升高(30.5~45.3mmol/L),均伴有酮症酸中毒。入院后均给予胰岛素治疗,酮症酸中毒纠正,血糖降至15mmol/L以下时,给予格列本脲替换胰岛素治疗,其中2例(50%)格列本脲用量分别为每天0.5mg/kg及0.6mg/kg时可完全停用胰岛素。随访至观察截止日分别为9个月及7个月,均仍然需服用格列本脲每天0.3mg/kg,血糖基本正常,未见明显副反应发生。例2患儿的KCNJ11基因中发现一个突变(R201H),其余3例未发现突变。结论部分NDM患儿应用格列本脲治疗有效,可免除胰岛素注射的痛苦,因此对确诊NDM的患儿应试用本药治疗;同时对NDM患儿应进行KCNJ11基因和ABCC8基因分析,有助于本病临床预后的判断。     

Incidence of neonatal diabetes in Austria–calculation based on the Austrian Diabetes Register

Wiedemann B, Schober E, Waldhoer T, Koehle J, Flanagan SE, Mackay DJG, Steichen E, Meraner D, Zimmerhackl LB, Hattersley AT, Ellard S and Hofer S. Incidence of neonatal diabetes in Austria–calculation based on the Austrian Diabetes Register.
Background: Neonatal diabetes mellitus (NDM) is a rare monogenic form of diabetes which is diagnosed in the first 6 months of life. Several studies in the last few years provide information on genetic causes for NDM.
Objective: The aim of this study was to identify all patients with diabetes in the first 6 months of life through the Austrian Diabetes Register, which is available since 1989. A retrospective data analyses was performed to calculate the current incidence of NDM.
Subjects and Methods: Ten patients were registered with diabetes onset within the first 6 months of life in the Austrian Diabetes Register. Evaluation of detailed clinical data was performed by sending a questionnaire to all diabetes centers.
Results: Ten patients from nine different families with NDM were diagnosed in Austria from 1989 until September 2007. Seven patients (one male, six females) had transient NDM (TNDM), three (two males, one female) showed a permanent course [permanent neonatal diabetes mellitus (PNDM)]. One had immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome and another showed aplasia of the pancreas; no genetic etiology was found in the third case. In three out of seven patients with a transient course of NDM a genetic diagnosis was possible. Two female siblings had activating point mutations in the ABCC8 gene, although one patient had paternal uniparental isodisomy of chromosome 6q24. One patient's family did not consent to genetic testing.
Conclusions: The incidence of NDM in Austria is 1/160 949, with an incidence of 1/ 536 499 for PNDM and 1/229 928 for TNDM.     

Successful sulfonylurea treatment of an insulin‐naïve neonate with diabetes mellitus due to a KCNJ11 mutation

Wambach JA, Marshall BA, Koster JC, White NH, Nichols CG. Successful sulfonylurea treatment of an insulin‐naïve neonate with diabetes mellitus due to a KCNJ11 mutation. Activating mutations in the K_ATP‐channel cause neonatal diabetes mellitus (NDM), and patients have been safely transitioned from insulin to sulfonylureas. We report a male infant with permanent NDM (PNDM), born to a PNDM mother. Blood glucose began to rise on day of life (DOL) 2, and sulfonylurea (glyburide) therapy was initiated on DOL 5. Glucose was subsequently well controlled and normal at 3 months. A K_ATP mutation (R201H; KCNJ11) was detected in the infant, the mother, and 6‐yr‐old sister with PNDM; both were also subsequently transitioned off insulin onto glyburide. To our knowledge, this is the youngest NDM patient to receive oral glyburide and, importantly, the only one deliberately initiated on sulfonylureas. Strikingly, the current dose (0.017 mg/kg/d) is below the reported therapeutic range and approximately 75‐fold lower than doses required by the affected sister and mother. Pancreatic insulin disappears in an animal model of K_ATP‐induced NDM, unless glycemia is well controlled, thus, a dramatically lower glyburide requirement in the infant may reflect preserved insulin content because of early sulfonylurea intervention. Safe and effective initiation of glyburide in an insulin‐naïve neonatal patient with K_ATP‐dependent PNDM argues for early detection and sulfonylurea intervention.     

Epidemiology,clinical characteristics,and genetic etiology of neonatal diabetes in Japan

Neonatal diabetes mellitus (NDM) is a rare but potentially devastating metabolic disorder, with a reported incidence of one per 300 000–500 000 births generally, and hyperglycemia develops within the first 6 months of life. NDM is classified into two categories clinically. One is transient NDM (TNDM), in which insulin secretion is spontaneously recovered by several months of age, but sometimes recurs later, and the other is permanent NDM (PNDM), requiring lifelong medication. Recent molecular analysis of NDM identified at least 12 genetic abnormalities: chromosome 6q24, KCNJ11, ABCC8, INS, FOXP3, GCK, IPF1, PTF1A, EIF2AK3, GLUT2, HNF1β, and GLIS3. Of these, imprinting defects on chromosome 6q24 and the KCNJ11 mutation have been recognized as the major causes of TNDM and PNDM, respectively, in Caucasian subjects. Although the pathogenesis and epidemiology of NDM in Japan seem to be clinically distinct, they are still unclear. In this review, we summarize the epidemiology, clinical characteristics, and genetic etiology in Japanese patients with NDM compared with the data on Caucasian patients.     

新生儿糖尿病研究进展

大部分新生儿糖尿病(NDM)发柄与基因突变有关,部分NDM应用磺脲类药物治疗可取得良好疗效。新近研究从分子水平上阐明了NDM的发病机制及磺脲类药物的作用机制。另有研究表明糖化白蛋白是反映NDM血糖控制的有用指标。文章综述近年对NDM研究的进展。