BDNF基因二核苷酸多态性与儿童孤独症的关联研究

目的探讨脑源性神经生长因子(BDNF)基因二核苷酸多态性与儿童孤独症的关系。方法2001—2004在四川大学华西医院心理卫生中心及华西医院第二医院按照ICD-10及CCMD-3儿童孤独症诊断标准纳入研究对象,以儿童孤独症评定量表判断疾病的严重程度,并用儿童生长发育调查记录表进行一般情况评估。在华西医院心理卫生中心门诊收集75例儿童孤独症患者的临床资料,以孤独症核心家系为研究对象,用PCR扩增进行神经发育相关的BDNF基因的二核苷酸重复多态性位点的检测,采用传递不平衡检验进行统计分析。结果BDNF基因二核苷酸重复多态性与重度儿童孤独症存在关联或连锁不平衡(χ2=7.31,P=0.025)。结论重度儿童孤独症的发病可能与BDNF基因二核苷酸多态性有关,BDNF基因二核苷酸多态性在轻-中度和重度儿童孤独症中可能具有不同的遗传学作用。     

孤独症患儿甲基化CpG结合蛋白2基因突变研究

目的 了解孤独症患儿甲基化CpG结合蛋白2基因(MeCP2基因)的突变情况,探讨MeCP2基因在孤独症发病中的作用.方法 2004-2007年对中国医科大学附属盛京医院发育儿科的30例男性孤独症患儿(年龄2.5～5.5岁)进行研究.患者生后16～22个月起出现发育倒退(语言、社交倒退)、兴趣狭窄及刻版行为,经检查符合DSM-IV孤独症的诊断标准.根据文献对MeCP2基因编码外显子及侧翼序列设计引物,PCR扩增,产物纯化后直接测序.结果 对30例患儿进行MeCP2基因编码区的突变检测,未发现编码区突变.结论 MeCP2基因编码区突变可能不是孤独症的主要机制,有必要对孤独症患儿进行MeCP2基因的非编码区及调控区的突变分析.     

智力低下和孤独症男童脆性X基因突变的研究

目的应用改良基因检测方法,探讨脆性X综合征致病基因(fragileXmentalretardation"1,FMR1)在中国人群智力低下和孤独症中的作用。方法收集2002～2006年小儿神经、遗传代谢门诊诊断的男性孤独症患儿44例、非家族性智力低下男性患儿40例,建立适用于男性的FMR1基因突变检查方法,对检查阳性者以pfxa3探针进行Southern杂交。结果在44例孤独症患儿中,发现1例pfxa3杂交片段约0.2kb,为FMR1前突变;40例智力低下患者中FMR1基因未见异常。结论在孤独症人群中发现的1例FMR1基因前突变,其致病意义有待进一步阐明。     

以孤独症为主要表型的MYT1L基因突变嵌合体1例并文献复习北大核心CSCD

对2019年4月河南省儿童医院康复医学科就诊的1例孤独症谱系障碍(ASD)的MYT1L基因突变患儿临床表型和基因型进行回顾性分析。对患儿进行全基因组测序及拷贝数异常(CNVs)检测,并复习相关文献。该患儿存在MYT1L基因15号外显子错义突变(c.2186T>G,p.Met729Arg),患儿为嵌合体,突变率约为10%,该突变未在父母及患儿哥哥中出现。检索到MYT1L相关基因异常报道共18篇文献,共53例患者(含本例),包括22种点突变及30例携带包含MYT1L基因区域在内的2p25.3染色体条带微缺失患者。患者孤独症行为发生率为45.0%(18/40例)、超重/肥胖发生率为70.2%(33/47例)、智力障碍/全面发育迟缓发生率为96.2%(51/53例),嵌合体的症状相对较轻。提示MYT1L基因是ASD重要的易感基因,但嵌合体的症状较轻。ASD患儿共患肥胖或超重时应警惕可能存在MYT1L基因突变,可进行基因检测协助诊断并注意嵌合体存在的可能性,本研究扩大了ASD基因突变谱。     

孤独症筛查量表M-CHAT与CHAT-23的临床应用研究

目的：分析并比较M-CHAT与CHAT-23量表在临床的适用性,以期为了解孤独症患儿早期特异性临床表现提供依据。方法：选取350例18～36月龄来我院发育儿科就诊的儿童,其中284例在筛查前未诊断为孤独症的儿童作为筛查对象;68例（包括从284名筛查对象中诊断为孤独症患儿2例）诊断为孤独症的患儿为孤独症组;除外284例筛查对象中6例被诊断为孤独症、精神发育迟滞和脑瘫的患儿,余278例儿童为对照组。采用M-CHAT与CHAT-23量表对筛查对象进行孤独症筛查;比较孤独症组与对照组筛查量表各项目阳性率差异;分析并比较M-CHAT和CHAT-23的评价指标,衡量不同判定标准筛查的效果。结果：孤独症患儿量表阳性率最高的项目为第9项;除第16项外孤独症组与对照组量表各项目阳性率差异均有统计学意义（P0.05）。结论：CHAT-23特异度较M-CHAT高,同时成本低、易填写、耗时短、结果易判定,更适合临床筛查孤独症。     

神经连接蛋白-4基因3’UTR区多态性与孤独症患儿的关系

目的探讨神经连接蛋白-4(Neuroligin-4)基因多态性与中国汉族儿童孤独症的关系。方法选取Neuroligin-4基因上3’UTR区2个多态性位点rs3810687和rs3810688作为遗传标记,应用双脱氧链终止测序法对92个孤独症核心家系276名成员进行等位基因和基因型测定。对孤独症患儿及其父母分别进行Hardy-Weinberg平衡检验。在孤独症核心家系中应用单体型相对危险度分析(HRR)及传递不平衡检验(TDT)分析等位基因与孤独症的关系。结果 1.孤独症患儿及其父母观察值和预期值间差异均无统计学意义(Pa>0.05),研究对象均符合Hardy-Weinberg遗传平衡法则。2.在92个孤独症核心家系中,TDT检验显示rs3810687位点存在传递不平衡,C等位基因由杂合子父母传递给患病子代的频率高于A等位基因,差异有统计学意义(χ2=4.500,P=0.044);rs3810688位点2等位基因传递差异无统计学意义(χ2=0.362,P=0.630),由杂合子父母传递给患病子女的等位基因频率未偏离50%理论值。3.HRR分析结果与TDT检验结果一致:rs3810687位点存在传递不平衡,差异有统计学意义(χ2=12.556,P=0.000);rs3810688位点未见传递不平衡,差异无统计学意义(χ2=0.326,P=0.568)。结论 Neuroligin-4基因rs3810687位点与儿童孤独症相关,支持Neuroligin-4基因是孤独症的候选基因。     

伴语言倒退孤独症儿童53例社交障碍临床研究

目的　探讨病前具有一定语言功能(倒退型)孤独症儿童的临床特征。方法　对2 0 0 1年11月至2 0 0 3年10月就诊于中南大学湘雅二院精神卫生研究所符合美国精神障碍诊断和统计手册第4版(DSM -Ⅳ)孤独症诊断标准的儿童孤独症5 3例,根据病前是否有语言功能分为两组,倒退型组2 3例,非倒退型组30例。结果　倒退型组孤独症儿童较非倒退型组儿童在语言和社交方面损害明显,同时倒退型组假性社交型的发生率较高。结论　及时发现和识别孤独症儿童语言倒退及假性社交,是早期诊断有一定语言功能的儿童孤独症的关键。     

儿童孤独症谱系障碍与癫癎共患病的研究

目的探讨儿童孤独症谱系障碍(ASD)与癫癎的相关性。方法选取ASD患儿190例,采用自编问卷、儿童孤独症评定量表和孤独症行为量表对儿童ASD与癫癎相关问题进行调查。结果 190例ASD患儿中,20例(10.5%)曾有癫癎发作,12例(6.3%)被诊断为癫癎。有癫癎发作的ASD儿童1岁前出现体格发育问题及听力问题的比例较无癫癎发作的ASD儿童显著增高(P0.05);被诊断为癫癎的患儿及正接受癫癎治疗的患儿1岁前出现体格发育问题的比例显著增高(P0.05)。有癫癎发作的ASD儿童其感觉反应能力和行为能力较无癫癎发作的ASD儿童差(P0.05)。癫癎治疗对ASD儿童行为有正向影响(P0.05)。结论儿童ASD与癫癎患病有显著关联,可根据儿童1岁前生长发育状况、感觉反应能力和行为能力及有无癫癎发作评估二者共患的可能性。     

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目的探讨孤独症患儿头围发育情况。方法研究对象为中国医科大学附属盛京医院2009年9月至2011年6月确诊的孤独症患儿(孤独症组)156例,其中≤3岁74例,>3岁82例。同时选择健康儿童141名作为正常对照组,其中≤3岁58名,>3岁83名。分别测量两组头围并进行组间比较。结果孤独症组≤3岁患儿头围平均值与大头所占比例均大于正常对照组,两组差异有统计学意义(P<0.05)。孤独症组>3岁患儿头围平均值与大头所占比例与健康儿童基本相似,两组差异无统计学意义(P>0.05)。在除外大头患儿后,两组头围平均值比较差异无统计学意义(P>0.05)。结论孤独症患儿生后早期头围偏大,并且常伴大头,头围异常也是患儿重要的临床特征之一。了解孤独症头围发育可为孤独症的发病机制提供参考依据。     

三种儿童孤独症行为评定量表临床应用比较

目的　儿童孤独症的诊断缺乏特异性的生物学指标,量表评定有重要的临床指导价值,目前有多 种量表用于评定。该文对孤独症行为评定量表(ABC)、儿童期孤独症评定量表(CARS或卡氏量表)、克氏孤独症 行为量表(CABS或克氏量表)进行比较,以期为临床应用提供借鉴。方法　对28例孤独症患儿和34例对照组儿 童分别采用ABC、CARS和CABS进行评估和比较。结果　三种评估方法在病例组与对照组间的评定结果均有极 显著差异(P<0.01);DSM Ⅳ儿童孤独症诊断标准判断结果与CARS评估结果的一致性最好(Kappa=1),与ABC 也有较好一致性(Kappa=0.87),但与CABS的一致性稍差(Kappa=0.60)。应用受试者工作特性曲线(ROC)进行 综合比较,ABC取31为筛查界线分最好,其特异性为0.97、敏感性为0.89、一致率为0.94、阳性预测值为0.96、阴 性预测值为0.92,且更适合3岁以上儿童使用;CARS取30为诊断界线分最好,敏感性、特异性、一致性、阳性预测 值与阴性预测值均为1.0,且与年龄无关;CABS取6为筛查界线分更为理想,其特异性为0.91,敏感性为0.82、一 致率为0.87、阳性预测值为0.88、阴性预测值为0.86,且3岁以上儿童使用优于3岁以下。结论　ABC、CARS及 CABS是辅助诊断孤独症的重要评估工具,相互间具有较好的一致性;但如果同     

中国儿童孤独症SHANK3拷贝数变异及其临床表型特征

目的 检测典型孤独症患儿SHANK3基因拷贝数变异(CNVs)发生率并描述其临床表型特征,并探讨临床应用多重连接依赖探针扩增技术(MLPA)进行孤独症病因学诊断的可行性.方法 收集本院确诊为典型孤独症的患儿及其直系亲属的基因组DNA,采用MRC P343-C1 AUTISM-1MLPA试剂盒进行CNVs筛查.结果 共收集来自102个家系的109例典型孤独症患儿,男女比例为4.45:1.发现2例患儿出现SHANK3微缺失,检出率约为2%(2/109).结论 SHANK3基因的CNVs可能解释约2%的典型孤独症病例,是孤独症的一个重要遗传学变异基础;阳性病例倾向于出现严重的三大核心症状及智力缺损的表型;MLPA作为快速、准确的CNVs检测方法,有助于临床开展孤独症的病因学研究.

Abstract：

Objective To explore possible relationship between copy-number variations (CNVs) in 15q11-13,16p11 and SHANK3 gene by using multiplex ligation-dependent probe amplification (MLPA) and the phenotypes in children with autism and to further explore the clinical application of MLPA to make an etiological diagnosis of Autism. Methods The diagnosed of autism was made according to the criteria of the ICD-10 and DSM-Ⅳ, with typical cluster of symptoms comprise social disability, communication impairments and repetitious behaviors. MLPA KIT P343-C1 AUTISM-1 was used to detect and describe the incidence of CNVs in these three domains. Results Among 109 cases collected from 102 autistic pedigrees, 2 individuals had SHANK3 microdeletion, accounting for approximately 2% (2/109) of cases,suggesting the proportion of SHANK3 microdeletion might contribute to typical autism. The phenotypic traits of patients with SHANK3 microdeletions showed homogenicity in severe core symptoms and mental retardation. Conclusions SHANK3 microdeletion is an important genetics component for autism, which may explain 2% typical autism cases. SHANK3 microdeletion might explain autistic core symptoms and mental retardation. MLPA is a sensitive and a high throughput technique to detect CNVs in specific DNA segments,which is beneficial for further investigation of etiology of autism.     

Exploring the borderlands of autistic disorder and specific language impairment: a study using standardised diagnostic instruments

BACKGROUND: Two studies were conducted to test claims that pragmatic language impairment (PLI - previously referred to as semantic-pragmatic disorder) is simply another term for autistic disorder or pervasive developmental disorder not otherwise specified (PDDNOS). METHOD: In Study 1, 21 children aged from 6 to 9 years with language impairments were subdivided on the basis of the Children's Communication Checklist into 13 cases of pragmatic language impairment (PLI) and eight cases of typical specific language impairment (SLI-T). Parents completed the Autism Diagnostic Interview - Revised (ADI-R) and the Social Communication Questionnaire (SCQ), and the children were given the Autism Diagnostic Observation Schedule - Generic (ADOS-G). In Study 2, a further 11 children with SLI-T and 18 with PLI were assessed using the SCQ and ADOS-G. In addition, six children diagnosed with high-functioning autism and 18 normally developing children were assessed. RESULTS: There was good agreement between ADI-R and SCQ diagnoses, but poor agreement between diagnoses based on these parental report measures and those based on ADOS-G. In many children, symptom profiles changed with age. Four PLI children from Study 1 and one from Study 2 met criteria for autistic disorder on both parental report (ADI-R or SCQ) and ADOS-G. Many of the others showed some autistic features, but there was a subset of children with pragmatic difficulties who were not diagnosed as having autism or PDDNOS by either instrument. These children tended to use stereotyped language with abnormal intonation/prosody, but they appeared sociable and communicative, had normal nonverbal communication, and showed few abnormalities outside the language/social communication domains. CONCLUSIONS: Presence of pragmatic difficulties in a child with communication problems should prompt the clinician to evaluate autistic symptomatology, but it is dangerous to assume that all children with pragmatic difficulties have autism or PDDNOS.     

叶酸和维生素B12与孤独症谱系障碍儿童症状和发育水平相关性研究

目的　探讨孤独症谱系障碍（ASD）儿童与正常儿童之间叶酸及维生素B12（VB12）水平的差异,并分析叶酸和VB12水平与ASD儿童症状及发育水平的相关性。方法　对2016—2017年海南省妇幼保健院康复中心的244例ASD儿童采用孤独症行为量表（ABC）、社交反应量表（SRS）评估ASD儿童的症状,采用Gesell发育量表（GDS）评估ASD儿童的发育水平,同期选取93名海口市幼儿园的健康儿童作为对照组,采用免疫测定法检测两组儿童血清叶酸、VB12水平。结果　244例ASD儿童血清叶酸水平（10.68±4.08）明显低于93名正常儿童（11.83±4.37）（P＝0.02）,VB12浓度在两组之间差异无统计学意义（P＞0.05）。叶酸和VB12浓度与ABC、SRS量表无相关关系。叶酸水平与GDS中的适应性行为（rs＝0.17,P＝0.01）、大运动（rs＝0.29,P＜0.01）、精细动作（rs＝0.13,P＝0.04）、语言（rs＝0.13,P＝0.04）以及个人-社会行为（rs＝0.14,P＝0.03）均有明显正相关关系。VB12与GDS各能区无相关关系。结论　ASD儿童较正常儿童叶酸水平更低。叶酸水平与ASD儿童症状量表无明显相关性,与其发育水平具有明显正相关关系,叶酸可能与神经心理发育水平关系密切,其补充可能成为ASD儿童的辅助治疗手段之一。     

Assessment of metallothionein and antibodies to metallothionein in normal and autistic children having exposure to vaccine-derived thimerosal

Allergic autoimmune reaction after exposure to heavy metals such as mercury may play a causal role in autism, a developmental disorder of the central nervous system. As metallothionein (MT) is the primary metal-detoxifying protein in the body, we conducted a study of the MT protein and antibodies to metallothionein (anti-MT) in normal and autistic children whose exposure to mercury was only from thimerosal-containing vaccines. Laboratory analysis by immunoassays revealed that the serum level of MT did not significantly differ between normal and autistic children. Furthermore, autistic children harboured normal levels of anti-MT, including antibodies to isoform MT-I (anti-MT-I) and MT-II (anti-MT-II), without any significant difference between normal and autistic children. Our findings indicate that because autistic children have a normal profile of MT and anti-MT, the mercury-induced autoimmunity to MT may not be implicated in the pathogenesis of autism.     

Executive functioning in high-functioning children with autism

Executive functioning was investigated in 34 children (24 boys and 10 girls) with developmental language disorder (DLD) and 21 children (18 boys and 3 girls) with high-functioning autistic disorder (HAD) matched on Full Scale IQ, Nonverbal IQ, age (mean age 9 year, 1 month), and SES. The DLD group had a Verbal IQ that was 10 points higher than the HAD group. These children were given the Wisconsin Card Sorting Test (WCST), the Mazes subtest from the WISC-R, the Underlining test, and the Rapid Automatized Naming test. In addition, these children were given the Vineland Scales of Adaptive Functioning and the Wing Diagnostic Symptom Checklist in order to assess severity of autistic symptomatology. Results indicated that the only significant difference between the two groups on the cognitive tasks was perseverative errors on the WCST; there was no significant difference on total number of categories achieved or total number of errors on the WCST or on the other executive function measures. There was also significant overlap in the scores between the two groups and the difference in perseverative errors was no longer significant when Verbal IQ was partialled out. Executive functioning was strongly related to all IQ variables in the DLD group and particularly related to Verbal IQ in the HAD group. Although there was a relationship in the HAD group between executive functioning and adaptive functioning, as well as between executive functioning and autistic symptomatology, these relationships were generally no longer significant in the HAD group after the variance due to Verbal IQ was accounted for. The results are interpreted to indicate that although impaired executive functioning is a commonly associated feature of autism, it is not universal in autism and is unlikely to cause autistic behaviors or deficits in adaptive function.     

孤独症儿童父母心理健康状态的研究

目的：研究孤独症患儿家长的心理健康状态。方法：采用症状自评量表(SCL-90)对34名孤独症儿童和35名健康儿童的父母亲进行评分。结果：孤独症儿童父母亲SCL-90总分分别为162.5±34.0,175.1±51.0,均高于正常儿童的父母亲(分别为142.4±82.8,152.3±40.6;P<0.05)。孤独症儿童的父亲在强迫症状、忧郁、焦虑、偏执等4个因子上的分数高于健康儿童的父亲（P<0.05）;孤独症儿童的母亲在强迫症状、人际关系敏感、忧郁、焦虑、偏执、敌对性、精神病性和睡眠/饮食等8个因子的分数较正常儿童的母亲高（P<0.05）;在人际关系敏感、焦虑、精神病性症状因子上,孤独症儿童的母亲得分较父亲高（P<0.05）。结论：在对孤独症儿童给与关爱和治疗的同时,也要关注孤独症儿童父母的心理健康。［中国当代儿科杂志,2010,12(12)：947-949］     

Autistic and dysphasic children. I: Clinical characteristics

Autism and dysphasia are behaviorally defined disorders of higher cerebral function which in preschool children share the common core symptom of impairment of language. In this study we describe the clinical characteristics of 314 autistic and 237 dysphasic nonautistic children evaluated by one child neurologist. There was no significant difference between autistic and dysphasic children in gestational age, birth weight, or prevalence of associated medical disorders, all of which were infrequent, although a positive history of resuscitation or ventilatory support was more common in dysphasic than autistic children (P = .03). As a group autistic children are more likely than dysphasic children to have language subtypes affecting central processing and formulation, a family history of psychiatric disorders and autism, and a history of regression of language and behavior. After excluding 12 girls with autistic symptoms who met the clinical criteria for Rett syndrome, we found that there was no significant difference in the number of autistic and dysphasic children with an abnormal sensorimotor examination. Girls with autism were more likely than boys to have severe mental deficiency (38% of autistic girls vs 23% of boys) (P = 0.012) and a motor deficit (27% vs 11%) (P = .0009).     

The incidence of autism in Olmsted County, Minnesota, 1976-1997: results from a population-based study

OBJECTIVE: To determine the incidence of autism among children in Olmsted County, Minnesota. DESIGN: Through the Rochester Epidemiology Project, all inpatient and outpatient diagnoses are indexed for computerized retrieval. This computerized diagnostic index was used to identify children with any developmental disorder. A glossary of symptoms of autism was used to review medical and school records of these children for symptoms consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for autistic disorder. SETTING: Olmsted County, Minnesota.Subjects All residents of Olmsted County 21 years or younger between 1976 and 1997.Main Outcome Measure The incidence of research-identified autism based on DSM-IV criteria for autistic disorder. RESULTS: The age-adjusted incidence of research-identified autism was 5.5 (95% confidence interval, 1.4-9.5) per 100 000 children from 1980 to 1983 and 44.9 (95% confidence interval, 32.9-56.9) from 1995 to 1997 (8.2-fold increase). This increase was confined to children younger than 10 years who were born after 1987. CONCLUSIONS: The incidence of research-identified autism increased in Olmsted County from 1976 to 1997, with the increase occurring among young children after the introduction of broader, more precise diagnostic criteria, increased availability of services, and increased awareness of autism. Although it is possible that unidentified environmental factors have contributed to an increase in autism, the timing of the increase suggests that it may be due to improved awareness, changes in diagnostic criteria, and availability of services, leading to identification of previously unrecognized young children with autism.     

Porphyrinuria in childhood autistic disorder is not associated with urinary creatinine deficiency

Background: Urinary metabolite measurements are often normalized to levels of the ubiquitous metabolite creatinine (CRT) to take account of variations in fluid export. Following CRT normalization, excesses of porphyrins and isoprostanes have been reported in the urines of children with neurodevelopmental disorders. It was suggested (Whiteley et al. , 2006, Pediatr. Int. 2006; 48 : 292–297) that urinary CRT levels may be depressed in children with autism spectrum disorders. This prompted re-evaluation of CRT levels in such children.
Methods: First matinal urinary CRT levels were compared between subjects in different diagnostic categories including autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS) and hyperactivity, before and after correction for age and gender. A larger reference group, consisting of subjects with unrelated disorders and Asperger disorder, with no reported porphyrin excess, was also compared to the group with autistic disorder, both for CRT and for porphyrin (coproporphyrin, COPRO) excess.
Results: No significant difference in CRT was observed between any of the categories analyzed, also when corrected for age and gender. In contrast, urinary COPRO levels were significantly higher in autistic disorder versus reference groups, either when expressed as absolute values (independent of CRT levels) or when normalized to CRT.
Conclusions: These data do not support a systematic reduction in urinary CRT levels in subjects with autism spectrum disorders including autistic disorder and PDD-NOS. Urinary COPRO excess in autistic disorder was not associated with or consequent upon urinary CRT deficiency. Differences between affected and control subjects in age and sampling time, as reported by Whiteley et al. , may underlie the apparent CRT reduction.