·編者按·
自閉癥
·編者按·
自閉癥(autism),又稱(chēng)孤獨(dú)癥或孤獨(dú)障礙,是廣泛性發(fā)育障礙的代表性疾病。基本的病理特征是情緒表達(dá)困難、社交互動(dòng)障礙、語(yǔ)言和非語(yǔ)言的溝通有問(wèn)題,以及日常上常見(jiàn)的,表現(xiàn)出限制的行為與重復(fù)的動(dòng)作,明顯的特定興趣。不能進(jìn)行正常的語(yǔ)言表達(dá)和社交活動(dòng),常做一些刻板和重復(fù)性的動(dòng)作和行為。智能發(fā)展不平衡,有“孤島”現(xiàn)象(即某一個(gè)方面的智能,如暗記力等特別優(yōu)秀)。1908年,德國(guó)醫(yī)師Bleuler最早使用自閉癥一詞描述曾為一般人士但卻突然無(wú)法再與他人溝通且具有極端孤立的成人精神分裂癥患者。1943年,美國(guó)醫(yī)師Kanner首次正式報(bào)道了11例具有共同自閉表現(xiàn)的患兒,將其命名為早發(fā)性嬰兒自閉癥(early infantile autism)。
到目前為止,人們對(duì)自閉癥的致病機(jī)制尚未完全闡明。國(guó)際上許多的研究者,把自閉癥的原因歸結(jié)為心因性的問(wèn)題,但其他一些研究者則把自閉癥歸結(jié)為生理學(xué)的原因。一般認(rèn)為,自閉癥的致病因素包括遺傳因素和環(huán)境因素。近幾十年來(lái),隨著生命科學(xué)的發(fā)展,對(duì)于自閉癥的研究和理解也越來(lái)越深入,從早期的臨床病理層面,逐步深入到細(xì)胞以及分子的病理層面,使得人們對(duì)于自閉癥的發(fā)生、病程進(jìn)展以及治療有了更全面和精細(xì)的了解。目前的研究結(jié)果顯示:自閉癥并不是神經(jīng)系統(tǒng)的嚴(yán)重的、器質(zhì)性的損傷,而是與神經(jīng)系統(tǒng)的發(fā)育過(guò)程密切相關(guān),其中最重要的則是與神經(jīng)突觸功能有關(guān)。
針對(duì)不同的影響因素,已有多種對(duì)自閉癥的干預(yù)方法。主要包括生物和非生物療法。生物療法包括:抗生素、藥物和飲食等。其他治療方法包括以促進(jìn)人際關(guān)系為基礎(chǔ)的療法、以技巧發(fā)展為基礎(chǔ)的干預(yù)療法、基于生理學(xué)的干預(yù)療法等。雖然這些療法都有患者在使用,也還沒(méi)有切實(shí)有效的針對(duì)核心癥狀的治療方法。2016年1 月26日,中科院上海生命科學(xué)研究院神經(jīng)科學(xué)研究所仇子龍研究組與該研究所蘇州非人靈長(zhǎng)類(lèi)研究平臺(tái)孫強(qiáng)團(tuán)隊(duì)在《自然》雜志發(fā)表論文,報(bào)道了他們成功構(gòu)建攜帶人類(lèi)自閉癥基因MeCP2突變的轉(zhuǎn)基因猴,并且通過(guò)分子遺傳學(xué)與行為學(xué)分析,發(fā)現(xiàn)MeCP2轉(zhuǎn)基因猴表現(xiàn)出類(lèi)人類(lèi)自閉癥的刻板行為與社交障礙等行為。該研究首次建立了攜帶人類(lèi)自閉癥基因的非人靈長(zhǎng)類(lèi)動(dòng)物模型,為深入研究自閉癥的病理與探索可能的治療干預(yù)方法提供了重要基礎(chǔ)。
本專(zhuān)題得到仇子龍研究員(中國(guó)科學(xué)院上海神經(jīng)科學(xué)研究所)、楊廣學(xué)教授(華東師范大學(xué))、白學(xué)軍教授(天津師范大學(xué))的大力支持。
·熱點(diǎn)數(shù)據(jù)排行·
截至2016年1月26日,中國(guó)知網(wǎng)(CNKI)和Web of Science(WOS)的數(shù)據(jù)報(bào)告顯示,以“自閉癥”為詞條可以檢索到的期刊文獻(xiàn)分別為2577與 7109條,本專(zhuān)題將相關(guān)數(shù)據(jù)按照:研究機(jī)構(gòu)發(fā)文數(shù)、作者發(fā)文數(shù)、期刊發(fā)文數(shù)、被引用頻次進(jìn)行排行,結(jié)果如下。
研究機(jī)構(gòu)發(fā)文數(shù)量排名(CNKI)
研究機(jī)構(gòu)發(fā)文數(shù)量排名(WOS)
作者發(fā)文數(shù)量排名(CNKI)
作者發(fā)文數(shù)量排名(WOS)
期刊發(fā)文數(shù)量排名(CNKI)
期刊發(fā)文數(shù)量排名(WOS)
根據(jù)中國(guó)知網(wǎng)(CNKI)數(shù)據(jù)報(bào)告,以“自閉癥”為詞條可以檢索到的高被引論文排行結(jié)果如下。
國(guó)內(nèi)數(shù)據(jù)庫(kù)高被引論文排行
根據(jù)Web of Science統(tǒng)計(jì)數(shù)據(jù),以“自閉癥”為詞條可以檢索到的高被引論文排行結(jié)果如下。
國(guó)外數(shù)據(jù)庫(kù)高被引論文排行
·經(jīng)典文獻(xiàn)推薦·
基于Web of Science檢索結(jié)果,利用Histcite軟件選取LCS(Local Citation Score,本地引用次數(shù))TOP 50文獻(xiàn)作為節(jié)點(diǎn)進(jìn)行分析,得到本領(lǐng)域推薦的經(jīng)典文獻(xiàn)如下。
本領(lǐng)域經(jīng)典文獻(xiàn)
Autism as a strongly genetic disorder: Evidence from a british twin study
Bailey, A; Lecouteur, A; Gottesman, I; et al.
來(lái)源出版物:Psychological Medicine, 1995, 25(1): 63-77
Face processing occurs outside the fusiform ‘face area’in autism: Evidence from functional MRI
Pierce, K; Muller, RA; Ambrose, J; et al.
來(lái)源出版物:Brain, 2001, 124(10): 2059-2073
Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism
Jamain, S; Quach, H; Betancur, C; et al.
來(lái)源出版物:Nature Genetics, 2003, 34(1): 27-29
Strong association of de novo copy number mutations with autism
Sebat, J; Lakshmi, B; Malhotra, D; et al.
來(lái)源出版物:Science, 2007, 316(5823): 445-449
Mapping autism risk loci using genetic linkage and chromosomal rearrangements
Szatmari, P; Paterson, AD,; Zwaigenbaum, L; et al.
來(lái)源出版物:Nature Genetics, 2007, 39(3): 319-328
·推薦綜述·
自閉癥的病因和治療方法研究進(jìn)展
段云峰1,吳曉麗1,2,金鋒1
自閉癥(autism或autistic disorder)又稱(chēng)孤獨(dú)癥,是一種具有生物基礎(chǔ)的發(fā)育障礙類(lèi)疾病,包括一系列復(fù)雜的神經(jīng)發(fā)育障礙。最新版的美國(guó)精神疾病診斷及統(tǒng)計(jì)手冊(cè)第五版(Diagnostic and Statistical Manual of Mental Disorders-V,DSM-V)已將自閉癥的核心癥狀歸結(jié)為社交障礙,溝通困難和有限的、重復(fù)和刻板的行為。自閉癥譜系障礙(autism spectrum disorder,ASD)是這類(lèi)疾病的總稱(chēng),較嚴(yán)重的狀況稱(chēng)為自閉癥或經(jīng)典自閉癥譜系障礙,其他的類(lèi)型有阿斯伯格綜合征(Asperger syndrome)、兒童期分裂障礙(childhood disintegrative disorder)和非特異的廣泛性發(fā)育障礙(pervasive developmental disorder not otherwise specified,PDDNOS)等。雖然ASD的特征和嚴(yán)重程度各異,但在各種族和經(jīng)濟(jì)階層中都會(huì)出現(xiàn),并對(duì)任何年齡段人群都可能造成影響。
不容樂(lè)觀的是自閉癥的患病人數(shù)在逐年增加,據(jù)美國(guó)疾病控制與預(yù)防中心統(tǒng)計(jì),截止到2010年,美國(guó)8歲的兒童中每68人中就有一人患有ASD,并且男性患病比例約為1/42,是女性的4~5倍。而2013年的報(bào)告顯示,在6~17歲的孩子中每50個(gè)孩子中就有1個(gè)患有自閉癥,增長(zhǎng)趨勢(shì)十分明顯。來(lái)自不同國(guó)家的統(tǒng)計(jì)表明,自閉癥在總?cè)丝诘幕疾”壤蛇_(dá)2%甚至更高。在美國(guó),每個(gè)自閉癥兒童一生的護(hù)理費(fèi)用超過(guò)320萬(wàn)美元,全國(guó)每年的花費(fèi)超過(guò)350億美元。然而,目前我國(guó)還缺乏官方的統(tǒng)計(jì)報(bào)告,據(jù)世衛(wèi)組織統(tǒng)計(jì),中國(guó)大陸的自閉癥兒童數(shù)量約為60~180萬(wàn)人,有學(xué)者則認(rèn)為實(shí)際數(shù)量可能達(dá)到260~800萬(wàn)人。自閉癥已經(jīng)成為兒童精神類(lèi)致殘的重要疾病,隨著發(fā)病率的升高,正在并將持續(xù)給家庭和社會(huì)帶來(lái)巨大的社會(huì)和經(jīng)濟(jì)負(fù)擔(dān)。
自閉癥由環(huán)境因素,生物和遺傳因素等共同作用引起,目前的治療措施主要包括行為干預(yù)和藥物干預(yù)。然而,到目前為止,人們對(duì)自閉癥的致病機(jī)制尚未完全闡明,也還沒(méi)有切實(shí)有效的針對(duì)核心癥狀的治療方法。本文將對(duì)近年來(lái)發(fā)現(xiàn)的致病因素和自閉癥的治療方法進(jìn)行綜述,著重從生物學(xué)相關(guān)的致病因素和治療方法進(jìn)行綜述,特別介紹了最具前景的腸道微生物相關(guān)療法,以期為廣大科研人員、醫(yī)療工作者和相關(guān)人員提供參考。
1自閉癥的致病因素
1.1遺傳因素
對(duì)自閉癥患者的雙生子和家庭成員的研究表明,一些患者存在明顯的遺傳易感性。同卵雙生子之一患有自閉癥,另一個(gè)的患病幾率可達(dá)60%,甚至90%;而異卵雙生子則只有5%的患病幾率,結(jié)合自閉癥的發(fā)病率,有研究推測(cè)自閉癥及類(lèi)似行為特征的遺傳性達(dá)90%。除此之外,直系親屬患病率也受遺傳因素影響,自閉癥患兒的兄弟姐妹患病風(fēng)險(xiǎn)會(huì)明顯增加;家庭中有一個(gè)孩子患有自閉癥,那再生一個(gè)孩子患病幾率可達(dá)5%~6%。研究者還發(fā)現(xiàn),自閉癥孩子的家庭成員出現(xiàn)較多的社交技能或重復(fù)性行為異常,以及某些情感障礙類(lèi)精神疾患,如躁郁癥等。還有理論認(rèn)為兩個(gè)具有重復(fù)、刻板、注重秩序和規(guī)則等超系統(tǒng)性(hyper-systemising)行為比較明顯的人結(jié)婚后更容易生出自閉癥的孩子。
自閉癥的遺傳學(xué)因素主要集中在基因突變和染色體異常,包括點(diǎn)突變、基因拷貝數(shù)變異、連鎖區(qū)域和microRNAs等。具有特定遺傳或染色體特征的人更容易患自閉癥,如脆性X染色體綜合征或結(jié)節(jié)性硬化癥(tuberous sclerosis)。雖然,基因是自閉癥的一個(gè)風(fēng)險(xiǎn)因素,然而,到目前為止尚未確定自閉癥基因,僅報(bào)道了一些潛在的易感或致病基因,如CNTNAP2(contactin associated protein like-2)基因、突觸蛋白基因SHANKs (SH3 and multiple ankyrin repeatdomains)和NLGN4X (neuroligin 4,X-linked)基因等。另外,結(jié)節(jié)性硬化癥基因可能與自閉癥相關(guān),據(jù)估計(jì),大約在1%~4%的自閉癥患者中能夠檢測(cè)到該基因異常。在某些自閉癥兒童體內(nèi)影響大腦發(fā)育的拓?fù)洚悩?gòu)酶相關(guān)基因(如TOP1)發(fā)生了突變導(dǎo)致表達(dá)量降低。自閉癥患者表現(xiàn)了高度的遺傳異質(zhì)性,仍不清楚這些基因是單獨(dú)或組合影響自閉癥的發(fā)生,如NRXN1(neurexin-1)基因是維持脊椎動(dòng)物神經(jīng)系統(tǒng)功能的細(xì)胞黏附分子和受體的一組蛋白家族基因,可能參與了自閉癥和精神分裂癥的形成,然而,大規(guī)模調(diào)查并沒(méi)有發(fā)現(xiàn)自閉癥兒童體內(nèi)相應(yīng)的編碼序列的異常,并且這個(gè)基因單獨(dú)并不會(huì)導(dǎo)致自閉癥,必須與其他因子一起才可能引起自閉癥。據(jù)估計(jì),大約3~12個(gè)基因協(xié)同作用才可能導(dǎo)致自閉癥,并且這些可疑的基因多位于第2號(hào)、5號(hào)、7號(hào)和16號(hào)染色體上??蒲腥藛T已經(jīng)構(gòu)建某些神經(jīng)生物學(xué)相關(guān)的基因異常的自閉癥動(dòng)物模型來(lái)進(jìn)一步研究。
盡管研究認(rèn)為自閉癥是一種復(fù)雜的多基因控制的遺傳性疾病,然而并沒(méi)有發(fā)現(xiàn)確切的自閉癥致病基因,仍不清楚它們之間的聯(lián)系機(jī)制。事實(shí)上,遺傳學(xué)因素大約能夠解釋10%~30%的自閉癥成因,它的發(fā)病率逐年迅速升高明顯偏離哈迪-溫伯格平衡(Hardy-Weinberg Equilibrium),提示自閉癥是遺傳和外部環(huán)境相互作用引起的疾病。而環(huán)境可能更是值得我們關(guān)注的因素。
1.2環(huán)境因素
(1) 生物異源物質(zhì)/重金屬 殺蟲(chóng)劑、農(nóng)藥、添加劑和防腐劑等正常人體不存在的生物異源物質(zhì)(xenobiotics)進(jìn)入體內(nèi)會(huì)對(duì)人體產(chǎn)生傷害。某些重金屬,如砷、鉛、汞、鎘、銻和錳等會(huì)對(duì)人體神經(jīng)系統(tǒng)產(chǎn)生毒害。有研究發(fā)現(xiàn),重金屬和生物異源物質(zhì)會(huì)引起硫代謝異常,氧化還原水平以及甲基化都會(huì)受到影響。
起初,人們注意到自閉癥兒童通常在發(fā)病前進(jìn)行過(guò)疫苗注射,并懷疑其中的防腐劑-硫柳汞(thimerosal)才是導(dǎo)致自閉癥的罪魁禍?zhǔn)?。但后續(xù)研究否定了這一發(fā)現(xiàn)。此外,疫苗中的抗體刺激蛋白和多糖與自閉癥并不相關(guān)。雖然研究結(jié)果不一,但為了謹(jǐn)慎起見(jiàn),世界衛(wèi)生組織已經(jīng)不再鼓勵(lì)在疫苗中使用硫柳汞作為防腐劑。
值得注意的是汞對(duì)人體健康的影響并不簡(jiǎn)單。在正常情況下,人體能夠?qū)⒐x為乙基汞(ethylmercury),大約18 d內(nèi)就被排出體外。然而,在體外,某些腸道微生物能夠?qū)⒐谆蛉ゼ谆?,甲基化的汞具有神?jīng)毒性,可破壞神經(jīng)系統(tǒng),引起腦萎縮。歷史上著名的環(huán)境污染事件“日本水俁事件”就是由于環(huán)境中的微生物將污水中的汞轉(zhuǎn)化為甲基汞而引起的中毒事件。此外,用抗生素清除大鼠(Rattus norvegicus)腸道中的微生物后,會(huì)導(dǎo)致組織中汞的含量增加,并且甲基汞的比例也明顯增加。因此,在研究物質(zhì)的毒性時(shí),需考慮微生物的影響,某些腸道微生物可能將本身無(wú)毒的物質(zhì)轉(zhuǎn)化為有毒的物質(zhì),對(duì)含汞疫苗的安全評(píng)價(jià)應(yīng)考慮特定腸道微生物的代謝。
除汞外,另一種環(huán)境中常見(jiàn)的重金屬-鉛在自閉癥患兒體內(nèi)的含量也顯著高于對(duì)照組。一項(xiàng)對(duì)5~16歲的55位自閉癥兒童和44位對(duì)照的研究發(fā)現(xiàn),重金屬在自閉癥患兒血液和尿液中含量更高,其中自閉癥組血液中鉛的含量高于對(duì)照組41%,尿液中的鉛、鉈、錫和鎢含量分別比對(duì)照組高74%、77%、115%和44%,而血液中鈣含量卻比對(duì)照組低19%,并且,自閉癥的嚴(yán)重程度與體內(nèi)的重金屬含量密切相關(guān)。
某些生物異源物質(zhì)也可能導(dǎo)致自閉癥。有研究通過(guò)使用致畸劑,如常用的抗痙攣(anticonvulsant)藥丙戊酸鈉(sodium valproate)處理懷孕的母鼠,丙戊酸鈉在母鼠體內(nèi)生成的丙戊酸(valproic acid,VPA)會(huì)導(dǎo)致后代出現(xiàn)類(lèi)似自閉癥癥狀的發(fā)育和行為異常,并持續(xù)到成年。目前,尚未有具體的影響機(jī)制報(bào)道,推測(cè)可能是丙戊酸通過(guò)影響葉酸代謝、組蛋白脫乙酰作用、氧化應(yīng)激、突觸可塑性和神經(jīng)細(xì)胞凋亡導(dǎo)致神經(jīng)系統(tǒng)發(fā)育異常。
(2) 懷孕 自閉癥的發(fā)病時(shí)間通常是三歲以?xún)?nèi),關(guān)鍵時(shí)期是出生之前、期間或出生后不久,這段時(shí)間正是幼兒生長(zhǎng)發(fā)育的關(guān)鍵時(shí)期,極易受到外界環(huán)境的影響。研究發(fā)現(xiàn),懷孕期間的多種影響因素都有可能影響孩子的神經(jīng)系統(tǒng)發(fā)育,如懷孕期子宮感染和孕期并發(fā)癥、接觸化學(xué)物質(zhì)、環(huán)境污染、圍產(chǎn)期和產(chǎn)后健康狀況等都將增高幼兒患病風(fēng)險(xiǎn)。
動(dòng)物研究發(fā)現(xiàn),產(chǎn)前應(yīng)激會(huì)使母鼠腦中五羥色胺(血清素serotonin或5-hydroxytryptamine,5-HT)的含量顯著升高,而它的代謝產(chǎn)物五羥吲哚乙酸會(huì)在后代中積累,導(dǎo)致后代嬰兒期出現(xiàn)行為缺陷。在懷孕和圍產(chǎn)期感染病毒也可導(dǎo)致后代患自閉癥和精神分裂癥的風(fēng)險(xiǎn)增加。有研究發(fā)現(xiàn),給懷孕母鼠注射人流感病毒后,其產(chǎn)生的后代會(huì)出現(xiàn)缺乏探究行為和交流行為等類(lèi)似自閉癥的異常行為??赡墚a(chǎn)前應(yīng)激在人體內(nèi)也會(huì)有類(lèi)似的影響。
有研究報(bào)道,父母生育孩子時(shí)的年齡越大孩子患自閉癥的風(fēng)險(xiǎn)越高,并且祖父母晚育也會(huì)增加第三代患自閉癥的風(fēng)險(xiǎn)。最近的一項(xiàng)研究表明,自閉癥兒童母親的年齡顯著高于對(duì)照組,且約有50%的患者曾經(jīng)有過(guò)產(chǎn)前并發(fā)癥。在懷孕期間服用藥物可能增加自閉癥風(fēng)險(xiǎn),如孕期服用處方藥丙戊酸和薩力多胺等。此外,母親孕期接觸可卡因和酒精,病毒感染以及甲狀腺功能減退等都可能提高孩子患自閉癥的風(fēng)險(xiǎn)。孕婦生活的環(huán)境會(huì)影響孩子,環(huán)境污染會(huì)增加自閉癥的發(fā)生率,研究發(fā)現(xiàn),懷孕期間以及在孩子出生后的第一年暴露于交通空氣污染中高濃度的二氧化氮,PM2.5和PM10會(huì)增加孩子患自閉癥的風(fēng)險(xiǎn)。因此,對(duì)自閉癥的診斷和預(yù)防可能并不需要等到孩子長(zhǎng)大,而是在孩子出生時(shí),孕期乃至在母親懷孕之前就應(yīng)該進(jìn)行后代自閉癥風(fēng)險(xiǎn)評(píng)估和干預(yù)。
(3) 腸腦 腸道里的神經(jīng)細(xì)胞在細(xì)胞類(lèi)型、神經(jīng)遞質(zhì)及感受器方面都與大腦極其相似,與大腦的神經(jīng)細(xì)胞數(shù)量相當(dāng),比脊髓里的還多,常見(jiàn)的5-HT、多巴胺(dopamin,DA)、谷氨酸、去甲腎上腺素、一氧化氮、阿片肽、P 物質(zhì)、促胃激素、促胰激素等神經(jīng)遞質(zhì)和激素在大腦和腸神經(jīng)系統(tǒng)都有廣泛分布,因此,腸道也被稱(chēng)為人的“第二腦”或“腸腦”。腸腦與頭腦之間雙向互通,它們之間通過(guò)腦-腸軸(brain-gut-axis)進(jìn)行聯(lián)接。腸腦能夠影響中樞神經(jīng)系統(tǒng),進(jìn)而影響人的情感,認(rèn)知和行為,并且腸道微生物可能在其中具有重要作用。自閉癥可能也受腦-腸軸的影響。
腸道是人體最大的消化器官,負(fù)責(zé)營(yíng)養(yǎng)物質(zhì)的消化和吸收,小分子物質(zhì)能夠被腸道直接吸收,某些大分子物質(zhì)需要通過(guò)特定的通道或受體才能被人體吸收。自閉癥患者通常伴有腸道異常,當(dāng)腸道出現(xiàn)炎癥時(shí),會(huì)引起腸道細(xì)胞腫脹,細(xì)胞間隙變大,引起腸漏(gut leakage),導(dǎo)致大分子物質(zhì)能夠穿透腸壁進(jìn)入體內(nèi),此外,嚴(yán)重的腸道問(wèn)題可能伴隨腸道的破損和潰瘍,大分子物質(zhì)就更容易進(jìn)入腸道。
研究發(fā)現(xiàn),2006—2010年,美國(guó)3~17歲的自閉癥兒童患有腹瀉或結(jié)腸炎的比例是正常人的7倍。最近的一項(xiàng)研究發(fā)現(xiàn),61%的自閉癥兒童同時(shí)伴有至少一種胃腸道癥狀,并且所有伴有消化道癥狀的兒童情感問(wèn)題都比較嚴(yán)重。此外,不同群體自閉癥患者同時(shí)伴隨胃腸道癥狀的比例不同,大約為9%~91%,這種巨大差異可能是由于調(diào)查過(guò)程中,自閉癥患者語(yǔ)言和溝通障礙造成的。自閉癥的胃腸道癥狀主要包括:淋巴結(jié)節(jié)性增生、小腸結(jié)腸炎、胃炎、食管炎、腸道通透性增加、雙糖酶活性不足、淋巴細(xì)胞種群密度較高、異常的細(xì)胞因子和免疫球蛋白(IgG)等。有研究發(fā)現(xiàn),患有自閉癥的兒童中有1/4伴有腹瀉,1/4伴有便秘,并且胃腸道炎癥影響患者對(duì)營(yíng)養(yǎng)物質(zhì)的吸收,有36.7%的自閉癥兒童腸道通透性增加,而進(jìn)行無(wú)酪蛋白/谷蛋白飲食控制的患者相比沒(méi)有進(jìn)行飲食控制的患者和對(duì)照,他們腸漏癥狀顯著減輕。
(4) 腸道微生物 近年來(lái)的研究發(fā)現(xiàn),人體攜帶有1~2 kg的微生物,這些微生物總數(shù)量達(dá)人體自身細(xì)胞數(shù)量的10~100倍,編碼的基因數(shù)量是人體自身的300多倍,被稱(chēng)為人體的“第二基因組”或“被遺忘的器官”。腸道微生物能夠幫助人體消化和吸收營(yíng)養(yǎng)物質(zhì),通過(guò)分泌各種酶類(lèi),合成某些維生素和生物活性物質(zhì)影響人體代謝、控制體重、塑造人體免疫系統(tǒng)以及幫助抵御病原微生物的侵入,并且血液中大約70%的物質(zhì)來(lái)自于腸道,其中36%的小分子物質(zhì)是由腸道微生物產(chǎn)生。腸道微生物的平衡對(duì)人體健康至關(guān)重要,這種平衡一旦被打破將可能導(dǎo)致多種疾病。
最近的研究顯示,糞便中有超過(guò)90%的DNA序列來(lái)自腸道微生物,這些微生物主要屬于兩個(gè)門(mén):擬桿菌門(mén)(Bacteriodetes)和厚壁菌門(mén)(Firmicutes),并且可以大致聚類(lèi)為以擬桿菌屬(Bacteroides)、普氏菌屬(Prevotella)和瘤胃球菌屬(Ruminococcus)3個(gè)屬的微生物為主的類(lèi)型,稱(chēng)為腸型(enterotypes)。腸型是穩(wěn)定的,幾乎不受飲食等因素的影響,可用于區(qū)分個(gè)體的腸道微生物特征,研究發(fā)現(xiàn),自閉癥兒童具有其獨(dú)特的腸型,他們大多為擬桿菌屬和瘤胃球菌屬腸型,而缺少普氏菌屬腸型。
腸道微生物可通過(guò)血液系統(tǒng),內(nèi)分泌系統(tǒng)和神經(jīng)系統(tǒng)影響大腦和行為,它們之間相互影響構(gòu)成了微生物-腸道-大腦軸(microbiome-gut-brain axis,也稱(chēng)菌-腸-腦軸)。腸道微生物不僅影響人體的生理健康,并可能通過(guò)神經(jīng)化學(xué)物質(zhì)的變化,影響人的心理和行為。腸道微生物還能夠影響記憶的形成,因而推論,自閉癥也受菌-腸-腦軸的影響。有研究發(fā)現(xiàn),自閉癥樣小鼠(Mus musculus)腸道通透性增大,腸道中微生物的代謝產(chǎn)物能夠進(jìn)入血液循環(huán)系統(tǒng)并且可以改變宿主特定的行為。
個(gè)體的發(fā)育不僅由父母垂直傳遞的基因決定,還受水平傳遞的、定植于腸道的微生物影響。個(gè)體腸道菌群有自己的生長(zhǎng)發(fā)育規(guī)律,嬰兒出生后微生物逐漸定植,一歲左右腸道微生物趨于穩(wěn)定,3歲左右與成人類(lèi)似或一致。早期研究認(rèn)為嬰兒在母體子宮中是完全無(wú)菌的,隨著測(cè)序技術(shù)的發(fā)展,在胎盤(pán)中也可檢測(cè)到微生物,它們有可能很早就定植在胎兒腸道中。此外,出生方式不同會(huì)導(dǎo)致嬰兒體內(nèi)定植的微生物群不同,剖腹產(chǎn)和順產(chǎn)的嬰兒其腸道菌群差異顯著。不同出生方式使嬰兒接觸微生物的時(shí)機(jī)和部位不同,導(dǎo)致腸道中微生物定植的差異。喂養(yǎng)方式也會(huì)導(dǎo)致微生物的差異,出生后采用母乳喂養(yǎng)與吃配方奶的嬰兒的腸道微生物構(gòu)成也存在顯著差異。母親直接哺乳可通過(guò)乳頭和乳汁向嬰兒傳遞有益細(xì)菌,而吃配方奶或使用奶瓶奶嘴則使嬰兒無(wú)法從母親體內(nèi)獲取特定的有益微生物,因此,微生物的傳遞被阻礙可能導(dǎo)致健康和大腦發(fā)育異常等一系列問(wèn)題。
自閉癥兒童的消化道癥狀可由特定的腸道微生物引起,并且腸道早期定植的微生物出現(xiàn)異??赡軙?huì)干擾大腦發(fā)育,引起或促進(jìn)后代出現(xiàn)自閉癥癥狀。值得注意的是,自閉癥兒童在一歲以前開(kāi)始出現(xiàn)癥狀,大多數(shù)發(fā)病都是在3歲以?xún)?nèi),這與嬰兒腸道菌群的發(fā)育過(guò)程的時(shí)間節(jié)點(diǎn)重疊,推測(cè)嬰兒的大腦發(fā)育需要伴隨腸道微生物的正常定植而完成。所以,自閉癥可能為嬰兒早期腸道微生物的發(fā)育異常導(dǎo)致。目前,已經(jīng)發(fā)現(xiàn)了一些疑似與自閉癥密切相關(guān)的腸道微生物或菌群組成紊亂,一些在正常人體內(nèi)出現(xiàn)的細(xì)菌缺失,或者出現(xiàn)了正常人體內(nèi)沒(méi)有的菌群,或者各種菌群的比例發(fā)生了明顯變化,有益菌減少,有害菌增加。
梭菌屬(Clostridium)細(xì)菌 最初,人們懷疑梭菌屬細(xì)菌可能跟自閉癥關(guān)系密切,如破傷風(fēng)梭菌(Clostridium tetani)、產(chǎn)氣莢膜梭菌(Clostridium perfringens)以及梭狀芽孢桿菌(Clostridium bolteaenovo sp.)等。梭菌是腸道中的“壞菌”,可產(chǎn)生酚類(lèi)、對(duì)甲酚或某些吲哚衍生物等毒性物質(zhì)或前體物質(zhì)。研究發(fā)現(xiàn),在晚發(fā)型自閉癥(late-onset/regressive autism)患者中,腸道菌群明顯紊亂,由梭菌產(chǎn)生的破傷風(fēng)毒素(tetanus antitoxin)的濃度異常高,腸道中梭菌和瘤胃球菌屬細(xì)菌數(shù)量明顯高于對(duì)照組,自閉癥兒童糞便中25種不同的梭菌,有9種梭菌在對(duì)照組中不存在,而對(duì)照組中有3種梭菌在自閉癥組中也沒(méi)有發(fā)現(xiàn),且自閉癥兒童的消化道上游和下游的微生物發(fā)生了明顯改變。然而,這一研究主要基于細(xì)菌培養(yǎng),也不能排除飲食干預(yù)的影響。另有研究發(fā)現(xiàn),自閉癥患者體內(nèi)的梭狀芽孢桿菌(Clostridium bolteae)是正常對(duì)照組的46倍,梭狀芽孢桿菌(Clostridium clusters)Ⅰ和Ⅺ則分別是正常對(duì)照組的9倍和3.5倍。自閉癥兒童腸道中的溶組織梭菌(Clostridium histolyticum)比例也明顯偏高,溶組織梭菌產(chǎn)生的毒素可能導(dǎo)致腸道異常和功能紊亂,并且還可能進(jìn)入血液系統(tǒng),再透過(guò)血腦屏障影響大腦發(fā)育。
脫硫弧菌屬(Desulfovibrio)和薩特菌屬(Sutterella)細(xì)菌。除梭菌外,最近也發(fā)現(xiàn)了其他可能與自閉癥相關(guān)的細(xì)菌。如脫硫弧菌屬(Desulfovibrio)和薩特菌屬(Sutterella)。在自閉癥兒童中,大約50%的患者中存在脫硫弧菌,其兄弟姐妹中有一部分存在,而正常人中幾乎沒(méi)有。這種硫酸鹽還原菌屬于革蘭氏陰性厭氧弧菌,能夠引起硫代謝異常,通過(guò)檢測(cè)自閉癥患者的血液和尿液,確實(shí)發(fā)現(xiàn)自閉癥兒童血液中硫含量較低,而尿液中硫含量較高,推測(cè)脫硫弧菌可能通過(guò)影響兒童體內(nèi)的硫代謝過(guò)程引起自閉癥。
美國(guó)哥倫比亞大學(xué)的研究人員發(fā)現(xiàn),有超過(guò)1/2的伴有胃腸功能障礙的自閉癥兒童腸道中存在另一種腸道微生物—薩特菌,而正常人中沒(méi)有發(fā)現(xiàn)。薩特菌屬于產(chǎn)堿菌科(Alcaligenaceae)可抵抗膽堿,約占腸道中全部細(xì)菌的1%~7%。然而,目前還不清楚其影響機(jī)制。
酵母菌(Yeast) 白色念球菌(Candida albicans)屬于酵母菌,是引起腸炎和陰道炎的一種致病真菌。有研究認(rèn)為自閉癥與真菌的過(guò)度增殖有關(guān),制霉菌素(nystatin)、氟康唑(fluconazole)和酮康唑(ketoconazole)等抗真菌素類(lèi)藥物或酵母抑制劑(yeast inhibitor)可改善自閉癥癥狀。白色念球菌能夠產(chǎn)生一種類(lèi)似γ-氨基丁酸(γ-aminobutyric acid,GABA)的β-丙氨酸,可越過(guò)血腦屏障與GABA進(jìn)行競(jìng)爭(zhēng),干擾GABA的正常功能。有研究發(fā)現(xiàn),自閉癥患者體內(nèi)β-丙氨酸顯著高于正常人,可能是由于自閉癥患者腸道中的白色念球菌產(chǎn)生了大量β-丙氨酸,透過(guò)血腦屏障后與抑制性神經(jīng)遞質(zhì)GABA進(jìn)行拮抗,導(dǎo)致大腦加速產(chǎn)生GABA,最終導(dǎo)致自閉癥患者在社會(huì)交往能力方面受到抑制。
其他腸道微生物 除了上述幾種微生物在自閉癥患者和正常人之間存在差異,最近的研究還發(fā)現(xiàn)自閉癥患者腸道中的厚壁菌門(mén)(Firmicutes)和擬桿菌門(mén)(Bacteroidetes)的比例比正常人低,而放線菌門(mén)和變形菌門(mén)在嚴(yán)重自閉癥患者中明顯增多,脫硫弧菌屬和普通擬桿菌(Bacteroides vulgatus)的比例也都顯著高于對(duì)照組。此外,糞桿菌屬(Faecalibacterium)和瘤胃球菌屬(Ruminococcus)在PDD-NOS患兒和健康對(duì)照兒童糞便樣品中含量更多,而喜熱菌屬(Caloramator)、八疊球菌屬(Sarcina)和梭狀芽胞桿菌屬在自閉癥兒童糞便中最多;與健康對(duì)照相比,毛螺旋菌科(Lachnospiraceae)的組成與PDD-NOS患兒顯著不同,特別是與自閉癥兒童差異更大;除了惰性真桿菌(Eubacterium siraeum)外,真桿菌科(Eubacteriaceae)在自閉癥兒童糞便中最少;擬桿菌屬和一些Alistipes 和Akkermansia 菌在PDD-NOS和自閉癥患兒糞便中最高;幾乎所有確認(rèn)的薩特菌科(Sutterellaceae)和腸桿菌科(Enterobacteriaceae)在自閉癥兒童糞便中均為最多,而與健康對(duì)照相比,自閉癥兒童糞便中雙歧桿菌卻明顯減少。
另有研究發(fā)現(xiàn),自閉癥兒童糞便中除了薩特菌(Sutterella spp.)比對(duì)照組明顯增多,伴隨有功能性胃腸疾病的自閉癥兒童糞便中毛圈瘤胃球菌(Ruminococcus torques)相比無(wú)功能性胃腸疾病的自閉癥兒童也明顯增多。
通過(guò)比較3~16歲的自閉癥兒童和正常兒童(每組20位)的腸道菌群、腸道癥狀和自閉癥癥狀,發(fā)現(xiàn)自閉癥兒童腸道菌群中普氏菌屬(Prevotella)、糞球菌屬(Coprococcus)和未分類(lèi)的韋榮球菌科(Veillonellaceae)明顯減少;自閉癥兒童腸道菌群多樣性與自閉癥癥狀相關(guān)性更強(qiáng);菌群整體的多樣性和個(gè)體菌屬豐度與自閉癥相關(guān)癥狀相關(guān),而與他們的飲食模式?jīng)]有相關(guān)性。表明腸道菌群豐度與自閉癥癥狀聯(lián)系更緊密,腸道菌群豐度低或腸道菌群紊亂可能導(dǎo)致自閉癥。
干預(yù)研究表明,通過(guò)調(diào)節(jié)或干預(yù)腸道微生物能夠?qū)ψ蚤]癥癥狀有所改善。在人類(lèi)中,嚴(yán)重的病毒感染會(huì)導(dǎo)致懷孕母親生出患有自閉癥的孩子,來(lái)自美國(guó)的研究人員通過(guò)模擬病毒感染引起母鼠出現(xiàn)免疫反應(yīng),出生的小鼠會(huì)出現(xiàn)自閉癥樣行為。通過(guò)這樣的處理構(gòu)建的自閉癥模型小鼠同時(shí)出現(xiàn)胃腸道異常癥狀,主要為通透性增加,而這種癥狀同樣存在于一些自閉癥兒童中。研究人員用益生菌-脆弱擬桿菌(Bacteroides fragillis)來(lái)處理自閉癥樣小鼠,結(jié)果小鼠的腸道通透性得到明顯改善,自閉癥樣行為也有所改善。不僅在動(dòng)物實(shí)驗(yàn)中,在自閉癥兒童體內(nèi)也發(fā)現(xiàn)了類(lèi)似的結(jié)果,在給予10名自閉癥兒童和9名他們的兄弟姐妹以及10名對(duì)照益生菌之后,自閉癥兒童體內(nèi)擬桿菌門(mén)/厚壁菌門(mén)的比例,脫硫弧菌屬和雙歧桿菌屬細(xì)菌的比例均得以恢復(fù)。這幾項(xiàng)研究既發(fā)現(xiàn)自閉癥患者腸道菌群的不同,又通過(guò)益生菌干預(yù)了腸道菌群,并改善了自閉癥樣行為,表明腸道菌群異??赡苁且l(fā)自閉癥重要原因。
腸道微生物對(duì)宿主的影響除了腸道微生物本身,還包括腸道微生物的代謝對(duì)宿主的影響,后續(xù)的研究除了需要檢測(cè)腸道微生物的差異,還要檢測(cè)腸道微生物的代謝物的變化,腸道的pH、氧化還原水平、氧氣、氫氣、短鏈脂肪酸和生物活性肽的含量等都會(huì)影響腸道微生物的分布和構(gòu)成。盡管發(fā)現(xiàn)自閉癥與腸道菌群有關(guān),這些研究難以排除一些干擾因素,如種族、飲食、并發(fā)癥和病人的信息反饋等。目前,尚不能確定腸道菌群是自閉癥的發(fā)病原因還是結(jié)果,或者只是混淆因素,因此,腸道菌群的研究仍需時(shí)日。
(5) 飲食和營(yíng)養(yǎng) 患有自閉癥的兒童通常對(duì)味道、質(zhì)地和氣味等感官刺激極端敏感,并對(duì)吃的東西極其挑剔。據(jù)估計(jì),有超過(guò)90%的自閉癥兒童存在飲食問(wèn)題。有一些父母反映他們患有自閉癥的孩子只吃五六種食物,更喜歡富含脂肪、淀粉類(lèi)食物、零食和加工食物,而厭惡大多數(shù)水果、蔬菜和蛋白質(zhì)。然而,父母有限的時(shí)間、繁重的工作和巨大的心理和經(jīng)濟(jì)壓力都有可能影響孩子的飲食習(xí)慣,目前,還不清楚自閉癥兒童的飲食特點(diǎn)是否受到其照料和監(jiān)管人的人為影響。
嬰兒時(shí)期的飲食習(xí)慣會(huì)對(duì)其身體健康狀況產(chǎn)生持續(xù)的、長(zhǎng)期的影響。挑食的兒童纖維素類(lèi)營(yíng)養(yǎng)更缺乏,而缺乏纖維素會(huì)導(dǎo)致胃腸道功能紊亂,尤其是便秘。有限的食物種類(lèi)必然導(dǎo)致?tīng)I(yíng)養(yǎng)不良,缺乏必需的營(yíng)養(yǎng)和一些酶類(lèi),會(huì)進(jìn)一步降低對(duì)食物的消化吸收能力,從而形成惡性循環(huán)。自閉癥兒童與正常兒童相比,營(yíng)養(yǎng)物質(zhì)攝入水平要顯著低很多,骨密度也比正常孩子低,自閉癥患者攝入維生素B6,B12,維生素E,D和C;微量元素鎂、鐵、鋅和鈣以及葉酸等嚴(yán)重不足,明顯低于推薦攝入量。自閉癥兒童的這種飲食特點(diǎn)并不是在患病之后才出現(xiàn)的,往往從嬰兒時(shí)期就開(kāi)始并持續(xù)很長(zhǎng)時(shí)間。
除了缺乏營(yíng)養(yǎng)物質(zhì),食物中的某些成分也可能引起食物不耐受或過(guò)敏。自閉癥患者的免疫球蛋白抗體,如IgG,IgE和IgA等水平普遍偏高。人們發(fā)現(xiàn),通過(guò)減少或杜絕某些食物能夠減輕自閉癥的某些癥狀,嚴(yán)格限制食物中的酪蛋白和谷蛋白后自閉癥患者癥狀明顯改善。可能由于自閉癥患者本身對(duì)這些食物成分不耐受或過(guò)敏,也有人認(rèn)為這兩種蛋白質(zhì)在自閉癥孩子體內(nèi)會(huì)被分解成某些引起大腦異常的類(lèi)神經(jīng)遞質(zhì),包括具有阿片活性的多肽或短的氨基酸聚合物外啡肽(exorphins),如谷啡肽(gluteomorphins)和β-酪啡肽(beta-casomorphins)。然而,目前對(duì)其具體的機(jī)制還不是很清楚。
食物在塑造和維持腸道微生物方面具有決定性作用。有研究發(fā)現(xiàn),母乳中含有多種共生微生物,是嬰兒體內(nèi)常見(jiàn)的乳酸菌和雙歧桿菌等有益微生物的絕佳來(lái)源。嬰兒出生時(shí),母乳提供嬰兒發(fā)育所需的各種營(yíng)養(yǎng)物質(zhì),以及一些保護(hù)性因子,而配方奶中缺乏這些物質(zhì),尤其是母乳中的共生微生物。此外,腸道菌群的紊亂會(huì)導(dǎo)致代謝異常,細(xì)菌產(chǎn)生的維生素B12、維生素H 和維生素K等會(huì)嚴(yán)重缺乏,也會(huì)導(dǎo)致明顯的營(yíng)養(yǎng)不良。
食品添加劑也可能增加兒童患自閉癥的風(fēng)險(xiǎn)。人工色素、防腐劑等常用的食品添加劑對(duì)兒童的大腦發(fā)育有不利影響,食品中的色素或苯甲酸鈉等能夠使3歲和8~9歲的兒童出現(xiàn)多動(dòng)癥。一項(xiàng)來(lái)自美國(guó)的調(diào)查顯示,從2005—2010年的5年間,在6~21歲的人群中,自閉癥患者升高了91%,但這種升高跟汞的攝入沒(méi)有關(guān)系,而與一種食品添加劑—果葡糖漿(high fructose corn syrup,HFCS)的消費(fèi)密切相關(guān),過(guò)多的果葡糖漿攝入會(huì)導(dǎo)致鋅、鈣、銅和磷等微量元素的攝入失衡。
(6) 代謝 自閉癥患者的營(yíng)養(yǎng)狀況不僅取決于他們從食物中攝取的營(yíng)養(yǎng)物質(zhì),還在于自身的代謝。自閉癥患者的氧化應(yīng)激水平升高,能量運(yùn)輸能力下降、硫酸鹽化作用和解毒能力降低,血液中存在低水平的生物素、谷胱甘肽、紅細(xì)胞活性腺苷甲硫氨酸、血尿苷、血三磷酸腺苷(adenosine triphosphate,ATP)、紅細(xì)胞煙酰胺腺嘌呤二核苷酸(nicotinamide adeninedinucleotid,NADH)、紅細(xì)胞煙酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH)、血硫酸鹽以及血色氨酸,還存在高水平的氧化應(yīng)激生物標(biāo)記物和血谷氨酸。只是到目前為止還沒(méi)有找到明確的自閉癥的生物標(biāo)記物。
氨基酸代謝 色氨酸是參與神經(jīng)發(fā)育和突觸發(fā)生的5-HT、喹啉酸和犬尿酸的前體物質(zhì)。喹啉酸是構(gòu)成脫氫煙酰胺腺嘌呤二核苷酸(NAD+)的前體,而NAD+是線粒體中重要的能量載體,是NADH的前體。喹啉酸和犬尿酸可影響免疫系統(tǒng)的活性,色氨酸的代謝異??赡軙?huì)影響這些物質(zhì)的產(chǎn)生,進(jìn)而影響大腦的發(fā)育,神經(jīng)免疫活性和線粒體功能。研究發(fā)現(xiàn),自閉癥患者的色氨酸代謝明顯減少,導(dǎo)致腦中NADH的產(chǎn)生減少,影響線粒體的能量代謝,神經(jīng)細(xì)胞的發(fā)育,軸突的生長(zhǎng)以及神經(jīng)的可塑性。從食物中攝入的色氨酸約有99%是通過(guò)犬尿氨酸代謝途徑(kynurenine pathway)進(jìn)行再加工,作為5-HT和褪黑素的主要前體,色氨酸的代謝直接影響它們的含量。此外,很多父母反映自閉癥患兒的排泄物有樟腦球的氣味(mothball-like odor),這是糞便中吲哚(indole)或糞臭素(skatole,也稱(chēng)三甲基吲哚(3-methyl-indole))特有的氣味。這些臭味物質(zhì)是腸道中的細(xì)菌代謝色氨酸產(chǎn)生的,一旦食物中的色氨酸或酪氨酸進(jìn)入大腸,就會(huì)在尿中檢測(cè)到大量的吲哚苷(indican)和吲哚3乙酸。通過(guò)檢測(cè)尿液中這些物質(zhì)的含量能夠間接反映自閉癥患者體內(nèi)氨基酸代謝水平,可用于自閉癥的篩查和檢測(cè),但其檢測(cè)準(zhǔn)確性有待驗(yàn)證。
5-HT是重要的神經(jīng)遞質(zhì),可調(diào)節(jié)大腦發(fā)育,包括細(xì)胞分裂、神經(jīng)元遷移、細(xì)胞分化以及突觸發(fā)生。30%~40%的自閉癥兒童全血的5-HT 水平明顯升高。大腦發(fā)育過(guò)程需要大量5-HT來(lái)滿(mǎn)足大腦發(fā)育,因此,兒童期5-HT的合成能力非常強(qiáng),是成年人的2倍,到5歲逐漸降低到與成年人類(lèi)似的水平,且女孩5-HT合成能力比男孩下降較早,而自閉癥兒童的5-HT合成能力明顯異常。自閉癥兒童體內(nèi)的5-HT明顯增多,大量合成的5-HT如果不能被及時(shí)有效地代謝掉,反而會(huì)影響大腦的發(fā)育,會(huì)引起下丘腦室旁核中催產(chǎn)素的降低,并增加杏仁核中降血鈣素相關(guān)基因多肽(calcitonin gene-related peptide,CGRP),從而影響到對(duì)自閉癥兒童至關(guān)重要的社會(huì)互動(dòng)行為。此外,自閉癥患者大腦中的5-HT轉(zhuǎn)運(yùn)綁定能力低于對(duì)照組,而DA轉(zhuǎn)運(yùn)綁定能力高于對(duì)照組。5-HT的水平可直接影響自閉癥的某些癥狀,如睡眠障礙和情感障礙,并且自閉癥患者體內(nèi)的褪黑素含量也低于對(duì)照組。
硫酸鹽代謝 硫酸鹽可由半胱氨酸代謝產(chǎn)生,在體內(nèi)參與解毒,兒茶酚胺的失活和合成腦組織黏蛋白的硫酸鹽化等多種代謝途徑,還影響血液中的神經(jīng)遞質(zhì)、類(lèi)固醇、黏多糖、酚類(lèi)、氨基酸和多肽等物質(zhì)的含量。通常自閉癥兒童血液中的硫酸鹽含量較正常人低,尿液中硫酸鹽、亞硫酸鹽、硫代硫酸鹽比正常人高,硫氰酸鹽的含量則比正常人低。大量的硫酸鹽隨尿液排出體外,而沒(méi)有進(jìn)入血液系統(tǒng)供人體利用,可能是自閉癥兒童血液中硫酸鹽含量較正常人低的原因。
還原型谷胱甘肽(reduced glutathione,GSH)是含有巰基的三肽,其活性基團(tuán)是半胱氨酸的巰基,具有抗氧化和解毒作用,可轉(zhuǎn)化為氧化型谷胱甘肽(oxidized glutathione,GSSG)。GSH一旦缺乏,會(huì)減弱機(jī)體的抗氧化能力,損傷機(jī)體,多數(shù)自閉癥兒童體內(nèi)GSH的量偏低,而GSSG的比例偏高,GSH/GSSG則明顯降低。有研究發(fā)現(xiàn)甲基代謝和葉酸代謝過(guò)程能夠影響GSH/GSSG的比例,對(duì)穩(wěn)定氧化還原狀態(tài)至關(guān)重要,并且能夠影響自由基的清除、體內(nèi)氧化還原的平衡、維持蛋白質(zhì)氧化還原狀態(tài)、酶的活性、細(xì)胞膜的完整性、信號(hào)轉(zhuǎn)導(dǎo)、解毒,以及細(xì)胞的分化和凋亡。
脂肪酸代謝 有研究發(fā)現(xiàn)自閉癥患者血液中脂肪酸水平明顯異常。一旦脂肪酸代謝出現(xiàn)異常,或攝入脂肪酸不足將會(huì)導(dǎo)致大腦發(fā)育異常,增加患自閉癥的風(fēng)險(xiǎn)。脂肪酸代謝過(guò)程能夠?yàn)闄C(jī)體提供大量能量,并且涉及多種脂肪酸的轉(zhuǎn)變,其中,中、短鏈脂肪酸不需載體可直接進(jìn)入線粒體進(jìn)行能量代謝,而長(zhǎng)鏈脂酰CoA需要肉毒堿轉(zhuǎn)運(yùn)才能進(jìn)入線粒體參與能量代謝。
丙酸(propionic acid,PPA)是一種由腸道微生物代謝產(chǎn)生的短鏈脂肪酸(short chain fatty acid,SCFA),在日常生活中通常被用作食物防腐劑。有研究發(fā)現(xiàn),給大鼠注射丙酸能引起類(lèi)似自閉癥的社會(huì)行為障礙,其他類(lèi)型的短鏈脂肪酸,如乙酸也可引起類(lèi)似的行為異常。此外,自閉癥患者血清中肉毒堿(carnitine)和丙酮酸(pyruvic acid)的含量明顯降低,而丙氨酸和氨的量明顯升高。肉毒堿在能量代謝中發(fā)揮重要作用,線粒體的異常可能導(dǎo)致能量代謝異常,而丙氨酸和氨能夠影響大腦的正常工作。通過(guò)磁共振波譜分析(magnetic resonance spectroscopy,MRS)發(fā)現(xiàn),自閉癥兒童體內(nèi)的能量代謝異常,患兒血液中乳酸明顯增加,而腦中的N-乙酰-天冬氨酸(N-acetyl-asparate,NAA)含量明顯降低,表明自閉癥兒童腦中出現(xiàn)神經(jīng)代謝紊亂并且神經(jīng)系統(tǒng)已經(jīng)受到一定程度的損傷。此外,理論上認(rèn)為在懷孕后期到出生后早期,孩子需要大量的不飽和脂肪酸來(lái)維持大腦的正常發(fā)育,然而,有研究發(fā)現(xiàn)自閉癥患者血液中omega-3多不飽和脂肪酸,特別是二十二碳六烯酸(docosahexaenoic acid,DHA)的量明顯升高,omega-3/6的比例也明顯升高,但由于其選取的被試年齡多為12~18歲,并不能很好地說(shuō)明自閉癥發(fā)病早期的狀況,其結(jié)果只能提示家長(zhǎng),要慎重考慮,是否給孩子補(bǔ)充不飽和脂肪酸。
氧化還原平衡 自閉癥患者體內(nèi)的氧化水平要高于正常人,而甲基化活動(dòng)則明顯比正常人少。自閉癥的氧化還原甲基化假說(shuō)(redox/methylation hypothesis)認(rèn)為環(huán)境因素在遺傳上敏感的個(gè)體更易引起氧化應(yīng)激反應(yīng)異常,導(dǎo)致異常的甲基化,引起神經(jīng)系統(tǒng)發(fā)育延遲,注意力缺陷和神經(jīng)網(wǎng)絡(luò)同步能力受損等。除了自閉癥孩子,患有自閉癥孩子的父母本身就代謝異常,他們的甲基化能力和依賴(lài)GSH的抗氧化和解毒能力都出現(xiàn)了異常。
S-腺苷甲硫胺酸(S-adenosylmethionine,SAM)是甲基供體,脫去甲基后生成S-腺苷高半胱氨酸(S-adenosylho-mocysteine,SAH),SAM/SAH 的比例可以作為甲基化能力的指標(biāo),在自閉癥患兒體內(nèi),SAM和SAM/SAH 都顯著降低,SAM/SAH 的降低引起DNA,RNA,蛋白質(zhì)和磷脂的低甲基化(hypomethylation),導(dǎo)致基因和蛋白表達(dá)下降,酶活性降低和膜磷脂含量減少,進(jìn)而影響正常的細(xì)胞功能。SAH 繼續(xù)代謝可生成同型半胱氨酸(homocysteine)和腺苷(adenosine),約有1/2的同型半胱氨酸會(huì)通過(guò)依賴(lài)葉酸的甲基化循環(huán)途徑分解為胱硫醚和半胱氨酸,而GSH是通過(guò)蛋氨酸轉(zhuǎn)硫基途徑合成的,半胱氨酸是GSH合成的限制氨基酸,因此,GSH的合成需要足夠的葉酸、蛋氨酸和SAM 提供的半胱氨酸。自閉癥兒童體內(nèi)的葉酸、蛋氨酸合成酶活性、GSH水平明顯降低,而同型半胱氨酸和SAH明顯升高,且男孩體內(nèi)GSH 比女孩更低,同型半胱氨酸比女孩更高,這可能是男性患病率更高的一個(gè)原因。SAM 和GSH具有協(xié)同作用,它們之間相互影響決定了體內(nèi)的氧化還原水平,而體內(nèi)氧化還原失去平衡可能導(dǎo)致自閉癥。氧化還原失衡會(huì)引起活性氧(reactiveoxygen species,ROS)的產(chǎn)生,ROS在體內(nèi)積累會(huì)對(duì)DNA、RNA、蛋白質(zhì)、脂質(zhì)、碳水化合物等產(chǎn)生化學(xué)修飾和功能改變,從而導(dǎo)致細(xì)胞功能出現(xiàn)障礙,而ROS 能夠被谷胱甘肽過(guò)氧化物酶及谷胱甘肽還原酶等GSH相關(guān)的酶清除。因此,改變自閉癥患者體內(nèi)的氧化還原狀態(tài)可能有助于自閉癥的恢復(fù)。
(7) 過(guò)敏和自體免疫 自閉癥與免疫關(guān)系密切,約有60%的自閉癥患者伴有一定程度的免疫異常癥狀,并有可能作為新的治療靶點(diǎn)。研究發(fā)現(xiàn)自體免疫性疾病與自閉癥有關(guān),自閉癥患者家庭成員中患有自體免疫性疾病的比例明顯增多,約有46%的自閉癥患兒家庭成員中有兩名以上曾患有自體免疫性疾病,患病人數(shù)越多則兒童患自閉癥的幾率也越大,常見(jiàn)的自體免疫性疾病包括Ⅰ型糖尿病、甲狀腺機(jī)能低下癥、乳糜瀉、風(fēng)濕性關(guān)節(jié)炎、系統(tǒng)性紅斑狼瘡、多發(fā)性硬化癥等。推測(cè)自閉癥也是自體免疫性疾病的一種,其他如精神分裂癥、抑郁癥和強(qiáng)迫癥等心理相關(guān)疾病也都與自體免疫相關(guān),并且在自閉癥患者體內(nèi)已檢測(cè)到自體免疫相關(guān)抗體,如神經(jīng)軸突絲蛋白(neuron-axon filament protein)、膠質(zhì)纖維酸性蛋白(glial fibrillary acidic protein)和髓鞘堿性蛋白(myelin basic protein)等物質(zhì)的自體抗體,可能是自體抗體和細(xì)菌抗體相互作用引起的免疫反應(yīng)導(dǎo)致自閉癥。此外,一項(xiàng)大型研究對(duì)比了2431位自閉癥患兒的母親和653位未經(jīng)選擇的育齡婦女血液中腦反應(yīng)性抗體的水平,發(fā)現(xiàn)自閉癥患者母親體內(nèi)腦反應(yīng)性抗體的水平可達(dá)對(duì)照組的4倍,且抗體多集中在與自閉癥關(guān)系密切的額葉皮質(zhì)、海馬和小腦區(qū),較高的腦反應(yīng)性抗體表明自體免疫水平較高,可能自閉癥兒童的母親的自體免疫水平會(huì)影響孩子的自體免疫狀態(tài),進(jìn)而引發(fā)自閉癥。
自閉癥可能還與免疫因子和精氨酸加壓素(arginine vasopressin)等神經(jīng)肽相關(guān),自閉癥患兒相比對(duì)照組血漿中細(xì)胞轉(zhuǎn)化生長(zhǎng)因子-β1(transforming growth factor beta 1,TGF- β1)和白介素-23(interleukin 23,IL-23)水平明顯降低,并且TGF-β1,IL-23和白介素-17(IL-17,interleukin 17)的含量與自閉癥的嚴(yán)重程度負(fù)相關(guān),而熱休克蛋白-70(heatshock protein 70,HSP-70)、細(xì)胞轉(zhuǎn)化生長(zhǎng)因子β2(transforming growth factor beta 2,TGF-2)、半胱天冬酶-7(caspase-7)以及干擾素-γ(interferon-γ,INF-γ)明顯升高。最近的一項(xiàng)研究再次表明,自閉癥患者血液中TGF-β1的量顯著低于對(duì)照組,自閉癥與TGF-β1的含量負(fù)相關(guān)。TGF-β1作為一種免疫抑制細(xì)胞因子是維持體內(nèi)免疫內(nèi)穩(wěn)態(tài)的關(guān)鍵,能夠誘導(dǎo)和激活T細(xì)胞,因此,TGF-β1在自閉癥患者血液中的低含量顯示體內(nèi)免疫狀態(tài)異常。
免疫球蛋白水平在自閉癥患者體內(nèi)也存在異常,如免疫球蛋白IgG4在自閉癥患者體內(nèi)顯著高于對(duì)照組,而IgG4是一種類(lèi)似于IgE的與過(guò)敏有關(guān)的抑制性單價(jià)抗體,在慢性應(yīng)激過(guò)程中發(fā)揮免疫調(diào)節(jié)作用。雖然,在過(guò)去的10年里,發(fā)現(xiàn)了很多與自閉癥相關(guān)的免疫異常,但還沒(méi)有確切的生物標(biāo)記物能夠用于自閉癥檢測(cè)。
自閉癥也有可能與“講衛(wèi)生”有關(guān)?!靶l(wèi)生假說(shuō)(thehygiene hypothesis)”是建立在對(duì)農(nóng)村和城市疾病分布差異的觀察之上的普遍哮喘和過(guò)敏性疾病的病因理論,流行病學(xué)調(diào)查顯示,相對(duì)于發(fā)展中國(guó)家,清潔環(huán)境條件較好的西方發(fā)達(dá)國(guó)家哮喘和過(guò)敏性疾病的發(fā)病率更高,提示過(guò)于清潔的環(huán)境使兒童遠(yuǎn)離微生物和寄生蟲(chóng),人體缺少微生物和寄生蟲(chóng)的刺激會(huì)影響免疫系統(tǒng)的發(fā)育,導(dǎo)致過(guò)敏和哮喘,而微生物是其中重要的影響因素。值得注意的是自閉癥與過(guò)敏和哮喘具有相近的發(fā)病趨勢(shì)、性別偏好和城鄉(xiāng)差異,并且都跟免疫系統(tǒng)密切相關(guān),很可能是“太干凈”導(dǎo)致的。其機(jī)理可能是自閉癥兒童從小生活的環(huán)境過(guò)于干凈,被微生物“接種”的機(jī)會(huì)變少,導(dǎo)致免疫系統(tǒng)刺激不足,發(fā)育受阻礙,引起大腦發(fā)育異常,進(jìn)而導(dǎo)致行為錯(cuò)亂、發(fā)育遲緩,影響語(yǔ)言和社會(huì)交往,最終引發(fā)自閉癥。
2自閉癥的治療方法
目前,還沒(méi)有治療自閉癥核心障礙的有效方法。然而,醫(yī)生、科研人員和患兒家長(zhǎng)嘗試了多種治療方法,積累了很多經(jīng)驗(yàn)。常見(jiàn)的治療方法有行為干預(yù)法、特殊教育法、藥物治療法、生物醫(yī)學(xué)干預(yù)法以及心理干預(yù)法等,其中,常用的是使用高度結(jié)構(gòu)化的和密集的技巧性訓(xùn)練來(lái)幫助兒童發(fā)展社會(huì)和語(yǔ)言技能的行為干預(yù)法,如應(yīng)用行為分析。此外,還有一些有爭(zhēng)議的治療或干預(yù)方法,如補(bǔ)充和替代療法(complementary and alternative medicines)。其中生物相關(guān)療法包括:抗生素、抗真菌、抗病毒藥物,胃腸道藥物,營(yíng)養(yǎng)補(bǔ)充劑療法,限制或特殊飲食療法,分泌素療法,螯合療法,高壓氧療法,靜脈注射免疫球蛋白療法等,其他非生物相關(guān)療法包括:聽(tīng)覺(jué)整合培訓(xùn)、針灸療法、顱骨療法、器械輔助溝通療法、按摩和氣功療法、互動(dòng)節(jié)拍器療法、靈氣療法、自然療法、經(jīng)顱刺激療法和瑜伽等。據(jù)統(tǒng)計(jì),約有50%~70%的自閉癥患者會(huì)采用生物相關(guān)療法,但大多缺乏完整有效的安全性和有效性評(píng)估,仍需更多的系統(tǒng)性的研究和評(píng)估。隨著對(duì)人體微生物和自閉癥關(guān)系研究的發(fā)展,與之相對(duì)應(yīng)的干預(yù)或治療方法,如食物干預(yù)、益生菌以及糞菌移植等逐步顯示出其獨(dú)特的安全性和有效性,是具有廣泛應(yīng)用前景的生物干預(yù)方法。
2.1藥物
目前,還沒(méi)有針對(duì)自閉癥的特效藥。現(xiàn)用的藥物并非針對(duì)自閉癥的核心癥狀,而主要是一些抗精神病藥物,用于治療焦慮、抑郁或強(qiáng)迫性精神障礙等,用于改變5-HT和DA等神經(jīng)生化系統(tǒng),并且只是針對(duì)部分自閉癥癥狀。其中,利培酮(risperidone)和阿立哌唑(aripiprazole)是唯一通過(guò)美國(guó)食品藥品監(jiān)督管理局(Food and Drug Administration,F(xiàn)DA)認(rèn)證的僅可用于5~16歲兒童的自閉癥藥物,其他選擇性5-HT再攝取抑制劑西酞普蘭(citalopram)、艾司西酞普蘭(escitalopram)和氟西?。╢luoxetine)等可以用于治療自傷行為和重復(fù)行為等嚴(yán)重的行為問(wèn)題。治療癲癇癥狀的抗痙攣藥物和治療注意力缺陷障礙的藥物可有效地幫助自閉癥患者減少?zèng)_動(dòng)和多動(dòng),抗過(guò)敏的藥物賽庚啶(cyproheptadine)對(duì)自閉癥癥狀也有所緩解。據(jù)估計(jì),有47%的患兒使用這些藥物。
1998年曾報(bào)道使用分泌素(secretin)來(lái)干預(yù)自閉癥,并取得了一定的效果,但由于只有三個(gè)樣本,隨后的研究發(fā)現(xiàn)分泌素的效果并不顯著,可能存在安慰劑效應(yīng),因此,并沒(méi)有得以推廣。但是,可能這種產(chǎn)生于腸道的激素將人們的關(guān)注點(diǎn)最終引向了腸道對(duì)大腦的影響,為自閉癥的治療帶來(lái)了新的希望。
雖然,醫(yī)生會(huì)給自閉癥患者開(kāi)藥,但藥物并不能對(duì)自閉癥的核心缺陷,即社交和溝通障礙起實(shí)質(zhì)治療作用。這些藥物的有效性也低于其他類(lèi)疾病,且都具有一定的副作用,在兒童用藥方面仍欠缺足夠的臨床經(jīng)驗(yàn),因此,有必要限制對(duì)自閉癥患者做大規(guī)模和長(zhǎng)期用藥治療。
2.2抗生素
在發(fā)現(xiàn)一些自閉癥的腸道癥狀后,人們開(kāi)始嘗試使用抗生素治療腸道癥狀,并對(duì)自閉癥癥狀也有所幫助。一些自閉癥病人口服兩種廣泛用于厭氧菌感染的萬(wàn)古霉素(vancomycin)和甲硝銼(metronidazole或flagyl)后都有一定的治療效果。其中,萬(wàn)古霉素可能主要通過(guò)影響革蘭氏陽(yáng)性厭氧菌發(fā)揮作用,高濃度的萬(wàn)古霉素還會(huì)清除艱難梭菌和大部分革蘭氏陰性厭氧菌。萬(wàn)古霉素用于自閉癥治療時(shí)其有效性是短期的,一旦停用后就會(huì)出現(xiàn)反復(fù),并且在治療的每個(gè)療程,每次中斷都會(huì)復(fù)發(fā),可能腸道中的某些微生物導(dǎo)致了自閉癥癥狀,如在萬(wàn)古霉素治療后,腸道中的厭氧球菌(Anaerobic cocci)消失了。
口服萬(wàn)古霉素不能進(jìn)入血液系統(tǒng),幾乎不被人體吸收,而主要通過(guò)影響腸道微生物發(fā)揮作用,停藥之后出現(xiàn)反復(fù)可能是腸道微生物產(chǎn)生了孢子,當(dāng)停止使用萬(wàn)古霉素時(shí),孢子活化為細(xì)菌繼續(xù)影響腸道和神經(jīng)系統(tǒng),可產(chǎn)生孢子的梭菌屬最值得懷疑。
需要注意的是,雖然某些抗生素不能被人體吸收,但當(dāng)腸道出現(xiàn)炎癥、潰瘍等異常時(shí),它們也會(huì)進(jìn)入血液。此外,萬(wàn)古霉素和慶大霉素(gentamycin)通常用于其他抗生素?zé)o效時(shí)的嚴(yán)重疾病,被認(rèn)為是對(duì)抗耐藥菌的最后一道防線,一旦錯(cuò)誤使用很容易引起細(xì)菌耐藥性。所以,應(yīng)慎重選擇此類(lèi)抗生素應(yīng)用于自閉癥治療。
2.3食物
對(duì)自閉癥的常規(guī)治療通常是基于行為療法、飲食療法與藥物治療的組合療法。而飲食療法相比其他療法易于掌握,風(fēng)險(xiǎn)和副作用相對(duì)較小,能夠與其他療法同時(shí)使用,所以更易被采用。適當(dāng)?shù)娘嬍衬軌驇椭颊邷p輕痛苦,改善心理和胃腸道癥狀。目前,已有多種飲食干預(yù)方法和理論,主要包括無(wú)麩質(zhì)/無(wú)酪蛋白飲食(gluten-free/casein-free diet,GF/CF)、特殊碳水化合物飲食(the specific carbohydrate diet,SCD)、腸道和心理綜合征飲食(gut and psychology syndromediet,GAPS)、低草酸飲食(low oxalate diet)、生酮飲食(ketogenic diet)和法因戈?duì)柕嘛嬍常╰he Feingold diet)等。某些飲食方式對(duì)自閉癥有一定的改善作用,獲得了一些患者家庭的認(rèn)可,但其機(jī)制仍缺乏科學(xué)根據(jù),相應(yīng)的研究也較欠缺,因此,只選取其中部分飲食干預(yù)方法加以介紹。
(1) 無(wú)麩質(zhì)/無(wú)酪蛋白飲食 自閉癥兒童常伴有食物不耐受或過(guò)敏,需要去除食譜中可能引起食物不耐受和過(guò)敏的食物。人們發(fā)現(xiàn)減少或杜絕含有谷蛋白和酪蛋白的食物能夠減輕自閉癥癥狀。GF/CF飲食干預(yù)法就是從食物中去除面粉、小麥(Triticum aestivum)、大麥(Hordeum vulgare)、燕麥(Avena sativa)可能含有谷蛋白的食物,并且杜絕所有奶和奶制品,包括牛奶、酸奶、奶酪以及奶昔等可能含有酪蛋白的食物。有研究顯示,有超過(guò)1/2的父母在嚴(yán)格限制孩子食物中的這兩種蛋白質(zhì)后自閉癥癥狀明顯改善,并且7~9歲的患者對(duì)食物干預(yù)的反應(yīng)較為明顯。一項(xiàng)來(lái)自丹麥的研究調(diào)查了GF/CF飲食對(duì)自閉癥兒童的社會(huì)交往行為的影響,經(jīng)過(guò)12個(gè)月的飲食干預(yù)后,采用自閉癥診斷觀察量表(autism diagnostic observation schedule scale,ADOS),Gillim自閉癥評(píng)價(jià)量表(Gillim autism rating scale,GARS)和文蘭適應(yīng)行為量表(Vineland adaptivebehavior scales,VABS)以及注意缺陷多動(dòng)障礙量表-Ⅳ(attentiondeficit hyperactivity disorder Ⅳ scale,ADHD-Ⅳ)進(jìn)行評(píng)估,發(fā)現(xiàn)干預(yù)后ADOS,GARS和ADHD-Ⅳ的得分明顯升高。此外,對(duì)10個(gè)孩子連續(xù)1年的GF/CF食物干預(yù)后發(fā)現(xiàn),使用食物干預(yù)的患者發(fā)育水平要比對(duì)照組明顯變好。
雖然,已有大量相關(guān)研究顯示GF/CF 食物干預(yù)對(duì)自閉癥癥狀具有較好的影響,但具體作用機(jī)制仍不是很清楚。阿片樣物質(zhì)過(guò)量理論(opioidexcess theory)認(rèn)為兒童攝入谷蛋白和酪蛋白會(huì)對(duì)其行為和發(fā)育造成的不利影響,或者是由于自閉癥兒童對(duì)食物過(guò)敏或本身患有腹腔疾病,在食物進(jìn)入腸道時(shí)會(huì)引起胃腸道不適,可能兒童表現(xiàn)出的不適應(yīng)行為正是對(duì)胃腸道不適的一種反應(yīng)。
這一療法在全球非常流行,但其作用機(jī)制仍不清楚,且并非對(duì)所有自閉癥兒童有效,還可能引起營(yíng)養(yǎng)不良等副作用,因此受到一些質(zhì)疑。在嚴(yán)格的雙盲試驗(yàn)條件下,對(duì)2~16歲的自閉癥兒童連續(xù)12周的GF/CF飲食干預(yù)后,發(fā)現(xiàn)GF/CF飲食并沒(méi)有對(duì)自閉癥癥狀顯示出統(tǒng)計(jì)學(xué)上明顯的改善,雖然有部分患兒的父母表示有改善作用。也有綜述文章系統(tǒng)地比較了多個(gè)相關(guān)研究,表明目前的研究還不能充分證明這種飲食方式可以治愈自閉癥。
(2) 特殊碳水化合物飲食 Gottschall于2004年首次介紹和描述了SCD療法,其目的是緩解患者的吸收障礙癥狀并防止致病性腸道微生物的增長(zhǎng)。此療法比GF/CF飲食要求更嚴(yán)格,不僅完全無(wú)麩質(zhì),也無(wú)淀粉。研究者認(rèn)為某些腸道微生物(腸道病原體)引起了胃腸道異常,并產(chǎn)生一些神經(jīng)毒性物質(zhì)影響自閉癥兒童的大腦,而這些有害腸道病原體的生存需依賴(lài)難以消化的碳水化合物,因此,減少這種碳水化合物能夠斷絕這些有害腸道病原體的食物,“餓死”它們,從而抑制這些有害腸道病原體產(chǎn)生神經(jīng)毒性物質(zhì)傷害大腦。
自閉癥患者腸道微生物發(fā)生紊亂時(shí),腸道微生物不能分解那些未消化的淀粉和多糖等大分子物質(zhì),這些物質(zhì)進(jìn)入大腸內(nèi)可能被有害菌加以利用生成毒性物質(zhì)。SCD療法嚴(yán)格限制了所有的淀粉和多糖類(lèi),絕大部分的酵母菌以及其他有害腸道病原體得以抑制,進(jìn)而保護(hù)腸道微生態(tài)系統(tǒng),減少腸道感染,恢復(fù)腸道健康。同時(shí)也建議攝入單糖、酸奶、酸乳酪或益生菌等,促進(jìn)腸道中有益微生物的生長(zhǎng),有助于消化功能的恢復(fù),改善行為、感知和語(yǔ)言發(fā)展。然而,這一療法相關(guān)的科學(xué)報(bào)道較少,仍缺乏有效性和安全性評(píng)價(jià)。
(3) 腸道和心理綜合征飲食 GAPS療法是由Natasha Campbell McBride 博士發(fā)明,并且她曾用這種療法治療自己患自閉癥的兒子。GAPS飲食是在SCD 飲食的基礎(chǔ)上制定的飲食和康復(fù)法,用于改善多種消化系統(tǒng)異常和相應(yīng)的心理問(wèn)題。其食物構(gòu)成中包括了主要的SCD成分,康復(fù)訓(xùn)練和營(yíng)養(yǎng)指導(dǎo),此外,GAPS療法還特別推薦發(fā)酵食物和家庭自制肉湯,并給出了生活方式和排毒建議。
GAPS療法與SCD療法依據(jù)的理論不盡相同,GAPS更強(qiáng)調(diào)促進(jìn)腸道菌群的平衡,而SCD飲食則注重控制病原微生物。因此,在食物類(lèi)型上兩者之間有所差別,如GAPS飲食中包括了在SCD飲食中不被允許的淀粉和糖等成分,GAPS的食物清單中還包括魚(yú)肝油、必需脂肪酸、益生菌、維生素和微量元素等,并特別強(qiáng)調(diào)了營(yíng)養(yǎng)補(bǔ)充劑的作用。目前,對(duì)這一療法還缺乏科學(xué)驗(yàn)證,也欠缺有效性和安全性評(píng)價(jià)。
(4) 營(yíng)養(yǎng)補(bǔ)充劑 褪黑素(melatonin)是一種動(dòng)物松果體產(chǎn)生的胺類(lèi)激素,由5-HT衍生而來(lái)。目前作為具有保健功能的膳食補(bǔ)充劑,具有促進(jìn)睡眠、調(diào)節(jié)時(shí)差、抗衰老等作用。有50%~80%的自閉癥患者伴隨有睡眠障礙,并且褪黑素的水平也較正常人低。有研究將這種激素用于自閉癥患者,發(fā)現(xiàn)他們的睡眠狀況得到改善。但褪黑素有潛在的副作用,有可能引起癲癇發(fā)作。
肌肽(carnosine)是一種二肽氨基酸,具有抗氧化特性。它可能會(huì)影響GABA受體,具有保護(hù)神經(jīng)的作用。雙盲和安慰劑對(duì)照試驗(yàn)發(fā)現(xiàn),給自閉癥患者服用左旋肌肽8周后,能明顯改善其語(yǔ)言能力,并且自閉癥癥狀有所減輕。
維生素B6/Mg 聯(lián)合使用能減輕自閉癥癥狀。早期研究發(fā)現(xiàn),給自閉癥患者服用維生素B6和鎂之后,44個(gè)嚴(yán)重自閉癥患者中有15個(gè)癥狀得到改善,警覺(jué)性有所提高,并且爆發(fā)、消極、自殘、刻板行為明顯減少。然而,單獨(dú)使用維生素B6或鎂的改善作用并不明顯,持續(xù)兩周給予自閉癥患者30 mg/kg維生素B6和10~15 mg/kg的鎂,與單獨(dú)使用鎂或維生素B6相比,同時(shí)給予時(shí)自閉癥癥狀改善明顯。
甲基化維生素B12作為重要的輔因子參與甲硫氨酸的生成,能為轉(zhuǎn)甲基和轉(zhuǎn)硫基提供必需的甲基供體。半胱氨酸和谷胱甘肽具有抗氧化作用,一旦缺乏,將會(huì)導(dǎo)致機(jī)體的抗氧化能力減弱,造成機(jī)體的損傷。大多數(shù)自閉癥兒童體內(nèi)GSH的量偏低,而GSH/GSSH 明顯升高。注射甲基維生素B12能夠明顯改善自閉癥患者的社會(huì)交往行為、語(yǔ)言能力和其他行為問(wèn)題。當(dāng)給自閉癥兒童使用甲基維生素B12持續(xù)一個(gè)月后,血漿中GSH的量明顯升高,遺憾的是研究中缺乏對(duì)改善行為方面的評(píng)價(jià)。
微量營(yíng)養(yǎng)物質(zhì)(micronutrients)主要包括各種微量元素和其他微量營(yíng)養(yǎng)物質(zhì)。由于自閉癥兒童常出現(xiàn)飲食異常,并且常伴有腸道問(wèn)題,導(dǎo)致他們對(duì)食物的消化和吸收存在異常。大部分自閉癥兒童存在營(yíng)養(yǎng)不良,多種維生素和微量元素在自閉癥兒童中普遍缺乏,其缺乏的程度與自閉癥嚴(yán)重程度相關(guān)。給自閉癥患兒補(bǔ)充維生素和微量元素,患兒睡眠情況和腸道癥狀明顯好轉(zhuǎn),141位自閉癥患者口服維生素和微量元素3個(gè)月后,他們的營(yíng)養(yǎng)狀況和代謝水平得到明顯改善,甲基水平、谷胱甘肽、氧化水平、硫酸鹽化水平、ATP、NADH和NADPH等都明顯升高,并且多動(dòng)和發(fā)脾氣等行為與安慰劑組相比也明顯減少。另一項(xiàng)研究發(fā)現(xiàn),補(bǔ)充維生素和微量元素有助于提高自閉癥兒童的營(yíng)養(yǎng)和代謝水平,增加體內(nèi)甲基化、谷胱甘肽氧化應(yīng)激、硫酸鹽化作用并提高ATP、NADH和NADPH的水平。此外,臨床研究還發(fā)現(xiàn)服用維生素和微量元素復(fù)合物3~6個(gè)月后,自閉癥患者在異常行為檢查表(aberrant behavior checklist,ABC),臨床整體印象(clinical global impression,CGI)以及自我傷害方面都獲得很好的改善。
Omega-3不飽和脂肪酸對(duì)大腦發(fā)育至關(guān)重要,是組成神經(jīng)膜鞘的重要物質(zhì),也是在細(xì)胞交流和免疫調(diào)節(jié)中的必不可少的類(lèi)花生酸的底物。Omega-3不飽和脂肪酸主要包括二十碳五烯酸(eicosapentaenoicacid,EPA)和DHA。自閉癥患者體內(nèi)缺乏Omega-3不飽和脂肪酸,給自閉癥患者服用EPA和DHA 6周后,與安慰劑組相比,在刻板、多動(dòng)和不當(dāng)言論等方面表現(xiàn)良好,干預(yù)12周后,多動(dòng)行為明顯減少,但在異常行為方面沒(méi)有顯著差異。
此外,在孕前和孕早期補(bǔ)充葉酸能夠降低患自閉癥的風(fēng)險(xiǎn)。其他一些營(yíng)養(yǎng)補(bǔ)充劑,如N-乙酰半胱氨酸(N-acetylcysteine,NAC)、左旋肌肽(L-carnosine)、抗壞血酸(ascorbic acid,維生素C)等都有報(bào)道對(duì)自閉癥癥狀有改善。其他有助于大腦發(fā)育的營(yíng)養(yǎng)物質(zhì),如谷氨酸鹽(glutamine)、低聚糖(prebiotic oligosaccharides)以及L-精氨酸(L-arginine)等也可改善自閉癥癥狀。
2.4益生菌
胃腸道癥狀和自閉癥之間存在關(guān)聯(lián),但它們之間的關(guān)系還不是很明確,因果關(guān)系仍不清楚。可能某些未知因素或病原菌引起了胃腸道癥狀和自閉癥,或者兩者之間相互影響,相互促進(jìn)。已有研究證明,改善腸道菌群健康狀況能夠改善自閉癥癥狀,自閉癥兒童服用一些益生菌或吃富含益生元的發(fā)酵食物,同時(shí),限制或避免能夠影響腸道微生物的抗生素,含酒精或加工食品等,自閉癥癥狀,特別是便秘、腹瀉、炎性腸炎或腸易激綜合征等腸道癥狀均得到了明顯改善,推測(cè)可能微生物-腸-腦共同參與了自閉癥的發(fā)病。近兩年來(lái),越來(lái)越多的研究表明,腸道微生物能夠影響大腦發(fā)育、心理和行為。因此,通過(guò)改變腸道微生物可影響宿主的心理和行為,從而為自閉癥的治療帶來(lái)新的希望。
益生菌是直接影響腸道微生物組成的活性微生物,相比食物干預(yù),干預(yù)目標(biāo)更明確,干預(yù)作用更直接和有效。富含益生菌和益生元的食物可提供大量有益細(xì)菌和促進(jìn)有益菌生長(zhǎng)的物質(zhì),通過(guò)發(fā)酵食品或額外補(bǔ)充益生菌可以明顯改善腸道微生物和多種消化問(wèn)題,然而,患有自閉癥的兒童經(jīng)常在食物選擇方面存在困難,他們選擇有限的食物種類(lèi),難以獲得足夠多的益生菌和益生元。因此,在自閉癥人群中,通過(guò)強(qiáng)制和短時(shí)補(bǔ)充大量活性益生菌的方式可能比食物干預(yù)更有效。
一項(xiàng)研究給33名自閉癥患者服用含有5種益生菌的膠囊和一種來(lái)自乳酸菌細(xì)胞裂解物的免疫激活劑21天后,88%的患者自閉癥所有癥狀都有明顯改善,包括語(yǔ)言溝通、社會(huì)交往、感覺(jué)和認(rèn)知意識(shí)以及身體健康和行為等方面,48%的患者腹瀉癥狀明顯減少,52%便秘癥狀明顯好轉(zhuǎn)。遺憾的是這個(gè)研究中沒(méi)有對(duì)被試設(shè)置納入和排除標(biāo)準(zhǔn)和對(duì)照組。最近,一項(xiàng)來(lái)自斯洛伐克的研究表明,給自閉癥兒童每天3次服用含有3種乳酸桿菌,2種雙歧桿菌和1種鏈球菌的益生菌產(chǎn)品4個(gè)月后,自閉癥兒童腸道中厚壁菌門(mén)顯著減少,擬桿菌/厚壁菌的比例得以恢復(fù),雙歧桿菌和脫硫弧菌屬顯著減少,而乳酸桿菌屬細(xì)菌的相對(duì)數(shù)量得以顯著升高,推測(cè)自閉癥是由梭菌屬和脫硫弧菌屬細(xì)菌的增加導(dǎo)致。
此外,益生菌能夠顯著降低自閉癥患者體內(nèi)真菌數(shù)量,明顯改善自閉癥癥狀。 L-阿拉伯糖醇(L-arabitol,LA)在哺乳動(dòng)物體內(nèi)產(chǎn)生,D-阿拉伯糖醇(D-arabitol,DA)作為真菌感染的檢測(cè)標(biāo)志只由真菌產(chǎn)生,自閉癥患者尿液中DA含量顯著高于正常人。在給22位自閉癥孩子服用嗜酸乳桿菌后,尿液中DA的含量明顯降低,并且DA/LA也顯著降低,同時(shí),眼神交流、社會(huì)交往和反饋行為等自閉癥的典型行為也明顯改善。
其他種類(lèi)的益生菌也可能對(duì)自閉癥患者有幫助。有研究人員用脆弱擬桿菌(Bacteroides fragillis)來(lái)處理自閉癥樣小鼠,小鼠的腸道通透性和自閉癥樣行為都得到明顯改善。給20位3~16歲的伴有便秘的自閉癥孩子服用4周的短雙歧桿菌(Bifidobacterium breve)后,便秘癥狀都得到了明顯改善,排便頻率增多、糞便硬度降低、糞尿失禁的頻率降低,并且腹痛癥狀也減少了。
雖然,這些研究存在樣本量少,缺乏對(duì)照和安慰劑實(shí)驗(yàn)等問(wèn)題,但其干預(yù)效果較為明顯,甚至有些對(duì)自閉癥的核心癥狀有所改善,表現(xiàn)出明顯的優(yōu)勢(shì)。益生菌用于改善自閉癥癥狀潛力巨大,但現(xiàn)在還不清楚是益生菌直接影響了自閉癥患者大腦中某些區(qū)域的功能,改善了自閉癥癥狀,還是通過(guò)先改善腸道菌群健康狀況,得到恢復(fù)的腸道菌群進(jìn)而影響自閉癥的癥狀,抑或同時(shí)都起作用。
無(wú)菌小鼠是研究腸道微生物作用的理想動(dòng)物模型。最近的研究發(fā)現(xiàn),無(wú)菌小鼠腦中海馬區(qū)5-HT含量顯著升高,并且在腸道菌群恢復(fù)后5-HT含量也恢復(fù)正常。無(wú)菌小鼠對(duì)壓力反應(yīng)更敏感,海馬和杏仁核區(qū)域的神經(jīng)內(nèi)分泌水平異常,表現(xiàn)出焦慮水平降低(進(jìn)入高架十字迷宮中的開(kāi)臂端更多,時(shí)間更長(zhǎng))和空間記憶喪失等。無(wú)菌小鼠腦中單胺類(lèi)神經(jīng)遞質(zhì)也發(fā)生了變化,而這種改變更多的出現(xiàn)在雄性個(gè)體中,表明雄性個(gè)體比雌性個(gè)體在神經(jīng)系統(tǒng)發(fā)育方面出現(xiàn)異常的發(fā)生率更高。在人類(lèi)中,男孩比女孩發(fā)病率更高可能也是基于類(lèi)似的機(jī)制。此外,無(wú)菌小鼠大腦中相應(yīng)的基因表達(dá)也出現(xiàn)異常,如腦源性神經(jīng)營(yíng)養(yǎng)因子(brain-derived neurotrophic factor,BDNF)顯著上調(diào),海馬齒狀回的5-HT受體5-ht1a子型以及杏仁核的N-甲基-D-天門(mén)冬氨酸(N-methyl- D-aspartic acid,NMDA)受體NR2B亞基(NMDA receptor 2B subunit)都明顯下調(diào)。BDNF可維持大腦的正常發(fā)育,5-HT受體缺乏會(huì)引起焦慮樣行為,而NMDA的NR2B受體亞基對(duì)杏仁核的發(fā)育和正常功能至關(guān)重要,與恐懼、情緒以及學(xué)習(xí)和記憶密切相關(guān)。
腸道菌群對(duì)正常的社交行為發(fā)育至關(guān)重要,無(wú)菌小鼠表現(xiàn)出明顯的社交障礙,特別是雄性小鼠,出現(xiàn)社交回避和刻板行為,對(duì)同類(lèi)興趣降低,對(duì)陌生個(gè)體的探究行為減少,而一些重復(fù)的行為增加,但當(dāng)恢復(fù)腸道微生物后,社交回避和重復(fù)行為得到了改善,而社會(huì)認(rèn)知障礙并沒(méi)有變化。自閉癥兒童表現(xiàn)出類(lèi)似的社交和溝通障礙以及重復(fù)的行為,并且男孩發(fā)病的比例遠(yuǎn)高于女孩,因此,自閉癥可能正是由于腸道菌群的改變導(dǎo)致的。已有的研究發(fā)現(xiàn),腸道微生物能夠影響大腦,不僅包括自閉癥,還包括焦慮、抑郁和精神分裂等。
2.5糞菌移植
糞菌移植(fecal microbiota transplantation,F(xiàn)MT)是將健康人糞便中的菌群移植到受體人的腸道中,幫助其恢復(fù)正常的胃腸道菌群,用于治療胃腸道及其他類(lèi)型的疾病。FMT在國(guó)外已有50余年的應(yīng)用歷史,而我國(guó)至少已經(jīng)有1700年的應(yīng)用歷史,全球已有數(shù)千例患者接受FMT治療。2013年5月,美國(guó)FDA將FMT作為研究性新藥納入監(jiān)管。目前,F(xiàn)MT作為一種器官移植方式,不僅用于治療人的胃腸道疾病,如難辨梭狀芽胞桿菌感染、抗生素相關(guān)性腹瀉、炎癥性腸病、腸易激綜合征、代謝綜合征、自身免疫性腸病、腸道食物過(guò)敏等,還用于神經(jīng)發(fā)育不良與神經(jīng)退行性疾病,并且可能對(duì)帕金森病和兒童自閉癥等精神疾病具有一定療效。目前,還缺乏FMT治療自閉癥的相關(guān)研究。
3研究展望
自閉癥并不是由單一因素引起的,受遺傳和環(huán)境共同影響。環(huán)境污染、生物異源物質(zhì)、母親孕期的健康狀況、腸道健康狀況、飲食和營(yíng)養(yǎng)等因素都可能引起自閉癥。但越來(lái)越多的證據(jù)表明,腸道微生物與自閉癥之間存在密切的聯(lián)系,上述因素或多或少地都對(duì)腸道微生物產(chǎn)生影響,因此,可能腸道微生物是引發(fā)自閉癥的關(guān)鍵因素。相應(yīng)的,針對(duì)上述影響因素,出現(xiàn)了多種治療方法,包括藥物、食物以及一些營(yíng)養(yǎng)補(bǔ)充劑等,其中益生菌是其中比較有前景的治療方法。隨著人們對(duì)腸道微生物和自閉癥關(guān)系的研究深入,越來(lái)越多的針對(duì)腸道微生物的干預(yù)和治療方法開(kāi)始出現(xiàn),然而,腸道微生物和自閉癥之間的具體影響機(jī)制還未闡明,仍不清楚究竟是某些腸道微生物的異常還是整個(gè)腸道微生態(tài)系統(tǒng)的構(gòu)成才是自閉癥的誘因,仍需更多研究。
雖然,目前已經(jīng)發(fā)現(xiàn)了一些可能跟自閉癥相關(guān)的腸道微生物或菌群組成,但由于大多數(shù)腸道微生物不能通過(guò)體外培養(yǎng),而潛在的能夠?qū)е伦蚤]癥的微生物可能正是不能體外培養(yǎng)的細(xì)菌,它們的數(shù)量也許非常少,也可能它們是黏附在腸黏膜上,在糞便中數(shù)量極少,還有可能它們主要分布在小腸中,在目前的技術(shù)條件下,還不能對(duì)它們進(jìn)行完整的取樣和分析。也可能自閉癥是腸道微生物生態(tài)系統(tǒng)出現(xiàn)問(wèn)題導(dǎo)致的,并不是其中一種或幾種菌導(dǎo)致的。當(dāng)然,不同類(lèi)型的自閉癥以及不同嚴(yán)重程度的自閉癥可對(duì)應(yīng)不同的腸道菌群,即使發(fā)現(xiàn)了某些特定的菌群,也要經(jīng)過(guò)類(lèi)似科赫法則的嚴(yán)格驗(yàn)證過(guò)程才能得出準(zhǔn)確的結(jié)論。通常情況下,自閉癥患兒腸道狀況得以改善后,自閉癥癥狀也會(huì)隨著減輕。益生菌改善自閉癥癥狀,可能并不是通過(guò)改變腸道健康狀況影響兒童的自閉癥癥狀,而是益生菌本身產(chǎn)生某些神經(jīng)活性物質(zhì)直接影響兒童神經(jīng)系統(tǒng)進(jìn)而改善自閉癥癥狀。益生菌的種類(lèi)眾多,乳酸菌、雙歧桿菌和酵母菌屬中都有一些菌對(duì)人體有益,但絕非所有菌種都有相同的作用,各種益生菌的作用機(jī)制也會(huì)存在差異。只有了解益生菌進(jìn)入體內(nèi)的實(shí)際作用,清楚地知道自身體內(nèi)腸道菌群的狀況,才能對(duì)癥選擇有效的益生菌。至今還有很多問(wèn)題需要解答,腸道微生物將成為自閉癥的重點(diǎn)方向。
每個(gè)個(gè)體擁有不同的遺傳背景、菌群組成和生活環(huán)境,因此,最理想的治療方式是根據(jù)不同個(gè)體采取個(gè)性化的治療和干預(yù)措施。雖然已經(jīng)出現(xiàn)了多種治療自閉癥的方法,但相關(guān)的研究卻相對(duì)滯后,需要進(jìn)一步研究干預(yù)方法的機(jī)理,對(duì)有效性和安全性進(jìn)行科學(xué)評(píng)估。雖然某些治療方法只能緩解特定的癥狀,并不能對(duì)自閉癥核心癥狀有所幫助,但即使這樣,出于提高患者生存質(zhì)量,減少患者和家人負(fù)擔(dān)的目的,仍需要積極主動(dòng)進(jìn)行治療,并且越早進(jìn)行治療和干預(yù)越好。自閉癥的發(fā)病可能在胎兒時(shí)期,甚至母親懷孕時(shí)已經(jīng)開(kāi)始了,應(yīng)該做到及早預(yù)防,在懷孕期間或懷孕之前,盡早咨詢(xún)相關(guān)醫(yī)生或?qū)<?,同時(shí)特別注意母親懷孕前和懷孕期間的營(yíng)養(yǎng)狀況和代謝情況。孩子出生之后,也應(yīng)密切注意孩子異常的啼哭,手捂肚子、拱起背部等行為,注意觀察孩子的糞便、腹瀉、便秘、打嗝及放屁等胃腸道異常等與腸道微生物狀態(tài)直接相關(guān)的狀況,從而盡可能地及早發(fā)現(xiàn)和降低孩子患自閉癥的風(fēng)險(xiǎn)。在自閉癥發(fā)病率相對(duì)較低的國(guó)家,孩子往往有更多的機(jī)會(huì)接觸大自然,泥土以及動(dòng)物,這些方式都是讓人獲得共生微生物的機(jī)會(huì),特別值得我們思考和借鑒。此外,可能自閉癥的發(fā)病率正是伴隨著食品工業(yè)的發(fā)展逐年升高,傳統(tǒng)的手工制作的嬰兒食品正在被大量的方便食品、加工食品以及人工合成添加劑取代,需要引起家長(zhǎng)們的關(guān)注。?
(摘自《中國(guó)科學(xué):生命科學(xué)》2015年9期。)
·高被引論文摘要·
被引頻次:83
福建省兒童孤獨(dú)癥流行病學(xué)調(diào)查
羅維武,林力,陳榕,等
摘要:目的:了解福建省兒童孤獨(dú)癥的患病及分布情況。方法:抽查福建省不同地區(qū)14歲以下兒童共10802人,采取ABC量表篩查、CCMD-2-R及DSM-Ⅲ-R確定診斷的方法。結(jié)果:確診為兒童孤獨(dú)癥的共3名,時(shí)點(diǎn)患病率為0.28‰。結(jié)論:福建省兒童孤獨(dú)癥的患病率在國(guó)外報(bào)道患病率范圍之內(nèi),應(yīng)加強(qiáng)對(duì)兒童孤獨(dú)癥的研究。
關(guān)鍵詞:兒童孤獨(dú)癥;患病率;流行病學(xué)
來(lái)源出版物:上海精神醫(yī)學(xué), 2000, 12(1): 3-5
被引頻次:68
自閉癥診斷與干預(yù)研究綜述
尤娜,楊廣學(xué)
摘要:本文概述了當(dāng)前國(guó)內(nèi)外有關(guān)自閉癥和“自閉類(lèi)”障礙的定義與診斷、病因和干預(yù)方案的研究,并簡(jiǎn)要分析了未來(lái)研究的重點(diǎn)和方向。
關(guān)鍵詞:自閉癥;“自閉類(lèi)”障礙;診斷;干預(yù)方案
來(lái)源出版物:中國(guó)特殊教育, 2006, 7(73): 26-31
被引頻次:65
孤獨(dú)癥患病率回顧
樊越波,揭曉鋒,鄒小兵
摘要:回顧歷年來(lái)國(guó)內(nèi)外孤獨(dú)癥患病率文獻(xiàn)報(bào)道,患病率有增加的趨勢(shì),對(duì)于患病率增加的原因,認(rèn)識(shí)的加深可能是主要原因,而發(fā)病率是否增加存在爭(zhēng)議。
關(guān)鍵詞:廣泛性發(fā)育障礙;孤獨(dú)癥譜系障礙;孤獨(dú)癥;患病率
來(lái)源出版物:中國(guó)兒童保健雜志, 2008, 16(4): 439-440
被引頻次:53
三種兒童孤獨(dú)癥行為評(píng)定量表臨床應(yīng)用比較
李建華,鐘建民,蔡蘭云,等
摘要:目的:兒童孤獨(dú)癥的診斷缺乏特異性的生物學(xué)指標(biāo),量表評(píng)定有重要的臨床指導(dǎo)價(jià)值,目前有多種量表用于評(píng)定。該文對(duì)孤獨(dú)癥行為評(píng)定量表(ABC)、兒童期孤獨(dú)癥評(píng)定量表(CARS或卡氏量表)、克氏孤獨(dú)癥行為量表(CABS或克氏量表)進(jìn)行比較,以期為臨床應(yīng)用提供借鑒。方法:對(duì)28例孤獨(dú)癥患兒和34例對(duì)照組兒童分別采用ABC、CARS和CABS進(jìn)行評(píng)估和比較。結(jié)果:三種評(píng)估方法在病例組與對(duì)照組間的評(píng)定結(jié)果均有極顯著差異(P<0.01);DSM Ⅳ兒童孤獨(dú)癥診斷標(biāo)準(zhǔn)判斷結(jié)果與CARS評(píng)估結(jié)果的一致性最好(Kappa=1),與ABC也有較好一致性(Kappa=0.87),但與CABS的一致性稍差(Kappa=0.60)。應(yīng)用受試者工作特性曲線(ROC)進(jìn)行綜合比較,ABC取31為篩查界線分最好,其特異性為0.97、敏感性為0.89、一致率為0.94、陽(yáng)性預(yù)測(cè)值為0.96、陰性預(yù)測(cè)值為0.92,且更適合3歲以上兒童使用;CARS取30為診斷界線分最好,敏感性、特異性、一致性、陽(yáng)性預(yù)測(cè)值與陰性預(yù)測(cè)值均為1.0,且與年齡無(wú)關(guān);CABS取6為篩查界線分更為理想,其特異性為0.91,敏感性為0.82、一致率為0.87、陽(yáng)性預(yù)測(cè)值為0.88、陰性預(yù)測(cè)值為0.86,且3歲以上兒童使用優(yōu)于3歲以下。結(jié)論:ABC、CARS及CABS是輔助診斷孤獨(dú)癥的重要評(píng)估工具,相互間具有較好的一致性;但如果同,同時(shí)兼顧敏感性、特異性、一致性、陽(yáng)性預(yù)測(cè)值及陰性預(yù)測(cè)值,CARS優(yōu)于ABC,而ABC又優(yōu)于CABS。
關(guān)鍵詞:孤獨(dú)癥;評(píng)估研究;孤獨(dú)癥行為評(píng)定量表;兒童期
來(lái)源出版物:中國(guó)當(dāng)代兒科雜志, 2005, 7(1): 59-62
被引頻次:53
孤獨(dú)癥行為量表試測(cè)報(bào)告
楊曉玲,黃悅勤,賈美香,等
摘要:采用孤獨(dú)癥行為量表(Autism Behavior Checklist)對(duì)國(guó)內(nèi)60名孤獨(dú)癥兒童,157名精神發(fā)育遲滯兒童及108名正常兒童的試測(cè),發(fā)現(xiàn)當(dāng)量表總分≥31分作為孤獨(dú)癥篩查界限分時(shí)其信度、效度均為1,檢驗(yàn)符合要求;當(dāng)總分≥62分時(shí),對(duì)診斷與鑒別診斷有較好的陽(yáng)性率。量表項(xiàng)目出現(xiàn)頻率提示,原量表項(xiàng)目在我國(guó)可以保留使用。性別、年齡因素對(duì)量表影響不大。
關(guān)鍵詞:孤獨(dú)癥;量表;效度;信度
來(lái)源出版物:中國(guó)心理衛(wèi)生雜志, 1993, 7(6): 279-280
被引頻次:50
自閉癥譜系障礙的癥狀、診斷與干預(yù)
陳順森,白學(xué)軍,張日昇
摘要:自閉癥譜系障礙(autism spectrum disorders,ASD)是一種廣泛發(fā)展障礙,以社會(huì)交往障礙、言語(yǔ)和非言語(yǔ)交流缺陷、興趣狹窄和行為刻板等為主要臨床特征。對(duì)ASD的準(zhǔn)確診斷是早期干預(yù)的關(guān)鍵,也對(duì)患者的康復(fù)及其家庭幸福產(chǎn)生積極作用。日漸增長(zhǎng)的發(fā)病率促進(jìn)了對(duì)早期識(shí)別、診斷評(píng)估、以事實(shí)為基礎(chǔ)干預(yù)的重視。在探索藥物治療ASD的基礎(chǔ)上,中國(guó)傳統(tǒng)醫(yī)學(xué)方法,尤其是“靳三針”治療ASD獲得越來(lái)越多的實(shí)證支持??梢愿鶕?jù)Simpson等人(2005)提出的指標(biāo)體系對(duì)各種干預(yù)和治療方法的療效進(jìn)行評(píng)價(jià)。今后研究將從認(rèn)知神經(jīng)科學(xué)的視角,尤其是將眼動(dòng)技術(shù)與ERP、fMRI相結(jié)合,探索ASD的核心癥狀表征以及各亞類(lèi)的特異性。
關(guān)鍵詞:自閉癥譜系障礙;流行病學(xué);診斷;康復(fù)
來(lái)源出版物:心理科學(xué)進(jìn)展, 2011, 19(1): 60-72
被引頻次:43
關(guān)于自閉癥的臨床、實(shí)驗(yàn)心理學(xué)的研究
徐光興
摘要:最近,國(guó)際上的臨床心理學(xué)、實(shí)驗(yàn)心理學(xué)對(duì)自閉癥的診斷、分類(lèi)、發(fā)生率以及教育與治療等,從各個(gè)角度展示了許多新的研究結(jié)果。實(shí)驗(yàn)心理學(xué)的調(diào)查結(jié)果表明,自閉癥兒童的注意力異常,對(duì)視、聽(tīng)、觸等感覺(jué)反應(yīng)處理樣式,不同于弱智兒童和正常兒童。語(yǔ)言障礙是自閉癥兒童發(fā)展障礙中的核心癥候,這與自閉癥在社會(huì)性和人際關(guān)系上存在障礙有著密切的關(guān)系。進(jìn)入90年代以后,對(duì)自閉癥“心的理論”的各種實(shí)驗(yàn)研究,引起各國(guó)研究者的注目和爭(zhēng)論。這不僅為自閉癥的科學(xué)研究,也為發(fā)展心理學(xué)及認(rèn)知心理學(xué),人類(lèi)系統(tǒng)工程學(xué)提供了許多新的研究課題,并對(duì)我國(guó)今后的自閉癥研究工作產(chǎn)生一定的啟示意義。
關(guān)鍵詞:自閉癥;心的理論;感情認(rèn)知障礙
來(lái)源出版物:心理科學(xué), 2000, 23(1): 38-41
被引頻次:41
關(guān)于兒童自閉癥行為矯治法的幾個(gè)理論問(wèn)題
黃偉合
摘要:了解兒童自閉癥行為矯治法有助于提高自閉癥治療的質(zhì)量和效果。本文討論了有關(guān)兒童自閉癥行為矯治法的幾個(gè)理論問(wèn)題。作者還介紹分析了中外自閉癥文獻(xiàn)中記載的兒童自閉癥行為矯治法的臨床實(shí)驗(yàn)及其治療效果。
關(guān)鍵詞:兒童自閉癥;行為矯治法;功能分析法;替代行為;前期干預(yù)
來(lái)源出版物:心理科學(xué), 2003, 26(3): 475-478
被引頻次:40
天津市2~6歲兒童孤獨(dú)癥調(diào)查
張欣,季成葉,李金水
摘要:目的:了解天津市兒童孤獨(dú)癥現(xiàn)患狀況及可能的影響因素,為預(yù)防康復(fù)提供依據(jù)。方法:采用分層整群抽樣,在天津市兩區(qū)縣抽取2~6歲7316名兒童為對(duì)象,篩查和診斷兒童孤獨(dú)癥。結(jié)果:天津市兒童孤獨(dú)癥現(xiàn)患率為1.1‰(8/7316);男∶女=7∶1;城、鄉(xiāng)患病率為1.4‰和0.8‰。孤獨(dú)癥患兒全部為智力低下者。結(jié)論:應(yīng)針對(duì)兒童孤獨(dú)癥的智力、精神和神經(jīng)損傷及早采取康復(fù)措施。
關(guān)鍵詞:孤獨(dú)癥;現(xiàn)患率;兒童;智力低下
來(lái)源出版物:中國(guó)生育健康雜志, 2005, 15(4): 206-208
被引頻次:40
10例孤獨(dú)癥兒童心理推測(cè)能力的測(cè)試分析
焦青
摘要:目的:探討孤獨(dú)癥兒童的心理推測(cè)能力。方法:本研究使用自編的測(cè)驗(yàn)故事為測(cè)量工具考察了學(xué)齡孤獨(dú)癥兒童的心理推測(cè)能力。結(jié)果:孤獨(dú)癥兒童能理解他人的生理性和社會(huì)性愿望,并能依據(jù)他人的愿望預(yù)測(cè)他人的行為;基本能理解他人的積極性和消極性情緒;但他們?cè)诶斫馑说奶摷傩拍顣r(shí)則表現(xiàn)出明顯的困難,并且不能理解他人由虛假信念所導(dǎo)致的認(rèn)知性情緒。結(jié)論:依據(jù)孤獨(dú)癥兒童在理解他人虛假信念上的表現(xiàn),提示孤獨(dú)癥兒童在理解他人虛假信念的能力上只存在著量上的差異而非質(zhì)上的差異。
關(guān)鍵詞:孤獨(dú)癥;心理推測(cè);愿望;情緒;信念
來(lái)源出版物:中國(guó)心理衛(wèi)生雜志, 2001, 15(1): 60-62
被引頻次:1309
Strong association of de novo copy number mutations with autism
Sebat, J; Lakshmi, B; Malhotra, D; et al.
Abstract: We tested the hypothesis that de novo copy number variation(CNV) is associated with autism spectrum disorders(ASDs). We performed comparative genomic hybridization(CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regionswere validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism(P=0.0005). Such CNVs were identified in 12 out of 118(10%) of patients with sporadic autism, in 2 out of 77(3%) of patients with an affected first-degree relative, and in 2 out of 196(1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
來(lái)源出版物:Science, 2007, 316(5823): 445-449
被引頻次:1279
Autism as a strongly genetic disorder: Evidence from a british twin study
Bailey, A; Lecouteur, A; Gottesman, I; et al.
Abstract: Two previous epidemiological studies of autistic twins suggested that autism was predominantly genetically determined, although the findings with regard to a broader phenotype of cognitive, and possibly social, abnormalities were contradictory. Obstetric and perinatal hazards were also invoked as enviro- nmentally determined aetiological factors. The first British twin sample has been re-examined and a second total population sample of autistic twins recruited. In the combined sample 60% of monozygotic(MZ) pairs were concordant for autism versus no dizygotic(DZ) pairs; 92% of MZ pairs were concordant for a broader spectrum of related cognitive or social abnormalities versus 10% of DZ pairs. The findings indicate that autism is under a high degree of genetic control and suggest the involvement of multiple genetic loci. Obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors. Few new cases had possible medical aetiologies, refuting claims that recognized disorders are common aetiological influences.
來(lái)源出版物:Psychological Medicine, 1995, 25(01): 63-77
被引頻次:867
Structural variation of chromosomes in autism spectrum disorder
Marshall, CR; Noor, A; Vincent, JB; et al.
Abstract: Structural variation(copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder(ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via singlenucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls(and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three(11%) of these individuals, two or more new variants were observed. De novo CNVs were found in similar to 7% and similar to 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/ overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Not with standing complexities, our results further implicate the SHANK3- NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9(synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2(P = 0.002)(with characteristics of a genomic disorder) at similar to 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
來(lái)源出版物:The American Journal of Human Genetics, 2008, 82(2): 477-488
被引頻次:865
A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: Report of 35 cases
Hagberg, B; Aicardi, J ; Dias, K; et al.
Abstract: Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurologicalabnormalities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior extensive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.
來(lái)源出版物:Annals of Neurology, 1983, 14(4): 471-479
被引頻次:824
Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism
Jamain, S; Quach, H; Betancur, C; et al.
Abstract: Many studies have supported a genetic etiology for autism. Here we report Mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect celladhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
來(lái)源出版物:Nature Genetics, 2003, 34(1): 27-29
被引頻次:786
Functional impact of global rare copy number variation inautism spectrum disorders
Pinto, Dalila; Pagnamenta, AT; Klei, L; et al.
Abstract: The autism spectrum disorders(ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable(similar to 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare(<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants(CNVs)(1.19 fold, P=0.012), especially so for loci previously implicated in either ASD and/or intellectual disability(1.69 fold, P=3.4 × 10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
來(lái)源出版物:Nature, 2010, 466(7304): 368-372
被引頻次:780
Association between microdeletion and microduplication at 16p11.2 and autism
Weiss, LA; Shen, YP; Korn, JM; et al.
Abstract: Background: Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. Methods: As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange(AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Results: Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. Conclusions: We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.
來(lái)源出版物:New England Journal of Medicine, 2008, 358(7): 667-675
被引頻次:779
Mapping autism risk loci using genetic linkage and chromosomal rearrangements
Szatmari, P; Paterson, AD; Zwaigenbaum, L; et al.
Abstract: Autism spectrum disorders(ASDs) are common,heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome hetero- geneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
來(lái)源出版物:Nature Genetics, 2007, 39(3): 319-328
被引頻次:719
Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism
Klin, A; Jones, W; Schultz, R; et al.
Abstract: Background: Manifestations of core social deficits in autism are more pronounced in everyday settings than in explicit experimental tasks. To bring experimental n Measures in line with clinical observation, we report a novel method of quantifying atypical strategies of social monitoring in a setting that simulates the demands of daily experience. Enhanced ecological validity, was intended to maximize between-group effect sizes and assess the predictive utility of experimental variables relative to outcome measures of social competence. Methods: While viewing social scenes, eye-tracking technology measured visual fixations in 15 cognitively able males with autism and 15 age-, sex-, and verbal IQ-matched control subjects. We reliably coded fixations on 4 regions: mouth, eyes, body, and objects. Statistical analyses compared fixation time on regions of interest between groups and correlation of fixation time with outcome measures of social competence(ie, standardized measures of daily social adjustment and degree of autistic social symptoms). Results: Significant between-group differences were obtained for all 4 regions. The best predictor of autism was reduced eye region fixation time. Fixation on mouths and objects was significantly correlated with social functioning: increased focus on mouths predicted improved social adjustment and less autistic social impairment, whereas more time on objects predicted the opposite relationship. Conclusions: When viewing naturalistic social situations, individuals with autism demonstrate abnormal patterns of social visual pursuit consistent with reduced salience of eyes and increased salience of mouths, bodies, and objects. Fixation times on mouths and objects but not on eyes are strong predictors of degree of social competence.
來(lái)源出版物:Archives of General Psychiatry, 2002, 59(9): 809-816
被引頻次:699
Infantile autism: A genetic study of 21 twin pairs
Folstein, S; Rutter, M
Abstract: A systematic study was made of a representative group of 21 same-sexed twin pairs(11 MZ and 10 DZ) in which at least one twin showed the syndrome of infantile autism. There was a 36 per cent pair-wise concordance rate for autism in MZ pairs compared with o per cent concordance in DZ pairs. The concordance for cognitive abnormalities was 82 per cent in MZ pairs and 10 per cent in DZ pairs. It was concluded that there were important hereditary influences concerning a cognitive deficit which included but was not restricted to autism. In 12 out of 17 pairs discordant for autism, the presence of autism was associated with a biological hazard liable to cause brain damage. It was concluded that brain injury in the infancy period may lead to autism on its own or in combination with a genetic predisposition. Uncertainty remains on both the mode of inheritance and exactly what is inherited.
來(lái)源出版物:Journal of Child Psychology and Psychiatry, 1977, 18(4): 297-321
·推薦論文摘要·
自閉癥譜系障礙兒童重復(fù)刻板行為研究綜述
寧寧,張永盛,楊廣學(xué)
摘要:重復(fù)刻板行為是自閉癥譜系障礙的核心缺陷之一,也是自閉癥譜系障礙的診斷標(biāo)準(zhǔn)之一。其類(lèi)型復(fù)雜、表現(xiàn)形式多樣,對(duì)自閉癥譜系障礙兒童的社會(huì)融合和社會(huì)技能的掌握有消極影響。通過(guò)對(duì)研究重復(fù)刻板行為的文獻(xiàn)進(jìn)行梳理,具體整理了重復(fù)刻板行為的分類(lèi)、表現(xiàn)以及成因解釋?zhuān)?duì)現(xiàn)有研究進(jìn)行反思,為以后研究提供參考。
關(guān)鍵詞:自閉癥譜系障礙;重復(fù)刻板行為;分類(lèi);表現(xiàn);成因
來(lái)源出版物:中國(guó)特殊教育, 2015, 2: 46-52
聯(lián)系郵箱:楊廣學(xué),yanggx2789@163.com
孤獨(dú)癥譜系障礙患兒血清25(OH)D水平的檢測(cè)
杜琳,單玲,王冰,等
摘要:目的:了解孤獨(dú)癥譜系障礙(ASD)患兒維生素D營(yíng)養(yǎng)狀況,探討維生素D水平與ASD的關(guān)系。方法:采用高效液相色譜-串聯(lián)質(zhì)譜法對(duì)117例新診斷的ASD患兒和109例健康對(duì)照兒童進(jìn)行血清25(OH)D檢測(cè),并根據(jù)血清25(OH)D水平,將維生素D狀況分為正常(>30 ng/mL)、不足(10~30 ng/mL)和缺乏(<10 ng/mL),比較兩組兒童維生素D營(yíng)養(yǎng)狀況。結(jié)果:ASD患兒25(OH)D水平(19±9 ng/mL)明顯低于對(duì)照組(36±13 ng/mL),差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。ASD患兒中維生素D缺乏和不足率為89.7%,明顯高于對(duì)照組(52.3%),差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。結(jié)論:ASD患兒存在維生素D缺乏或不足,維生素D缺乏和不足有可能是ASD發(fā)病的環(huán)境/遺傳因素。
關(guān)鍵詞:孤獨(dú)癥譜系障礙;維生素D;環(huán)境因素;遺傳因素;兒童
來(lái)源出版物:中國(guó)當(dāng)代兒科雜志, 2015, 17(1): 68-71
DSM孤獨(dú)癥譜系障礙診斷分類(lèi)標(biāo)準(zhǔn)的演變、影響與展望
卜凡帥,徐勝
摘要:準(zhǔn)確的診斷分類(lèi)是孤獨(dú)癥譜系障礙有效干預(yù)服務(wù)的前提,而準(zhǔn)確的診斷分類(lèi)離不開(kāi)科學(xué)的診斷分類(lèi)標(biāo)準(zhǔn)。美國(guó)《精神障礙診斷與統(tǒng)計(jì)手冊(cè)》(DSM)作為目前使用最廣泛的精神類(lèi)障礙診斷分類(lèi)標(biāo)準(zhǔn)之一,為基礎(chǔ)與臨床神經(jīng)科學(xué)、認(rèn)知與行為科學(xué)以及殘疾研究等領(lǐng)域的相關(guān)人員對(duì)包括孤獨(dú)癥譜系障礙在內(nèi)的精神障礙的診斷分類(lèi)提供了重要依據(jù)。新出版的DSM-5有關(guān)孤獨(dú)癥譜系障礙診斷分類(lèi)標(biāo)準(zhǔn)的變化主要包括障礙分類(lèi)合并、診斷標(biāo)準(zhǔn)簡(jiǎn)化以及依障礙程度劃分三方面。受此影響,對(duì)孤獨(dú)癥譜系障礙的患病群體、臨床研究以及教育及相關(guān)社會(huì)服務(wù)等方面帶來(lái)了一定的變化。未來(lái),納入社會(huì)-心理性因素的考量、與ICD系統(tǒng)進(jìn)一步兼容以及孤獨(dú)癥譜系障礙診斷分類(lèi)標(biāo)準(zhǔn)的本土化則可能是ASD診斷分類(lèi)標(biāo)準(zhǔn)的重點(diǎn)研究領(lǐng)域。
關(guān)鍵詞:孤獨(dú)癥譜系障礙;精神障礙診斷與統(tǒng)計(jì)手冊(cè);診斷分類(lèi)標(biāo)準(zhǔn);綜述
來(lái)源出版物:中國(guó)心理衛(wèi)生雜志, 2015, 29(6): 425-430
青少年孤獨(dú)癥靜息態(tài)腦突顯網(wǎng)絡(luò)的功能影像學(xué)研究
戚晨皓,黃永明,金石,等
摘要:目的:探討青少年孤獨(dú)癥患者的腦突顯網(wǎng)絡(luò)的異常。方法:對(duì)15例青少年孤獨(dú)癥患者(研究組)和15名健康對(duì)照者(對(duì)照組)進(jìn)行3.0T靜息態(tài)腦功能磁共振掃描,使用獨(dú)立成分分析法對(duì)影像學(xué)結(jié)果進(jìn)行分析。結(jié)果:與對(duì)照組相比,研究組突顯網(wǎng)絡(luò)的左眶部額下回、左距狀裂周?chē)?、左額中回、右楔葉功能連通性減弱,右顳下回、右海馬旁回、右枕中回功能連通性增強(qiáng)。結(jié)論:青少年孤獨(dú)癥患者的靜息態(tài)腦突顯網(wǎng)絡(luò)存在多個(gè)腦區(qū)的功能連通性改變。
關(guān)鍵詞:孤獨(dú)癥;功能磁共振;突顯網(wǎng)絡(luò);獨(dú)立成分分析
來(lái)源出版物:精神醫(yī)學(xué)雜志, 2015, 28(4): 241-244
高功能孤獨(dú)癥兒童的統(tǒng)合型房樹(shù)人繪畫(huà)測(cè)驗(yàn)特征
李雪;曹白丹;楊文
摘要:目的:探討高功能孤獨(dú)癥兒童的統(tǒng)合型房樹(shù)人(S-HTP)繪畫(huà)測(cè)驗(yàn)特征及其社會(huì)性發(fā)展。方法:對(duì)符合美國(guó)精神障礙診斷與統(tǒng)計(jì)手冊(cè)第4版(Diagnostic and Statistical Manual of Mental Disorders,F(xiàn)ourth Edition,DSM-Ⅳ)的35例高功能孤獨(dú)癥兒童和年齡、性別、智商相匹配的70例正常對(duì)照兒童進(jìn)行S-HTP繪畫(huà)測(cè)驗(yàn),分析高功能孤獨(dú)癥兒童S-HTP繪畫(huà)測(cè)驗(yàn)特征(整體評(píng)價(jià)15個(gè)項(xiàng)目、房屋評(píng)價(jià)9個(gè)項(xiàng)目、樹(shù)木評(píng)價(jià)5個(gè)項(xiàng)目和人物評(píng)價(jià)14個(gè)項(xiàng)目)。結(jié)果:在S-HTP繪畫(huà)測(cè)驗(yàn)中,高功能孤獨(dú)癥兒童繪畫(huà)特征與正常兒童存在明顯差異。在主要反映社交互動(dòng)水平的整體評(píng)價(jià)中有8個(gè)項(xiàng)目存在差異,如孤獨(dú)癥患兒繪畫(huà)的畫(huà)面統(tǒng)合性強(qiáng)的比例明顯低于正常兒童[5.7%(2/35)vs.67.1%(47/70),P<0.05];在主要反映家庭關(guān)系的房屋評(píng)價(jià)中的有4個(gè)項(xiàng)目存在差異,如孤獨(dú)癥兒童繪畫(huà)中人只在房屋外面的比例明顯高于正常兒童[100%(35/35)vs.85.7%(60/70),P<0.05];在主要反映無(wú)意識(shí)的自我形象的樹(shù)木評(píng)價(jià)中有4個(gè)項(xiàng)目存在差異,如孤獨(dú)癥兒童樹(shù)木簡(jiǎn)化的比例明顯高于正常兒童[73.5%(25/35)vs.24.3%(17/70),P<0.05];在主要反映有意識(shí)的自我形象和人際關(guān)系的人物評(píng)價(jià)中有8個(gè)項(xiàng)目存在差異,如孤獨(dú)癥兒童繪畫(huà)人物數(shù)目2人以上的比例明顯低于正常兒童[20.0%(7/35)vs.68.6% (48/70),P<0.05]。結(jié)論:高功能孤獨(dú)癥兒童統(tǒng)合型房樹(shù)人繪畫(huà)測(cè)驗(yàn)繪畫(huà)特征反映出其社會(huì)性發(fā)展落后于正常同齡兒童,主要表現(xiàn)在社交互動(dòng)、人際關(guān)系、自我概念和家庭關(guān)系方面。
關(guān)鍵詞:高功能孤獨(dú)癥;統(tǒng)合型房樹(shù)人繪畫(huà)測(cè)驗(yàn);社交互動(dòng);橫斷面研究
來(lái)源出版物:中國(guó)心理衛(wèi)生雜志, 2014, 28(4): 260-266
孤獨(dú)癥譜系障礙鏡像神經(jīng)元功能的研究現(xiàn)狀
胡霄,黃頤
摘要:鏡像神經(jīng)元假說(shuō)被認(rèn)為是一種較全面地解釋孤獨(dú)癥譜系障礙的臨床癥狀和神經(jīng)生物學(xué)異常的神經(jīng)-認(rèn)知理論。本文綜述了國(guó)內(nèi)外近年來(lái)在孤獨(dú)癥譜系障礙中鏡像神經(jīng)元功能的研究,分別探討了神經(jīng)電生理、神經(jīng)影像學(xué),神經(jīng)心理學(xué)等方面研究結(jié)果,提示這些患者存在部分的鏡像神經(jīng)元功能損害,這些損害與孤獨(dú)癥譜系障礙患者其他的神經(jīng)認(rèn)知和社會(huì)認(rèn)知功能損害有著密切關(guān)系。
關(guān)鍵詞:孤獨(dú)癥譜系障礙;鏡像神經(jīng)元;綜述
來(lái)源出版物:中國(guó)心理衛(wèi)生雜志, 2014, 28(11): 823-827
聯(lián)系郵箱:黃頤,huangyi0421@126.com
引導(dǎo)式教育聯(lián)合融合教育的護(hù)理方法對(duì)孤獨(dú)癥患兒社交能力的影響
呂復(fù)莉,謝曉鳳,張玲,等
摘要:目的:建立引導(dǎo)式教育聯(lián)合融合教育的護(hù)理方法,探討其對(duì)孤獨(dú)癥患兒社交能力的影響。方法:選擇符合納入標(biāo)準(zhǔn)的120例孤獨(dú)癥患兒作為研究對(duì)象,按照隨機(jī)化原則分為干預(yù)組和對(duì)照組各60例。干預(yù)組在結(jié)構(gòu)化教育的基礎(chǔ)上,結(jié)合引導(dǎo)式教育聯(lián)合融合教育的護(hù)理方法,采取醫(yī)療機(jī)構(gòu)及社區(qū)中心干預(yù)與家庭干預(yù)相結(jié)合;對(duì)照組僅接受結(jié)構(gòu)化教育治療及護(hù)理。分別在干預(yù)前和干預(yù)6個(gè)月后,應(yīng)用孤獨(dú)癥治療評(píng)估量表(Autism Treatment Eva-luation checklist,ATEC)對(duì)兩組患兒進(jìn)行評(píng)估,判斷其對(duì)患兒社交能力的影響。結(jié)果:干預(yù)6個(gè)月后,干預(yù)組ATEC癥狀總分差值、社交能力障礙下降程度均高于對(duì)照組,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。同時(shí),干預(yù)組患兒感知覺(jué)項(xiàng)、語(yǔ)言功能的改善明顯優(yōu)于對(duì)照組患兒,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。但是在行為方面的得分差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。結(jié)論:引導(dǎo)式教育聯(lián)合融合教育的護(hù)理方法,能激發(fā)孤獨(dú)癥患兒的興趣,促進(jìn)人格發(fā)育,提高社會(huì)交流的自信心。
關(guān)鍵詞:孤獨(dú)性障礙;兒童;引導(dǎo)式教育;融合教育
來(lái)源出版物:中華護(hù)理雜志, 2014, 49(010): 1194-1198
聯(lián)系郵箱:吳德,845177603@qq.com
孤獨(dú)癥兒童的情緒共情能力及情緒表情注意方式
馬偉娜,朱蓓蓓
摘要:研究探討了孤獨(dú)癥兒童的情緒共情能力及情緒表情注意方式的特點(diǎn)。各選取15名孤獨(dú)癥兒童以及作為對(duì)照組的智力障礙兒童和普通兒童各15名,完成情緒共情實(shí)驗(yàn),同時(shí)使用生物反饋儀記錄自主生理反應(yīng),眼動(dòng)儀記錄眼動(dòng)軌跡。結(jié)果發(fā)現(xiàn)孤獨(dú)癥兒童對(duì)情緒表情的自動(dòng)模仿及感知能力顯著低于智力障礙兒童與普通兒童;對(duì)面孔的總注視時(shí)間、總注視點(diǎn)數(shù)均顯著少于智力障礙兒童、普通兒童;對(duì)眼部、嘴部的注視時(shí)間比及注視點(diǎn)數(shù)比均顯著低于普通兒童;對(duì)高興和悲傷表情的注意較多而對(duì)恐懼則較少。這提示孤獨(dú)癥兒童的情緒共情能力不足、對(duì)情緒表情的注意方式異常。
關(guān)鍵詞:孤獨(dú)癥兒童;情緒共情;眼動(dòng);自主生理反應(yīng)
來(lái)源出版物:心理學(xué)報(bào), 2014, 46(4): 528-539
聯(lián)系郵箱:馬偉娜,mwn505@hznu.edu.cn
孤獨(dú)癥兒童的性別差異及其解釋模型
關(guān)文軍,鄧猛
摘要:孤獨(dú)癥作為一種由環(huán)境和遺傳因素共同導(dǎo)致的神經(jīng)發(fā)育障礙,男童發(fā)病比例高于女童已成為共識(shí),但對(duì)其原因我們?nèi)匀恢跎?。本文系統(tǒng)回顧和分析了孤獨(dú)癥兒童在發(fā)病率和臨床表現(xiàn)上的性別差異,并介紹了目前比較有代表性的幾個(gè)解釋模型。本文認(rèn)為,孤獨(dú)癥性別差異的解釋模型符合人類(lèi)對(duì)殘疾本質(zhì)理解的發(fā)展過(guò)程,多學(xué)科、多方法的綜合研究是今后孤獨(dú)癥兒童病理研究的方向,在尚未明晰孤獨(dú)癥病理前,教育和康復(fù)對(duì)孤獨(dú)癥兒童的積極發(fā)展具有不可替代的作用。
關(guān)鍵詞:孤獨(dú)癥;性別差異;解釋模型
來(lái)源出版物:中國(guó)特殊教育, 2013, 12: 52-58
Explaining the increase in the prevalence of autism spectrum disorders the proportion attributable to changes in reporting practices
Hansen, SN; Schendel, DE; Parner, ET
Abstract: IMPORTANCE: The prevalence of autism spectrum disorders(ASDs) has increased markedly in recent decades, which researchers have suggested could be caused in part by nonetiologic factors such as changes in diagnosis reporting practices. To our knowledge, no study has quantified the degree to which changes in reporting practices might explain this increase. Danish national health registries have undergone a change in diagnostic criteria in 1994 and the inclusion of outpatient contacts to health registries in 1995. OBJECTIVE: To quantify the effect of changes in reporting practices in Denmark on reported ASD prevalence. DESIGN, SETTING, AND PARTICIPANTS: We used a population-based birth cohort approach that includes information on all individuals with permanent residence in Denmark. We assessed all children born alive from January 1, 1980, through December 31, 1991, in Denmark(n=677915). The children were followed up from birth until ASD diagnosis, death, emigration, or the end of follow-up on December 31, 2011, whichever occurred first. The analysis uses a stratified Cox proportional hazards regression model with the changes in reporting practices modeled as time-dependent covariates. EXPOSURES: The change in diagnostic criteria in 1994 and the inclusion of outpatient diagnoses in 1995. MAIN OUTCOMES AND MEASURES: Autism spectrum disorders. RESULTS: For Danish children born during the study period, 33%(95% CI, 0-70%) of the increase in reported ASD prevalence could be explained by the change in diagnostic criteria alone; 42%(95% CI, 14%-69%), by the inclusion of outpatient contacts alone; and 60%(95% CI, 33%-87%), by the change in diagnostic criteria and the inclusion of outpatient contacts. CONCLUSIONS AND RELEVANCE: Changes in reporting practices can account for most(60%) of the increase in the observed prevalence of ASDs in children born from 1980 through 1991 in Denmark. Hence, the study supports the argument that the apparent increase in ASDs in recent years is in large part attributable to changes in reporting practices.
來(lái)源出版物:Jama Pediatrics, 2015, 169(1): 56-62
聯(lián)系郵箱:Hansen, SN; stefanh@biostat.au.dk
Severe multisensory speech integration deficits in high-functioning school-aged children with autism spectrum disorder(ASD) and their resolution during early adolescence
Foxe, JJ; Molholm, S; Del Bene, VA; et al.
Abstract: Under noisy listening conditions, visualizing a speaker’s articulations substantially improves speech intelligibility. This multisensory speech integration ability is crucial to effective communication, and the appropriate development of this capacity greatly impacts a child's ability to successfully navigate educational and social settings. Research shows that multisensory integration abilities continue developing late into childhood. The primary aim here was to track the development of these abilities in children with autism, since multisensory deficits are increasingly recognized as a component of the autism spectrum disorder(ASD) phenotype. The abilities of high-functioning ASD children(n=84) to integrate seen and heard speech were assessed cross-sectionally, while environmental noise levels were systematically manipulated, comparing them with age-matched neurotypical children(n=142). Severe integration deficits were uncovered in ASD, which were increasingly pronounced as background noise increased. These deficits were evident in school-aged ASD children(5–12 year olds), but were fully ameliorated in ASD children entering adolescence(13–15 year olds). The severity of multisensory deficits uncovered has important implications for educators and clinicians working in ASD. We consider the observation that the multisensory speech system recovers substantially in adolescence as an indication that it is likely amenable to intervention during earlier childhood, with potentially profound implications for the development of social communication abilities in ASD children.
關(guān)鍵詞:autism spectrum disorders; cross-modal; development; sensory integration; speech-in-noise
來(lái)源出版物:Cerebral Cortex, 2015, 25(2): 298-312
聯(lián)系郵箱:Foxe, JJ; john.foxe@einstein.yu.edu
The idiosyncratic brain: Distortion of spontaneous connectivity patterns in autism spectrum disorder
Hahamy, A; Behrmann, M; Malach, R
Abstract: Autism spectrum disorder(ASD) has been associated with a reduction in resting state functional connectivity, though this assertion has recently been challenged by reports of increased connectivity in ASD. To address these contradictory findings, we examined both inter-and intrahemispheric functional connectivity in several resting state data sets acquired from adults with high-functioning ASD and matched control participants. Our results reveal areas of both increased and decreased connectivity in multiple ASD groups as compared to control groups. We propose that this heterogeneity stems from a previously unrecognized ASD characteristic: idiosyncratic distortions of the functional connectivity pattern relative to the typical, canonical template. The magnitude of an individual's pattern distortion in homotopic interhemispheric connectivity correlated significantly with behavioral symptoms of ASD. We propose that individualized alterations in functional connectivity organization are a core characteristic of high-functioning ASD, and that this may account for previous discrepant findings.
來(lái)源出版物:Nature Neuroscience, 2015, 18(2): 302-309
聯(lián)系郵箱:Malach, R; rafi.malach@gmail.com
Heritability of autism spectrum disorder in a UK population-based twin sample
Colvert, E; Tick, B; McEwen, F; et al.
Abstract: IMPORTANCE: Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population. OBJECTIVES: To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder(ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD. DESIGN, SETTING, AND PARTICIPANTS: We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and wales from January 1, 1994, through December 31, 1996. We performed joint continuousordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test(CAST)(6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment(DAWBA)(359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule(ADOS)(203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview- Revised(ADI-R)(205 pairs; mean age, 13.2 years), and a best-estimate diagnosis(207 pairs). MAIN OUTCOMES AND MEASURES: Participants underwent screening using a population-based measure of autistic traits(CAST assessment), structured diagnostic assessments(DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis. RESULTS: On all ASD measures, correlations among monozygotic twins(range, 0.77-0.99) were significantly higher than those for dizygotic twins(range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status(DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors(76%-95%). For the ADI-R only, shared environmental influences were significant(30% [95% CI, 8%-47%]) but smaller than genetic influences(56% [95% CI, 37%-82%]). CONCLUSIONS AND RELEVANCE: The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD.
來(lái)源出版物:Jama Psychiatry, 2015, 72(5): 415-423
聯(lián)系郵箱:Tick, B; beata.b.tick@kcl.ac.uk
Genotype to phenotype relationships in autism spectrum disorders
Chang, J; Gilman, SR; Chiang, AH; et al.
Abstract: Autism spectrum disorders(ASDs) are characterized by phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and nontruncating de novo mutations contribute to autism, with a bias against truncating mutations in early embryonic development. We find that functional mutations are preferentially observed in geneslikely to be haploinsufficient. Multiple cell types and brain areas are affected, but the impact of ASD mutations appears to be strongest in cortical interneurons, pyramidal neurons and the medium spiny neurons of the striatum, implicating cortical and corticostriatal brain circuits. In females, truncating ASD mutations on average affect genes with 50%-100% higher brain expression than in males. Our results also suggest that truncating de novo mutations play a smaller role in the etiology of high-functioning ASD cases. Overall, we find that stronger functional insults usually lead to more severe intellectual, social and behavioral ASD phenotypes.
來(lái)源出版物:Nature Neuroscience, 2015, 18(2): 191-198
聯(lián)系郵箱:Vitkup, D; dv2121@columbia.edu
Autism
Lai, MC; Lombardo, MV; Baron-Cohen, S; et al.
Abstract: Autism is a set of heterogeneous neurodevelopmental conditions, characterised by early-onset difficulties in social communication and unusually restricted, repetitive behaviour and interests. The worldwide population prevalence is about 1%. Autism affects more male than female individuals, and comorbidity is common(>70% have concurrent conditions). Individuals with autism have atypical cognitive profiles, such as impaired social cognition and social perception, executive dysfunction, and atypical perceptual and information processing. These profiles are underpinned by atypical neural development at the systems level. Genetics has a key role in the aetiology of autism, in conjunction with developmentally early environmental factors. Large-effect rare mutations and small-effect common variants contribute to risk. Assessment needs to be multi- disciplinary and developmental, and early detection is essential for early intervention. Early comprehensive and targeted behavioural interventions can improve social communication and reduce anxiety and aggression. Drugs can reduce comorbid symptoms, but do not directly improve social communication. Creation of a supportive environment that accepts and respects that the individual is different is crucial.
來(lái)源出版物:Lancet, 2014, 383(9920): 896-910
聯(lián)系郵箱:Lai, MC; mcl45@cam.ac.uk
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
Pinto, D; Delaby, E; Merico, D; et al.
Abstract: Rare copy-number variation(CNV) is an important source of risk for autism spectrum disorders(ASDs). We analyzed 2446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups(1.41-fold, P=1.0 × 10-5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability(odds ratio=12.62, P=2.7×10-15, ~3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes(CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, andHDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs(P=0.017) and were also overrepresented among subjects with fragile X syndrome protein targets(P=0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
來(lái)源出版物:The American Journal of Human Genetics, 2014, 94(5): 677-694
聯(lián)系郵箱:Betancur, C; catalina.betancur@inserm.fr
The familial risk of autism
Sandin, S; Lichtenstein, P; Kuja-Halkola, R; et al.
Abstract: IMPORTANCE: Autism spectrum disorder(ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains s unresolved. OBJECTIVE: To provide estimates of familial aggregation and heritability of ASD. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort including 2049973 Swedish children born 1982 through 2006. We identified 37570 twin pairs, 2642064 full sibling pairs, 432281 maternal and 445531 paternal half sibling pairs, and 5799875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained. MAIN OUTCOMES AND MEASURES: The relative recurrence risk(RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis(exposed) compared with the risk in a participant with no diagnosed family member(unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of theprobability of developing ASD can be related to genetic(additive and dominant) and environmental(shared and nonshared) factors. RESULTS: In the sample, 14516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100000 person-years for ASD among monozygotic twins was estimated to be 153.0(95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed); for dizygotic twins, 8.2(95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3(95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3(95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9(95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0(95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude. We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50(95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54(95% CI, 0.44-0.64). CONCLUSIONS AND RELEVANCE: Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.
來(lái)源出版物:Jama, 2014, 311(17): 1770-1777
聯(lián)系郵箱:Sandin, S; sven.sandin@ki.se
The contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I; O’Roak, BJ; Sanders, SJ; et al.
Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting(LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient(IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP- associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
來(lái)源出版物:Nature, 2014, 515(7526): 216-221
聯(lián)系郵箱:Shendure, J; shendure@uw.edu
Patches of disorganization in the neocortex of children with autism
Stoner, R; Chow, ML; Boyle, MP; et al.
Abstract: Background: Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development. Methods: To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years. Results: We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches. Conclusions: In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Ourdata support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages.
來(lái)源出版物:New England Journal of Medicine, 2014, 370(13): 1209-1219
聯(lián)系郵箱:Courchesne, E; ecourchesne@ucsd.edu
Traffic-related air pollution, particulate matter, and autism
Volk, HE; Lurmann, F; Penfold, B; et al.
Abstract: Context: Autism is a heterogeneous disorder with genetic and environmental factors likely contributing to its origins. Examination of hazardous pollutants has suggested the importance of air toxics in the etiology of autism, yet little research has examined its association with local levels of air pollution using residence-specific exposure assignments. Objective: To examine the relationship between traffic-related air pollution, air quality, and autism. Design: This population-based case-control study includes data obtained from children with autism and control children with typical development who were enrolled in the Childhood Autism Risks from Genetics and the Environment study in California. The mother's address from the birth certificate and addresses reported from a residential history questionnaire were used to estimate exposure for each trimester of pregnancy and first year of life. Traffic-related air pollution was assigned to each location using a line-source air-quality dispersion model. Regional air pollutant measures were based on the Environmental Protection Agency’s Air Quality System data. Logistic regression models compared estimated and measured pollutant levels for children with autism and for control children with typical development. Setting: Case-control study from California. Participants: A total of 279 children with autism and a total of 245 control children with typical development. Main Outcome Measures: Crude and multivariable adjusted odds ratios(AORs) for autism. Results: Children with autism were more likely to live at residences that had the highest quartile of exposure to traffic-related air pollution, during gestation(AOR, 1.98 [95% CI, 1.20-3.31]) and during the first year of life(AOR, 3.10 [95% CI, 1.76-5.57]), compared with control children. Regional exposure measures of nitrogen dioxide and particulate matter less than 2.5 and 10 mu m in diameter(PM2.5and PM10) were also associated with autism during gestation(exposure to nitrogen dioxide: AOR, 1.81 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.08 [95% CI, 1.93-2.25]; exposure to PM10: AOR, 2.17 [95% CI, 1.49-3.16) and during the first year of life(exposure to nitrogen dioxide: AOR, 2.06 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.12 [95% CI, 1.45-3.10]; exposure to PM10: AOR, 2.14 [95% CI, 1.46-3.12]). All regional pollutant estimates were scaled to twice the standard deviation of the distribution for all pregnancy estimates. Conclusions: Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5, and PM10during pregnancy and during the first year of life was associated with autism. Further epidemiological and toxicological examinations of likely biological pathways will help determine whether these associations are causal.
來(lái)源出版物:Jama Psychiatry, 2013, 70(1): 71-77
聯(lián)系郵箱:Volk, HE; hvolk@usc.edu
編輯:王微
【作者單位:1. 中國(guó)科學(xué)院心理研究所,心理健康重點(diǎn)實(shí)驗(yàn)室;2. 中國(guó)科學(xué)院大學(xué)】
Abstract: Processing the human face is at the focal point of most social interactions, yet this simple perceptual task is difficult for individuals with autism, a population that spends limited amounts of time engaged in face-to-face eye contact or social interactions in general. Thus, the study of face processing in autism is not only important because it may be integral to understanding the social deficits of this disorder, but also, because it provides a unique opportunity to study experiential factors related to the functional specialization of normal face processing. In short, autism may be one of the only disorders where affected individuals spend reduced amounts of time engaged in face processing from birth. Using functional MRI, haemodynamic responses during a face perception task were compared between adults with autism and normal control subjects. Four regions of interest(ROIs), the fusiform gyrus(FG), inferior temporal gyrus, middle temporal gyrus and amygdala were manually traced on non-spatially normalized images and the percentage ROI active was calculated for each subject. Analyses in Talairach space were also performed. Overall results revealed either abnormally weak or no activation in FG in autistic patients, as well as significantly reduced activation in the inferior occipital gyrus, superior temporal sulcus and amygdala. Anatomical abnormalities, in contrast, were present only in the amygdala in autistic patients, whose mean volume was significantly reduced as compared with normals. Reaction time and accuracy measures were not different between groups. Thus, while autistic subjects could perform the faceperception task, none of the regions supporting face processing in normals were found to be significantly active in the autistic subjects. Instead, in every autistic patient, faces maximally activated aberrant and individual-specific neural sites(e.g. frontal cortex, primary visual cortex, etc.), which was in contrast to the 100% consistency of maximal activation within the traditional fusiform face area(FFA) for every normal subject. It appears that, as compared with normal individuals, autistic individuals 'see' faces utilizing different neural systems, with each patient doing so via a unique neural circuitry. Such a pattern of individualspecific, scattered activation seen in autistic patients in contrast to the highly consistent FG activation seen in normals, suggests that experiential factors do indeed play a role in the normal development of the FFA.
Abstract: Many studies have supported a genetic etiology for autism. Here we report Mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synapto- genesis may predispose to autism.
Abstract: We tested the hypothesis that de novo copy number variation(CNV) is associated with autism spectrum disorders(ASDs). We performed comparative genomic hybridization(CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism(P=0.0005). Such CNVs were identified in 12 out of 118(10%) of patients with sporadic autism, in 2 out of 77(3%) of patients with an affected first-degree relative, and in 2 out of 196(1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Abstract: Autism spectrum disorders(ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamaterelated genes as promising candidates for contributing to ASDs.
Abstract:Two previous epidemiological studies of autistic twins suggested that autism was predominantly genetically determined, although the findings with regard to a broader phenotype of cognitive, and possibly social, abnormalities were contradictory. Obstetric and perinatal hazards were also invoked as environmentally determined aetiological factors. The first British twin sample has been re-examined and a second total population sample of autistic twins recruited. In the combined sample 60% of monozygotic(MZ) pairs were concordant for autism versus no dizygotic(DZ) pairs; 92% of MZ pairs were concordant for a broader spectrum of related cognitive or social abnormalities versus 10% of DZ pairs. The findings indicate that autism is under a high degree of genetic control and suggest the involvement of multiple genetic loci. Obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors. Few new cases had possible medical aetiologies, refuting claims that recognized disorders are common aetiological influences.