自闭症涉及到非典型性的大脑发育,在孩子三岁之前,这种发育尤其在社会行为发展中变得明显。它的特征是社交和沟通障碍,以及兴趣受限和呆板行为,并且该特征与任何潜在的神经缺陷无关[5][6]。其他特征包括在他们的行为和感官兴趣中可以到类似重复的情况发生[7]。本文分别是用术语自闭症和自闭症谱系障碍来表示典型自闭症以及自闭症临床症状与表现的广泛分布。
自闭症的因果关系理论并不完善[1]。长期以来,人们一直推测对于自闭症特有的三种症状在遗传、认知和神经层面上有一个共同的原因[8]。 然而,研究者越来越怀疑产生自闭症并非单一原因,而是一种具有一系列不同核心且独特病因所致的复杂疾病[8][9]。通常推测大脑不同的潜在功能障碍会导致自闭症的常见症状发生,就像完全不同的大脑问题会导致智力缺陷一样。自闭症或自闭症谱系障碍涵盖了多种疾病过程[10]。尽管猜测这些不同的原因经常同时发生[9],但也有人认为这些原因之间的相关性被夸大了[11]。自20世纪80年代以来,已知患有自闭症的人数急剧增加,至少部分原因由于诊断方式发生了变化。目前还不清楚患病率是否也有所上升[12]。
主流自闭症研究者的共识是遗传因素占主导地位。据称环境因素会导致自闭症或加剧其症状的发生,或可能在未来研究中成为需要考虑的重要因素,其中包括某些食品、[13] 传染病、重金属、溶剂、柴油废气、多氯联苯、邻苯二甲酸酯和塑料制品中使用的苯酚、杀虫剂、溴化阻燃剂、酒精、吸烟和一些非法药品[12]。在这些影响因素中,疫苗引起了广泛关注,因为父母可能在常规疫苗接种时首先意识到孩子患有自闭症,父母对疫苗的担忧导致儿童接种率下降,麻疹爆发的可能性增加[14][15]。然而,大量的科学证据表明麻疹-腮腺炎-风疹疫苗和自闭症之间没有因果关系,也没有科学证据表明疫苗防腐剂硫柳汞会导致自闭症[4][16]。
遗传因素可能是导致自闭症谱系障碍最重要的原因。双胞胎的早期遗传率评估研究超过90%,这意味着从遗传学角度可以解释90%以上的儿童是否会患上自闭症[2]。然而,这这个结果可能被过高的估计,因为新的双胞胎遗传率研究评估结果在60-90%之间[17][18]。许多非自闭症的同卵双胞胎有学习或社交障碍。对于成年兄弟姐妹来说,具有自闭症广泛表型的一个或多个特征的风险可能高达30%[19]。
然而,尽管自闭症遗传性很强,但是近期没有家族史证据的大多数病例偶有发生。据推测,父亲精子或母亲卵子中自发突变可能易导致幼儿患自闭症[20]。 有两条证据可以支持这一假设。首先,自闭症患者的繁殖力显著降低,他们生孩子的可能性比平均水平低20倍,因此减少了自闭症谱系障碍基因在一个家庭中多代人之间的持续突变[21]。其次,随着父亲年龄的增长,孩子患自闭症的可能性会增加[22],因为精子的突变率会在男人一生中逐渐积累增加[23]。
研究人员在20世纪90年代初发现了第一批明显会导致自闭症风险的基因,他们研究了由X染色体突变引起的特定性别自闭症。男孩脆性X智力低下1号基因FMR1启动子中CGG三核苷酸重复序列的扩增导致X染色体综合征,至少20%有这种突变的男孩有与自闭症谱系障碍一致的行为[24]。诱导基因MECP2失活的突变导致雷特综合征,这与女孩的自闭症行为有关,而男孩的这种突变是胚胎致死[25]。
除了这些早期的案例,当基因芯片技术达到足够的分辨率允许检测人类基因组中的拷贝数变异(CNV)时,在自闭症谱系障碍中新生突变的作用首次变得如此明显[26][27]。 CNVs是基因组中最常见的结构变异类型,包括DNA缺失和复制,其大小从千碱基到几兆碱基不等。基因芯片分析表明,与正常发育中的兄弟姐妹和不相关的对照组相比,偶发性自闭症病例中的新生CNVs发生率要高得多。一系列研究表明,ASD患者中新生CNVs基因突变的发生率约为对照组的4倍,约占5-10%[20][28][29][30]。基于这些研究,预计有130-234个与自闭症相关的CNV基因位点[30]。第一次全基因组测序研究以比基因芯片研究高得多的分辨率全面编目了新的结构变异,研究表明,突变率约为20%,与兄弟姐妹对照组相比,自闭症患者的突变率并未升高[31]。 然而,自闭症患者个体的结构变异要大得多,破坏基因的可能性要比正常人高出四倍,与CNV研究的结果一致[31]。
CNV研究紧随其后的是外显子组测序研究,该研究对编码蛋白质的基因组(“外显子组”)的1-2%进行测序。这些研究发现,大约20%的自闭症患者出现了新的基因失活突变,相比之下,未受影响的兄弟姐妹这一比例仅为10%,这表明大约10%的自闭症患者的病因是由这些突变引起的[32][33][34][35][36][37]。预计有350-450个基因在受到重新失活突变的影响时,会显著增加自闭症谱系障碍的易感性[38]。另外预测有12%的病例是由蛋白质改变异义突变引起的,异义突变改变氨基酸,但不会使基因失活[34]。因此,大约30%的自闭症患者有一个自发巨大的CNV发生,它删除或复制基因,或改变单个基因氨基酸编码的突变。另有5-10%的病例在已知与自闭症相关的位点遗传了结构变异,这些已知的结构变异可能在受影响儿童的父母中重新出现[31]。
基于对不同个体中反复突变的观察,已经确定了数十个基因和CNVs,并发现了100多个其他基因的提示性证据[39]。 西蒙斯(Simons)基金会自闭症研究计划(SFARI)详细说明了与自闭症相关的每个基因位点的依据[40]。
这些早期基因和CNV的发现表明,与每种潜在突变相关的认知和行为特征是变化的。每个突变本身都与各种临床诊断相关,也可以在少数没有临床诊断的个体中发现[41][42]。因此,包括自闭症在内的的家族遗传疾病并不是自闭症特有的。临床结果反映出突变本身具有有相当大的可变性特点,通常只有一部分突变携带者符合自闭症的标准。这种多变的表达能力导致不同个体具有相同的突变,其观察到的特定特征的严重程度有很大差异[43]。
最近这些关于新发突变的研究的结论是自闭症的谱系正在分裂成由遗传学定义的大量个体疾病[43]。
一个与自闭症相关的基因SHANK2被发现[44]。 这钟基因的突变起主导作用。并且此种基因的突变似乎会导致神经元之间的超级连接。
自闭症的风险与几个产前风险因素有关,包括父母中任何一方的高龄、糖尿病、出血和母亲在怀孕期间使用精神药物[47]。 自闭症也被认为与出生后八周内的先天缺陷因素有关,尽管这些病例很少发生[48]。
产前病毒感染被称为自闭症的主要非遗传原因。产前暴露于风疹或巨细胞病毒会激活母亲的免疫反应,并可能大大增加小鼠患自闭症的风险[49]。先天性风疹综合征是自闭症最具有说服力的环境原因[50]。早孕与感染相关的免疫活动对神经发育的影响可能大于妊娠晚期的感染,不仅对自闭症,而且对推测为神经发育起源的精神疾病,特别是精神分裂症同样适用[51]。
致畸剂是导致出生缺陷的环境因素。一些理论上导致出生缺陷的因素也被认为是潜在的自闭症风险因素,尽管几乎没有科学证据支持这种说法。其中包括胚胎暴露于丙戊酸[52]、 扑热息痛[53]、 沙利度胺或米索前列醇[54]。但这些这些病例很少[55]。也有人提出异议酒精(谷物酒精)是否可能增加自闭症风险,作为胎儿酒精综合症或酒精相关出生缺陷病症发生的部分原因[54]。通常所有已知的致畸物似乎在受孕后的前八周内起作用,尽管这并不能排除自闭症会在以后的一段时期所触发或被影响,但有说服力的证据表明自闭症在发育的早期就会出现[3]。
母体炎症和自身免疫疾病会损害胚胎和胎儿组织,致使遗传问题严重或损害神经系统[56]。
据推测,在妊娠8-12周导致母亲甲状腺素缺乏的甲状腺问题会导致胎儿大脑受到影响,从而导致自闭症。甲状腺素缺乏可能是由于饮食中碘不足,以及干扰碘摄取或对抗甲状腺激素的环境因素造成的。可能的环境因素包括食物中的类黄酮、烟草烟雾和大多数除草剂的使用。但这一假设尚未得到验证[57]。
母亲怀孕期间患糖尿病是自闭症的一个重要风险因素;2009年的一项荟萃分析发现妊娠糖尿病导致自闭症的的风险增加两倍。2014年的一项调查还发现,母亲糖尿病与自闭症风险的增加有显著关联[58]。尽管糖尿病会导致代谢和激素异常以及氧化应激反应,但还不明确妊娠期糖尿病和自闭症风险之间的生物学机制[47]。
怀孕期间的母亲肥胖也可能增加自闭症的风险,尽管还需要进一步的研究[59]。
孕前和孕期母体营养不良将会影响胎儿神经发育。足月和早产儿宫内在发育受限都可能会导致自闭症[60]。
据推测,怀孕期间摄入的叶酸可以通过表观遗传机制调节基因表达,从而在减少自闭症患病中发挥作用。这一假设得到了多项研究的支持[61]。
产前的精神压力,包括需要处理生活琐碎或其他环境干扰因素,使孕妇经常感到苦恼,这些被推测可能导致自闭症的原因,也是基因-环境相互作用的一部分原因。据报道,自闭症与产前精神压力有关,根据回顾性研究来探索压力来源,如失业和家庭不和,也有涉及产前置身于暴风雨的自然实验;动物研究报告称,产前压力会干乱大脑发育,产生类似自闭症症状的行为[62]。 然而,其他研究对这种联系提出了质疑,特别是在英国和瑞典基于人口学的研究发现具有压力的生活事件和自闭症之间没有关联[63]。
胎儿睾丸素理论假设,母亲羊水中较高水平的睾丸素会推动大脑发育,从而提高观察模式和分析复杂系统的能力,同时减少交流和移情,强调“男性”的特征而不是“女性”,或者用怜惜制度理论来解释,强调“系统化”而不是“同情心”。一个发表多篇报告的研究表明,高水平的胎儿睾丸素会产生与自闭症患者类似的行为[64]。
基于部分动物研究,结果表明怀孕期间进行的诊断超声波检测被认为会增加孩子患自闭症的风险。这一假设没有得到相关研究的支持,对母亲接受超声波诊断的新生儿的相关检查中没有发现不利的影响[65]。
其他研究表明,孕妇在怀孕期间接触选择性血清素再摄取抑制剂会增加患自闭症的风险,但尚不清楚两者之间是否有因果关系[66]。举例来说,有证据表明,这种联系可能是母亲精神疾病造成的[67]。
科研人员已经提出了许多导致自闭症的产后因素,包括胃肠道或免疫系统异常、过敏以及儿童接触药物、疫苗、感染、某些食物或重金属。这些危险因素的证据只是一种说法,还未研究证实其真实性[71]。
这一理论假设,大脑中杏仁体的早期发育失败会级联到调节视觉社会感知的皮质区域的发育上。腹侧通路的梭形面区会被牵连。其观点是,它涉及社会知识和社会认知,该网络的缺陷是导致自闭症的重要因素[72]。
该理论假设,针对大脑或大脑代谢元素的自身抗体可能导致或加剧自闭症。它与产妇感染理论有关,除了它假设影响是由个体自身抗体引起的以外,还可能是由于出生后的环境导致。它也与其他几个假设的原因有关;例如,病毒感染被猜测可能通过自身免疫机制导致自闭症[73]。
免疫系统和神经系统之间的相互作用在胚胎形成的早期就开始了,神经发育成功依赖于免疫反应平衡。在神经发育的关键时期,免疫活动异常可能是导致某些形式自闭症障碍的部分作用机制[74]。通常在出生前,有一小部分自闭症患者与感染有关。其免疫研究的结果是矛盾的。在特定的亚组中发现了一些异常,其中一部分已经被复制。目前还不清楚这些异常是否与自闭症的病理学有关,例如通过感染或自身免疫,或者它们是否继发于疾病的过程[75]。 由于自身抗体存在于自闭症以外的疾病中,并且并不总是存在于自闭症患者中[76], 因此免疫紊乱和自闭症之间的关系仍不清楚,当然也存在争议[77]。2015年的一项系统回顾和荟萃分析研究发现,有自身免疫性疾病家族史的儿童比没有这种病史的儿童患自闭症的风险更大[78]。
当潜在的母体自身免疫疾病存在时,胎儿循环的抗体可能会导致自闭症谱系障碍的形成[79]。
胃肠问题是自闭症患者最常见的疾病之一[80]。这些都与最常见的社会障碍、易怒、行为和睡眠问题、语言障碍和情绪变化有关,所以假设提出了它们是重叠综合征理论[80][81]。研究表明,胃肠炎症、免疫球蛋白E介导或细胞介导的食物过敏、谷蛋白相关疾病(乳糜泻、小麦过敏、非乳糜泻谷蛋白过敏)、内脏高敏感性、自主神经失调和胃食管反流可能是两者联系的发病机制[81]。
2016年的一篇综述得出结论,肠道神经系统异常可能在包括自闭症在内的多种神经系统疾病中发挥作用。神经细胞间的连接和免疫系统是一种可能让肠道疾病传播到大脑的通路[82]。2018年的一篇报道指出,胃肠疾病和自闭症的频繁关联是由于肠脑轴系的异常[80]。
“肠漏症”假说在患有自闭症儿童的父母中很流行。它基于肠道屏障的缺陷导致肠道通透性的过度增加,使得肠道中存在的物质,包括细菌、环境毒素和食物抗原进入血液。但是支持这一理论的数据比较有限且矛盾,因为自闭症患者肠道通透性增加和正常通透性都有记录。对小鼠的研究为这一理论提供了一些支持,并显示肠道菌群的重要性,表明肠道屏障的正常化与某些自闭症样行为的改善有关[82]。对自闭症患者亚组的研究表明,血浆中存在高水平的zonulin(一种调节肠壁“孔”通透性的蛋白质)以及肠道生物失调(双歧杆菌水平降低,粘蛋白阿克曼氏菌、大肠杆菌、梭菌和念珠菌丰度增加),这些都会促进促炎细胞因子的产生,所有这些都会导致过度的肠道通透性[83]。而这允许细菌内毒素从肠道进入血流,刺激肝细胞分泌肿瘤坏死因子α,调节血脑屏障通透性。对自闭症患者的研究表明,肿瘤坏死因子α级联产生促炎细胞因子,导致外周炎症和大脑小胶质细胞活化,这表明已经患有神经炎症[83]。此外,来自消化食物的神经活性阿片肽已被证明会渗漏到血流中并通过血脑屏障,影响神经细胞并导致自闭症[83]。
在1998年对三名接受分泌素输注治疗的自闭症儿童进行初步研究后,报告显示胃肠功能改善,行为能力显著提高,许多父母寻求分泌素治疗,这种激素的在黑市发展迅速[84]。 后来的研究发现分泌素显然对治疗自闭症无效[85]。
1979年,Jaak Panksepp提出自闭症和阿片剂之间的联系,指出在幼年的实验动物中注射少量阿片剂会诱发与自闭症儿童相似的症状[86]。1991年,Kalle Reichelt首次提出自闭症可能与谷蛋白和酪蛋白摄入之间的关系[87]。
阿片理论假设孤独症是一种代谢紊乱的结果,其中阿片肽胶质多芬(又名谷多芬)和酪啡肽是通过麸质(存在于小麦和相关谷物中)和酪蛋白(存在于乳制品中)的代谢产生,穿过异常渗透性的肠壁,然后通过与阿片受体结合并对神经传递产生影响。据推测,阿片类药物过量会影响大脑的发育成熟,并导致自闭症症状,包括行为困难、注意力问题、交流能力以及社会认知功能的改变[87][88]。
尽管尿液中的这些阿片类物质含量很高,但有证据表明,仅有一小部分会进入大脑,从而干扰信号传输并影响正常活动。三项研究报告称,自闭症患者的尿样显示24小时肽排泄增加[87]。 一项对照实验研究发现,自闭症患者尿液样本中阿片类物质水平与对照组相比没有明显差异[83]。两项研究显示自闭症患者脑脊液中阿片类物质水平升高[87]。
该理论进一步指出,从儿童饮食中去除阿片前体可能会让这些行为停止,并使幼儿的神经发育恢复正常[89]。]截至2014年,没有确切的证据表明无谷蛋白饮食有益于自闭症的标准治疗[90][91][92]。在进行的研究中可以观察到的问题,包括怀疑存在饮食违规情况,如谷蛋白或酪蛋白肽具有长期的残留效应,那么缺乏洗脱期可能会降低治疗的有效性,这在短期研究中尤其重要[92]。针对谷蛋白过敏的人群,在有限的证据支持下,表明无谷蛋白饮食可能改善一些自闭症的行为[90][93][94]。
有假设认为在生物学上维生素D缺乏在自闭症中所起的作用是合理的,但是没有相关研究[95]。
铅中毒被认为是自闭症的一个可能的危险因素,因为据报道自闭症儿童的血铅水平明显高于正常儿童[96]。自闭症儿童的非典型饮食行为,习惯性的随处咀嚼和异食癖,致使很难确定铅含量的增加是自闭症的原因还是后果[96]。
该理论假设自闭症行为至少部分病因取决于发育失调,该失调导致蓝斑-去甲肾上腺素能系统功能受损。蓝斑-去甲肾上腺素能系统与唤醒和注意力密切相关;例如,它与大脑获取和使用环境因素有关[97]。
这一理论假设自闭症与汞中毒有关,基于一些自闭症儿童对汞或其生物标志物的相似症状和报告[98]。这一观点在科学界几乎没有受到重视,因为汞毒性的典型症状与自闭症的症状有很大不同[99]。人类接触有机汞的主要来源是食用鱼类,无机汞的主要来源是牙科的汞合金。到目前为止,普遍认为自闭症和出生后接触汞之间的关联是间接的,因为没有直接的测试报告,也没有证据表明自闭症和出生后接触任何神经毒剂之间的关联[100]。2007年发表的一项荟萃分析得出结论,汞和自闭症之间没有联系[101]。
这个理论假设毒性和氧化应激在某些情况下可能会导致自闭症。证据包括代谢途径的遗传效应、抗氧化能力的降低、酶的变化和氧化应激生物标志物的增强;然而,总体证据的说服力比氧化应激与精神分裂症等疾病的关系要弱[102]。有一种理论认为,出生后压力会损害小脑的浦肯野细胞,谷胱甘肽也可能参与其中[103]。自闭症儿童总谷胱甘肽水平较低,氧化谷胱甘肽水平较高[104]。 基于这一理论,抗氧化剂可能是治疗自闭症的有效方法[105]。
许多研究提供了支持和反对自闭症与出生后病毒感染相关联的证据。感染博尔纳病病毒的实验大鼠表现出一些类似于自闭症的症状,但是自闭症儿童的血液研究没有显示出感染这种病毒的证据。疱疹病毒家族的成员可能在自闭症中发挥作用,但迄今为止的证据只是传闻。长期以来,病毒一直被怀疑是免疫介导疾病如多发性硬化症的诱因,但在这些疾病中很难显示出病毒病因的直接作用机制,病毒感染可能导致自闭症的机制还只是猜测[49]。
社会构建理论认为正常和异常之间的界限是主观的和武断的,所以自闭症并不是作为一个客观实体存在的,而是社会构建形成的。它进一步认为自闭症患者自己也有部分是社会构建而存在[106]。
阿斯伯格综合症和高功能自闭症是社会因素决定自闭症含义的理论的特定目标。该理论假设患有这些疾病的个体具有各自特性,并通过抵制或认可自闭症的特性来提升他们的幸福感[107]。
布鲁诺·贝特尔海姆认为自闭症与幼儿创伤有关,几十年来,他的工作在医学和大众领域都有广泛的影响。
自闭症患者的父母,尤其是母亲,被指责通过抑制情感导致了他们孩子患病[108]。利奥·坎纳,第一个描述自闭症的人[109], 他认为父母的冷漠可能会导致孩子患有自闭症[110]。 尽管坎纳最终放弃了这一理论,但贝特尔海姆在他的医学和流行病学的书籍中几乎完全支持这一理论。基于这些理论的治疗未能帮助自闭症儿童,在贝特尔海姆去世后,他报告的治愈率(约85%)被发现存在欺诈性[111]。
科学研究驳斥了疫苗接种和自闭症之间的因果关系[112][113][114] 。尽管如此,一些父母认为接种疫苗会导致自闭症,因此推迟或避免给他们的孩子接种疫苗,例如在“疫苗过量”假设下,一次接种许多疫苗可能会压垮孩子的免疫系统并导致自闭症[115],这一假设没有科学证据,从生物学上讲也不可信[116]。由于麻疹等疾病可能导致严重残疾和死亡,未接种疫苗的儿童死亡或残疾的风险高于接种疫苗的儿童[117]。尽管如此,反疫苗行动仍在继续。一种不断发展的策略大概是希望“促进无关的研究作为几个有问题的或外围相关研究的积极集合,去试图证明一个可疑的主张背后的科学道理”[118]。
麻风腮三联疫苗
麻风腮三联疫苗作为自闭症的一个原因,是关于自闭症起源最广泛争论的假说之一。Andrew Wakefield等人报道了一项对12名患有自闭症和肠道症状儿童的研究,据称,有些儿童在接种MMR后发病[119]。尽管这篇报道后来被《华尔街日报》收回[119],得出结论是“我们没有证明麻疹、流行性腮腺炎和风疹疫苗与所描述的综合症之间的联系”[120]。维克菲尔德在1998年的一次新闻发布会上指出,给儿童注射三种不同剂量的疫苗比单剂疫苗更安全。
2004年,维克菲尔德的12位合著者中有10位正式撤回了对MMR疫苗和自闭症之间因果关系的解释[121]。撤回之前,《星期日泰晤士报》进行了一项调查,称韦克菲尔德的“行为不诚实且不负责任”[122]。 疾病控制和预防中心[123], 国家科学院医学研究所[124], 以及英国国家卫生服务中心[125] 都得出结论,没有证据表明麻疹疫苗和自闭症之间有联系。
2010年2月,发表维克菲尔德研究的《柳叶刀》杂志在一名独立审计师发现该研究存在缺陷后完全撤回该研究[119]。2011年1月,发表在《BMJ》杂志上的一项调查将维克菲尔德的研究描述为蓄意欺诈和编造数据的结果[126][127][128][129]。
硫柳汞(硫柳汞钠)
也许最广为人知的假说是关于汞和自闭症涉及到汞基化合物硫柳汞的使用,这种防腐剂已经在包括美国和欧盟在内的多个发达国家的大多数儿童疫苗接种中被淘汰[130]。在常规疫苗接种前后,父母可能首先意识到他们孩子的自闭症症状。没有科学证据表明硫柳汞和自闭症之间存在因果关系,但是父母对硫柳汞争议的担忧导致儿童免疫接种率下降[4],这导致疾病爆发的可能性增加[131][132]。1999年,由于担心婴儿接触到一定剂量的汞,美国公共卫生服务局建议从儿童疫苗中去除硫柳汞,截止到2002年,流感疫苗是唯一含有痕量以上硫柳汞的儿童疫苗。尽管如此,在美国或其他国家也从儿童疫苗中去除硫柳汞,但自闭症的发病率在去除硫柳汞后并没有下降[133]。
硫柳汞和自闭症之间的因果联系假说已被国际科学和医学专业机构驳回[134], 包括美国医学协会[135]、 美国儿科学会[136]、美国医学毒理学学院[137]、美国国家科学院[124]、食品和药物管理局[138]、疾病控制和预防中心[123]、世界卫生组织[139]、加拿大公共卫生局[140]、和欧洲药品管理局[141]。
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