Abstract:
Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen\'s d\' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.
摘要:
自闭症谱系障碍(ASD)是一种神经发育障碍,影响36名儿童中的1名,并与生理异常有关。最值得注意的是线粒体功能障碍,至少在一部分个体中。这项系统评价和荟萃分析发现了204篇相关文章,这些文章评估了ASD个体线粒体功能障碍的生物标志物。乳酸(17%)患病率显著升高(所有p<0.01),丙酮酸盐(41%),在ASD中发现丙氨酸(15%)和肌酸激酶(9%)。与平均丙酮酸对照相比,ASD患者具有中等至较大效应大小(Cohen'sd'≥0.6)的显着差异(所有p<0.01),乳酸与丙酮酸的比例,ATP,和肌酸激酶.一些研究发现与ASD相关的TCA循环代谢异常。13项对照研究报告了血液中ASD组的线粒体DNA(mtDNA)缺失或变异,外周血单核细胞,淋巴细胞,白细胞,粒细胞,和大脑。荟萃分析发现mtDNA整体拷贝数和ND1、ND4和CytB基因存在显著差异(p<0.01)。四项研究将特定的mtDNA单倍群与ASD联系起来。一系列研究发现了线粒体呼吸升高的ASD亚组,这与线粒体对生理应激源和神经发育退化的敏感性增加有关。乳酸,丙酮酸,乳酸与丙酮酸的比例,肉碱,酰基肉碱与临床特征相关,如语言延迟,社交互动,认知,运动技能,重复的行为和胃肠道症状,尽管并非所有研究都发现了关联。乳酸,肉碱,酰基肉碱,ATP,辅酶Q10,以及mtDNA变体,异质体,单倍群和拷贝数与ASD严重程度相关.在生物标志物研究中发现变异性主要是由于收集和处理技术的差异以及ASD群体的内在异质性。一些研究报告了ASD儿童母亲和发展ASD的新生儿线粒体代谢的变化。针对线粒体的治疗,特别是肉碱和泛醇,在ASD中似乎是有益的。ASD中的线粒体功能障碍与ASD患者的常见生理异常之间的联系,包括胃肠道疾病,氧化应激,并概述了免疫功能障碍。讨论了ASD中线粒体功能障碍的几种亚型,包括一个与神经发育退化有关的,另一个与微生物组代谢物的改变有关,另一个与酰基肉碱的升高有关。概述了将线粒体功能异常与产前脑发育和出生后脑功能改变联系起来的机制。考虑到一些患有ASD的个体的多系统复杂性,这篇综述提供了证据,表明线粒体是ASD的核心,它有助于大脑发育异常,认知,和合并症,如免疫和胃肠道功能障碍以及神经发育退化。概述了识别ASD中线粒体功能障碍的诊断方法。从这个证据来看,很明显,许多ASD患者的线粒体功能发生了改变,这可能需要解决以达到最佳临床结局.线粒体代谢的改变可能在怀孕期间和最终发展为ASD的个体的生命早期发现,这一事实为ASD的早期生命预测生物标志物提供了希望。进一步的研究可以通过更好地定义亚组和理解驱动ASD患者线粒体功能中发现的一些独特变化的分子机制来提高对线粒体在ASD中的作用的理解。