Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors
Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors
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DOI：
10.1007/978-3-030-30402-7_4
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发表时间：
2020-01-01
期刊：
影响因子：
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通讯作者：
Kuhad, Anurag
中科院分区：
文献类型：
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作者：
Bhandari, Ranjana;Paliwal, Jyoti K.;Kuhad, Anurag
自闭症谱系障碍(ASD)是一种复杂的、异质性的普及性发育障碍(PDD)联合体，其范围从非典型自闭症、自闭症和影响发育期大脑的阿斯伯格综合征。这种衰弱的神经发育障碍既会导致核心症状，也会导致相关症状。自闭症患者的核心症状是缺乏社交、无处不在、刻板印象和受限的行为，而相关症状包括易怒、焦虑、攻击性和几种共病障碍。自闭症是一种多基因疾病，由多因素引起。调控突触发生和信号通路的几个基因的拷贝数变异(CNV)是自闭症发病的主要因素之一。各种CNV的复杂整合导致编码参与细胞黏附、电压门控离子通道、支架蛋白以及信号通路(PTEN和mTOR通路)的分子的基因发生突变。这些突变的基因通过引起可塑性障碍而影响突触传递，进而导致ASD的表达。影响DNA转录的表观遗传修饰以及出生前和出生后暴露于各种环境因素也是ASD发生的诱发因素。所有这些共同导致谷氨酸能信号的失调和兴奋性的失衡：抑制通路导致胶质细胞激活和炎性介质的释放，导致在自闭症患者中观察到的异常社会行为。在本章中，我们回顾并洞察到各种遗传、表观遗传和环境因素的复杂整合，这些因素在这种紊乱的发病机制中扮演主要角色，以及这种整合背后的机制途径。
Autism spectrum disorder (ASD) is a complex heterogeneous consortium of pervasive development disorders (PDD) which ranges from atypical autism, autism, and Asperger syndrome affecting brain in the developmental stage. This debilitating neurodevelopmental disorder results in both core as well as associated symptoms. Core symptoms observed in autistic patients are lack of social interaction, pervasive, stereotyped, and restricted behavior while the associated symptoms include irritability, anxiety, aggression, and several comorbid disorders.ASD is a polygenic disorder and is multifactorial in origin. Copy number variations (CNVs) of several genes that regulate the synaptogenesis and signaling pathways are one of the major factors responsible for the pathogenesis of autism. The complex integration of various CNVs cause mutations in the genes which code for molecules involved in cell adhesion, voltage-gated ion-channels, scaffolding proteins as well as signaling pathways (PTEN and mTOR pathways). These mutated genes are responsible for affecting synaptic transmission by causing plasticity dysfunction responsible, in turn, for the expression of ASD.Epigenetic modifications affecting DNA transcription and various pre-natal and post-natal exposure to a variety of environmental factors are also precipitating factors for the occurrence of ASD. All of these together cause dysregulation of glutamatergic signaling as well as imbalance in excitatory: inhibitory pathways resulting in glial cell activation and release of inflammatory mediators responsible for the aberrant social behavior which is observed in autistic patients.In this chapter we review and provide insight into the intricate integration of various genetic, epigenetic, and environmental factors which play a major role in the pathogenesis of this disorder and the mechanistic approach behind this integration.