Child Study Center, Yale School of Medicine, New Haven, Connecticut.
Department of Psychiatry, Columbia University, New York, New York.
JAMA Psychiatry. 2018 May 1;75(5):514-523. doi: 10.1001/jamapsychiatry.2017.4685.
Autism spectrum disorder (ASD) is a highly prevalent disorder, and community psychiatrists are likely to treat many individuals with ASD during their clinical practice. This clinical case challenge describes a routine evaluation of irritability and self-injury in a preschool-aged child who meets the criteria for ASD. The case also illustrates the importance of known risk factors for ASD, such as chromosomal deletion and prematurity. This clinical neuroscience article seeks to educate the clinician of current avenues of research that can inform and may already affect clinical practice for this patient, while providing a preview of research that may yield biological treatments for ASD within the next decade.
A diagnosis of ASD is defined behaviorally; therefore, many genetic and environmental risk factors, working singly or in concert, are linked to ASD. The prenatal period of brain development is particularly sensitive to risk factors such as gene mutation or drug exposure that affect brain development and circuitry formation. Currently, neuroimaging researchers can detect changes in brain connectivity of children with ASD as young as 6 months, followed by an atypical trajectory of brain development through preschool age and ongoing connectivity inefficiencies across the lifespan. Animal and cellular model systems have provided a means for defining the molecular and cellular changes associated with risk factors for ASD. The ability to connect specific treatments to particular subgroups of people with ASD is the defining hope of precision medicine initiatives.
The advent of next-generation sequencing technology, advanced imaging techniques, and cutting-edge molecular techniques for modeling ASD has allowed researchers to define ASD risk-related biological pathways and circuits that may, for the first time, unify the effects of disparate risk factors into common neurobiological mechanisms. The path from these mechanisms to biological treatments that improve the lives of individuals with autism remains unclear, but the cumulative output of multiple lines of research suggests that subtyping by genetic risk factors may be a particularly tractable way to capitalize on individual differences amenable to specific treatments.
自闭症谱系障碍（ASD）是一种高度流行的疾病，社区精神科医生在临床实践中可能会治疗许多 ASD 患者。这个临床案例挑战描述了对符合 ASD 标准的学龄前儿童易激惹和自残的常规评估。该案例还说明了 ASD 的已知风险因素的重要性，例如染色体缺失和早产。这篇临床神经科学文章旨在为临床医生提供当前研究途径的教育，这些途径可以为该患者的临床实践提供信息，并可能已经产生影响，同时为未来十年内可能为 ASD 提供生物学治疗的研究提供预览。
自闭症的诊断是通过行为定义的；因此，许多遗传和环境风险因素，单独或协同作用，与 ASD 有关。大脑发育的产前阶段对基因突变或药物暴露等风险因素特别敏感，这些因素会影响大脑发育和电路形成。目前，神经影像学研究人员可以检测到 6 个月大的 ASD 儿童的大脑连接变化，随后是学龄前儿童大脑发育的非典型轨迹以及整个生命周期中的大脑连接效率低下。动物和细胞模型系统为定义与 ASD 风险因素相关的分子和细胞变化提供了一种手段。将特定治疗方法与 ASD 患者的特定亚群联系起来的能力是精准医学计划的决定性希望。
下一代测序技术、先进的成像技术和用于建模 ASD 的前沿分子技术的出现，使研究人员能够定义 ASD 风险相关的生物途径和电路，这可能首次将不同风险因素的影响统一到共同的神经生物学机制中。从这些机制到改善自闭症患者生活的生物学治疗的途径尚不清楚，但多条研究路线的累积产出表明，通过遗传风险因素进行亚分型可能是利用特定治疗方法可处理的个体差异的一种特别可行的方法。
