Behavioral and Neurobiological Phenotyping of ASD with Megalencephaly

项目2 -概要 非典型的，快速的早期脑增大是一种独特的神经表型，在15%的男性自闭症患者中观察到 谱系障碍（ASD）。这种表型被称为“不成比例的巨脑畸形自闭症” （ASD-DM），因为头部和大脑的生长与身高不成比例。UC Davis MIND的数据 研究所自闭症表型组项目表明，患有ASD-DM的儿童中有更高比例的语言能力最低 在3岁的时候。到5岁时，具有这种表型的儿童在智商上的提高比他们的 与正常大脑大小的ASD患者相对应。在学龄期，更高比例的ASD-DM的智商在 智力残疾的范围。本项目的一个短期目标是确认ASD-DM的预后较差 比其他自闭症儿童要多长期目标是充分了解认知过程和神经系统 这些缺陷背后的系统，以便可以制定有针对性的干预措施，以改善预后， 有这种表型的孩子。为了实现这些目标，将对一批新的2-3.5岁儿童进行培训， 在招聘和保留核心的帮助下招聘。四组：正常脑体积ASD（ASD-N）， ASD伴不成比例巨脑畸形（ASD-DM）和典型发育（TD）伴正常或增大 将评估大脑大小。将在两个时间点对儿童进行纵向评估，一次是在研究入组时（2- 3.5 2岁），两年后随访（4-5.5岁）。在第一个目标中， 行为评估，包括标准化评估和有效的眼动跟踪任务， 将对注意力、记忆力和语言的特定认知过程进行测试。眼动追踪任务 预计比标准化措施对细微的表型差异更敏感， 制定有针对性的干预措施。在第二个和第三个目标中，进一步评估神经系统 将进行不成比例的巨脑畸形表型的基础研究。结构和功能 MRI和听觉事件相关电位将被用来询问损伤的神经基础 在这种表型中观察到的，重点是涉及注意力、语言和记忆的神经系统。 识别与行为缺陷有关的神经系统不仅可以提供线索， 病因学，但也将提供可用作测量治疗反应的生物标志物的神经靶点 在未来的研究中。项目2的参与者将被邀请参加项目3，该项目旨在产生诱导 多能干细胞（iPSC），以研究ASD中巨脑畸形的细胞机制。 数据管理和统计核心将管理来自两个项目的数据，并将促进项目间 分析。实现这些目标将使研究小组能够为此制定有针对性的干预措施 具有临床意义的表型，在发育早期存在，在出生后的头几年很容易识别。 生活

PROJECT 2 – SUMMARY Atypical, rapid early brain enlargement is a distinct neurophenotype that is observed in 15% of males with autism spectrum disorder (ASD). This phenotype has been labeled “autism with disproportionate megalencephaly” (ASD-DM) because head and brain growth is disproportionate to height. Evidence from the UC Davis MIND Institute Autism Phenome Project suggests that a higher proportion of children with ASD-DM are minimally verbal at 3 years of age. By 5 years of age, children with this phenotype have made fewer gains in IQ than their counterparts with ASD and normal brain size. At school age, a higher proportion of ASD-DM have IQs in the range of intellectual disability. A short-term goal of this project is to confirm that ASD-DM have a poorer prognosis than other children with ASD. The long-term objective is to fully understand the cognitive processes and neural systems underlying these deficits so that targeted interventions can be developed to improve the prognosis of children with this phenotype. To accomplish these objectives, a new cohort of 2-3.5-year old children will be recruited with aid from the Recruitment and Retention Core. Four groups, ASD with normal brain size (ASD-N), ASD with disproportionate megalencephaly (ASD-DM) and typical development (TD) with normal or enlarged brain sizes will be evaluated. Children will be assessed longitudinally at two time points, once at study entry (2- 3.5 years of age) with a follow up visit two years later (4-5.5 years of age). In the first aim, a comprehensive behavioral evaluation that includes both standardized assessments and well-validated eye-tracking tasks that test specific cognitive processes of attention, memory, and language will be conducted. The eye-tracking tasks are expected to be more sensitive to subtle phenotypic differences than standardized measures and could guide development of targeted interventions. In the second and third aims, further evaluation of the neural underpinnings of the disproportionate megalencephaly phenotype will be carried out. Structural and functional MRI and auditory event-related potentials will be utilized to interrogate the neural basis of the impairments observed in this phenotype with emphasis on neural systems involved in attention, language, and memory. Identifying the neural systems that are involved in the behavioral deficits will provide clues not only to underlying etiologies, but will also provide neural targets that could be used as biomarkers for measuring treatment response in future studies. Participants in Project 2 will be invited to participate in Project 3, which aims to generate induced pluripotent stem cells (iPSCs) in order to investigate cellular mechanisms underlying megalencephaly in ASD. The Data Management and Statistics Core will manage data from both projects and will facilitate inter-project analyses. Accomplishing these aims will enable the research team to develop targeted interventions for this clinically meaningful phenotype that is present early in development and is easily identifiable in the first years of life.