Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
Infant Development, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
Acta Neuropathol Commun. 2015 Oct 13;3:63. doi: 10.1186/s40478-015-0241-z.
Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.1 duplication syndrome [dup(15)], autism, ID and epilepsy; eight age-matched subjects diagnosed with autism of unknown etiology (idiopathic autism) and seven control individuals was to establish whether defects of neuronal soma growth are a common denominator of developmental pathology in idiopathic and syndromic autism and how genetic modifications alter the trajectory of neuronal soma growth in dup(15) autism.
Application of the Nucleator software to estimate neuronal size revealed significant neuronal soma volume deficits in 11 of 25 structures and their subregions (44 %) in subjects diagnosed with dup(15) autism, including consistent neuronal soma volume deficits in the limbic system (sectors CA2, 3 and 4 in Ammon's horn, the second and third layers of the entorhinal cortex and in the amygdala), as well as in the thalamus, nucleus accumbens, external globus pallidus, and Ch3 nucleus in the magnocellular basal complex, and in the inferior olive in the brainstem. The second feature distinguishing dup(15) autism was persistent neuronal soma deficits in adolescents and young adults, whereas in idiopathic autism, neuronal volume deficit is most prominent in 4- to 8-year-old children but affects only a few brain regions in older subjects.
This study demonstrates that alterations in the trajectory of neuronal growth throughout the lifespan are a core pathological features of idiopathic and syndromic autism. However, dup(15) causes persistent neuronal volume deficits in adolescence and adulthood, with prominent neuronal growth deficits in all major compartments of the limbic system. The more severe neuronal nuclear and cytoplasic volume deficits in syndromic autism found in this study and the more severe focal developmental defects in the limbic system in dup(15) previously reported in this cohort may contribute to the high prevalence of early onset intractable epilepsy and sudden unexpected death in epilepsy.
自闭症是在与智力障碍（ID）和癫痫相关的多种遗传和基因组发育障碍中诊断出来的，这些障碍与高风险基因和基因座重叠，这些基因和基因座是智力障碍和癫痫的基础。本研究采用体视学方法对 8 名 9 至 26 岁个体的 25 个脑结构及其亚区的神经元胞体体积进行了研究，这些个体被诊断为 15q11.2-13.1 号染色体重复综合征[dup(15)]、自闭症、ID 和癫痫；8 名年龄匹配的被诊断为病因不明的自闭症（特发性自闭症）和 7 名对照个体。本研究的目的是确定神经元胞体生长缺陷是否是特发性和综合征性自闭症发育病理学的共同特征，以及遗传修饰如何改变 dup(15)自闭症中神经元胞体生长的轨迹。
应用 Nucleator 软件估计神经元大小的结果显示，在被诊断为 dup(15)自闭症的个体中，有 11 个脑结构及其亚区（44%）的神经元胞体体积明显减少，包括边缘系统的一致神经元胞体体积减少（Ammon 角的 CA2、3 和 4 区、内嗅皮质的第二和第三层以及杏仁核），以及丘脑、伏隔核、外苍白球、大细胞基底复合体的 Ch3 核和脑干中的下橄榄核。dup(15)自闭症的第二个特征是青少年和年轻成人持续存在神经元胞体缺陷，而在特发性自闭症中，神经元体积缺陷在 4 至 8 岁儿童中最为明显，但在年龄较大的儿童中仅影响少数脑区。
本研究表明，整个生命周期中神经元生长轨迹的改变是特发性和综合征性自闭症的核心病理特征。然而，dup(15)导致青春期和成年期持续的神经元体积减少，边缘系统的所有主要结构都有明显的神经元生长减少。在本研究中发现的综合征性自闭症中更严重的神经元核和胞质体积减少，以及此前在本队列中报道的 dup(15)中更严重的边缘系统局灶性发育缺陷，可能导致早发性难治性癫痫和癫痫猝死的高发病率。
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