Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy.
Autism Res. 2010 Oct;3(5):237-52. doi: 10.1002/aur.151.
Autism is a complex neurodevelopmental disorder, likely encompassing multiple pathogenetic components. The aim of this study is to begin identifying at least some of these components and to assess their association with biological endophenotypes. To address this issue, we recruited 245 Italian patients with idiopathic autism spectrum disorders and their first-degree relatives. Using a stepwise approach, patient and family history variables were analyzed using principal component analysis ("exploratory phase"), followed by intra- and inter-component cross-correlation analyses ("follow-up phase"), and by testing for association between each component and biological endophenotypes, namely head circumference, serotonin blood levels, and global urinary peptide excretion rates ("biological correlation phase"). Four independent components were identified, namely "circadian & sensory dysfunction," "immune dysfunction," "neurodevelopmental delay," and "stereotypic behavior," together representing 74.5% of phenotypic variance in our sample. Marker variables in the latter three components are positively associated with macrocephaly, global peptiduria, and serotonin blood levels, respectively. These four components point toward at least four processes associated with autism, namely (I) a disruption of the circadian cycle associated with behavioral and sensory abnormalities, (II) dysreactive immune processes, surprisingly linked both to prenatal obstetric complications and to excessive postnatal body growth rates, (III) a generalized developmental delay, and (IV) an abnormal neural circuitry underlying stereotypies and early social behaviors.
自闭症是一种复杂的神经发育障碍，可能包含多种发病机制成分。本研究旨在确定这些成分中的至少一些，并评估它们与生物学内表型的关联。为了解决这个问题，我们招募了 245 名意大利特发性自闭症谱系障碍患者及其一级亲属。我们使用逐步方法，使用主成分分析（“探索阶段”）分析患者和家族史变量，然后进行内部分和组件间交叉相关分析（“随访阶段”），并测试每个组件与生物学内表型（即头围、血清素水平和全球尿肽排泄率）之间的关联（“生物学相关性阶段”）。确定了四个独立的成分，分别为“昼夜节律和感觉功能障碍”、“免疫功能障碍”、“神经发育迟缓”和“刻板行为”，它们共同代表了我们样本中 74.5%的表型变异。后三个组件中的标记变量与大头围、全球肽尿症和血清素水平呈正相关。这四个成分指向与自闭症相关的至少四个过程，分别是：（一）与行为和感觉异常相关的昼夜节律紊乱，（二）异常反应性免疫过程，令人惊讶的是，它与产前产科并发症和产后过度生长速度有关，（三）广泛的发育迟缓，以及（四）刻板行为和早期社会行为背后的异常神经回路。
