Principal pathogenetic components and biological endophenotypes in autism spectrum disorders

Abstract

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.

Endocannabinoid Signaling in Autism

“…Finally, neuroinflammation is also a frequent finding in postmortem brains of autistic individuals [64,65]. It may represent a nonspecific consequence of insufficient neurite pruning and abnormal wiring of neural networks, resulting in elevated oxidative stress (possibly a common feature shared by several neurodevelopmental disorders) [66], but it could also stem from a broader immune dysfunction which, together with gastrointestinal disturbances and recurrent infections, collectively qualifies ASD as a systemic disorder [67][68][69][70][71].…”

Urinaryp-cresol is elevated in young French children with autism spectrum disorder: a replication study

“…Diagnostic screening procedures used to exclude syndromic forms have been previously described (Sacco et al, 2010). Briefly, patients fulfilling Diagnostic and Statistical Manual IV (DSM-IV) diagnostic criteria for Autistic Disorder, Asperger Disorder or PDDNOS were screened for nonsyndromic autism using MRI, EEG, audiometry, urinary aminoacid and organic acid measurements, cytogenetic and fragile-X testing.…”

Autism genetics: Methodological issues and experimental design

“…In fact, macrocephaly (i.e., head circumference >97th percentile) has been consistently described in approximately 20% of autistic children [55,58,59], serotonin blood levels are elevated in 20%50% of autistic subjects [47], and increased urinary excretion rates of oligopeptides and multiple solutes is found in 20-60% of autistic patients, with significant interethnic differences [50,60,61]. The implementation of these endophenotypes in our studies is detailed in the following section.…”

“…We aim at refining our morphometric analysis in the future, by collecting photographs of each patient in frontal and lateral view by web-cam, and applying one of several available automated morphometric analysis methods to the face and the head [56,57,66,67]. Finally, we have designed a simple ad hoc questionnaire currently including 36 patient-and family-history variables [60], exploring the following areas:…”

“…In another study we searched for basic mechanisms underlying ASD by analyzing the clinical variables present in our ad hoc questionnaire on data collected from 245 Italian patients [60]. We identified at least four principal components that could play a relevant role in the pathogenesis of this disease: (i) "sensory dysfunction and abnormalities in the sleep-wake rhythm", (ii) "immune system abnormality" also including medical complications during pregnancy and repeated spontaneous abortions; (iii) "cognitive/motor developmental delay", and (iv) "repetitive behaviour".…”