title: 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.
authors.affiliation: Laboratory of Molecular Psychiatry and Neurogenetics, University "Campus Bio-Medico", Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.forename: Paolo
authors.initials: P
authors.lastname: Curatolo
authors.forename: Barbara
authors.initials: B
authors.lastname: Manzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Militerni
authors.forename: Carmela
authors.initials: C
authors.lastname: Bravaccio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Frolli
authors.forename: Carlo
authors.initials: C
authors.lastname: Lenti
authors.forename: Monica
authors.initials: M
authors.lastname: Saccani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Elia
authors.forename: Karl-Ludvig
authors.initials: KL
authors.lastname: Reichelt
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pascucci
authors.forename: Stefano
authors.initials: S
authors.lastname: Puglisi-Allegra
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000453:epidemiology* / Q000378:metabolism* / Q000473:pathology; D002675:Child, Preschool; D021081:Chronobiology Disorders / Q000453:epidemiology; D015897:Comorbidity; D002658:Developmental Disabilities / Q000453:epidemiology*; D058068:Endophenotypes / Q000097:blood / Q000378:metabolism* / Q000652:urine; D005260:Female; D006801:Humans; D007154:Immune System Diseases / Q000453:epidemiology*; D007558:Italy / Q000453:epidemiology; D008297:Male; D058627:Megalencephaly / Q000453:epidemiology; D009422:Nervous System Diseases / Q000453:epidemiology*; D010455:Peptides / Q000652:urine; D025341:Principal Component Analysis; D012678:Sensation Disorders / Q000453:epidemiology; D012701:Serotonin / Q000097:blood; D013239:Stereotyped Behavior; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D010455:Peptides; D012701:Serotonin