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Background: Restricted and repetitive behaviors (RRB) in autism spectrum disorder (ASD) encompass several distinct domains. However, commonly used general ASD measures provide broad RRB scores rather than assessing separate RRB domains. The main objective of the current investigation was to conduct a psychometric evaluation of the ability of the Social Responsiveness Scale (SRS-2), the Social Communication Questionnaire (SCQ), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) to capture different RRB constructs., Methods: Exploratory Structural Equation Modeling (ESEM) was conducted using individual item-level data from the SRS-2, SCQ, ADI-R and the ADOS. Data were obtained from five existing publicly available databases. For the SRS-2, the final sample consisted of N = 16,761 individuals (M age  = 9.43, SD = 3.73; 18.5% female); for the SCQ, of N = 15,840 (M age  = 7.99, SD = 4.06; 18.1% female); for the ADI-R, of N = 8985 (M age  = 8.86, SD = 4.68; 19.4% female); and for the ADOS, of N = 6314 (M age  = 12.29, SD = 6.79; 17.7% female)., Results: The three-factor structure provided the most optimal and interpretable fit to data for all measures (comparative fit index ≥ .983, Tucker Lewis index ≥ .966, root mean square error of approximation ≤ .028). Repetitive-motor behaviors, insistence on sameness and unusual or circumscribed interests factors emerged across all instruments. No acceptable fit was identified for the ADOS., Limitations: The five datasets used here afforded a large as well as wide distribution of the RRB item scores. However, measures used for establishing convergent and divergent validity were only available for a portion of the sample., Conclusions: Reported findings offer promise for capturing important RRB domains using general ASD measures and highlight the need for measurement development.

Background: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort., Methods: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model., Results: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status., Limitations: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments., Conclusions: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures., Trial Registration: ClinicalTrials.gov Identifier NCT02461446.

Background: The aim of this paper was to provide an initial validation of a newly developed parent questionnaire-the Stanford Social Dimensions Scale (SSDS), designed to capture individual differences across several key social dimensions including social motivation in children and adolescents with and without psychiatric disorders., Methods: The initial validation sample was comprised of parents of 175 individuals with autism spectrum disorder (ASD) (35 females, 140 males; M age = 7.19 years, SD age = 3.96) and the replication sample consisted of 624 parents of children who were either typically developing or presented with a range of neurodevelopmental and neuropsychiatric disorders (302 females, 322 males; M age = 11.49 years, SD age = 4.48). Parents from both samples completed the SSDS and the Social Responsiveness Scale (SRS-2)., Results: Exploratory Structural Equation Modeling indicated that a 5-factor model provided adequate to excellent fit to the data in the initial ASD sample (comparative fit index [CFI] = .940, Tucker-Lewis Index [TLI] = .919, root mean square error of approximation [RMSEA] = .048, standardized root mean square residual [SRMR] = .038). The identified factors were interpreted as Social Motivation, Social Affiliation, Expressive Social Communication, Social Recognition, and Unusual Approach. This factor structure was further confirmed in Sample 2 (CFI = 946, TLI = .930, RMSEA = .044, SRMR = .026). Internal consistency for all subscales was in the good to excellent range across both samples as indicated by Composite Reliability scores of ≥ .72. Convergent and divergent validity was strong as indexed by the pattern of correlations with relevant SRS-2 and Child Behavior Checklist domains and with verbal and non-verbal intellectual functioning scores in Sample 1 and with the Need to Belong Scale and Child Social Preference Scale scores in Sample 2. Across both samples, females had higher social motivation and expressive social communication scores. Discriminant validity was strong given that across all SSDS subscales, the ASD sample had significantly higher impairment than both the typically developing group and the group with other clinical conditions, which in turn, had significantly higher impairment than the typically developing group., Conclusions: Our findings provide initial validation of a new scale designed to comprehensively capture individual differences in social motivation and other key social dimensions in ASD., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD ( N  = 112)., Findings: Anandamide concentrations significantly differentiated ASD cases ( N  = 59) from controls ( N  = 53), such that children with lower anandamide concentrations were more likely to have ASD ( p  = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children ( p  = 0.034)., Conclusions: These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD., Competing Interests: All research procedures were approved by the Stanford University Institutional Review Board prior to participant enrollment. Participants’ parents provided written consent prior to initiation of any experimental procedures, and written assent was obtained from participants when appropriate (e.g., children ≥ 7 years of age and deemed intellectually capable).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation., Methods: Data were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels., Results: Non-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families-this effect was accentuated for male children in female ASD-containing families-or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families., Conclusions: Sex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis.