Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome.

BACKGROUND: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data. METHODS: We evaluated a single-center cohort of 64 individuals with XYY aged 5-25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis. RESULTS: Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features. CONCLUSIONS: By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls."

Psychometric Evaluation of the Caregiver Burden Inventory in Children and Adolescents With PANS.

Objectives: To establish the psychometric properties of the Caregiver Burden Inventory (CBI) in patients with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), which is characterized by the abrupt onset of obsessive-compulsive disorder and/or restricted eating and at least two additional psychiatric symptoms. Parents of patients with PANS have reported high caregiver burden. However, no validated instrument of burden exists for this population. Methods: Study took place at a community-based PANS clinic where the CBI is administered as part of routine clinical care. The first CBI available during an active disease flare was analyzed (N =104). Construct validity was evaluated within a confirmatory factor analytic framework. Associations between the CBI and patient/family characteristics were explored, and preliminary normative data for this population are presented. Results: Item-factor loadings were strong, and the overall fit of the model was good (root mean square error of approximation = .061). Strict/metric measurement invariance was demonstrated across age. The mean Total Score in this sample was 36.72 ± 19.84 (interquartile range 19-53). Total Scores on the CBI were significantly elevated for parents of children who switched schools because of their illness (Cohen's d = 0.75, 95% confidence interval [CI] 0.28-1.22) and for those who had reduced work hours to accommodate the child's illness (Cohen's d = 0.65, 95% CI 0.10-1.20). However, in this relatively high-status sample, socioeconomic variables did not predict Total Scores. Conclusions: Parents of patients with PANS experience high caregiver burden. The CBI may be confidently used to assess caregiver burden in this population.

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero.

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.