Alterations in Brain Volume and White Matter Microstructure Predict Symptoms of Autism in Angelman Syndrome

Background: Angelman syndrome (AS) is a neurogenetic disorder that is characterized by severe mental retardation, lack of speech, ataxia, seizures, and frequent outbursts of laughter. Previous studies have indicated overlap of autism and AS. Objectives: To examine the neuroanatomical correlates and the disruptions in white matter pathways that contribute to symptoms of autism in AS. Methods: We utilized diffusion tensor imaging (DTI) and quantitative magnetic resonance imaging (MRI) to characterize all patients. Fourteen deletion positive patients with AS between the ages of 8-17 were enrolled; and 13 typically-developing controls with comparable age and gender were enrolled. Patients with AS received the Bayley Scales of Infant Development-III, Vineland Adaptive Behavior Scales-II, Autism Diagnostic Observation Schedule, and the Aberrant Behavior Checklist. Results: The results of quantitative MRI indicated that after controlling for total intracranial volume and age, AS patients have reduced volumes compared to controls in the cerebellum (p<.01), caudate (p<.001), globus pallidus (p=.013), amygdala (p<.01), and corpus callosum (p<.05). Reduced volume in the corpus callosum was associated with more impairments in socialization (p<.05), play (p<.05), and higher levels of stereotypic behaviors (p<.05). Reduced volume in the amygdala was associated with more stereotyped behaviors (p<.05), and greater impairment in social communication (p<.05) and social interaction (p<.05). Reduced volume in the globus pallidus was associated with more impairment in social communication (p<.05) and play skills (p<.05). On DTI studies, we observed reduced fractional anisotropy (FA), higher radial diffusivity (RD), and higher apparent diffusion coefficient (ADC) values in the arcuate fasciculus (AF) and the uncinate fasciculus (UF) (a pathway related to social engagement/affect) in individuals with AS compared to controls. High RD and reduced FA in the AF in children with AS correlated with lower expressive and receptive language, deferred imitation, and more impaired socialization and play skills. Higher RD, higher ADC, and reduced FA in the UF corresponded to increased social withdrawal. Within this study, seven patients with AS exceeded ADOS cutoff scores for the criteria of autism, while seven patients did not exceed these cutoffs. When examining volumetric differences, we found that children with AS and autism had reduced volumes in the amygdala (p<.05) compared to children with AS alone. On DTI, patients with AS and autism exhibited lower FA and higher RD in the UF and the AF compared to those with AS alone (p<.05). Conclusions: Compared to controls, patients with AS exhibit changes to brain structure and white matter pathways that are related to social engagement, stereoptyped behaviors, and play skills. Although prior studies have demonstrated some overlap with AS and autism, this study also demonstrates within-group differences in brain structure and white matter pathways such that patients with autism and AS show even more brain-based alterations as compared to their peers with AS alone. Taken together, our findings seem to suggest that the AS gene, UBE3A, is expressed throughout the brain and that disruptions in UBE3A lead to disruptions in cortical and subcortical regions as well as white matter pathways that contribute to core deficits of autism.