Disproportionate Megalencephaly: A Clinically Meaningful Neurophenotype in Autism Spectrum Disorder
Increased head size was noted in the earliest descriptions of children with autism spectrum disorder (ASD). However, the prevalence of abnormal head size in ASD has been continually debated and uncertainty remains regarding any potential clinical implications. Recent findings suggest that children with ASD may exhibit accelerated growth in body length as well, but this has not routinely been accounted for in definitions of abnormal head size.
We sought to identify and characterize differences in gray and white matter of the brain in young boys with ASD who also exhibited disproportionate megalencephaly (ASD-DM).
Children below the age of 5 with ASD as well as age-matched typically developing controls were recruited through the MIND Institute of the University of California Davis as part of the Autism Phenome Project. Diagnostic assessments were conducted by licensed clinical psychologists using the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and the Autism Diagnostic Interview-Revised (ADI-R). Magnetic resonance imaging scans were collected during natural nocturnal sleep and included both T1 and diffusion-weighted sequences. The ASD-DM male subgroup was defined as individuals with a cerebral volume to height ratio 1.5 standard deviations above the typically developing mean.
Cortical thickness and surface area were measured in 4 lobes and 34 automatically parcellated brain regions in each hemisphere. Axial diffusivity, radial diffusivity, mean diffusivity, and fractional anisotropy were assessed along the length of 18 white matter tracts. Results in ASD-DM males were compared to results in all other males with ASD as well as to typically developing controls.
ASD-DM males exhibited cortical surface area alterations in the rostral middle frontal, fusiform, and rostral anterior cingulate regions as well as greater hemisphere asymmetry in frontal lobe surface area. Results from white matter analyses indicate diffusivity alterations principally in the anterior thalamic radiations, corticospinal tracts and uncinate fasciculus. Finally, behavioral assessments indicated the ASD-DM group performed more poorly on the social affect and communication and social interaction subscales of the ADOS compared to males with ASD and normal brain volumes.
ASD-DM males display additional brain alterations not seen in other males with ASD. In conjunction with poorer scores on multiple behavioral measures, this suggests ASD-DM males may represent a more severely affected group of children within ASD. While additional characterization of ASD-DM males is necessary, identification of a subset of males with ASD who exhibit neurological and behavioral distinctions is an important starting point for delineation of specific autism phenotypes. Identification of subgroups within ASD will likely assist in the development of more effective therapies and treatments as well as inform efforts aimed at providing earlier diagnosis of ASD.