Persistence of megalencephaly in a subgroup of young boys with autism spectrum disorder

Abstract

A recurring finding in autism spectrum disorder research is that head and brain growth is disproportionate to body growth in early childhood. Nordahl et al. (2011) demonstrated that this occurs in approximately 15% of boys with autism. While the literature suggests that brain growth normalizes at older ages, this has never been evaluated in a longitudinal study. The current study evaluated head circumference and total cerebral volume in 129 male children with autism and 49 age-matched, typically developing controls. We determined whether 3-year-old boys with brain size disproportionate to height (which we call disproportionate megalencephaly) demonstrated an abnormal trajectory of head growth from birth and whether they maintained an enlarged brain at 5 years of age. Findings were based on longitudinal, structural MRI data collected around 3, 4, and 5 years of age and head circumference data from medical records. At 3 years of age, 19 boys with autism had enlarged brains while 110 had brain sizes in the normal range. Boys with disproportionate megalencephaly had greater total cerebral, gray matter, and white matter volumes from 3-5 years compared to boys with autism and normal sized brains and typically developing boys, but no differences in body size. While head circumference did not differ between groups at birth, it was significantly greater in the disproportionate megalencephaly group by around 2 years. These data suggest that there is a subgroup of boys with autism who have brains disproportionate to body size and that this continues until at least 5 years of age. Autism Res 2016, 9: 1169-1182. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Keywords: MRI; autism spectrum disorder; brain development; disproportionate megalencephaly; longitudinal.

Figure 1

Distribution of subjects. The percentage of subjects in each bin for each group (ASD and TD) based on their standardized total cerebral volume (TCV) to height ratio. Z-scores are based on the TD distribution.

Figure 2

Results from longitudinal analyses of total cerebral volume. (A) Total cerebral volume data for ASD and TD subjects. Each line connects the data points collected from an individual subject. (B) Individual subject data are represented as individual data points. The lines represent the predicted growth trajectories of total cerebral volume for TD boys and all boys with ASD. All ASD boys combined had significantly greater TCV at the earliest age, and a slight but not significant increase in the rate of TCV growth over time, compared to TD boys.

Figure 3

Results from longitudinal analyses of total cerebral volume for subgroups. (A) Total cerebral volume data for the three subgroups: ASD-DM, ASD-N, and TD boys. Each line connects the data points from each individual subject. The ASD-DM group (red) falls in the upper end of the distribution, while there is almost complete overlap between the ASD-N (green) and TD (blue) participants. (B) Individual subject data are represented as individual data points. The lines represent the predicted growth trajectories of total cerebral volume for each of the three subgroups, ASD-DM, ASD-N, and TD. ASD-DM boys had significantly greater TCV at the earliest age and also a significantly greater rate of growth from ages 3–5 years, compared to ASD-N and TD boys.

Figure 4

Results from longitudinal analyses of head circumference. (A) Head circumference data for ASD and TD subjects collected retrospectively from medical records. Each line connects the data points collected from an individual subject. A total of 1162 measurements (6.5 measurements per subject on average) were collected from medical records, spanning from birth to 36 months of age. (B) Predicted growth trajectories for head circumference for TD boys and all boys with ASD. Dashed lines indicate the lower and upper bounds of the 95% confidence intervals. There were no differences between ASD and TD boys in head circumference at birth, but the ASD boys had a significantly greater final overall head circumference and a significantly greater rate of growth

Figure 5

Results from longitudinal analyses of head circumference for subgroups. (A) Data for head circumference for participants from each of the three subgroups: ASD-DM, ASD-N, and TD. Each line connects the data points from each individual subject. The ASD-DM group (red) fall in the upper end of the distribution, while there is a large amount of overlap between the ASD-N (green) and TD (blue) boys. (B) Predicted growth trajectories for head circumference for each of the three subgroups. Dashed lines indicate the lower and upper bounds of the 95% confidence intervals. The ASD-DM group did not differ in head circumference at birth, but reached a significantly larger final overall head size compared to the ASD-N and TD boys.

Figure 6

Distribution of height for subjects in this study. Based on these distributions of height we obtained the predicted linear growth trajectories for body height for each subgroup as indicated by the solid lines. No significant differences were found between the three subgroups for height or rate of growth for height.