Persistence of Megalencephaly in Early Childhood in a Subset of Children with Autism Spectrum Disorder

Background:  Accelerated brain growth in early childhood in autism spectrum disorder (ASD) has been widely reported. This pattern of excessive growth leads to enlarged brain size and head circumference (HC) in young children with ASD and is purported to plateau in growth (normalization) by adolescence. Although enlarged brain size and HC appear to be a common finding, longitudinal studies specifically examining brain growth in early childhood in individuals with ASD are needed to confirm these conclusions. The current study utilizes a longitudinal dataset of young children with ASD to examine the developmental trajectory of overall brain volume and HC in children with and without ASD.

Objectives:  We evaluated total cerebral volume (TCV) and HC longitudinally in a large cohort of preschool-aged children with ASD and age-matched typically developing (TD) controls.

Methods:  Participants were enrolled in the Autism Phenome Project. We acquired structural T1-weighted MRIs in 150 children with ASD (122 male/28 female) and 62 TD controls (40 male/22 female) at Time 1 (mean age: 3.1 years). The same participants returned at two time points, resulting in the collection of 99 ASD (80 male/19 female) and 47 TD (31 male/16 female) MRI scans at Time 2 (mean age: 4.2 years), and 79 ASD (64 male/15 female) and 38 TD (25 male/13 female) MRIs at Time 3 (mean age: 5.3 years). Height measurements were collected at each time point. Head circumference at birth was acquired from retrospective examination of medical records, and HC was measured at the Time 1 and Time 3 MRI scans. TCV was measured using a template-based automated method. Individuals with a standardized ratio of TCV to height that was 1.5 standard deviations above the mean for the TD group were classified as having disproportionate megalencephaly (ASD-DM).

Results:  At Time 1, 21 ASD children were classified as ASD-DM (19 male/2 female), while 129 ASD children (103 male/26 female) remained in the normal range of TCV (ASD-norm). Head circumference did not significantly differ at birth between any of the groups, but was significantly higher for ASD-DM children, compared to the ASD-norm and TD groups, at Time 1 and Time 3. No significant differences in height were found between ASD-DM, ASD-norm, and TD children at any of the time points. By Time 3, two ASD-DM children were no longer in the DM range while two ASD-norm from Time 1 could newly be classified as DM.

Conclusions:  These data suggest there is a subgroup of children with ASD who have brain enlargement, which cannot be accounted for by body size, while most children with ASD remain within the normal range of TCV from ages 3 to 5 years. Contrary to prevailing views, we find that the vast majority of ASD-DM children continue having enlarged brains and greater HC at 5 years of age, with no plateau in growth. In sum, the developmental pattern of brain growth is accelerated only for a subset of ASD children with DM, who persist in having disproportionate megalencephaly across early childhood.