Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autism

Abstract

To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18–42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior.

What Can We Learn about Autism from Studying Fragile X Syndrome?

“…Hoeft et al [78] and Meguid et al [79] have reported differences in the direction of morphologic abnormalities in the two types of ASD. Individuals with FXS, with or without ASD, have a larger caudate nucleus and smaller amygdala than their counterparts with idiopathic ASD [80]. Although these distinctions could be accounted for by methodological issues, they support the notion that ASD is a neurobiologically heterogeneous behavioral syndrome [81].…”

Fragile X-associated disorders: a clinical overview

“…The most replicated findings to date include increased volume of the caudate nucleus [134][135][136][137][138][139][140] and reduced volume of the cerebellum [136,141,142] compared to both healthy comparison groups and those with ASD. Other findings noted in some studies include increased volume of the lateral ventricles [135,143,144]; hippocampus [145][146][147]; parietal lobes [136,139], and brainstem [139] and reduced volume of the cerebellar vermis [141].…”

Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome

“…Several studies have analyzed how hippocampal volume changes in FXS using a variety of techniques. Some studies have reported an increase in hippocampal volume (Reiss et al, 1994, Kates et al, 1997, Hazlett et al, 2009, one has reported a decrease (Hoeft et al, 2008), while others have found no change in hippocampal volume (Jakala et al, 1997. While it is difficult to obtain a consensus from the studies to date, it is likely that these discrepancies arise from a number of factors that include small sample sizes as well as differences in the age, sex, and number of CGG repeats among patients studied.…”