A Pilot Neuroimaging Study of Phelan Mcdermid Syndrome

Background:   Deletions and mutations of the SHANK3 gene, located at 22q13.3, are one of the more common monogenic causes of autism spectrum disorders (ASD). Loss of one copy of SHANK3results in Phelan McDermid Syndrome (PMS), characterized by global developmental delay, hypotonia, delayed or absent speech, and ASD features. While the association between PMS and ASD is well documented at the behavioral level, there is a striking paucity of data on the underlying abnormal neural systems. Qualitative clinical profiling suggests above average rates of neuropathology in PMS, but no studies so far have included comparison data.

Objectives:   The goal of this study is to investigate the effect of SHANK3deficiency on brain structure and function and contribute to parsing the heterogeneity in ASD. Individuals with PMS are compared with individuals with idiopathic autism (iASD). Here we present data from diffusion tensor imaging (DTI) and functional MRI.

Methods:   In this preliminary study, 11 children with PMS and 9 comparison children with idiopathic autism underwent MRI under light sedation. All PMS participants met ADOS and ADI criteria for ASD; severity of autism symptoms and developmental quotient did not differ significantly between groups. The fMRI paradigm was a passive auditory task, developed by Pelphrey and colleagues, which presented communicative (e.g., speech, vocalizations of agreement, disgust) and non-communicative sounds (e.g, sneezing, walking, water).

Results: Tract-based spatial statistics revealed significantly reduced fractional anisotropy (FA) bilaterally in the PMS group relative to the iASD group in numerous association, commissural, and projection tracts. All major long-range tracts were more impaired in the PMS than iASD group, which is striking given that ASD has been associated with significant reductions in FA in long-range tracts relative to typically developing controls.

With respect to fMRI, previous research has shown that the superior temporal gyrus/sulcus (STG/STS) is sensitive to communicative versus non-communicative sounds. Here, selective STG activity was detected in the PMS group during communicative relative to non-communicative sounds, but not in the iASD group. Moreover, better orienting toward social sounds was positively correlated with activity in the STG and medial prefrontal cortex (MPFC), relevant for theory of mind, in the PMS group. Interestingly, activity in STG and MPFC was inversely related to ASD symptom severity in both groups, but in different domains - the social affect domain for the PMS group and the repetitive behavior domain for the iASD group.

Conclusions:   These initial findings suggest that long-range structural connectvity may be more compromised in PMS than in iASD. In contrast, selective functional activity in the STG appeared to be sensitive to communicative versus non-communicative sounds in the PMS group despite severe receptive and expressive language impairment. While caution is warranted given the small sample size, these data represent a first step in characterizing the neural phenotype of PMS and identifying common and distinct neurobiological substrates with ASD more broadly.