Altered Functional and Structural Brain Connectivity in ASD Individuals with SHANK3 Defect

Background:  SHANK3 is a postsynaptic scaffolding protein, whose molecular variations is thought to be responsible for 22q13 deletion syndrome (Phelan-McDermid Syndrome) and autism spectrum disorders (ASD). However, it remains unclear how SHANK3 defect are related to abnormal brain development in ASD.

Objectives:  To assess the GM and WM development of SHANK3 defect children ascertained for ASD and explore the relationship with clinical phenotypes.

Methods:  MLPA and Sanger sequencing were carried out to confirm the SHANK3 deficiency of 8 Chinese children with ASD (SHANK3 group), followed by systematic and comprehensive evaluations. Then we recruited 24 ASD children without SHANK3deficiency (ASD group) and 25 typically developing controls (TD group). ADOS scale was applied to examine the severity of autism and Griffith scale was used to assess the development level of SHANK3 group and ASD group. In addition, MRI scans of the three groups were analyzed using voxel-based morphometry (VBM) and Diffusion tensor imaging (DTI). Normalized modulated GM maps were statistically analyzed using the general linear model. The integrity of WM fiber was evaluated using fractional anisotropy (FA).

Results:  Six participants lacked the whole gene of SHANK3, one lacked part of it, and one with de novo SHANK3 mutation was included. The sample was characterized by high rates (100%) of ASD, developmental delay, hypotonia, several dysmorphologies and perception abreaction. As to the clinic phenotypes, there was no significant statistical difference between SHANK3 and ASD group. Whereas SHANK3 defect children displayed severer developmental delay in language, performance and other items comparing with ASD group (p<0.0005). As to the MRI performance, VBM showed that SHANK3 group showed significant gray matter volume decrease in the left middle frontal gyrus, right postcentral and left dorso-lateral superior frontal gyrus, compared with TD and ASD group (p<0.001). What’s more, SHANK3 group had significantly less gray matter in the left cerebellar crus, left triangle inferior frontal gyrus, left inferior parietal and left fusiform gyrus than ASD group (p<0.001). Additionally, as to the DTI result, corpus callosum (body, splenium and genu) tracts in SHANK3 group displayed significantly lower FA than ASD and TD group (p<0.001). Other tracts, such as middle cerebellar peduncle, bilateral superior and anterior corona radiate and bilateral superior longitudinal fasciculus, also had significant abnormalities (p<0.001).

Conclusions:  These results imply that SHANK3 defect associated with ASD may be rooted in neural anatomy, and autism symptoms in individuals with SHANK3 defect and ASD might have, at least partially, different underlying etiologies. Moreover, an obvious phenomenon of imbalance between left and right side in SHANK3 defect children was existed, which may be associated with the different functions of each brain region and the diversity of clinical phenotypes.