29897
Altered Striatum Centered Connectivity in SHANK3-Deficient Patients
Neuroimaging has been used extensively to dissect the pathophysiology underlying autism spectrum disorder (ASD). However, most studies are conducted on subjects that etiologies are unknown and expected to be heterogeneous. These may create a challenge for data interpretation and reproducibility. SHANK3 is a master synaptic scaffolding protein enriched at the postsynaptic density (PSD) of excitatory synapses and plays a crucial role for synaptic development and function. Genetic defect of SHANK3 is one of the most frequent causes found in individuals with ASD from recent ASD genomics studies. SHANK3 causing ASD present a unique opportunity to dissect the pathophysiology of ASD by neuroimaging.
Objectives:
To investigate the neuromorphometry and clinical characteristics of Chinese children with SHANK3 deficiency by neuroimaging and neurobehavioral evaluation.
Methods:
This is a case control study. Subjects were recruited and conducted from Aug 1, 2015 to Aug 31, 2017 in the Neurodevelopment Clinic of Children’s Hospital of Fudan University. Among the total of 72 children participating in the study, 14 children have confirmed SHANK3 genetic mutations, 26 have idiopathic ASD without SHANK3 and other common genetic defect, and 32 were typically developing children as controls. Genetic tests, comprehensive clinical and neurobehavioral evaluations, as well as brain imaging were conducted for these subjects. Genetic mutations including chromosomal deletions and point mutations of SHANK3 were identified or confirmed by MLPA, chromosome microarray, WES or Sanger sequencing methods. Comprehensive clinical and neurodevelopment evaluations including diagnostic evaluation of ASD were performed by experienced development pediatrician or certified ADOS and ADI-R administrators. Differences in quantitative grey matter indices were assessed using voxel-based morphometry (VBM) while in white matter were analyzed with tract-based spatial statistics.
Results:
Among 14 subjects with SHANK3 mutations, 12 have heterozygous deletions including SHANK3 ranging from 0.1 to 75 Mb size in the chromosome 22q13.3 and two have novel pathogenic point mutations in the SHANK3 gene. Phenotypically, we described several previously unreported clinical features and manifestations including nostril eversion (100%), sensory stimulus seeking (64%), dental abnormalities (43%), hematological problem (21%) and prominent granulation tissue (7%), as well as common features of SHANK3-related ASD and chromosome 22q13.3 deletion (i.e. Phelan-McDermid syndrome, PMS) consisting of hypotonia, global developmental delay, and mild dysmorphic features. For the grey matter, VBM analysis revealed decreased gray matter volume (GMV) in dorsal striatum, amygdala, hippocampus and parahippocampal gyrus (P < 0.05, corrected for family-wise error, FWE). For the white matter, tract-based spatial statistics (TBSS) results demonstrated decreased FA in multiple tracts mainly with projection fibers and association fibers, including internal capsule, external capsule, cerebral peduncle, sagittal stratum, and etc. (P < 0.05, FWE corrected).
Conclusions:
This was the first major neuroimaging study of SHANK3 deficiency related ASD. We have found a disrupted striatum centered connectivity associated with SHANK3 genetic defects. These findings from human are consistent with the reports from the studies of Shank3-deficient mouse models. The cross species approach clarify the underlying neuropathological mechanisms of SHANK3 in the human brain, thus may provide the target areas for the novel therapeutic.