• subcortical grey matter
• imprinting disorders
• VBM
• MRI shape analysis
• voxel-based morphometry
• Angelman syndrome
• quantitative MRI
• magnetic resonance imaging
• cortical grey matter

Background: Angelman syndrome (AS) is a neurogenetic disorder caused by loss of expression of the maternally imprinted gene UBE3A. It is characterized by intellectual disability, speech impairment, peculiar behavior phenotype, seizures and movement disorder. Despite the severe neurobehavioral phenotype of AS, routine brain magnetic resonance imaging (MRI) is usually normal, although mild cortical atrophy or dysmyelination have been described. Advance quantitative MRI approaches for examining brain structure may provided important insight into potential neuroanatomical mechanisms contributing to AS. Our objective was to adopt a voxel-based morphometry (VBM) and vertex-wise shape analyses for comprehensive exploration of the cortical and subcortical grey matter (GM) structures in children with AS.
Material and Methods: Molecularly conformed 18 AS children due to deletions of the maternally inherited UBE3A gene located in the chromosome 15q11.2-q13 (mean age 7.19 ± 3.46 years, seven males) and 17 healthy controls (mean age 6.85 ± 2.62 years, six males) underwent MRI examination with sedation. High resolution T1-weighted MRI images were used for optimised VBM protocol, brain segmentation and vertex-wise shape analysis of the subcortical structures. Between groups comparison was done by independent sample t test or non-parametric Mann-Whitney U-tests. The analysis after adjusting for covariates (intracranial volume, age and sex) was carried out by general linear model (GLM) with categorical variables as fixed effect and continuous variables as covariates. Statistical dependance between volume of the structures and age was assessed by Sperman’s rank correlation. For voxel-wise VBM analysis, threshold-free cluster enhancement option was applied with 5000 permutations with age as a nuisance covariate. For vertex-wise shape analysis cluster-based option was used with 5000 permutations, as recommended. The level of p < 0.05, controlled for family-wise error rate, was was considered as significant for all voxel-wise statistics.
Results: The whole-brain VBM analysis demonstrates GM loss in AS children compared to controls in the cerebellar hemispheres and vermis, the right and left striatum, the frontal cortex bilaterally and the limbic structures (hippocampi, amygdalae, parahippocampal and cingulate cortices). The cortical grey/white matter and subcortical structures’ volumes were significantly lower for AS children compared to controls even after regressing out the effects of age, intracranial volume and gender. Vertex-wise shape analysis of subcortical structures showed local displacement with inward deflection of vertices in the caudate nuclei and amygdalae bilaterally, while deformations were noted on the right hemisphere in the head of the hippocampus, putamen and ventromedial surface of the palladium.
Conclusions: Our results demonstrated, for the first time, regional specific GM loss in the cortical and subcortical structures in children with AS that might reflect brain regions with the loss and/or marked reduction of maternal-specific expression of UBE3A. Applying in vivo advance MRI, we conformed the results of animal studies demonstrating that AS children have lower total cortical volume, as well as remarkable GM volume loss of all subcortical structures. The lateralized shape deformation patterns with inward deflection of vertices were found for subcortical structures more
prominent on the right hemisphere that may possibly indicate the differential maternal expression levels of the UBE3A in the left and right subcortical structures.