From Cortical and Subcortical Grey Matter Abnormalities to Neurobehavioral Phenotype of Angelman Syndrome: A Voxel-Based Morphometry Study

Gayane Aghakhanyan, Paolo Bonanni, Giovanna Randazzo, Sara Nappi, Federica Tessarotto, Lara De Martin, Francesca Frijia, Daniele De Marchi, Francesco De Masi, Beate Kuppers, Francesco Lombardo, Davide Caramella, Domenico Montanaro, Gayane Aghakhanyan, Paolo Bonanni, Giovanna Randazzo, Sara Nappi, Federica Tessarotto, Lara De Martin, Francesca Frijia, Daniele De Marchi, Francesco De Masi, Beate Kuppers, Francesco Lombardo, Davide Caramella, Domenico Montanaro

Abstract

Angelman syndrome (AS) is a rare neurogenetic disorder due to loss of expression of maternal ubiquitin-protein ligase E3A (UBE3A) gene. It is characterized by severe developmental delay, speech impairment, movement or balance disorder and typical behavioral uniqueness. Affected individuals show normal magnetic resonance imaging (MRI) findings, although mild dysmyelination may be observed. In this study, we adopted a quantitative MRI analysis with voxel-based morphometry (FSL-VBM) method to investigate disease-related changes in the cortical/subcortical grey matter (GM) structures. Since 2006 to 2013 twenty-six AS patients were assessed by our multidisciplinary team. From those, sixteen AS children with confirmed maternal 15q11-q13 deletions (mean age 7.7 ± 3.6 years) and twenty-one age-matched controls were recruited. The developmental delay and motor dysfunction were assessed using Bayley III and Gross Motor Function Measure (GMFM). Principal component analysis (PCA) was applied to the clinical and neuropsychological datasets. High-resolution T1-weighted images were acquired and FSL-VBM approach was applied to investigate differences in the local GM volume and to correlate clinical and neuropsychological changes in the regional distribution of GM. We found bilateral GM volume loss in AS compared to control children in the striatum, limbic structures, insular and orbitofrontal cortices. Voxel-wise correlation analysis with the principal components of the PCA output revealed a strong relationship with GM volume in the superior parietal lobule and precuneus on the left hemisphere. The anatomical distribution of cortical/subcortical GM changes plausibly related to several clinical features of the disease and may provide an important morphological underpinning for clinical and neurobehavioral symptoms in children with AS.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. The two-dimensional biplot shows the…
Fig 1. The two-dimensional biplot shows the projection of the data on the first two PCs.
It colors each point according to the gender and shows the loading of each variable on the first two principal components with a circle of correlation.
Fig 2. A chart of the correlation…
Fig 2. A chart of the correlation matrix.
The distribution of each variable is shown on the diagonal. On the bottom of the diagonal: the bivariate scatter plots with a fitted line are displayed. On the top of the diagonal: the value of the correlation plus the significance level as stars. Abbreviations: CSF, cerebrospinal fluid; GM, grey matter; WM, white matter; PC, principal component.
Fig 3. Between-group VBM analysis: the statistical…
Fig 3. Between-group VBM analysis: the statistical map is overlaid on the study-specific grey matter template (created by FSL-VBM protocol) on axial plane.
Red-yellow clusters show grey matter volumetric reduction in children with Angelman syndrome compared to controls.
Fig 4. Single group VBM analysis with…
Fig 4. Single group VBM analysis with additional covariates (PCs): the statistical map represents the correlation between PC2 and GM volume in AS children overlaid on the study-specific grey matter template (created by FSL-VBM protocol) on the sagittal, coronal and axial plane.

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