White Matter Pathology in Angelman Syndrome and Its Potential as an Outcome Measure in Clinical Trials

项目总结

PROJECT SUMMARY White matter (WM) pathway deficits are common in neurodevelopmental disorders, including Angelman syndrome (AS). The few imaging studies performed to date suggest that AS individuals have loss of WM volume and possibly delayed myelination. However, these abnormalities remain poorly defined, making it difficult to link them to behavioral phenotypes and, consequently, to establish their value as therapeutic biomarkers. Accordingly, a major unmet need is to elucidate the anatomical and pathophysiological basis of abnormal WM development in AS, and to test whether prevention or reversal of WM deficits leads to improvement in core behavioral domains. Our preliminary light and electron microscopy studies of AS model mice suggest that impairments in axon growth precipitate delays in myelination and culminate in lifelong deficits in axon caliber and WM volume. Our preliminary magnetic resonance imaging (MRI) coupled with diffusion tensor imaging (DTI) data from children with AS demonstrate a conserved deficit in WM volume and indicate a similar delay in myelination. Importantly, we find in motor systems that the degree of WM insult strongly correlates with the severity of motor dysfunction in AS patients. Here we will leverage the experimental tractability of AS model mice and our unique access to AS individuals through the UNC Angelman Syndrome Clinic (the first AS clinic established in the United States) to reveal the developmental basis of WM deficits in AS. Specifically, we will test our data-driven central hypothesis that WM pathway abnormalities and associated AS phenotypes arise from deficits in the radial growth of axons and associated delays in myelination, which can be prevented by reinstatement of UBE3A expression in neurons. To achieve our goals, we aim to (1) Define the developmental trajectory and underlying anatomical basis for WM deficits in AS model mice, (2) Establish neuroimaging correlates of these deficits and test the hypothesis that they are a biomarker for motor phenotypes in children with AS, and (3) Model the efficacy of early versus late therapeutic intervention toward the normalization of WM development and motor outcomes in AS. Through our research, we seek to inform treatment strategies for AS and to establish WM integrity as a novel outcome measure for upcoming AS clinical trials.