White Matter Fiber Tract Pathology in a Genetically-Defined Neurodevelopmental Disorder

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PROJECT SUMMARY White matter pathway deficits are common in neurodevelopmental disorders, including Angelman syndrome (AS). The few imaging studies performed to date suggest that AS individuals have generalized white matter deficits, including loss of volume and possibly delayed myelination. However, white matter deficits in AS 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 for white matter deficits in AS, and to test whether prevention or reversal of these deficits leads to improvement in core behavioral domains. Preliminary data from children with AS show reductions in white matter volume and integrity of white matter fiber tracts, as well as strong relationships between these WM deficits and motor delays. Our preliminary data in AS model mice demonstrate that they exhibit white matter pathway impairments that recapitulate those found in AS individuals. The white matter deficits in the AS model mice are quantifiable at all levels of analysis, from macroscopic magnetic resonance imaging (MRI) coupled with diffusion tensor imaging (DTI) to ultrastructural electron microscopy (EM). 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 precise anatomical and pathophysiological underpinnings of white matter deficits in AS. Our research constitutes a novel effort to directly link white matter deficits in a human neurodevelopmental disorder with its mouse model, and will test our data-driven central hypothesis that white matter pathway impairments and associated AS phenotypes arise from delayed myelination and a loss of large-diameter axons that can be prevented by reinstatement of UBE3A expression in neurons. To achieve our goals, we aim to (1) Delineate white matter pathway deficits and test the hypothesis that they are a biomarker for motor phenotypes in children with AS, (2) Define the developmental trajectory and underlying anatomical basis for white matter deficits in AS model mice, and (3) Model the efficacy of early versus late therapeutic intervention toward the normalization of white matter deficits and motor outcomes in AS. Through our research, we seek to inform treatment strategies for AS and to establish WM integrity as a novel endpoint for upcoming AS clinical trials.