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

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $612,696

## Abstract

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.

## Key facts

- **NIH application ID:** 9974549
- **Project number:** 5R01HD093771-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Heather Cody Hazlett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $612,696
- **Award type:** 5
- **Project period:** 2018-09-12 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974549

## Citation

> US National Institutes of Health, RePORTER application 9974549, White Matter Pathology in Angelman Syndrome and Its Potential as an Outcome Measure in Clinical Trials (5R01HD093771-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974549. Licensed CC0.

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