# Comparative profiling of white matter development in the human and mouse brain reveals volumetric deficits and delayed myelination in Angelman syndrome

## TL;DR

This study shows that Angelman syndrome causes significant white matter deficits in children and delayed myelination in a mouse model, offering new insights into the disorder's neuropathology.

## Contribution

First large-scale measurement of white matter volume reduction in Angelman syndrome children and identification of delayed myelination in a mouse model.

## Key findings

- AS children show 26% white matter reduction by age 6–12, twice that seen in adult AS mouse models.
- AS mouse models exhibit a global delay in myelination caused by neuronal UBE3A loss, not glial UBE3A deficiency.
- Ultrastructural analyses found no abnormalities in myelinated or unmyelinated axons in AS mouse models.

## Abstract

Angelman syndrome (AS), a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A gene, is marked by changes in the brain’s white matter (WM). The extent of WM abnormalities seems to correlate with the severity of clinical symptoms, but these deficits are still not well characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the underlying neuropathology by examining the progression of myelination in an AS mouse model.

We conducted magnetic resonance imaging (MRI) on children with AS (n=32) and neurotypical controls (n=99) aged 0.5–12 years. In parallel, we examined myelination in postnatal Ube3a maternal-null mice (Ube3am−/p+; AS model), Ube3a paternal-null mice (Ube3am+/p−), and wildtype controls (Ube3am+/p+) using immunohistochemistry, Western blotting, and electron microscopy.

Our data revealed that AS individuals exhibit significant reductions in brain volume by ~1 year of age, with WM reduced by 26% and gray matter by 21% by 6–12 years of age—approximately twice the reductions observed in the adult AS mouse model. In our AS mouse model, we saw a global delay in the onset of myelination, which normalized within days (likely corresponding to months or years in human development). This myelination delay is caused by the loss of UBE3A in neurons rather than UBE3A haploinsufficiency in oligodendrocytes. Interestingly, ultrastructural analyses did not reveal any abnormalities in myelinated or unmyelinated axons.

It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS.

This study reveals WM deficits as a hallmark in children with AS, demonstrating for the first time that these deficits are already apparent at 1 year of age. Parallel studies in a mouse model of AS show that these deficits may be associated with delayed onset of myelination due to the loss of neuronal (but not glial) UBE3A. These findings emphasize the potential of WM as both a therapeutic target for interventions and a valuable biomarker for tracking the progression of AS and the effectiveness of potential treatments.