ArticleMolecular autism2024
Comparative profiling of white matter development in the human and mouse brain reveals volumetric deficits and delayed myelination in Angelman syndrome.
Article in Molecular autism, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed.
- Targeting UBE3A and downstream estrogen receptor-β signaling to restore oligodendroglial homeostasis in Angelman syndrome.bioRxiv : the preprint server for biology · 2026Article
- A dual-reporter mouse for therapeutic discovery in Angelman syndrome.JCI insight · 2026Article
- Crossing the finish line towards a disease-modifying treatment for Angelman syndrome.Journal of neurodevelopmental disorders · 2026Review
- Review
- Mouse model of Angelman syndrome exhibits reduced retinal activity during development.Frontiers in neuroscience · 2026Article
- Increased Extra-Axial Cerebrospinal Fluid Volume in Children with Angelman Syndrome: Links to Sleep Problems and Seizures.Annals of the Child Neurology Society · 2025Article
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Abstract
backgroundAngelman 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 poorly characterized or understood. This study provides the first large-scale measurement of WM volume reduction in children with AS. Furthermore, we probed the possibility of underlying WM neuropathology by examining the progression of myelination in an AS mouse model.
methodsWe 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 (Ube3a
resultsOur data revealed that AS individuals exhibit significant reductions in brain volume by ~ 1 year of age, and by 6-12 years of age WM is reduced by 26% and gray matter by 21%-approximately twice the reductions observed in the adult AS mouse model. Our AS mouse model 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 abnormalities in myelinated or unmyelinated axons. LIMITATIONS: It is difficult to extrapolate the timing and duration of the myelination delay observed in AS model mice to individuals with AS.
conclusionsThis 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 these deficits occur alongside the delayed onset of myelination, which results from the loss of neuronal (but not glial) UBE3A, though the causal relationship between these phenotypes remains to be determined. 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.
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