Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss‐of‐function mutations in the maternal copy of the UBE3A gene. AS is characterized by intellectual disability, impaired speech and motor skills, epilepsy, and sleep disruptions. Multiple treatment strategies to re‐express functional neuronal UBE3A from the dormant paternal allele were successful in rodent models of AS and have now moved to early phase clinical trials in children. Developing reliable and objective AS biomarkers is essential to guide the design and execution of current and future clinical trials. Our prior work quantified short daytime electroencephalograms (EEGs) to define promising biomarkers for AS. Here, we asked whether overnight sleep is better suited to detect AS EEG biomarkers. We retrospectively analyzed EEGs from 12 overnight sleep studies from individuals with AS with age and sex‐matched Down syndrome and neurotypical controls, focusing on low frequency (2–4 Hz) delta rhythms and sleep spindles. Delta EEG rhythms were increased in individuals with AS during all stages of overnight sleep, but overnight sleep did not provide additional benefit over wake in the ability to detect increased delta. Abnormal sleep spindles were not reliably detected in EEGs from individuals with AS during overnight sleep, suggesting that delta rhythms represent a more reliable biomarker. Overall, we conclude that periods of wakefulness are sufficient, and perhaps ideal, to quantify delta EEG rhythms for use as AS biomarkers. Lay Summary Electroencephalography (EEG) is a safe and reliable way of measuring abnormal brain activity in Angelman syndrome. We found that low‐frequency “delta” EEG rhythms are increased in individuals with Angelman syndrome during all stages of overnight sleep. Delta rhythms can be used as a tool to measure improvement in future clinical trials.

Modulating social learning-induced evaluation updating during human sleep

“…At Cz (or C3 if Cz was marked as a bad channel). We detected overnight N2 spindles (relative power = 0.2, correlation = 0.65, RMS = 1.5) 84 , 85 and N3 spindles (relative power = None, correlation = None, RMS = 1.5) 82 , 86 . The results related to N3 spindles are provided in Supplementary Fig.…”

Behavioural sleep problems in children and adults with intellectual disabilities: An integrative literature review

“…In addition, specific genetic conditions have been linked to a predisposition for sleep disturbance. Genetic conditions linked to sleep disturbances include people with Down's Syndrome with and without obstructive sleep apnoea (Al‐Khudhairy et al, 2019; Bassell et al, 2015; Chawla, Howard, et al, 2021; Esbensen et al, 2018; Heubi et al, 2021; Stores, 2019; Worley et al, 2015), Tuberous sclerosis complex (Trickett et al, 2018), Mowat–Wilson Syndrome (Di Pisa et al, 2019; Evans et al, 2016), Cornelia de Lange Syndrome (Zambrelli et al, 2016), Angelman syndrome (den Bakker et al, 2018; den Bestern et al, 2021; Levin et al, 2022; Pearson et al, 2018; Trickett et al, 2018), Smith‐Magenis syndrome (Mullegama et al, 2015; Rive Le Gouard et al, 2021; Smith et al, 2019; Trickett et al, 2020), Fragile X syndrome (Budimirovic et al, 2022; Mullegama et al, 2015). In addition to rare conditions which are linked to sleep disturbances such as Christianson Syndrome (Gruber et al, 2022), Dup15q Syndrome (Barstein et al, 2021), Pallister‐Killian Syndrome (Fetta et al, 2022), Phelan‐McDermid Syndrome and SYNGAP1‐ID (Smith‐Hicks et al, 2021), MBD5‐associated neurodevelopmental disorder (Gandhi et al, 2021), Arboleda‐Tham syndrome (Smith & Harris, 2021), Bosch‐Boonstra‐Schaaf optic atrophy syndrome (Rech et al, 2020) and emerging genetic variants including microdeletion syndrome at 2q22.1q22.3 and de novo DDX3X variants (Chen et al, 2020; Verhoeven et al, 2020).…”

Emerging concepts involving inhibitory and activating RNA functionalization towards the understanding of microcephaly phenotypes and brain diseases in humans

“…It was characterized by unusual arm position and jerky movement ( Kishino et al, 1997 ). Major characteristics include severe intellectual disability, lack of speech, sleep disruption, and microcephaly ( Levin et al, 2022 ). Mouse models for Angelman syndrome frequently exhibit motor dysfunction and deficits in learning and memory.…”