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Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.

ABSTRACT: BACKGROUND:Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits (?3, ?5, ?3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes. METHODS:We compared spectral power of clinical EEG recordings from children (1-18 years of age) with a deletion genotype (n = 37) or a nondeletion genotype (n = 21) and typically developing children without Angelman syndrome (n = 48). RESULTS:We found elevated theta power (peak frequency: 5.3 Hz) and diminished beta power (peak frequency: 23 Hz) in the deletion genotype compared with the nondeletion genotype as well as excess broadband EEG power (1-32 Hz) peaking in the delta frequency range (peak frequency: 2.8 Hz), shared by both genotypes but stronger for the deletion genotype at younger ages. CONCLUSIONS:Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype. Our work improves the understanding of AS pathophysiology and has direct implications for the development of AS treatments and biomarkers.

SUBMITTER: Frohlich J

PROVIDER: S-EPMC6482952 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.

Frohlich Joel J Miller Meghan T MT Bird Lynne M LM Garces Pilar P Purtell Hannah H Hoener Marius C MC Philpot Benjamin D BD Sidorov Michael S MS Tan Wen-Hann WH Hernandez Maria-Clemencia MC Rotenberg Alexander A Jeste Shafali S SS Krishnan Michelle M Khwaja Omar O Hipp Joerg F JF

Biological psychiatry 20190119 9

<h4>Background</h4>Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits (β3, α5, γ3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroence ...[more]

PMID: 30826071

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Project description:BackgroundAngelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal-specific loss of expression of UBE3A (ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (> 80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS.MethodsWe used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported in Ube3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light-dark cycles, sleep stages and sleep spindles in Ube3a-del and WT mice.ResultsUbe3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated that Ube3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model.LimitationsThis study was limited to the exon 2 deletion mouse model, and future work will investigate the rat model of AS, containing a complete Ube3a deletion and pair EEG with behavior.ConclusionsOur data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing.

Dataset Information

Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.

Publications

Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.

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