Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.
Angelman syndrome
Biomarkers
EEG
GABA
GABRB3-GABRA5-GABRG3 gene cluster
UBE3A
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
04
09
2018
revised:
11
12
2018
accepted:
04
01
2019
pubmed:
4
3
2019
medline:
31
3
2020
entrez:
4
3
2019
Statut:
ppublish
Résumé
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 electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes. 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). 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. 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.
Sections du résumé
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 (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 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.
Identifiants
pubmed: 30826071
pii: S0006-3223(19)30034-4
doi: 10.1016/j.biopsych.2019.01.008
pmc: PMC6482952
mid: NIHMS1522841
pii:
doi:
Banques de données
ClinicalTrials.gov
['NCT00296764']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
752-759Subventions
Organisme : NIMH NIH HHS
ID : R01 MH100186
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD061222
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS088583
Pays : United States
Organisme : NCRR NIH HHS
ID : U54 RR019478
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS100766
Pays : United States
Organisme : NEI NIH HHS
ID : K99 EY028964
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD093771
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD087101
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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