Joel Frohlich1, Meghan T Miller2, Lynne M Bird3, Pilar Garces2, Hannah Purtell4, Marius C Hoener2, Benjamin D Philpot5, Michael S Sidorov5, Wen-Hann Tan6, Maria-Clemencia Hernandez2, Alexander Rotenberg4, Shafali S Jeste7, Michelle Krishnan2, Omar Khwaja2, Joerg F Hipp8. 1. Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center, Roche Pharma Research and Early Development, Basel, Switzerland; Center for Autism Research and Treatment, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles. Electronic address: joelfrohlich@gmail.com. 2. Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center, Roche Pharma Research and Early Development, Basel, Switzerland. 3. Department of Pediatrics, University of California, San Diego, Massachusetts; Division of Genetics/Dysmorphology, Rady Children's Hospital San Diego, San Diego, Massachusetts. 4. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 5. Neuroscience Center, Carolina Institute for Developmental Disabilities, Chapel Hill, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 6. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 7. Center for Autism Research and Treatment, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles. 8. Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center, Roche Pharma Research and Early Development, Basel, Switzerland. Electronic address: joerg.hipp@roche.com.
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 (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.
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.
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