Analysis of EEG patterns and genotypes in patients with Angelman syndrome
Highlights
► Here we delineate the EEG findings in Angelman syndrome. ► We correlate EEG features with specific genotypes. ► EEG patterns may be an important biomarker in Angelman syndrome. ► EEG patterns may suggest the underlying genetic etiology in ambiguous cases.
Introduction
Angelman syndrome (AS) is caused by lack of expression of the maternal copy of UBE3A and other genes on chromosome 15q11–13 [1]. AS is associated clinically with severe mental retardation, absence of language development, happy disposition, epilepsy, movement disorders, and autistic features in some. The molecular defects of AS are heterogeneous including a maternally derived 4 Mb+ deletion of 15q11–q13 (70%), UBE3A mutations (10%), and paternal uniparental disomy or imprinting center defects (15%) [2]. To date, EEG has not been considered a valuable predictor of specific clinical (mental retardation, dysmorphic features, epilepsy) and genetic abnormalities in AS. The EEG features, including rhythmic delta or theta activity, interictal epileptiform discharges, and posterior rhythm slowing, are considered by some authors as useful biomarkers of Angelman syndrome, but not particularly specific in nature [3]. Although there has been discussion of correlation of genotypes with neurophysiologic parameters, no direct data has been presented before [4]. The aims of this study were to (1) delineate the EEG features in a large cohort of AS followed longitudinally in the Angelman Natural History Study, and (2) to test a new algorithm which may correlate distinct EEG features with specific genotypes of AS.
Section snippets
Patient recruitment
Children (N = 160) were prospectively enrolled between 2006 and 2010 in the Angelman Syndrome Natural History Study (ClinicalTrials.gov Identifier: NCT00296764) being conducted by the Angelman, Rett, and Prader–Willi Syndromes Consortium of the NIH Rare Diseases Clinical Research Network at four study sites (Brady Children's Hospital, San Diego, Texas Children's Hospital, Greenwood Genetic Center, and Children's Hospital Boston). Institutional review board (IRB) approvals were obtained prior to
EEG and seizure characteristics
One-hundred-sixty AS patients were enrolled between the years 2006 and 2010. Of the 115 who had complete data [58 boys and 57 girls, median age 3.6 years (0.4–25)], every patient had an abnormal EEG. The most common EEG findings were intermittent rhythmic delta waves (83.5%) (Fig. 1), interictal epileptiform discharges (74.2%) (Fig. 2), intermittent rhythmic theta waves in < 50% of EEG recording in each subject (43.5%), and posterior rhythm slowing (43.5%) (Fig. 3). Repeat EEGs obtained in 29
Discussion
The various genetic abnormalities in AS involve the 15q11–13 chromosome segment. Most cases (about 70%) are related to deletions of the long arm of the maternally inherited chromosome, while in a small percentage, AS is caused by paternal UPD, when both chromosomes 15 are inherited from the father [1]. Imprinting anomalies during gametogenesis, or mutations of the maternal UBE3A gene, which encodes for the E6AP-3A ubiquitin protein ligase found in Purkinje cells and the hippocampus, are also
Acknowledgments
We would like to acknowledge Wen-Hann Tan, MD for his valuable suggestions in the development of this manuscript. The NHS study was supported by grant number NICHD(5U54HD061222).
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2019, Biological PsychiatryCitation Excerpt :The most prominent difference between AS genotypes, however, was not anticipated by our hypotheses: oscillatory activity in the theta frequency range, which is present only for the deletion AS genotype. Rhythmic theta in AS has been qualitatively described in previous publications (23,24,55,56), but to the best of our knowledge, our work is the first to quantify excess theta oscillations and to link them to the deletion AS genotype. Given that GABAA receptors are critically involved in shaping neuronal dynamics reflected in EEG oscillations (37–39), deletion of the GABRB3-GABRA5-GABRG3 gene cluster is the most likely cause of the AS genotype differences observed in our study.