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 (b3, a5, g3). 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.

Emergence of consciousness and complexity amidst diffuse delta rhythms: the paradox of Angelman syndrome

“…EEG recordings were acquired in a clinical setting using an international 10-20 EEG montage (19 channels), and sleep EEG data were collected and marked by a technician as children slept naturally during the EEG session. Consistent with prior studies of AS [36][37][38][39]47 , qualitative inspection of EEG recordings revealed strongly abnormal EEG patterns in both sleep and wakefulness (see Fig. 1A,E for examples from a participant without seizures or medications).…”

“…Although our study found that delta power was indeed modulated by diminished consciousness (i.e., sleep) in AS, the effect sizes in both comparisons (d median = 0.60-0.74) were a fraction of that yielded by a prior comparison of delta power between TD control children and children with AS in the awake state (d = 1.22) 36 . Expressed as a percent change referenced to wakefulness, delta power increases when children with AS sleep by a maximum of 162% ( Fig.…”

“…In apparent contradiction to the above arguments and data, children with Angelman syndrome (AS) display the rich spectrum of purposeful behavior that implies conscious awareness (as seen here) [33][34][35] while exhibiting the chanting EEG phenotype typical of states of reduced consciousness ( Fig. 1) [36][37][38][39] . Although the AS EEG phenotype has long been described in clinical reports 40 , we are the first to characterize the degree to which the awake EEG in children with AS can support complex dynamics and, moreover, that these dynamics are demonstrably lowered as consciousness decreases during sleep.…”

“…Its clinical phenotype encompasses global developmental delay, intellectual disability, microcephaly, epilepsy, and sleep difficulties [42][43][44] . Puzzlingly, awake state EEG recordings from children with AS display diffuse, slow rhythmic oscillations at delta (1-4 Hz) frequencies [36][37][38] reminiscent of those seen in slow wave sleep. In fact, spectral power at the delta peak frequency (2.8 Hz) in awake children with AS exceeds that observed in typically developing (TD) children by > 1000% 36 .…”

“…Puzzlingly, awake state EEG recordings from children with AS display diffuse, slow rhythmic oscillations at delta (1-4 Hz) frequencies [36][37][38] reminiscent of those seen in slow wave sleep. In fact, spectral power at the delta peak frequency (2.8 Hz) in awake children with AS exceeds that observed in typically developing (TD) children by > 1000% 36 . At face value, either the core ideas of IIT do not generalize to the hypersynchronized, but wakeful and conscious, brain in AS, or amidst the pathologically slow chanting rhythm observed in awake children with AS, sufficiently complex interactions nonetheless arise and persist over time despite the periodic presence of the widespread interburst silence at the trough of each delta wave, generally assumed to interrupt the flow of consciousness 4,[28][29][30] .…”