Mechanisms underlying the EEG biomarker in Dup15q syndrome

Abstract

Background Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABA A ) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype. Methods To test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome ( n = 27) to (1) the pharmacological effects of the GABA A modulator midazolam ( n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children ( n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A -silenced allele). Results Peak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels ( f = 23.0 Hz) as Dup15q syndrome ( f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort. Conclusions Our results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome. Electronic supplementary material The online version of this article (10.1186/s13229-019-0280-6) contains supplementary material, which is available to authorized users.

Properties of beta oscillations in Dup15q syndrome

“…For studies 1 and 2 (relation to clinical and behavioral features), EEG data were analyzed at site 1 as an extension of recent work elucidating the mechanism of the EEG biomarker [5] using a combination of in-house tools and the MATLAB software toolbox Fieldtrip [34]. EEG signals were bandpass filtered 1-45 Hz using a finite impulse response filter (FIR).…”

“…Functional loss of the UBE3A protein causes Angelman syndrome, another rare genetic NDD whose clinical features (e.g., ID and epilepsy) and etiology (e.g., UBE3A dysfunction) [15] partially overlap with Dup15q syndrome. However, the beta EEG phenotype found in cases of maternal Dup15q syndrome is also seen in paternal duplications, in which UBE3A is minimally impacted [5]. This suggests a crucial role for nonimprinted 15q genes, rather than UBE3A, in generating the EEG phenotype.…”

“…Spontaneous, high amplitude beta (12-30 Hz) oscillations represent an EEG biomarker of Dup15q syndrome [4][5][6]. This beta EEG phenotype was first noted in a comprehensive case series of children with interstitial duplications, based on clinical EEGs obtained for epilepsy monitoring [6,17].…”

“…Recently, we quantified a robust electroencephalography (EEG) biomarker of the copy number variant syndrome caused by duplications of chromosome 15q11.2-q13.1 (Dup15q syndrome) [4][5][6]. Dup15q syndrome is highly penetrant for autism spectrum disorder (ASD), accounting for 1-3% of cases [7,8].…”

Increased aperiodic gamma power in young boys with Fragile X Syndrome is associated with better language ability

“…3). Interestingly, robust increases in spontaneous frontocentral beta oscillations (peaking at 23 Hz) have also been observed in children with Dup15q syndrome (63). Further investigation of what mechanistically drives ~ 30 Hz oscillations may shed further light on the pathophysiology of FXS.…”