Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review

“…However, studies show a reduced percentage of REM sleep compared to a longer time spent in SWS, especially in young girls aged between 2 and 5 years, with an electroencephalographic tracing characterized by increased delta activity during NREM sleep and an intense gamma activity in the occipital leads. This activity seems to decrease at later ages, supporting the hypothesis of an increased expression of glutamate receptors in younger affected subjects ( 62 , 91 , 142 ). Both ionotropic and metabotropic glutamate receptors appear to be involved in the pathogenic mechanism underlying RTT ( 91 ).…”

“…C-terminal Domain seems to intervene in histone binding and transcriptional activation of brain-derived neurotrophic factor through the S421 serine residue ( 49 , 61 ). Moreover, CDKL5 and FOXG1 seem to converge on MECP2, which is involved in forebrain differentiation ( 62 ). De novo mutations affect more frequently the paternal germ line, with a greater involvement of females.…”

“…Electrical brain activity (EEG) that could be recorded both in patients and animal models, is a useful tool for studying abnormalities in brain functioning. In particular polysomnography can investigate abnormalities associated with sleep disturbances and epileptiform activity, which in RTT patients may be more frequently recorded during sleep than during wakefulness ( 19 , 62 ). Boban et al conducted a study, aimed at assessing the management and impact of sleep disorders in a group of 364 families with a child with RTT, registered in the International RTT phenotype database.…”

“…This findings are consistent with studies in RTT patients which showed an impaired slow wave sleep pattern and a specular glutamate load ( 91 , 135 ). The five-sleep stage was described first by Rechtschaffen and Kales, using polysomnography: REM sleep (REM, rapid eye movements) with an EEG similar to wakefulness, NREM sleep, during which there is a progressive transition from drowsiness to deep sleep and then a progressive increase in slow-wave activity ( 62 ). RTT patients show a reduction in the absolute duration of overnight SWS.…”

Effect of presentation rate on auditory processing in Rett Syndrome: ERP study

“…No study examined the auditory ERPs in RS in response to more slowly presented stimuli, with ISI longer than 2 seconds. However, as the speed of signal processing is reported to be low in RS as indicated with delayed ERP components [15][16][17] these patients might bene t from the slower presentation rate. Thus, we hypothesize that by increasing the inter stimulus interval from 0.9 to 3.6 seconds we might see recovery of auditory ERP components in RS that will get more typical.…”