Atypical brain responses to 40-Hz click trains in girls with Rett syndrome: Auditory steady-state response and sustained wave.

AIM: The current study aimed to infer neurophysiological mechanisms of auditory processing in children with Rett syndrome (RTT)-rare neurodevelopmental disorders caused by MECP2 mutations. We examined two brain responses elicited by 40-Hz click trains: auditory steady-state response (ASSR), which reflects fine temporal analysis of auditory input, and sustained wave (SW), which is associated with integral processing of the auditory signal. METHODS: We recorded electroencephalogram findings in 43 patients with RTT (aged 2.92-17.1 years) and 43 typically developing children of the same age during 40-Hz click train auditory stimulation, which lasted for 500 ms and was presented with interstimulus intervals of 500 to 800 ms. Mixed-model ancova with age as a covariate was used to compare amplitude of ASSR and SW between groups, taking into account the temporal dynamics and topography of the responses. RESULTS: Amplitude of SW was atypically small in children with RTT starting from early childhood, with the difference from typically developing children decreasing with age. ASSR showed a different pattern of developmental changes: the between-group difference was negligible in early childhood but increased with age as ASSR increased in the typically developing group, but not in those with RTT. Moreover, ASSR was associated with expressive speech development in patients, so that children who could use words had more pronounced ASSR. CONCLUSION: ASSR and SW show promise as noninvasive electrophysiological biomarkers of auditory processing that have clinical relevance and can shed light onto the link between genetic impairment and the RTT phenotype.

Clinical EEG of Rett Syndrome: Group Analysis Supplemented with Longitudinal Case Report.

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by MECP2 gene abnormalities, is characterized by atypical EEG activity, and its detailed examination is lacking. We combined the comparison of one-time eyes open EEG resting state activity from 32 girls with RTT and their 41 typically developing peers (age 2-16 years old) with longitudinal following of one girl with RTT to reveal EEG parameters which correspond to the RTT progression. Traditional measures, such as epileptiform abnormalities, generalized background activity, beta activity and the sensorimotor rhythm, were supplemented by a new frequency rate index measured as the ratio between high- and low-frequency power of sensorimotor rhythm. Almost all studied EEG parameters differentiated the groups; however, only the elevated generalized background slowing and decrease in our newly introduced frequency rate index which reflects attenuation in the proportion of the upper band of sensorimotor rhythm in RTT showed significant relation with RTT progression both in longitudinal case and group analysis. Moreover, only this novel index was linked to the breathing irregularities RTT symptom. The percentage of epileptiform activity was unrelated to RTT severity, confirming previous studies. Thus, resting EEG can provide information about the pathophysiological changes caused by MECP2 abnormalities and disease progression.

Electrophysiological and Behavioral Evidence for Hyper- and Hyposensitivity in Rare Genetic Syndromes Associated with Autism.

Our study reviewed abnormalities in spontaneous, as well as event-related, brain activity in syndromes with a known genetic underpinning that are associated with autistic symptomatology. Based on behavioral and neurophysiological evidence, we tentatively subdivided the syndromes on primarily hyper-sensitive (Fragile X, Angelman) and hypo-sensitive (Phelan-McDermid, Rett, Tuberous Sclerosis, Neurofibromatosis 1), pointing to the way of segregation of heterogeneous idiopathic ASD, that includes both hyper-sensitive and hypo-sensitive individuals. This segmentation links abnormalities in different genes, such as FMR1, UBE3A, GABRB3, GABRA5, GABRG3, SHANK3, MECP2, TSC1, TSC2, and NF1, that are causative to the above-mentioned syndromes and associated with synaptic transmission and cell growth, as well as with translational and transcriptional regulation and with sensory sensitivity. Excitation/inhibition imbalance related to GABAergic signaling, and the interplay of tonic and phasic inhibition in different brain regions might underlie this relationship. However, more research is needed. As most genetic syndromes are very rare, future investigations in this field will benefit from multi-site collaboration with a common protocol for electrophysiological and event-related potential (EEG/ERP) research that should include an investigation into all modalities and stages of sensory processing, as well as potential biomarkers of GABAergic signaling (such as 40-Hz ASSR).

40-Hz Auditory Steady-State Response (ASSR) as a Biomarker of Genetic Defects in the SHANK3 Gene: A Case Report of 15-Year-Old Girl with a Rare Partial SHANK3 Duplication.

SHANK3 encodes a scaffold protein involved in postsynaptic receptor density in glutamatergic synapses, including those in the parvalbumin (PV)+ inhibitory neurons-the key players in the generation of sensory gamma oscillations, such as 40-Hz auditory steady-state response (ASSR). However, 40-Hz ASSR was not studied in relation to SHANK3 functioning. Here, we present a 15-year-old girl (SH01) with previously unreported duplication of the first seven exons of the SHANK3 gene (22q13.33). SH01's electroencephalogram (EEG) during 40-Hz click trains of 500 ms duration binaurally presented with inter-trial intervals of 500-800 ms were compared with those from typically developing children (n = 32). SH01 was diagnosed with mild mental retardation and learning disabilities (F70.88), dysgraphia, dyslexia, and smaller vocabulary than typically developing (TD) peers. Her clinical phenotype resembled the phenotype of previously described patients with 22q13.33 microduplications (≈30 reported so far). SH01 had mild autistic symptoms but below the threshold for ASD diagnosis and microcephaly. No seizures or MRI abnormalities were reported. While SH01 had relatively preserved auditory event-related potential (ERP) with slightly attenuated P1, her 40-Hz ASSR was totally absent significantly deviating from TD's ASSR. The absence of 40-Hz ASSR in patients with microduplication, which affected the SHANK3 gene, indicates deficient temporal resolution of the auditory system, which might underlie language problems and represent a neurophysiological biomarker of SHANK3 abnormalities.