Neurophysiologic Biomarkers in Rett Syndrome

Study Overview
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Brief Summary
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The goal of this observational study is to identify candidate biomarkers in individuals with Rett Syndrome (RTT). The main questions it aims to answer are: Do these biomarkers change during clinical changes in individuals with RTT? Are biomarkers stable over time in clinically stable individuals? Do these biomarkers correlate with severity of RTT? Participants will be asked to undergo an electroencephalogram (EEG) with measurements of Evoked Potentials (EP) to measure electrical activity in the brain. Researchers will compare findings in individuals with RTT to those in typically developing individuals to see if there are differences between the two groups.

Detailed Description
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The main goal of the project is to identify potential biomarkers that can become measures for intervention and other translational studies and, at the same time, provide insight into abnormal synaptic activity and pathogenesis of RTT. Therefore, the proposed assessments will be performed with females with RTT and age matched typically developing females. These electrophysiological assessments will be compared to established clinical outcome measures from previous work in the NIH funded Rett and Rett related disorders natural history study. The neurophysiological parameters for RTT will be correlated with each other and also to disease staging, overall clinical severity scores and through exploratory analyses with specific clinical features. The investigators will also be testing procedures to perform the recordings, electrode types and placement, and ways to reduce movement and artifact within the data to establish best practices.

Official Title
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Characterization of Translatable Neurophysiological Biomarkers to Enhance Therapeutic Development in Rett Syndrome

Conditions
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RTT, Rett Syndrome, Rett Syndrome, Atypical

Intervention / Treatment
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* Other: EEG and Auditory and Visual Evoked Potentials (AEP and VEP)
* Other: Clinical assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rett Group: Females ages 3-18 (inclusive) with a clinical diagnosis of RTT with a likely pathogenic or known pathogenic variant in MECP2. Likely Rett Group: Females from 1 year to < 5 years of age with MECP2 variant if regression has not yet occurred or child is within 6 months of last skill loss. Typically developing (TD) Group: Females age matched to RTT population (1-18) with no developmental or cognitive concerns as assessed using the Child/Adult Behavioral Checklist, Survey of Well-Being of Young Children (<5yo), or the Wide Range Achievement Test-4 (>5 yo). Exclusion Criteria: Rett and Likely Rett Groups: Presence of a duplication in MECP2 or any other identified pathogenic mutation in another gene. Active medical conditions not typically found in RTT. Typically Developing Group: Score below norms on the performance tests Have a known neurological disorder (excluding migraine) Being on neuroactive medications.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| RTT Females<br>Females with Rett Syndrome | Other: EEG and Auditory and Visual Evoked Potentials (AEP and VEP)<br>* Through up to seven standardized sessions, participants will undergo AEP and VEP, as well as resting state EEG.<br>Other: Clinical assessment<br>* Established clinical measures for RTT will be collected for RTT participants<br>|
| Controls<br>Females with typical development | Other: EEG and Auditory and Visual Evoked Potentials (AEP and VEP)<br>* Through up to seven standardized sessions, participants will undergo AEP and VEP, as well as resting state EEG.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Auditory Evoked Potential (AEP) latency (ms) | Calculated N1, P1 latencies in Cz and other electrodes [posterior temporal region (T5/P3/T3) electrodes], will be used for analysis. | 5 years | 
| Auditory Evoked Potential (AEP) amplitude | Amplitude of P1, P2 and N1 peaks (uV) | 5 years | 
| Visual Evoked Potential (VEP) latencies (ms) | The latencies of the N1, P1, and N2 components will be identified primarily at occipital electrodes with Oz will be the primary electrode of analysis. N1-P1 time will be analyzed. | 5 years | 
| Visual Evoked Potential (VEP) amplitude | N1-P1 amplitude at Oz and other occipital electrodes will be calculated. | 5 years | 
| EEG Analysis | EEG Root mean square (RMS) amplitude, Amplitude variability, 1/f constant, power bands in typical bands (Delta, theta, alpha, Beta, gamma) and ratios will be calculated. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AEP spectral analysis, dipole determination and spatial distribution | spectral analysis of the individual waveforms, dipole determination of N1 and P1 peaks and spatial distribution of peak values. | 5 years | 
| VEP spectral analysis, dipole determination and spatial distribution | spectral analysis of the individual waveforms, dipole determination of N1 and P1 peaks and spatial distribution of peak values. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EEG, Biomarker, Evoked Potentials, MECP2