Neurophysiologic Biomarkers in Rett Syndrome

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

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.

Study Overview

• Status: Recruiting
• Conditions: Rett Syndrome; Rett Syndrome, Atypical; RTT
• Intervention / Treatment: Other: Clinical assessment; Other: EEG and Auditory and Visual Evoked Potentials (AEP and VEP)

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 202

Contacts and Locations

• Study Contact: Name: Holly Dubbs, MS. CGC; Phone Number: 215-590-1719; Email: dubbsh@chop.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital of Los Angeles
      • Principal Investigator: Shefali Spurling Jeste, MD
      • Sub-Investigator: Payal Kenia Gu, MD
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
      • Principal Investigator: Timothy Benke, MD, PhD
  • Massachusetts
    • Brookline, Massachusetts, United States, 02445
      • Recruiting
      • Boston Children's Hospital
      • Principal Investigator: April Levin, MD
      • Sub-Investigator: David Lieberman, MD, PhD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Principal Investigator: Eric Marsh, MD, PhD
      • Contact: Holly Dubbs, MS, CGC; Phone Number: 215-590-1719; Email: dubbsh@chop.edu
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Principal Investigator: Jeffrey Neul, MD, PhD
      • Contact: Nicole Thompson; Phone Number: 615-343-4586; Email: Nicole.i.thompson@vumc.org
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
      • Principal Investigator: Bernhard Suter, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Enrolled participants with Rett syndrome will include individuals receiving clinical care through the Rett Syndrome clinics at participating sites. Typically developing individuals will be recruited using study recruitment centers or family members of Rett participants at each site. Each of the sites are International Rett Syndrome Foundation Centers of Excellence (Rettsyndrome.org).

Description

Inclusion Criteria:

1. Rett Group: Females ages 3-18 (inclusive) with a clinical diagnosis of RTT with a likely pathogenic or known pathogenic variant in MECP2.
2. 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.
3. 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:

1. Presence of a duplication in MECP2 or any other identified pathogenic mutation in another gene.
2. Active medical conditions not typically found in RTT.

Typically Developing Group:

1. Score below norms on the performance tests
2. Have a known neurological disorder (excluding migraine)
3. Being on neuroactive medications.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
RTT Females; Females with Rett Syndrome	Other: Clinical assessment; Established clinical measures for RTT will be collected for RTT participants; Other: EEG and Auditory and Visual Evoked Potentials (AEP and VEP); Through up to eight standardized sessions, participants will undergo AEP and VEP, as well as resting state EEG.
Controls; Females with typical development	Other: EEG and Auditory and Visual Evoked Potentials (AEP and VEP); Through up to eight standardized sessions, participants will undergo AEP and VEP, as well as resting state EEG.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Vanderbilt University Medical Center
• Investigators: Principal Investigator: Eric Marsh, MD, PhD, Children's Hospital of Philadelphia; Principal Investigator: Jeffrey Neul, MD, PhD, Vanderbilt University Medical Cener

Publications and helpful links

General Publications

• LeBlanc JJ, DeGregorio G, Centofante E, Vogel-Farley VK, Barnes K, Kaufmann WE, Fagiolini M, Nelson CA. Visual evoked potentials detect cortical processing deficits in Rett syndrome. Ann Neurol. 2015 Nov;78(5):775-86. doi: 10.1002/ana.24513. Epub 2015 Sep 18.
• Saby JN, Peters SU, Roberts TPL, Nelson CA, Marsh ED. Evoked Potentials and EEG Analysis in Rett Syndrome and Related Developmental Encephalopathies: Towards a Biomarker for Translational Research. Front Integr Neurosci. 2020 May 28;14:30. doi: 10.3389/fnint.2020.00030. eCollection 2020.
• Saby JN, Benke TA, Peters SU, Standridge SM, Matsuzaki J, Cutri-French C, Swanson LC, Lieberman DN, Key AP, Percy AK, Neul JL, Nelson CA, Roberts TPL, Marsh ED. Multisite Study of Evoked Potentials in Rett Syndrome. Ann Neurol. 2021 Apr;89(4):790-802. doi: 10.1002/ana.26029. Epub 2021 Feb 4.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2023
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: June 27, 2023
• First Submitted That Met QC Criteria: June 27, 2023
• First Posted (Actual): July 6, 2023

Study Record Updates

• Last Update Posted (Estimated): October 20, 2025
• Last Update Submitted That Met QC Criteria: October 17, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Biomarker; EEG; MECP2; Evoked Potentials
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; X-Linked Intellectual Disability; Rett Syndrome; Rett Syndrome, Atypical; Musculoskeletal and Neural Physiological Phenomena; Physiological Phenomena; Evoked Potentials; Cortical Excitability; Electrophysiological Phenomena; Nervous System Physiological Phenomena; Ocular Physiological Phenomena; Evoked Potentials, Visual; asparaginylendopeptidase
• Other Study ID Numbers: 22-020633; 1R61NS130216-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators intend to submit deidentified patient data into the National Database for Autism Research (NDAR) and database of Genotypes and Phenotypes (dbGaP). Study protocols and data analysis methods will be shared through future publications.
• IPD Sharing Time Frame: Available data from this observational study will be released to the repository and will become available to the scientific community one year after publication of planned analyses, or after a period of 5 years from the date when the data were collected, whichever comes first.
• IPD Sharing Access Criteria: National Institute of Mental Health (NIMH) Data Archive (NDA) policy will govern access criteria.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No