Rare Diseases Clinical Research Network: Neurophysiological Correlates

NCT ID: NCT03077308

Last Updated: 2021-08-05

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 185 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-01-02
• Study Completion Date: 2021-07-31

Brief Summary

The overall purpose of this project is to advance understanding of the neurophysiological features of Rett syndrome (RTT), MECP2 Duplication (MECP2 Dup) and RTT-related disorders (CDKL5, FOXG1) to gain insight into disease pathogenesis, with an emphasis on identifying biomarkers of disease evolution and severity. This specific study is intertwined to the core study Natural History of Rett Syndrome and Related Disorders (RTT5211), which characterizes range of clinical involvement and genotype-phenotype correlations and will provide phenotypical data for determining the clinical relevance of the neurophysiologic parameters; study subjects here are co- and primarily enrolled in RTT5211. The proposed studies will serve as basis of future translational investigations, including further refinement of biomarkers, development of outcome measures, and clinical trials per se.

Detailed Description

Individuals with RTT, MECP2 Dup and RTT-related disorders have significant abnormalities on a number of neurophysiological measures such as EEG and Evoked Potentials (EP). Studies in representative animal models reproduce many of these abnormalities. Little is known about the relationship between these neurophysiological findings to disease evolution, severity and specific clinical features. Therefore, it is considered likely that detailed understanding of such neurophysiological features would provide additional insight into disease pathogenesis and will lead to biomarkers of disease state and severity of different features. Consequently, specialized neurophysiological assessments will be acquired, without sedation or any other type of pharmacological manipulation, on a subset of 170 subjects: 60 RTT, 18 MECP2 Dup, 32 RTT-related disorders, and 60 age-matched typically developing controls (30 females, 30 males). Primary evaluations will include auditory ERP (AEP) and visual ERP (VEP), as well as secondary analyses of specific rhythms/band activities obtained during the ERP acquisitions (gamma band changes and frontal alpha band asymmetry). Individuals will be recruited across the spectra of ages and severity. 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, MECP2 Dup, and RTT-related disorders. Therefore, the proposed assessments will be performed in all three groups of subjects enrolled in this consortium (RTT5211): RTT, MECP2 Dup, and RTT-related disorders. Findings in each set of disorders will be linked to the objectives of the the longitudinal clinical and neurobehavioral data (RTT5211) as well as to biological factors and genotyping that may be linked to clinical severity (RTT5213). The neurophysiological parameters for RTT, MECP2 Dup, and RTT-related disorders will not only be correlated with each other but also to disease staging, overall clinical severity scores and through exploratory analyses with specific clinical features; these will be repeated up to 3 times (i.e., annual [every 10-14 month] evaluations, in the context of visits for the RTT5211 protocol) during the course of study. For this purpose, linear regression and linear mixed models will be used. Preliminary and published data indicate that RTT and MECP2 Dup have distinct patterns of cortical processing on AEP, VEP demonstrates disorder and age/disease-stage dependent changes. Phenotypic severity may be related to specific ERP parameters, as some modest effects of (severity) category of mutations were observed. In addition, the secondary analyses of specific EEG rhythms/band activities will expand our preliminary studies demonstrating alpha band asymmetry as a marker of an anxiety-like response in RTT.

Conditions

Rett Syndrome, Preserved Speech Variant; Mecp2 Duplication Syndrome; Rett-related Disorders

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Rett Syndrome

Auditory and Visual event-related potentials (ERP) and EEG in 60 individuals with Rett syndrome.

Auditory and Visual Event-related Potentials and EEG

Intervention Type: PROCEDURE

Specifically, through up to three standardized sessions (i.e., annual \[every 10-14 months\]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures.

MECP2 Duplication Syndrome

Auditory and Visual event-related potentials (ERP) and EEG in 18 individuals with MECP2 Duplication syndrome.

Auditory and Visual Event-related Potentials and EEG

Intervention Type: PROCEDURE

Specifically, through up to three standardized sessions (i.e., annual \[every 10-14 months\]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures.

Rett-related disorders

Auditory and Visual event-related potentials (ERP) and EEG in 18 individuals with CDKL5 syndrome and 14 individuals with FOXG1 syndrome.

Auditory and Visual Event-related Potentials and EEG

Intervention Type: PROCEDURE

Specifically, through up to three standardized sessions (i.e., annual \[every 10-14 months\]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures.

Controls

Auditory and Visual event-related potentials (ERP) and EEG in 60 Control individuals (30 males and 30 females).

Auditory and Visual Event-related Potentials and EEG

Intervention Type: PROCEDURE

Specifically, through up to three standardized sessions (i.e., annual \[every 10-14 months\]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures.

Interventions

Auditory and Visual Event-related Potentials and EEG

Specifically, through up to three standardized sessions (i.e., annual \[every 10-14 months\]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

A cohort of 60 typically developing girls and boys (30 each) will be enrolled to serve as controls. Typical development in the control group will be confirmed by normal intelligence quotient scores or equivalent scores on developmental tests using standardized measures and negative psychiatric diagnoses on a standardized diagnostic interview administered to their mothers, fathers or guardians (Diagnostic Interview for Children and Adolescents, Revised: Parents' Version). All control subjects must have a negative history of neurologic impairment or neuropsychiatric conditions and show no clinical evidence of a genetic disorder.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Children's Hospital of Philadelphia

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: collaborator

University of South Florida

OTHER

Sponsor Role: collaborator

International Rett Syndrome Foundation Rettsyndrome.org

UNKNOWN

Sponsor Role: collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Alan Percy

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Eric Marsh, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

Locations

University of Colorado Denver

Denver, Colorado, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

Countries

United States

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Other Identifiers

RDCRN 5212

Identifier Type: -

Identifier Source: org_study_id