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Rare Diseases Clinical Research Network: Neurophysiological Correlates

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ClinicalTrials.gov Identifier: NCT03077308
Recruitment Status : Recruiting
First Posted : March 10, 2017
Last Update Posted : April 20, 2018
Sponsor:
Collaborators:
Children's Hospital of Philadelphia
University of Colorado, Denver
Boston Children’s Hospital
Vanderbilt University
University of Rochester
University of South Florida
International Rett Syndrome Foundation Rettsyndrome.org
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Alan Percy, University of Alabama at Birmingham

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.

Condition or disease Intervention/treatment
Rett Syndrome, Preserved Speech Variant Mecp2 Duplication Syndrome Rett-related Disorders Procedure: Auditory and Visual Event-related Potentials and EEG

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.

Study Type : Observational
Estimated Enrollment : 250 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Rett Syndrome, MECP2 Duplication, and Rett-Related Disorders Consortium, Rare Disease Clinical Research Network: Neurophysiologic Correlates
Actual Study Start Date : January 2, 2017
Estimated Primary Completion Date : July 31, 2019
Estimated Study Completion Date : July 31, 2019


Group/Cohort Intervention/treatment
Rett Syndrome
Auditory and Visual event-related potentials (ERP) and EEG in 60 individuals with Rett syndrome.
Procedure: 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.

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

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

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




Primary Outcome Measures :
  1. Auditory Event-related potentials [ Time Frame: 3 years ]
    EEG will be filtered between 0.5 and 400Hz. The EEG will be segmented around each stimulus presentation. 200msec prior to 1000msec post each stimulus will be collected and averaged for each trial for each electrode. The electrodes with highest averaged N1 waveforms, predicted to be posterior temporal (T5/P3/T3) electrodes, will be used for subsequent analysis. The averaged waveforms will be analyzed for latency to N1 and P1 peak frm which the auditory event related potentials will be the main parameter for statistical analysis.

  2. Visual Event-related potentials [ Time Frame: 3 years ]
    VEP analysis will be similar to the AEP analysis. EEG will be prepared using the same methodology but using occipital electrodes with Oz as the primary electrode of analysis. The EEG will be averaged from 200msec prior to 1000ms post stimulus. The N1, P1, and N2 components will be identified and will be averaged and the latency and amplitude of the peaks quantified. P1 latency and N1-P1 time will be the primary end point of the study. The latency will be used for the statistical parameter.

  3. EEG [ Time Frame: 3 years ]
    For frequency based analysis, 10-20 ten-second epochs of noise free EEG without clear eye blinks during wakefulness and eyes open; 10 ten-second epochs of wakefulness and eyes closed (assessed by video); and 10-20 ten-second epochs of EEG during each stage of sleep will be analyzed. A prescreen of EEG using a template matching algorithm (EEGlab) can be used to reduce amount of data to be reviewed. For theta and gamma band activity, the EEG will be band passed filtered between 2-10 and 25-70Hz, respectively, and a FFT performed on the filtered data. Spike location, frequency, and activity (change with sleep, eye closure, stimulation) will be calculated.



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Ages Eligible for Study:   2 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Females and males with specific disorders as well as 30 female and male controls.2
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Individuals with RTT, MECP2 Dup, and RTT-related disorders (mutations or deletions in CDKL5 and FOXG1 genes) who are also enrolled in the RTT5211 Protocol, which collects longitudinal clinical and neurobehavioral data in the above mentioned disorders. Participants will be linked to the RTT5211 Protocol by their RDCRN identification numbers. All participants will be tested for MECP2, CDKL5, and/or FOXG1 mutations; those with RTT phenotype will be assessed in terms of diagnostic criteria for classic or atypical RTT. No phenotypic selection will be performed; the cohort will be representative of each disorder.

60 typically developing girls and boys (30 each) will be enrolled to serve as controls for all three cohorts with age matching to the RTT/CDKL5 girls and MECP2 Dup/FOXG1 boy cohorts.

Criteria

Inclusion Criteria: Individuals with RTT, MECP2 Dup, and RTT-related disorders (mutations or deletions in CDKL5 and FOXG1 genes) who are also enrolled in the RTT5211 Protocol, which collects longitudinal clinical and neurobehavioral data will be linked to the RTT5211 Protocol by their RDCRN identification numbers. No phenotypical selection of subjects will be performed; we expect the cohort will be representative of each disorder.

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.

Exclusion Criteria: Individuals who do not meet the above criteria will be excluded.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03077308


Contacts
Contact: Alan Percy, MD 205-996-4927 apercy@uab.edu
Contact: Jane Lane, RN, BSN 205-996-4927 jlane@uab.edu

Locations
United States, Colorado
University of Colorado Denver Recruiting
Denver, Colorado, United States, 80045-2571
Contact: Gina VanderVeen    720-777-5514    Gina.VanderVeen@childrenscolorado.org   
Principal Investigator: Tim Benke, MD, PhD         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115-5724
Contact: Mustafa Sahin, MD, PhD    617-355-8994    mustafa.sahin@childrens.harvard.edu   
Contact: Lindsay Swanson    617-355-8994    lindsay.swanson@childrens.harvard.edu   
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14627-0140
Contact: To be named         
Principal Investigator: Alex Paciorkowski, MD, PhD         
Sub-Investigator: Laurie Seltzer, MD         
United States, Ohio
Cincinnati Children's Hospital Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Max Mays    513-803-7935    Maxwell.Mays@cchmc.org   
Principal Investigator: Shannon Standridge, DO         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104-4318
Contact: Casey Gorman    267-426-5171    GormanC@email.chop.edu   
Principal Investigator: Eric Marsh, MD, PhD         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37212
Contact: Nicole Thompson    615-343-4586    Nicole.i.thompson@vanderbilt.edu   
Principal Investigator: Sar Peters, PhD         
Sub-Investigator: Cary Fu, MD         
Sponsors and Collaborators
University of Alabama at Birmingham
Children's Hospital of Philadelphia
University of Colorado, Denver
Boston Children’s Hospital
Vanderbilt University
University of Rochester
University of South Florida
International Rett Syndrome Foundation Rettsyndrome.org
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Principal Investigator: Eric Marsh, MD, PhD Children's Hospital of Philadelphia

Publications:
17. Wechsler DL (1991). The Wechsler Intelligence Scale for Children -III. San Antonio: The Psychological Corporation.
18. Reich MJ, Shayka T, Taibleson C (1991) The Diagnostic Interview for Children and Adolescents-Revised. St Louis: Washington University Press.

Responsible Party: Alan Percy, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT03077308     History of Changes
Other Study ID Numbers: RDCRN 5212
First Posted: March 10, 2017    Key Record Dates
Last Update Posted: April 20, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be submitted to NDAR/dbGAP.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alan Percy, University of Alabama at Birmingham:
Auditory ERP, Visual ERP, EEG

Additional relevant MeSH terms:
Rett Syndrome
Syndrome
Rare Diseases
Mental Retardation, X-Linked
Disease
Pathologic Processes
Disease Attributes
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System