Biobanking of Rett Syndrome and Related Disorders

August 3, 2021 updated by: Alan Percy, University of Alabama at Birmingham

Biobanking of Rett Syndrome and Related Disorders Protocol

The overarching purpose of this study is to advance understanding of the natural history of Rett syndrome (RTT), MECP2-duplication disorder (MECP2 Dup), RTT-related disorders including CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT. Although all these disorders are the result of specific genetic changes, there remains broad clinical variation that is not entirely accounted for by known biological factors. Additionally, clinical investigators currently do not have any biomarkers of disease status, clinical severity, or responsiveness to therapeutic intervention. To address these issues, biological materials (DNA, RNA, plasma, cell lines) will be collected from affected individuals and in some cases from unaffected family members, initial evaluation performed to identify additional biological factors contributing to disease severity, and these materials will be stored for future characterization.

Study Overview

Status

Completed

Conditions

Detailed Description

At the present time, effective treatments for RTT, MECP2 Dup, or Rett-related disorders are lacking. Investigators have made substantial progress in RTT over the past eleven years such that this study represents a narrowing of focus to mutations or duplications of the MECP2 gene and related disorders, including those with phenotypic overlap. Understanding of RTT has advanced remarkably well through the Rett Syndrome Natural History Clinical Protocol (NHS) and correspondingly advancement in the basic science realm has moved forward with equivalent success. Thus, progress in clinical and basic science has led to the establishment of clinical trials and other translational studies that hold promise for additional clinical trials in future. In the process, however, investigators became aware of additional MECP2- and RTT-related disorders that were unknown at the time the original proposal was conceived and further were impressed by the substantial clinical variability in individuals with RTT that cannot be explained by differences in mutations alone. In fact, variability among individuals with identical mutations has led investigators to search for additional explanations. At the time of the initial application (2002), just three years after the identification of the gene, MECP2, as the molecular link to RTT, investigators were not aware of the variation in clinical disorders related to MECP2 mutations or to the related but quite different MECP2 Dup. Each disorder is characterized by significant neurodevelopmental features related either to alterations in the MECP2 gene or related to phenotypes closely resembling those seen in individuals with RTT. Further, the phenotypic overlap with RTT due to mutations in CDKL5 and FOXG1 was also unexplored. The investigators propose in this new study to build on the substantial progress made in understanding both classic and variant RTT and to add these related disorders, MECP2 Dup and the Rett-related disorders including CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT. In conjunction with the longitudinal clinical assessment performed via the natural history component, investigators will systematically collect from all willing participant's blood and isolate plasma, DNA, and RNA. All participants in the Natural History Study will be asked to contribute samples at the initial visit, whereas samples will be collected repeatedly on a subset of participants in order to look for changes over time. In order to identify factors that distinguish between affected and unaffected individuals, as well as to have the potential to characterize the heritability and potential consequences of genetic changes in families, samples will be collected from unaffected family members. Additionally, on a subset of individuals chosen because of unique clinical features skin biopsies and/or hair follicles will be collected to establish cell lines. Investigators will ask all individuals providing samples to agree to potential future whole-genome sequencing in order to be able to potentially evaluate for genetic modifiers of these diseases.

These materials will be stored at a central repository (Greenwood Genetics Laboratory). The main purpose of these samples is to serve as durable materials for future analyses, however, a set of defined analyses will be performed on all samples. For the samples collected in the Rett syndrome cohort, investigators will perform X-chromosome inactivation studies and evaluate common polymorphisms in Brain derived neurotrophic factor (BDNF) and determine the contribution of these known factors to disease severity. For MECP2 Dup cohort investigators will characterize inflammatory markers in the plasma and correlate these with clinical features. Also for MECP2 Dup cohort investigators will perform detailed genomic breakpoint and gene content analysis and correlate this with disease severity. Similar analysis of genomic breakpoints and gene content will be performed on people with FOXG1 Duplications. Finally, in a pilot study, investigators will perform metabolic profiling on people from all disorders and evaluate for metabolic features correlated with disease severity, and metabolic features common or unique between these disorders. This work will provide a durable resource for future analysis, extend understanding of genotype/phenotype correlations, identify other biological factors contributing to disease severity, as well as provide the framework for the development of biomarkers of disease state and severity.

Study Type

Observational

Enrollment (Actual)

752

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama at Birmingham
    • California
      • Oakland, California, United States, 94709
        • UCSF Benioff Children's Hospital Oakland
      • San Diego, California, United States, 92123
        • University of California San Diego
    • Colorado
      • Denver, Colorado, United States, 80045-2571
        • University of Colorado Denver
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Rush University Medical Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Children's Hospital Boston
    • Minnesota
      • Minneapolis, Minnesota, United States, 55101
        • Gillette Children's Specialty Healthcare
    • Missouri
      • Saint Louis, Missouri, United States, 63110-1093
        • Washington University School of Medicine and St. Louis Children's Hospital
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-4318
        • Children's Hospital of Philadelphia
    • South Carolina
      • Greenwood, South Carolina, United States, 29646
        • Greenwood Genetic Center
    • Tennessee
      • Nashville, Tennessee, United States, 37212
        • Vanderbilt University
    • Texas
      • Houston, Texas, United States, 77030
        • Baylor College of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Females and males of all ages must have complete testing for MECP2, FOXG1, and CDKL5 genes mutations AND must meet these requirements:

Gene positive for a sequence mutation, duplication or deletion in one of these 3 genes.

OR Meet consensus criteria for Rett syndrome (typical or atypical)

Description

Inclusion Criteria:

  • Individuals of both genders and of all ages, with RTT, MECP2 Dup, and, RTT-related disorders including those with mutations or deletions in CDKL5 and FOXG1 genes, or those with RTT (atypical or typical) who are mutation negative. Additionally, unaffected family members of those people who meet the disease specific criteria stated will eligible.

Exclusion Criteria:

  • Individuals who do not meet the above criteria will be excluded.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Rett syndrome
This is a biobanking project for individuals with mutations in MECP2 or meeting diagnostic criteria for classic (typical) or variant (atypical) Rett syndrome in order to identify other genetic factors such as X-chromosome inactivation or genetic background that may explain the variations noted in these individuals, including those with the same MECP2 mutation. No interventions are anticipated.
MECP2 Duplication disorder
This is a biobanking project for individuals with MECP2 duplications to understand the difference in the size of the duplication and the potential impact of other genes in the duplicated segment. No interventions are anticipated.
Rett-related disorders: CDKL5, FOXG1
This is a biobanking project for individuals with mutations in MECP2, CDKL5, and FOXG1 to understand the interplay of mutations in these individuals and the resultant phenotypic expression; for example, individuals with mutations in MECP2 but not meeting diagnostic criteria for Rett syndrome or individuals with mutations in CDKL5 or FOXG1 who may or may not meet diagnostic criteria for atypical Rett syndrome. No interventions are anticipated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
X-chromosome inactivation in Rett syndrome (RTT)
Time Frame: 5 years
Characterize X-chromosome inactivation in RTT and correlate with clinical severity.
5 years
Bdnf polymorphisms in RTT
Time Frame: 5 years
Characterize Bdnf polymorphisms in RTT and correlate with clinical severity.
5 years
Inflammation markers in MECP2 duplication syndrome
Time Frame: 5 years
Evaluate inflammation markers in MECP2 duplication syndrome and correlate with disease severity.
5 years
Biobanking of blood for Rett syndrome (RTT), MECP2 duplication syndrome, FOXG1, CDKL5, and MECP2 mutations not producing RTT
Time Frame: 5 years
Blood will be collected and stored from participants with RTT, MECP2 duplication, FOXG1, CDKL5, and MECP2 mutations without RTT to analyze factors noted in Outcomes 1-3 and in secondary outcome 5 to correlate with disease severity.
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Breakpoints and gene content of MECP2 and FOXG1 duplications
Time Frame: 5 years
Characterize breakpoints and gene content of MECP2 and FOXG1 duplications and correlate with disease severity
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Alabama at Birmingham

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Office of Rare Diseases (ORD)

Investigators

  • Study Chair: Jeffrey L Neul, MD, PhD, UCSD

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2017

Primary Completion (Actual)

July 31, 2021

Study Completion (Actual)

July 31, 2021

Study Registration Dates

First Submitted

November 22, 2015

First Submitted That Met QC Criteria

March 9, 2016

First Posted (Estimate)

March 10, 2016

Study Record Updates

Last Update Posted (Actual)

August 5, 2021

Last Update Submitted That Met QC Criteria

August 3, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RDCRN # 5213
  • U54HD061222 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

The data sharing agreement approved by the Rare Disease Clinical Research Network will be employed.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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