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Biobanking of Rett Syndrome and Related Disorders

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ClinicalTrials.gov Identifier: NCT02705677
Recruitment Status : Recruiting
First Posted : March 10, 2016
Last Update Posted : March 9, 2020
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Center for Advancing Translational Science (NCATS)
Office of Rare Diseases (ORD)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Alan Percy, University of Alabama at Birmingham

Tracking Information
First Submitted Date November 22, 2015
First Posted Date March 10, 2016
Last Update Posted Date March 9, 2020
Actual Study Start Date September 1, 2017
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: March 9, 2016)
  • X-chromosome inactivation in Rett syndrome (RTT) [ Time Frame: 5 years ]
    Characterize X-chromosome inactivation in RTT and correlate with clinical severity.
  • Bdnf polymorphisms in RTT [ Time Frame: 5 years ]
    Characterize Bdnf polymorphisms in RTT and correlate with clinical severity.
  • Inflammation markers in MECP2 duplication syndrome [ Time Frame: 5 years ]
    Evaluate inflammation markers in MECP2 duplication syndrome and correlate with disease severity.
  • 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.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: March 9, 2016)
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
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Biobanking of Rett Syndrome and Related Disorders
Official Title Biobanking of Rett Syndrome and Related Disorders Protocol
Brief Summary 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.
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
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
DNA and RNA from blood, plasma, hair follicles, skin biopsies
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)

Condition
  • Rett Syndrome
  • MECP2 Duplication
  • CDKL5
  • FOXG1 Disorders
Intervention Not Provided
Study Groups/Cohorts
  • 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.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: March 9, 2016)
1200
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 2020
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

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.
Sex/Gender
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers No
Contacts
Contact: Alan K Percy, MD 2059964927 apercy@uab.edu
Contact: Jane B Lane, RN, BSN 2059964927 jlane@uab.edu
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT02705677
Other Study ID Numbers RDCRN # 5213
U54HD061222 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: Yes
Plan Description: The data sharing agreement approved by the Rare Disease Clinical Research Network will be employed.
Responsible Party Alan Percy, University of Alabama at Birmingham
Study Sponsor University of Alabama at Birmingham
Collaborators
  • National Institutes of Health (NIH)
  • National Center for Advancing Translational Science (NCATS)
  • Office of Rare Diseases (ORD)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Study Chair: Jeffrey L Neul, MD, PhD UCSD
Study Director: Walter E Kaufmann, MD Greenwood Genetic Center
PRS Account University of Alabama at Birmingham
Verification Date March 2020