Biobanking of Rett Syndrome and Related Disorders

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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


Primary Outcome

X-chromosome inactivation in Rett syndrome (RTT)

Secondary Outcome

 Breakpoints and gene content of MECP2 and FOXG1 duplications

Condition

Rett Syndrome


Study Arms / Comparison Groups

 Rett syndrome
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

752

Start Date

September 1, 2017

Completion Date

July 31, 2021

Primary Completion Date

July 31, 2021

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.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Jeffrey L Neul, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02705677

Organization ID

RDCRN # 5213

Secondary IDs

U54HD061222

Responsible Party

Principal Investigator

Study Sponsor

University of Alabama at Birmingham

Collaborators

 National Institutes of Health (NIH)

Study Sponsor

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


Verification Date

August 2021