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Biobanking of Rett Syndrome and Related Disorders

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ClinicalTrials.gov Identifier: NCT02705677
Recruitment Status : Completed
First Posted : March 10, 2016
Last Update Posted : August 5, 2021
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

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.

Condition or disease
Rett Syndrome MECP2 Duplication CDKL5 FOXG1 Disorders

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.

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Study Type : Observational
Actual Enrollment : 752 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Biobanking of Rett Syndrome and Related Disorders Protocol
Actual Study Start Date : September 1, 2017
Actual Primary Completion Date : July 31, 2021
Actual Study Completion Date : July 31, 2021


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.



Primary Outcome Measures :
  1. X-chromosome inactivation in Rett syndrome (RTT) [ Time Frame: 5 years ]
    Characterize X-chromosome inactivation in RTT and correlate with clinical severity.

  2. Bdnf polymorphisms in RTT [ Time Frame: 5 years ]
    Characterize Bdnf polymorphisms in RTT and correlate with clinical severity.

  3. Inflammation markers in MECP2 duplication syndrome [ Time Frame: 5 years ]
    Evaluate inflammation markers in MECP2 duplication syndrome and correlate with disease severity.

  4. 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.


Secondary Outcome Measures :
  1. 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


Biospecimen Retention:   Samples With DNA
DNA and RNA from blood, plasma, hair follicles, skin biopsies


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

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.

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): NCT02705677


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, California
UCSF Benioff Children's Hospital Oakland
Oakland, California, United States, 94709
University of California San Diego
San Diego, California, United States, 92123
United States, Colorado
University of Colorado Denver
Denver, Colorado, United States, 80045-2571
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Minnesota
Gillette Children's Specialty Healthcare
Minneapolis, Minnesota, United States, 55101
United States, Missouri
Washington University School of Medicine and St. Louis Children's Hospital
Saint Louis, Missouri, United States, 63110-1093
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
United States, South Carolina
Greenwood Genetic Center
Greenwood, South Carolina, United States, 29646
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37212
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
University of Alabama at Birmingham
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
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Study Chair: Jeffrey L Neul, MD, PhD UCSD
Additional Information:
Publications:
Neul, J.L. Rett Syndrome and MECP2-Related Disorders. in Autism Spectrum Disorders (eds. Amaral, D., Geschwind, D. & Dawson, G.) 776-800 (Oxford University Press, New York, 2011).

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Responsible Party: Alan Percy, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02705677    
Other Study ID Numbers: RDCRN # 5213
U54HD061222 ( U.S. NIH Grant/Contract )
First Posted: March 10, 2016    Key Record Dates
Last Update Posted: August 5, 2021
Last Verified: August 2021
Individual Participant Data (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.
Additional relevant MeSH terms:
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Rett Syndrome
Syndrome
Disease
Pathologic Processes
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System