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Natural History of Rett Syndrome & Related Disorders

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02738281
Recruitment Status : Completed
First Posted : April 14, 2016
Last Update Posted : August 5, 2021
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Rare Diseases Clinical Research Network
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

Study Description
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Brief Summary:
The purpose of this study is to advance understanding of the natural history of Rett syndrome (RTT), MECP2-duplication disorder (MECP2 Dup), CDKL5, FOXG1, and individuals with MECP2 mutations who do not have RTT including the range of clinical involvement and to correlate genotype-phenotype over a broad spectrum of phenotypes. While much has been learned about RTT, improvements are required in understanding the role of factors such as X chromosome inactivation, genetic background, and others including the environment, on the great variability observed even between individuals with the same MECP2 mutation. These data will be essential to the development and conduct of clinical trials that are anticipated from ongoing studies in animal models for RTT. This study will not include clinical trials, but should set the stage for such trials and other translational research projects (e.g., development of biomarkers).

Condition or disease
Rett Syndrome MECP2 Duplication dIsorder CDKL5 Disorder FOXG1 Syndrome

Detailed Description:
At the present time, effective treatments for RTT, MECP2 Dup, or Rett-related disorders are lacking. Substantial progress has been made 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, additional MECP2- and RTT-related disorders that were unknown at the time the original proposal have been identified. In addition, substantial clinical variability in individuals with RTT that cannot be explained by differences in mutations alone must be explored further. In fact, variability among individuals with identical mutations has led to the 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, the variation in clinical disorders related to MECP2 mutations or to the related but quite different MECP2 Dup were unknown. 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. This new study will 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. A comprehensive clinical research program will be performed including clinical, neurophysiologic, and molecular and biochemical markers across these different, but related disorders. This protocol will address the natural history components only and will serve as the basis for other study protocols including the neurophysiologic and biomarker studies. Thereby, these studies will represent a continuing pathway to focus and inform not only the ongoing but also the emerging clinical trials.
Study Design
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Study Type : Observational
Actual Enrollment : 1044 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Rett Syndrome, MECP2 Duplication Disorder, and Rett- Related Disorders Natural History Protocol
Study Start Date : November 2015
Actual Primary Completion Date : July 31, 2021
Actual Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Rett Syndrome

Groups and Cohorts
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Group/Cohort
Rett Syndrome
This is a prospective natural history study examining the phenotypic variations of individuals with mutations in MECP2 or meeting the diagnostic criteria for classic (typical) or variant (atypical) Rett syndrome. The overwhelming majority will be female, but males meeting diagnostic criteria will be included. No interventions are planned.
MECP2 Duplication
This is a prospective natural history study examining the phenotypic variations of individuals with MECP2 duplications. The majority are expected to be males, but females expressing a duplication will be included. No interventions are planned.
RTT related disorders
This is a prospective natural history study examining individuals, both females and males who do not meet criteria for Rett syndrome, but have a mutation in MECP2, CDKL5, or FOXG1. No interventions are planned.


Outcome Measures
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Primary Outcome Measures :
  1. Clinical longitudinal assessments in Rett syndrome (RTT) as measured by mean growth over 5 years. [ Time Frame: at 5 years after enrollment ]
    subject's height will be measured in inches at baseline and at 5 years. The change will be calculated and then the mean change will be reported.

  2. Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by mean change in head circumference over 5 years [ Time Frame: at 5 years after enrollment ]
    the mean change in head circumference (measured in Centimeters) will be reported

  3. Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by mean number of stereotypic movements at 5 years [ Time Frame: at 5 years after enrollment ]
    The mean number of stereotypic movements in a 24 hour period at 5 years.

  4. Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with reported epilepsy at 5 years [ Time Frame: 5 years after enrollment ]
    The Percent of subjects reporting epilepsy by 5 years

  5. Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with reported scoliosis at 5 years [ Time Frame: at 5 years after enrollment ]
    Percent of subjects with reported scoliosis

  6. Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with MECP2 mutations at 5 years [ Time Frame: at 5 years after enrollment ]
    % of subjects with MECP2 mutations to 5 years

  7. Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as reported by the mean Clinical Severity Scale (CSS) at 5 years [ Time Frame: at 5 years after enrollment ]
    The CSS is the clinical severity scale.

  8. Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by the mean Motor Behavioral Assessment (MBA) at 5 years [ Time Frame: at 5 years after enrollment ]
    the MBA is the motor behavioral (performance) score

  9. Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: mean growth rate over 5 years with subjects having MECP2 duplication syndrome [ Time Frame: at 5 years after enrollment ]
    subject's height will be measured in inches at baseline and at 5 years. The change will be calculated and then the mean change will be reported.

  10. Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: mean change in head circumference 5 years with subjects having MECP2 duplication syndrome [ Time Frame: at 5 years after enrollment ]
    the mean change in head circumference (measured in Centimeters) will be reported

  11. Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: mean number of stereotypic movements in a 24 hour period at 5 years with subjects having MECP2 duplication syndrome [ Time Frame: at 5 years after enrollment ]
    The mean number of stereotypic movements in a 24 hour period at 5 years.

  12. Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: percent of subjects reporting scoliosis 5 years with subjects having MECP2 duplication syndrome [ Time Frame: at 5 years after enrollment ]
    Percent of subjects with reported scoliosis

  13. Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: percent of subjects surviving at 5 years with subjects having MECP2 duplication syndrome [ Time Frame: at 5 years after enrollment ]
    Percent of subjects surviving at 5 years after start of study

  14. Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: the mean CSS score at 5 years with subjects having MECP2 duplication syndrome [ Time Frame: at 5 years after enrollment ]
    the CSS........

  15. Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: the mean MAB score at 5 years with subjects having MECP2 duplication syndrome [ Time Frame: at 5 years after enrollment ]
    the MBA........


Secondary Outcome Measures :
  1. Quality of Life Measures in RTT [ Time Frame: at 5 years post enrollment ]
    Summative data are provided by the quality of life assessments for children (CHQ), the mean score will.be reported

  2. Quality of Life Measures in MECP2 duplication syndrome [ Time Frame: at 5 years post enrollment ]
    Summative data are provided by the quality of life assessments for children (CHQ), the mean scores will be reported.

  3. Quality of Life Measures in RTT-related disorders. [ Time Frame: at 5 years post enrollment ]
    Summative data are provided by the quality of life assessments for children (CHQ), the mean score will be reported.

  4. Quality of Life Measures in RTT [ Time Frame: at 5 years post enrollment ]
    Summative data are provided by the quality of life assessments from the principal caregiver (SF-36), the mean score will be reported.

  5. Quality of Life Measures in MECP2 duplication syndrome [ Time Frame: at 5 years post enrollment ]
    Summative data are provided by the quality of life assessments from the principal caregiver (SF-36), the mean score will be reported.

  6. Quality of Life Measures in RTT-related disorders [ Time Frame: at 5 years post enrollment ]
    Summative data are provided by the quality of life assessments from the principal caregiver (SF-36), the mean score will be reported.


Eligibility Criteria
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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.

Exclusion Criteria:

  • Individuals who do not meet the above criteria will be excluded.
Contacts and Locations
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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): NCT02738281


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, California
UCSF Oakland Benioff Children's Hospital
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
Saint Paul, 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, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Cleveland Clinic
Cleveland, Ohio, United States, 44195
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 Sciences (NCATS)
Rare Diseases Clinical Research Network
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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Principal Investigator: Alan K Percy, MD University of Alabama at Birmingham
Study Director: Jeffrey L Neul, MD, PhD Vanderbilt University
More Information
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Additional Information:

Publications of Results:

Other 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).

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Alan Percy, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT02738281    
Other Study ID Numbers: RDCRN 5211
First Posted: April 14, 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: This consortium will follow the RDCRN agreement to share data. This plan releases data five years after acquisition.
Additional relevant MeSH terms:
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Rett Syndrome
Disease
Syndrome
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