Natural History of Rett Syndrome & Related Disorders

Rett Syndrome, MECP2 Duplication Disorder, and Rett- Related Disorders Natural History Protocol

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).

Study Overview

• Status: Completed
• Conditions: Rett Syndrome; CDKL5 Disorder; MECP2 Duplication 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 Type: Observational
• Enrollment (Actual): 1044

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Oakland, California, United States, 94709
      • UCSF Oakland Benioff Children's Hospital
    • 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
    • Saint Paul, 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
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • 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

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.

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical longitudinal assessments in Rett syndrome (RTT) as measured by mean growth over 5 years.	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.	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by mean change in head circumference over 5 years	the mean change in head circumference (measured in Centimeters) will be reported	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by mean number of stereotypic movements at 5 years	The mean number of stereotypic movements in a 24 hour period at 5 years.	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with reported epilepsy at 5 years	The Percent of subjects reporting epilepsy by 5 years	5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with reported scoliosis at 5 years	Percent of subjects with reported scoliosis	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with MECP2 mutations at 5 years	% of subjects with MECP2 mutations to 5 years	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as reported by the mean Clinical Severity Scale (CSS) at 5 years	The CSS is the clinical severity scale.	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by the mean Motor Behavioral Assessment (MBA) at 5 years	the MBA is the motor behavioral (performance) score	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: mean growth rate over 5 years with subjects having MECP2 duplication syndrome	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.	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: mean change in head circumference 5 years with subjects having MECP2 duplication syndrome	the mean change in head circumference (measured in Centimeters) will be reported	at 5 years after enrollment
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	The mean number of stereotypic movements in a 24 hour period at 5 years.	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: percent of subjects reporting scoliosis 5 years with subjects having MECP2 duplication syndrome	Percent of subjects with reported scoliosis	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: percent of subjects surviving at 5 years with subjects having MECP2 duplication syndrome	Percent of subjects surviving at 5 years after start of study	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: the mean CSS score at 5 years with subjects having MECP2 duplication syndrome	the CSS........	at 5 years after enrollment
Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: the mean MAB score at 5 years with subjects having MECP2 duplication syndrome	the MBA........	at 5 years after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life Measures in RTT	Summative data are provided by the quality of life assessments for children (CHQ), the mean score will.be reported	at 5 years post enrollment
Quality of Life Measures in MECP2 duplication syndrome	Summative data are provided by the quality of life assessments for children (CHQ), the mean scores will be reported.	at 5 years post enrollment
Quality of Life Measures in RTT-related disorders.	Summative data are provided by the quality of life assessments for children (CHQ), the mean score will be reported.	at 5 years post enrollment
Quality of Life Measures in RTT	Summative data are provided by the quality of life assessments from the principal caregiver (SF-36), the mean score will be reported.	at 5 years post enrollment
Quality of Life Measures in MECP2 duplication syndrome	Summative data are provided by the quality of life assessments from the principal caregiver (SF-36), the mean score will be reported.	at 5 years post enrollment
Quality of Life Measures in RTT-related disorders	Summative data are provided by the quality of life assessments from the principal caregiver (SF-36), the mean score will be reported.	at 5 years post enrollment

Collaborators and Investigators

• 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); Rare Diseases Clinical Research Network; National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Alan K Percy, MD, University of Alabama at Birmingham; Study Director: Jeffrey L Neul, MD, PhD, Vanderbilt University

Publications and helpful links

General Publications

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Helpful Links

• International Rett Syndrome Foundation website

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• 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: April 8, 2016
• First Posted (Estimate): April 14, 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: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Syndrome; Disease; Rett Syndrome
• Other Study ID Numbers: RDCRN 5211

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: This consortium will follow the RDCRN agreement to share data. This plan releases data five years after acquisition.