Clinical trial NCT02738281: Natural History of Rett Syndrome & Related Disorders
Official title: Rett Syndrome, MECP2 Duplication Disorder, and Rett- Related Disorders Natural History Protocol
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Rett Syndrome
MECP2 Duplication dIsorder
CDKL5 Disorder
FOXG1 Syndrome
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Center for Advancing Translational Sciences (NCATS)
name: Rare Diseases Clinical Research Network
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2016-04-14
Enrollment: 1044
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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)

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).

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.

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.

Exclusion Criteria:

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

Primary outcomes:
measure: Clinical longitudinal assessments in Rett syndrome (RTT) as measured by mean growth over 5 years.
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by mean change in head circumference over 5 years
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by mean number of stereotypic movements at 5 years
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with reported epilepsy at 5 years
timeFrame: 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with reported scoliosis at 5 years
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as the percent of subjects with MECP2 mutations at 5 years
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as reported by the mean Clinical Severity Scale (CSS) at 5 years
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in Rett syndrome (RTT) as measured by the mean Motor Behavioral Assessment (MBA) at 5 years
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: mean growth rate over 5 years with subjects having MECP2 duplication syndrome
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: mean change in head circumference 5 years with subjects having MECP2 duplication syndrome
timeFrame: at 5 years after enrollment
measure: 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
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: percent of subjects reporting scoliosis 5 years with subjects having MECP2 duplication syndrome
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: percent of subjects surviving at 5 years with subjects having MECP2 duplication syndrome
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: the mean CSS score at 5 years with subjects having MECP2 duplication syndrome
timeFrame: at 5 years after enrollment
measure: Clinical and neurobehavioral longitudinal assessments in MECP2 duplication syndrome: the mean MAB score at 5 years with subjects having MECP2 duplication syndrome
timeFrame: at 5 years after enrollment
Secondary outcomes:
measure: Quality of Life Measures in RTT
timeFrame: at 5 years post enrollment
measure: Quality of Life Measures in MECP2 duplication syndrome
timeFrame: at 5 years post enrollment
measure: Quality of Life Measures in RTT-related disorders.
timeFrame: at 5 years post enrollment
measure: Quality of Life Measures in RTT
timeFrame: at 5 years post enrollment
measure: Quality of Life Measures in MECP2 duplication syndrome
timeFrame: at 5 years post enrollment
measure: Quality of Life Measures in RTT-related disorders
timeFrame: at 5 years post enrollment
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Oakland
country: United States
facility: UCSF Oakland Benioff Children's Hospital
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: Denver
country: United States
facility: University of Colorado Denver
state: Colorado
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Saint Paul
country: United States
facility: Gillette Children's Specialty Healthcare
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine and St. Louis Children's Hospital
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Greenwood
country: United States
facility: Greenwood Genetic Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: University of Alabama at Birmingham
name: Alan K Percy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University
name: Jeffrey L Neul, MD, PhD
role: STUDY_DIRECTOR
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