Natural History of Rett Syndrome & Related Disorders

Rett Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02738281
• Other study ID #: RDCRN 5211
• Status: Completed
• Start date: November 2015
• Est. completion date: July 31, 2021

Study information

• Verified date: August 2021
• Source: University of Alabama at Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1044
• Est. completion date: July 31, 2021
• Est. primary completion date: July 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• CDKL5 Disorder
• Disease
• FOXG1 Syndrome
• MECP2 Duplication dIsorder
• Rett Syndrome
• Syndrome

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Rush University Medical Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	University of Colorado Denver	Denver	Colorado
United States	Greenwood Genetic Center	Greenwood	South Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	Vanderbilt University	Nashville	Tennessee
United States	UCSF Oakland Benioff Children's Hospital	Oakland	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Washington University School of Medicine and St. Louis Children's Hospital	Saint Louis	Missouri
United States	Gillette Children's Specialty Healthcare	Saint Paul	Minnesota
United States	University of California San Diego	San Diego	California

Sponsors (6)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Advancing Translational Science (NCATS), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Rare Diseases Clinical Research Network

Country where clinical trial is conducted

United States, 

References & Publications (73)

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Ward CS, Huang TW, Herrera JA, Samaco RC, Pitcher MR, Herron A, Skinner SA, Kaufmann WE, Glaze DG, Percy AK, Neul JL. Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome. PLoS One. 2016 Nov 9;11(11):e0165550. doi: 10.1371/journal.pone.0165550. eCollection 2016. — View Citation

Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, Evans J, Clarke A, Pelka GJ, Tam PP, Watson C, Lahooti H, Ellaway CJ, Bennetts B, Leonard H, Gécz J. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004 Dec;75(6):1079-93. Epub 2004 Oct 18. — View Citation

Yang T, Ramocki MB, Neul JL, Lu W, Roberts L, Knight J, Ward CS, Zoghbi HY, Kheradmand F, Corry DB. Overexpression of methyl-CpG binding protein 2 impairs T(H)1 responses. Sci Transl Med. 2012 Dec 5;4(163):163ra158. doi: 10.1126/scitranslmed.3004430. — View Citation

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* Note: There are 73 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   International Rett Syndrome Foundation website