Natural History of Rett Syndrome & Related Disorders

NCT02738281 | Completed DMC

• 1 other identifier: RDCRN 5211
• Study Type: observational
• Target: 1,044
• Locations: 1 country
• Sites: 14

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).

Conditions

Rett Syndrome; MECP2 Duplication dIsorder; CDKL5 Disorder; FOXG1 Syndrome

Outcome Measures

Primary Outcomes (15)

• 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 Outcomes (6)

• Quality of Life Measures in RTT

  at 5 years post enrollment

• Quality of Life Measures in MECP2 duplication syndrome

  at 5 years post enrollment

• Quality of Life Measures in RTT-related disorders.

  at 5 years post enrollment

• Quality of Life Measures in RTT

  at 5 years post enrollment

• Quality of Life Measures in MECP2 duplication syndrome

  at 5 years post enrollment

Study Arms (3)

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.

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• National Institutes of Health (NIH): collaborator
• National Center for Advancing Translational Sciences (NCATS): collaborator
• Rare Diseases Clinical Research Network: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (14)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

UCSF Oakland Benioff Children's Hospital

Oakland, California, 94709, United States

Location

University of California San Diego

San Diego, California, 92123, United States

Location

University of Colorado Denver

Denver, Colorado, 80045-2571, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, 55101, United States

Location

Washington University School of Medicine and St. Louis Children's Hospital

St Louis, Missouri, 63110-1093, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4318, United States

Location

Greenwood Genetic Center

Greenwood, South Carolina, 29646, United States

Location

Vanderbilt University

Nashville, Tennessee, 37212, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

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• Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, Cances C, Ville D, Afenjar A, Rio M, Heron D, N'guyen Morel MA, Arzimanoglou A, Philippe C, Jonveaux P, Chelly J, Bienvenu T. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008 Oct;131(Pt 10):2647-61. doi: 10.1093/brain/awn197. Epub 2008 Sep 12.

  PMID: 18790821 BACKGROUND

• Fehr S, Wilson M, Downs J, Williams S, Murgia A, Sartori S, Vecchi M, Ho G, Polli R, Psoni S, Bao X, de Klerk N, Leonard H, Christodoulou J. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet. 2013 Mar;21(3):266-73. doi: 10.1038/ejhg.2012.156. Epub 2012 Aug 8.

  PMID: 22872100 BACKGROUND

• Melani F, Mei D, Pisano T, Savasta S, Franzoni E, Ferrari AR, Marini C, Guerrini R. CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life. Dev Med Child Neurol. 2011 Apr;53(4):354-60. doi: 10.1111/j.1469-8749.2010.03889.x. Epub 2011 Feb 11.

  PMID: 21309761 BACKGROUND

• Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology. 2008 Sep 23;71(13):997-9. doi: 10.1212/01.wnl.0000326592.37105.88.

  PMID: 18809835 BACKGROUND

• 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.

  PMID: 27828991 BACKGROUND

• Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, Zoghbi H, Percy A, Glaze DG. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008 Apr 15;70(16):1313-21. doi: 10.1212/01.wnl.0000291011.54508.aa. Epub 2008 Mar 12.

  PMID: 18337588 RESULT

• Kirby RS, Lane JB, Childers J, Skinner SA, Annese F, Barrish JO, Glaze DG, Macleod P, Percy AK. Longevity in Rett syndrome: analysis of the North American Database. J Pediatr. 2010 Jan;156(1):135-138.e1. doi: 10.1016/j.jpeds.2009.07.015.

  PMID: 19772971 RESULT

• Tarquinio DC, Motil KJ, Hou W, Lee HS, Glaze DG, Skinner SA, Neul JL, Annese F, McNair L, Barrish JO, Geerts SP, Lane JB, Percy AK. Growth failure and outcome in Rett syndrome: specific growth references. Neurology. 2012 Oct 16;79(16):1653-61. doi: 10.1212/WNL.0b013e31826e9a70. Epub 2012 Oct 3.

  PMID: 23035069 RESULT

• Kalman LV, Tarleton JC, Percy AK, Aradhya S, Bale S, Barker SD, Bayrak-Toydemir P, Bridges C, Buller-Burckle AM, Das S, Iyer RK, Vo TD, Zvereff VV, Toji LH. Development of a genomic DNA reference material panel for Rett syndrome (MECP2-related disorders) genetic testing. J Mol Diagn. 2014 Mar;16(2):273-9. doi: 10.1016/j.jmoldx.2013.11.004. Epub 2014 Feb 7.

  PMID: 24508304 RESULT

• Cuddapah VA, Pillai RB, Shekar KV, Lane JB, Motil KJ, Skinner SA, Tarquinio DC, Glaze DG, McGwin G, Kaufmann WE, Percy AK, Neul JL, Olsen ML. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 2014 Mar;51(3):152-8. doi: 10.1136/jmedgenet-2013-102113. Epub 2014 Jan 7.

  PMID: 24399845 RESULT

• Neul JL, Lane JB, Lee HS, Geerts S, Barrish JO, Annese F, Baggett LM, Barnes K, Skinner SA, Motil KJ, Glaze DG, Kaufmann WE, Percy AK. Developmental delay in Rett syndrome: data from the natural history study. J Neurodev Disord. 2014;6(1):20. doi: 10.1186/1866-1955-6-20. Epub 2014 Jul 22.

  PMID: 25071871 RESULT

• Killian JT, Lane JB, Cutter GR, Skinner SA, Kaufmann WE, Tarquinio DC, Glaze DG, Motil KJ, Neul JL, Percy AK. Pubertal development in Rett syndrome deviates from typical females. Pediatr Neurol. 2014 Dec;51(6):769-75. doi: 10.1016/j.pediatrneurol.2014.08.013. Epub 2014 Aug 29.

  PMID: 25283752 RESULT

• Tarquinio DC, Hou W, Neul JL, Lane JB, Barnes KV, O'Leary HM, Bruck NM, Kaufmann WE, Motil KJ, Glaze DG, Skinner SA, Annese F, Baggett L, Barrish JO, Geerts SP, Percy AK. Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis. Pediatr Neurol. 2015 Jun;52(6):585-91.e2. doi: 10.1016/j.pediatrneurol.2015.02.007. Epub 2015 Feb 16.

  PMID: 25801175 RESULT

• Killian JT Jr, Lane JB, Lee HS, Pelham JH, Skinner SA, Kaufmann WE, Glaze DG, Neul JL, Percy AK. Caretaker Quality of Life in Rett Syndrome: Disorder Features and Psychological Predictors. Pediatr Neurol. 2016 May;58:67-74. doi: 10.1016/j.pediatrneurol.2015.12.021. Epub 2016 Jan 11.

  PMID: 26995066 RESULT

• Sajan SA, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, Glaze DG, Kaufmann WE, Skinner SA, Annese F, Friez MJ, Lane J, Percy AK, Neul JL. Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2. Genet Med. 2017 Jan;19(1):13-19. doi: 10.1038/gim.2016.42. Epub 2016 May 12.

  PMID: 27171548 RESULT

• Lane JB, Salter AR, Jones NE, Cutter G, Horrigan J, Skinner SA, Kaufmann WE, Glaze DG, Neul JL, Percy AK. Assessment of Caregiver Inventory for Rett Syndrome. J Autism Dev Disord. 2017 Apr;47(4):1102-1112. doi: 10.1007/s10803-017-3034-3.

  PMID: 28132121 RESULT

• Tarquinio DC, Hou W, Neul JL, Kaufmann WE, Glaze DG, Motil KJ, Skinner SA, Lee HS, Percy AK. The Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders. Pediatr Neurol. 2015 Nov;53(5):402-11. doi: 10.1016/j.pediatrneurol.2015.06.003. Epub 2015 Jun 26.

  PMID: 26278631 RESULT

• Neul JL, Benke TA, Marsh ED, Suter B, Silveira L, Fu C, Peters SU, Percy AK; Rett syndrome Natural History Study Group. Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study. J Neurodev Disord. 2023 Oct 13;15(1):33. doi: 10.1186/s11689-023-09502-z.

  PMID: 37833681 DERIVED

• Saby JN, Peters SU, Benke TA, Standridge SM, Swanson LC, Lieberman DN, Olson HE, Key AP, Percy AK, Neul JL, Nelson CA, Roberts TPL, Marsh ED. Comparison of evoked potentials across four related developmental encephalopathies. J Neurodev Disord. 2023 Mar 4;15(1):10. doi: 10.1186/s11689-023-09479-9.

  PMID: 36870948 DERIVED

• Buchanan CB, Stallworth JL, Joy AE, Dixon RE, Scott AE, Beisang AA, Benke TA, Glaze DG, Haas RH, Heydemann PT, Jones MD, Lane JB, Lieberman DN, Marsh ED, Neul JL, Peters SU, Ryther RC, Skinner SA, Standridge SM, Kaufmann WE, Percy AK. Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study. J Neurodev Disord. 2022 May 14;14(1):31. doi: 10.1186/s11689-022-09432-2.

  PMID: 35568815 DERIVED

Related Links

• International Rett Syndrome Foundation website

MeSH Terms

Conditions

Rett Syndrome; CDKL5 deficiency disorder

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System

Study Officials

• Alan K Percy, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

• Jeffrey L Neul, MD, PhD

  Vanderbilt University

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 22, 2015
• First Posted: April 14, 2016
• Study Start: November 1, 2015
• Primary Completion: July 31, 2021
• Study Completion: July 31, 2021
• Last Updated: August 5, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will share

Locations

US (14)