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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Center for Advancing Translational Sciences (NCATS) | NIH |
| Rare Diseases Clinical Research Network | NETWORK |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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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)
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| Name | Affiliation | Role |
|---|---|---|
| Alan K Percy, MD | University of Alabama at Birmingham | Principal Investigator |
| Jeffrey L Neul, MD, PhD | Vanderbilt University | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham | Birmingham | Alabama | 35294 | United States | ||
| UCSF Oakland Benioff Children's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 6638958 | Background | Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann Neurol. 1983 Oct;14(4):471-9. doi: 10.1002/ana.410140412. | |
| 21154482 | Background | Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Zappella M, Renieri A, Huppke P, Percy AK; RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010 Dec;68(6):944-50. doi: 10.1002/ana.22124. |
| Label | URL |
|---|---|
| International Rett Syndrome Foundation website | View source |
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This consortium will follow the RDCRN agreement to share data. This plan releases data five years after acquisition.
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| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
| NIH |
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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| 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 |
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 |
| Oakland |
| California |
| 94709 |
| United States |
| University of California San Diego | San Diego | California | 92123 | United States |
| University of Colorado Denver | Denver | Colorado | 80045-2571 | United States |
| Rush University Medical Center | Chicago | Illinois | 60612 | United States |
| Children's Hospital Boston | Boston | Massachusetts | 02115 | United States |
| Gillette Children's Specialty Healthcare | Saint Paul | Minnesota | 55101 | United States |
| Washington University School of Medicine and St. Louis Children's Hospital | St Louis | Missouri | 63110-1093 | United States |
| Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | 45229 | United States |
| Cleveland Clinic | Cleveland | Ohio | 44195 | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104-4318 | United States |
| Greenwood Genetic Center | Greenwood | South Carolina | 29646 | United States |
| Vanderbilt University | Nashville | Tennessee | 37212 | United States |
| Baylor College of Medicine | Houston | Texas | 77030 | United States |
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| 21107515 | Background | Nectoux J, Fichou Y, Cagnard N, Bahi-Buisson N, Nusbaum P, Letourneur F, Chelly J, Bienvenu T. Cell cloning-based transcriptome analysis in cyclin-dependent kinase-like 5 mutation patients with severe epileptic encephalopathy. J Mol Med (Berl). 2011 Feb;89(2):193-202. doi: 10.1007/s00109-010-0699-x. Epub 2010 Nov 24. |
| 19740913 | Background | Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V. CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery. Hum Mol Genet. 2009 Dec 1;18(23):4590-602. doi: 10.1093/hmg/ddp426. Epub 2009 Sep 9. |
| 15492925 | Background | 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, Gecz 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. doi: 10.1086/426462. Epub 2004 Oct 18. |
| 18266744 | Background | Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gerard M, Giuliano F, Motte J, Heron D, Morel MA, Plouin P, Richelme C, des Portes V, Dulac O, Philippe C, Chiron C, Nabbout R, Bienvenu T. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia. 2008 Jun;49(6):1027-37. doi: 10.1111/j.1528-1167.2007.01520.x. Epub 2008 Feb 7. |
| 18790821 | Background | 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. |
| 22872100 | 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. |
| 21309761 | 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. |
| 18809835 | 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. |
| 27828991 | 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. |
| 18337588 | Result | 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. |
| 19772971 | 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. |
| 23035069 | 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. |
| 24508304 | 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. |
| 24399845 | 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. |
| 25071871 | 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. |
| 25283752 | 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. |
| 25801175 | 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. |
| 26995066 | 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. |
| 27171548 | 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. |
| 28132121 | 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. |
| 26278631 | 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. |
| 37833681 | Derived | 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. |
| 36870948 | 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. |
| 35568815 | 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. |
| ID | Term |
|---|---|
| D015518 | Rett Syndrome |
| C564064 | CDKL5 deficiency disorder |
| ID | Term |
|---|---|
| D038901 | X-Linked Intellectual Disability |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D020271 | Heredodegenerative Disorders, Nervous System |
Not provided
Not provided