Abstract
Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS). Using data from the Rett Natural History Study (n = 649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS. The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and convergent validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire. These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test–retest and inter-rater agreement, are needed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Deidentified data from this study are available through a data use agreement upon request.
References
Aman, M. G., & Singh, N. B. (1994). Aberrant behavior checklist—Community. Slosson Educational Publications.
Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23(2), 185–188. https://doi.org/10.1038/13810
Amir, R. E., & Zoghbi, H. Y. (2000). Rett syndrome: Methyl-CpG-binding protein 2 mutations and phenotype–genotype correlations. American Journal of Medical Genetics, 97(2), 147–152. https://doi.org/10.1002/1096-8628(200022)97:2%3C147::aid-ajmg6%3E3.0.co;2-o
Barnes, K. V., Coughlin, F. R., O’Leary, H. M., Bruck, N., Bazin, G. A., Beinecke, E. B., & Kaufmann, W. E. (2015). Anxiety-like behavior in Rett syndrome: Characteristics and assessment by anxiety scales. Journal of Neurodevelopmental Disorders, 7(1), 1–14. https://doi.org/10.1186/s11689-015-9127-4
Benjamin, K., Vernon, M. K., Patrick, D. L., Perfetto, E., Nestler-Parr, S., & Burke, L. (2017). Patient-reported outcome and observer-reported outcome assessment in rare disease clinical trials: An ISPOR COA emerging good practices task force report. Value in Health, 20(7), 838–855. https://doi.org/10.1016/j.jval.2017.05.015
Berry-Kravis, E., Hessl, D., Abbeduto, L., Reiss, A. L., Beckel-Mitchener, A., Urv, T. K., Group, O. M. W. (2013). Outcome measures for clinical trials in fragile X syndrome. Journal of Developmental and Behavioral Pediatrics, 34(7), 508. https://doi.org/10.1097/dbp.0b013e31829d1f20
Buchanan, C. B., Stallworth, J. L., Scott, A. E., Glaze, D. G., Lane, J. B., Skinner, S. A., & Kaufmann, W. E. (2019). Behavioral profiles in Rett syndrome: Data from the natural history study. Brain and Development, 41(2), 123–134. https://doi.org/10.1016/j.braindev.2018.08.008
Bushby, K., & Connor, E. (2011). Clinical outcome measures for trials in Duchenne muscular dystrophy: Report from International Working Group meetings. Clinical Investigation, 1(9), 1217. https://doi.org/10.4155/cli.11.113
Corchón, S., Carrillo-López, I., & Cauli, O. (2018). Quality of life related to clinical features in patients with Rett syndrome and their parents: A systematic review. Metabolic Brain Disease, 33(6), 1801–1810. https://doi.org/10.1007/s11011-018-0316-1
Cuddapah, V. A., Pillai, R. B., Shekar, K. V., Lane, J. B., Motil, K. J., Skinner, S. A., & Olsen, M. L. (2014). Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. Journal of Medical Genetics, 51(3), 152–158. https://doi.org/10.1530/boneabs.7.p118
Esbensen, A. J., Hooper, S. R., Fidler, D., Hartley, S. L., Edgin, J., d’Ardhuy, X. L., Group, O. M. W. (2017). Outcome measures for clinical trials in Down syndrome. American Journal on Intellectual and Developmental Disabilities, 122(3), 247–281. https://doi.org/10.1352/1944-7558-122.3.247
Esbensen, A. J., Rojahn, J., Aman, M. G., & Ruedrich, S. (2003). Reliability and validity of an assessment instrument for anxiety, depression, and mood among individuals with mental retardation. Journal of Autism and Developmental Disorders, 33, 617–629. https://doi.org/10.1023/b:jadd.0000005999.27178.55
Farmer, C., Kaat, A. J., Berry-Kravis, E., & Thurm, A. (2022). Psychometric perspectives on developmental outcome and endpoint selection in treatment trials for genetic conditions associated with neurodevelopmental disorder. In International review of research in developmental disabilities (Vol. 62, pp. 1–39). Academic Press.
Fischer, J. S., Rudick, R. A., Cutter, G. R., Reingold, S. C., National MS Society Clinical Outcomes Assessment Task Force. (1999). The multiple sclerosis functional composite measure (MSFC): An integrated approach to MS clinical outcome assessment. Multiple Sclerosis Journal, 5(4), 244–250. https://doi.org/10.1177/135245859900500409
Food and Drug Administration (March, 2023). FDA approves first treatment for Rett Syndrome. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-rett-syndrome#:~:text=FDA%20has%20approved%20Daybue%20(trofinetide,orally%20or%20via%20gastrostomy%20tube. Accessed November 30, 2023.
Fu, C., Armstrong, D., Marsh, E., Lieberman, D., Motil, K., Witt, R., & Benke, T. (2020). Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatrics Open. https://doi.org/10.1136/bmjpo-2020-000717
Glaze, D. G., Neul, J. L., Kaufmann, W. E., Berry-Kravis, E., Condon, S., Stoms, G., & Percy, A. K. (2019). Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology, 92(16), e1912–e1925. https://doi.org/10.1212/wnl.0000000000007316
Glaze, D. G., Neul, J. L., Percy, A., Feyma, T., Beisang, A., Yaroshinsky, A., & Jones, N. E. (2017). A double-blind, randomized, placebo-controlled clinical study of trofinetide in the treatment of Rett syndrome. Pediatric Neurology, 76, 37–46. https://doi.org/10.1016/j.pediatrneurol.2017.07.002
Guy, J., Gan, J., Selfridge, J., Cobb, S., & Bird, A. (2007). Reversal of neurological defects in a mouse model of Rett syndrome. Science, 315(5815), 1143–1147. https://doi.org/10.3410/f.1066718.519633
Hagberg, B., Aicardi, J., Dias, K., & Ramos, O. (1983). A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: Report of 35 cases. Annals of Neurology, 14(4), 471–479. https://doi.org/10.1002/ana.410140412
Hou, W., Bhattacharya, U., Pradana, W. A., & Tarquinio, D. C. (2020). Assessment of a clinical trial metric for Rett syndrome: Critical analysis of the Rett syndrome behavioural questionnaire. Pediatric Neurology, 107, 48–56. https://doi.org/10.1016/j.pediatrneurol.2020.01.009
Hurley, E. N., Ellaway, C. J., Johnson, A. M., Truong, L., Gordon, R., Galettis, P., & Lawson, J. A. (2022). Efficacy and safety of cannabidivarin treatment of epilepsy in girls with Rett syndrome: A phase 1 clinical trial. Epilepsia, 63(7), 1736–1747. https://doi.org/10.1111/epi.17247
Katz, D. M., Bird, A., Coenraads, M., Gray, S. J., Menon, D. U., Philpot, B. D., & Tarquinio, D. C. (2016). Rett syndrome: Crossing the threshold to clinical translation. Trends in Neurosciences, 39(2), 100–113. https://doi.org/10.1016/j.tins.2015.12.008
Killian, J. T., Jr., Lane, J. B., Lee, H. S., Pelham, J. H., Skinner, S. A., Kaufmann, W. E., & Percy, A. K. (2016). Caretaker quality of life in Rett syndrome: Disorder features and psychological predictors. Pediatric Neurology, 58, 67–74. https://doi.org/10.1016/j.pediatrneurol.2015.12.021
Landgraf, J. M., Abetz, L., & Ware, J. E. (1996). The CHQ user’s manual (1st ed.). The Health Institute, New England Medical Center.
Lane, J. B., Lee, H. S., Smith, L. W., Cheng, P., Percy, A. K., Glaze, D. G., & Krischer, J. P. (2011). Clinical severity and quality of life in children and adolescents with Rett syndrome. Neurology, 77(20), 1812–1818. https://doi.org/10.1212/wnl.0b013e3182377dd2
Leonard, H., Bower, C., & English, D. (1997). The prevalence and incidence of Rett syndrome in Australia. European Child & Adolescent Psychiatry, 6(Suppl 1), 8–10. PMID: 9452912.
Leonard, H., Gold, W., Samaco, R., Sahin, M., Benke, T., & Downs, J. (2022). Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome. Orphanet Journal of Rare Diseases, 17(1), 1–15. https://doi.org/10.1186/s13023-022-02240-w
Mount, R. H., Charman, T., Hastings, R. P., Reilly, S., & Cass, H. (2002). The Rett syndrome behaviour questionnaire (RSBQ): Refining the behavioural phenotype of Rett syndrome. Journal of Child Psychology and Psychiatry, 43(8), 1099–1110. https://doi.org/10.1111/1469-7610.00236
Muthén, L. K. and Muthén, B. O. (1998–2017). Mplus user’s guide (8th ed.). Muthén & Muthén
National Library of Medicine (2023a). Safety and Efficacy of TSHA-102 in Adult Females With Rett Syndrome (REVEAL Adult Study). https://clinicaltrials.gov/study/NCT05606614. Accessed November 29, 2023.
National Library of Medicine (2023b). A Novel, Regulated Gene Therapy (NGN-401) Study for Female Children With Rett Syndrome. https://clinicaltrials.gov/study/NCT05898620. Accessed November 29, 2023.
Neul, J. L., Benke, T. A., Marsh, E. D., Suter, B., Silveira, L., Fu, C., … & Percy, A. K. (2023). Top caregiver concerns in Rett syndrome and related disorders; Data from the U. S. Natural History Study. Preprint: https://www.researchsquare.com/article/rs-2566253/v1
Neul, J. L., Benke, T. A., Marsh, E. D., Skinner, S. A., Merritt, J., Lieberman, D. N., & Percy, A. K. (2019). The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 180(1), 55–67. https://doi.org/10.1002/ajmg.b.32707
Neul, J. L., Fang, P., Barrish, J., Lane, J., Caeg, E. B., Smith, E. O., & Glaze, D. G. (2008). Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology, 70(16), 1313–1321. https://doi.org/10.1212/01.wnl.0000291011.54508.aa
Neul, J. L., Glaze, D. G., Percy, A. K., Feyma, T., Beisang, A., Dinh, T., & Jones, N. E. (2015). Improving treatment trial outcomes for Rett syndrome: The development of Rett-specific anchors for the clinical global impression scale. Journal of Child Neurology, 30(13), 1743–1748. https://doi.org/10.1177/0883073815579707
Neul, J. L., Kaufmann, W. E., Glaze, D. G., Christodoulou, J., Clarke, A. J., Bahi-Buisson, N., RettSearch Consortium (Members listed in the Appendix). (2010). Rett syndrome: Revised diagnostic criteria and nomenclature. Annals of Neurology, 68(6), 944–950. https://doi.org/10.1002/ana.22124
Neul, J. L., Lane, J. B., Lee, H. S., Geerts, S., Barrish, J. O., Annese, F., & Percy, A. K. (2014). Developmental delay in Rett syndrome: Data from the natural history study. Journal of Neurodevelopmental Disorders, 6(1), 1–9. https://doi.org/10.1186/1866-1955-6-20
Neul, J. L., Percy, A. K., Benke, T. A., Berry-Kravis, E. M., Glaze, D. G., Marsh, E. D., & Youakim, J. M. (2023). Trofinetide for the treatment of Rett syndrome: A randomized Phase 3 study. Nature Medicine. https://doi.org/10.1038/s41591-023-02398-1
Neul, J. L., Percy, A. K., Benke, T. A., Berry-Kravis, E. M., Glaze, D. G., Peters, S. U., & Youakim, J. M. (2022). Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemporary Clinical Trials, 114, 106704. https://doi.org/10.1016/j.cct.2022.106704
Panayotis, N., Ehinger, Y., Felix, M. S., & Roux, J. C. (2023). State-of-the-art therapies for Rett syndrome. Developmental Medicine & Child Neurology, 65(2), 162–170. https://doi.org/10.1111/dmcn.15383
Pozzo-Miller, L., Pati, S., & Percy, A. K. (2015). Rett syndrome: Reaching for clinical trials. Neurotherapeutics, 12(3), 631–640. https://doi.org/10.1007/s13311-015-0353-y
Raspa, M., Bann, C. M., Gwaltney, A., Benke, T. A., Fu, C., Glaze, D. G., & Neul, J. L. (2020). A psychometric evaluation of the motor-behavioral assessment scale for use as an outcome measure in Rett syndrome clinical trials. American Journal on Intellectual and Developmental Disabilities, 125(6), 493–509. https://doi.org/10.1352/1944-7558-125.6.493
Ricceri, L., De Filippis, B., & Laviola, G. (2008). Mouse models of Rett syndrome: From behavioural phenoty** to preclinical evaluation of new therapeutic approaches. Behavioural Pharmacology, 19(5–6), 501–517. https://doi.org/10.1097/fbp.0b013e32830c3645
Robinson, L., Guy, J., McKay, L., Brockett, E., Spike, R. C., Selfridge, J., & Cobb, S. R. (2012). Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain, 135(9), 2699–2710. https://doi.org/10.1093/brain/aws096
Ross, C. A., Aylward, E. H., Wild, E. J., Langbehn, D. R., Long, J. D., Warner, J. H., & Tabrizi, S. J. (2014). Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nature Reviews Neurology, 10(4), 204–216. https://doi.org/10.1038/nrneurol.2014.24
Schreiber, J. B., Nora, A., Stage, F. K., Barlow, E. A., & King, J. (2006). Reporting structural equation modeling and confirmatory factor analysis results: A review. The Journal of Educational Research, 99(6), 323–338. https://doi.org/10.3200/joer.99.6.323-338
Singh, J., Fiori, F., Law, M. L., Ahmed, R., Ameenpur, S., Basheer, S., & Santosh, P. (2022). Development and psychometric properties of the multi-system profile of symptoms scale in patients with Rett syndrome. Journal of Clinical Medicine, 11(17), 5094. https://doi.org/10.3390/jcm11175094
Tavakol, M., & Dennick, R. (2011). Making sense of Cronbach’s alpha. International Journal of Medical Education, 2, 53–55. https://doi.org/10.5116/ijme.4dfb.8dfd
Tropea, D., Giacometti, E., Wilson, N. R., Beard, C., McCurry, C., Fu, D. D., & Sur, M. (2009). Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proceedings of the National Academy of Sciences, 106(6), 2029–2034. https://doi.org/10.1073/pnas.0812394106
Whittal, A., Meregaglia, M., & Nicod, E. (2021). The use of patient-reported outcome measures in rare diseases and implications for health technology assessment. The Patient – Patient-Centered Outcomes Research, 14(5), 485–503. https://doi.org/10.1007/s40271-020-00493-w
Funding
This work was supported by funding from the National Institutes of Health Grants U54HD061222 (AKP), U54HD083211 (JLN), HD083181 (JLN), the Vanderbilt Institute for Clinical and Translational Research (UL1TR000445 and UL1TR002243), and the Rett Syndrome Research Trust (0281901.096). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Eunice Kennedy Shriver Child Health and Human Development Institute (NICHD), or the Rett Syndrome Research Trust.
Author information
Authors and Affiliations
Contributions
MR, AG, CB, JH, JLN contributed to the study conception and design. Material preparation, data collection, and data analysis were performed by AG, CB, TAB, EDM, SUP, AA, AKP, and JLN. MR, AG, and JLN prepared the first draft of the manuscript and all authors provided comments. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Ethical Approval
Prior to conducting the analyses, the study was review by RTI International’s Institutional Review Board. The study received a determination of Human Subjects Research, Not Engaged given all data was de-identified and there was no contact with study participants.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Raspa, M., Gwaltney, A., Bann, C. et al. Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS). J Autism Dev Disord (2024). https://doi.org/10.1007/s10803-024-06238-0
Accepted:
Published:
DOI: https://doi.org/10.1007/s10803-024-06238-0