{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:52:08Z","timestamp":1781632328877,"version":"3.54.5"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":26,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100013394","name":"REGENXBIO","doi-asserted-by":"publisher","award":["REGENXBIO"],"award-info":[{"award-number":["REGENXBIO"]}],"id":[{"id":"10.13039\/100013394","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neuronopathic mucopolysaccharidosis type II (MPS II) is a rare genetic disorder characterized by multisystem impairments that include profound cognitive and behavioral impairment and global developmental delay. Developmental function is considered a sensitive indicator of disease progression and a relevant outcome to evaluate the efficacy of existing and novel therapies. The Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) has been recommended by expert consensus to assess treatment effect in the disease. The current study aimed to better understand what constitutes a meaningful change on the BSITD-III in response to treatment of neuronopathic MPS II according to caregivers and to investigate the functional relevance of items on the BSITD-III to daily function. Ten semi-structured interviews were conducted with caregivers of children aged 2\u20136 years old in the UK and USA. The interviews included hypothetical vignettes describing a change on the BSITD-III in response to an intervention over 1 year. Caregivers were asked to rate the level of change, discuss whether the changes were clinically meaningful and to describe any relevance to daily function. Qualitative and quantitative analyses were undertaken.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Interviews involved 12 caregivers of 11 children. Caregiver perceptions support a meaningful change on the BSITD-III being as small as a change of 1\u20132 months in Age Equivalent values: increases in age-equivalent scores of 2 months were reported to be associated with meaningful changes (Caregiver Global Impression of Change rating of minimal or greater improvement) over 1 year by 97.1% of caregivers (all subtests) and increases of 1 month for the Fine Motor and Expressive Communication subtests were considered meaningful by 81.8% and 90.9% of caregivers, respectively. Caregivers reported that the BSITD-III Cognitive, Expressive Communication, and Fine Motor items outlined in the hypothetical vignettes were functionally relevant to their children with MPS II and provided practical examples of item relevance in their child\u2019s daily activities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support the use of BSITD-III as an appropriate clinical outcome assessment for measuring changes in developmental skills in children with neuronopathic MPS II.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04205-9","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T14:09:28Z","timestamp":1769004568000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Defining Bayley Scales of Infant and Toddler Development Third Edition (BSITD-III) meaningful change and item relevance in children with neuronopathic MPS II: a caregiver interview-based study"],"prefix":"10.1186","volume":"21","author":[{"given":"Dawn","family":"Phillips","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"4205_CR1","doi-asserted-by":"crossref","unstructured":"D\u2019Avanzo F, Rigon L, Zanetti A, Tomanin R. Mucopolysaccharidosis type II: one hundred years of research, diagnosis, and treatment. Int J Mol Sci. 2020;21(4).","DOI":"10.3390\/ijms21041258"},{"key":"4205_CR2","doi-asserted-by":"publisher","first-page":"e1258","DOI":"10.1542\/peds.2010-1274","volume":"127","author":"J Holt","year":"2011","unstructured":"Holt J, Poe M, Escolar M. Natural progression of neurological disease in mucopolysaccharidosis type II. Pediatrics. 2011;127:e1258\u201365.","journal-title":"Pediatrics"},{"issue":"6","key":"4205_CR3","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1136\/jmg.19.6.408","volume":"19","author":"ID Young","year":"1982","unstructured":"Young ID, Harper PS, Newcombe RG, Archer IM. A clinical and genetic study of hunter\u2019s syndrome. 2. Differences between the mild and severe forms. J Med Genet. 1982;19(6):408\u201311.","journal-title":"J Med Genet"},{"issue":"1","key":"4205_CR4","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1186\/s13023-021-02118-3","volume":"16","author":"KS Yee","year":"2021","unstructured":"Yee KS, Wu Y, Harrington M, Waisbren SE. Analysis of cognitive ability and adaptive behavior assessment tools used in an observational study of patients with mucopolysaccharidosis II. Orphanet J Rare Dis. 2021;16(1):501.","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"4205_CR5","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1186\/s13023-020-01548-9","volume":"15","author":"F Hoffmann","year":"2020","unstructured":"Hoffmann F, Hoffmann S, Kunzmann K, Ries M. Challenging behavior in mucopolysaccharidoses types I-III and day-to-day coping strategies: a cross sectional explorative study. Orphanet J Rare Dis. 2020;15(1):275.","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"4205_CR6","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ymgme.2021.03.002","volume":"133","author":"EG Shapiro","year":"2021","unstructured":"Shapiro EG, Eisengart JB. The natural history of neurocognition in MPS disorders: A review. Mol Genet Metab. 2021;133(1):8\u201334.","journal-title":"Mol Genet Metab"},{"issue":"Suppl 2","key":"4205_CR7","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s13052-018-0561-2","volume":"44","author":"R Barone","year":"2018","unstructured":"Barone R, Pellico A, Pittala A, Gasperini S. Neurobehavioral phenotypes of neuronopathic mucopolysaccharidoses. Ital J Pediatr. 2018;44(Suppl 2):121.","journal-title":"Ital J Pediatr"},{"key":"4205_CR8","doi-asserted-by":"publisher","first-page":"S97","DOI":"10.1016\/j.ymgme.2022.01.076","volume":"135","author":"D Phillips","year":"2022","unstructured":"Phillips D, Cho Y, Mulatya C, Nevoret M-L, Poe M, Escolar M. Natural history of neurodevelopment in neuronopathic mucopolysaccharidosis type II (MPS II): Mullen scales of early learning (MSEL) cognitive, motor and Language developmental trajectories. Mol Genet Metab. 2022;135:S97.","journal-title":"Mol Genet Metab"},{"key":"4205_CR9","unstructured":"U.S. Food and Drug Administration. FDA-Requested Listening Session - Hunter Syndrome\/MPS II 2020. Available from: https:\/\/www.fda.gov\/media\/141462\/download. Accessed 02 April 2025."},{"key":"4205_CR10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ymgme.2017.09.007","volume":"122S","author":"EG Shapiro","year":"2017","unstructured":"Shapiro EG, Escolar ML, Delaney KA, Mitchell JJ. Assessments of neurocognitive and behavioral function in the mucopolysaccharidoses. Mol Genet Metab. 2017;122S:8\u201316.","journal-title":"Mol Genet Metab"},{"issue":"2","key":"4205_CR11","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ymgme.2017.05.004","volume":"121","author":"JH n der Lee","year":"2017","unstructured":"n der Lee JH, Morton J, Adams HR, Clarke L, Ebbink BJ, Escolar ML, et al. Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: results of a consensus procedure. Mol Genet Metab. 2017;121(2):70\u20139.","journal-title":"Mol Genet Metab"},{"issue":"1\u20132","key":"4205_CR12","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ymgme.2020.08.007","volume":"131","author":"JH n der Lee","year":"2020","unstructured":"n der Lee JH, Morton J, Adams HR, Clarke L, Eisengart JB, Escolar ML, et al. Therapy development for the mucopolysaccharidoses: updated consensus recommendations for neuropsychological endpoints. Mol Genet Metab. 2020;131(1\u20132):181\u201396.","journal-title":"Mol Genet Metab"},{"key":"4205_CR13","volume-title":"Bayley scales of infant development and toddler development administration manual","author":"N Bayley","year":"2006","unstructured":"Bayley N. Bayley scales of infant development and toddler development administration manual. 3rd ed. San Antonio: X: PsychCorp (Harcourt Assessment); 2006.","edition":"3"},{"issue":"2","key":"4205_CR14","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1136\/archdischild-2020-319063","volume":"106","author":"C Del Rosario","year":"2021","unstructured":"Del Rosario C, Slevin M, Molloy EJ, Quigley J, Nixon E. How to use the Bayley scales of infant and toddler development. Arch Dis Child Educ Pract Ed. 2021;106(2):108\u201312.","journal-title":"Arch Dis Child Educ Pract Ed"},{"issue":"7","key":"4205_CR15","first-page":"28","volume":"4","author":"J Busner","year":"2007","unstructured":"Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28\u201337.","journal-title":"Psychiatry (Edgmont)"},{"issue":"4","key":"4205_CR16","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1080\/2159676X.2019.1628806","volume":"11","author":"V Braun","year":"2019","unstructured":"Braun V, Clarke V. Reflecting on reflexive thematic analysis. Qual Res Sport Exerc Health. 2019;11(4):589\u201397.","journal-title":"Qual Res Sport Exerc Health"},{"key":"4205_CR17","unstructured":"British Healthcare Business Intelligence Association. Legal and Ethical Guidelines for Healthcare Market Research. 2020."},{"key":"4205_CR18","unstructured":"Food US, Administration D. FDA patient-focused drug development guidance series for enhancing the incorporation of the patient\u2019s voice in medical product development and regulatory decision making 2025. Available from: https:\/\/www.fda.gov\/drugs\/development-approval-process-drugs\/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical. Accessed 02 April 2025."},{"issue":"3","key":"4205_CR19","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/s00431-007-0635-4","volume":"167","author":"JE Wraith","year":"2008","unstructured":"Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir L, Guffon N, et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008;167(3):267\u201377.","journal-title":"Eur J Pediatr"},{"key":"4205_CR20","first-page":"100549","volume":"22","author":"JB Eisengart","year":"2020","unstructured":"Eisengart JB, King KE, Shapiro EG, Whitley CB, Muenzer J. The nature and impact of neurobehavioral symptoms in neuronopathic Hunter syndrome. Mol Genet Metab Rep. 2020;22:100549.","journal-title":"Mol Genet Metab Rep"},{"key":"4205_CR21","unstructured":"Scarpa M, Lampe C. Mucopolysaccharidosis type II. GeneReviews\u00ae. 2025."},{"key":"4205_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ymgme.2017.08.009","volume":"122S","author":"EG Shapiro","year":"2017","unstructured":"Shapiro EG, Jones SA, Escolar ML. Developmental and behavioral aspects of mucopolysaccharidoses with brain manifestations - Neurological signs and symptoms. Mol Genet Metab. 2017;122S:1\u20137.","journal-title":"Mol Genet Metab"},{"key":"4205_CR23","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.ymgme.2017.09.010","volume":"122S","author":"ML Escolar","year":"2017","unstructured":"Escolar ML, Jones SA, Shapiro EG, Horovitz DDG, Lampe C, Amartino H. Practical management of behavioral problems in mucopolysaccharidoses disorders. Mol Genet Metab. 2017;122S:35\u201340.","journal-title":"Mol Genet Metab"},{"key":"4205_CR24","first-page":"129","volume":"13","author":"KA Delaney","year":"2014","unstructured":"Delaney KA, Rudser KR, Yund BD, Whitley CB, Haslett PA, Shapiro EG. Methods of neurodevelopmental assessment in children with neurodegenerative disease: Sanfilippo syndrome. JIMD Rep. 2014;13:129\u201337.","journal-title":"JIMD Rep"},{"issue":"3","key":"4205_CR25","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1308\/205016817821931006","volume":"6","author":"IJ Mills","year":"2017","unstructured":"Mills IJ. A person-centred approach to holistic assessment. Prim Dent J. 2017;6(3):18\u201323.","journal-title":"Prim Dent J"},{"key":"4205_CR26","doi-asserted-by":"crossref","unstructured":"McDonald CM, Elkins JS, Dharmarajan S, Gooch K, Ciobanu T, Lansdall CJ, et al. Caregiver global impression observations from EMBARK: a phase 3 study evaluating delandistrogene moxeparvovec in ambulatory patients with duchenne muscular dystrophy. Neurol Ther. 2024.","DOI":"10.1007\/s40120-024-00685-8"},{"issue":"1","key":"4205_CR27","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s13023-024-03034-y","volume":"19","author":"KS Yee","year":"2024","unstructured":"Yee KS, Lewis S, Evans E, Romano C, Alexanderian D. Caregiver experiences and observations of intrathecal idursulfase-IT treatment in a phase 2\/3 trial in pediatric patients with neuronopathic mucopolysaccharidosis II. Orphanet J Rare Dis. 2024;19(1):110.","journal-title":"Orphanet J Rare Dis"},{"key":"4205_CR28","doi-asserted-by":"publisher","first-page":"1305878","DOI":"10.3389\/fpubh.2024.1305878","volume":"12","author":"DA do Valle","year":"2024","unstructured":"do Valle DA, Bara TDS, Furlin V, Santos M, Cordeiro ML. Psychobehavioral factors and family functioning in mucopolysaccharidosis: preliminary studies. Front Public Health. 2024;12:1305878.","journal-title":"Front Public Health"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04205-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04205-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04205-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:55:19Z","timestamp":1781628919000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13023-026-04205-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4205"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04205-9","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]},"assertion":[{"value":"29 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was not required. Rare Disease Research Partners (RDRP) conducted the research in accordance with the British Healthcare Business Intelligence Association\u2019s Legal and Ethical Guidelines. Online informed consent was obtained from all participants in their local language prior to the interviews. Proof that informed consent was obtained is available upon request for each of the pseudonymized participants. Optional consent for the use of direct quotes was obtained.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent was obtained from participants for the use of quotes and publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"CW and VF are employees of REGENXBIO Inc. DP was an employee of REGEXNBIO at the time of the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"60"}}