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However, limited data exist on the outcomes of individuals with 4 copies of\n                    <jats:italic>SMN2<\/jats:italic>\n                    , and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of\n                    <jats:italic>SMN2<\/jats:italic>\n                    from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4\n                    <jats:italic>SMN2<\/jats:italic>\n                    copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.\n                  <\/jats:p>","DOI":"10.1007\/s00415-024-12188-5","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T23:40:12Z","timestamp":1708990812000},"page":"2787-2797","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of 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Orphanet J Rare Dis 16(1):153","journal-title":"Orphanet J Rare Dis"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-024-12188-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-024-12188-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-024-12188-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T03:17:42Z","timestamp":1714187862000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-024-12188-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,27]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["12188"],"URL":"https:\/\/doi.org\/10.1007\/s00415-024-12188-5","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,27]]},"assertion":[{"value":"30 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"AB has received travel expenses and speaker fees from Roche, Novartis, Sanofi Genzyme, Biogen and Santhera. AH has received speaker fees and honoraria for advisor activities from Biogen, Roche, and Novartis Gene Therapies, and research grants from Novartis Gene Therapies. AL is a member of Advisory Boards of Roche Pharma AG, Biogen, Alector and Amylyx. He received compensation for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx and the company Streamed Up! GmbH. He is involved in trials which are sponsored by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, the European Union, BMBF, Biogen and Orphazyme, Ionis Pharmaceuticals, QurAlis and Alector. AM has received advisory board honoraria from Hormosan and Sanofi, outside of the submitted work. AP received compensation for advisory boards, training activities and research grants from Novartis and Biogen. AR received honoraria as speaker from Amylyx Pharmaceuticals and as consultant in advisory boards from Biogen and Argenx. RS received honoraria as speaker from ITF Pharma. AZ received compensation for advisory boards and speaker fees from Biogen, Novartis and Roche. He received research compensation from Biogen. CDW has received honoraria from Biogen as an advisory board member and for lectures and as a consultant and advisory board member from Hoffmann\u2011La Roche. She also received travel expenses from Biogen. CK has received compensation for advisory boards and speaker honoraria from Biogen, Roche and Ipsen, and unrestricted travel grants from Merz and Ipsen, outside of the submitted work. CN has received personal fees from Biogen and Hoffmann\u2013La Roche outside of the submitted work for advisory boards. CW has received honoraria for advisory boards and presentations and travel expenses from Biogen, Avexis\/Novartis and Roche. DZ received compensation from Biogen for participation on advisory boards, from Novartis for consultancy work, and travel compensation from Angelini Pharma outside of the submitted work. GMzH received compensation for serving on scientific advisory boards (Alexion, Roche, LFB, Immunovant) and speaker honoraria (Alexion, LFB). He has received scientific project funding from Biogen and Merck. GW has received advisory board honoraria and speaker fees from Alnylam, Biogen, Hormosan, Pfizer and Sobi outside of the submitted work. HK is serving on a scientific advisory board for Avexis and received travel expenses and speaker honoraria from Biogen, Pfizer, Roche, and Sanofi-Aventis. JJ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis\/Novartis, Biogen, ITF, Roche, PTC, Pfizer and Sarepta Therapeutics. JK received compensation for research and\/or educational and consultancy activities from Biogen, Avexis\/Novartis, Roche and Scholar Rock. KV has received received honoraria as an advisory board member, travel expenses and speaker fees from Biogen, Santhera, Orchard, ITF and Novartis. MB received compensation for advisory boards and speakers honoraria from Novartis, Biogen and Roche. MCW received speaker fees and compensation for advisory boards and consultancy activities from Biogen, Avexis\/Novartis, Roche. MD has received personal fees as speaker\/consultant from Biogen and Roche. MFB has received consultant fees from Biogen, Novartis and Hoffmann-La Roche and Biogen. MG has received an advisory board honorarium from Hoffmann-La Roche and a speaker fee from Novartis outside of the submitted work. MS received compensation for advisory boards from Roche, Eisai and Takeda. MW received advisory board and consultant honoraria from Biogen and Hoffmann-La Roche, and speaker honoraria and travel support for conference attendance from Biogen, outside of the submitted work. OS has served as a member of a scientific advisory board for Avexis and received travel expenses and speaker fees from Biogen. RT received speaker fees and compensation for advisory boards from Biogen, Roche, and PTC. SI received compensation for advisory board and speakers honoraria from Novartis and Roche. SG received consulting fees and speaker fees from Novartis. SP has received speaker fees, non-financial support and research support from Biogen, Roche, AL-S Pharma, Amylyx, Cytokinetics, Ferrer, ITF-Pharma, Zambon, PTC and Sanofi and served on advisory boards of Amylyx, Biogen, Roche, Zambon and ITF Pharma and research grants from the German Neuromuscular Society (DGM) and Neurodegenerative Research outside of the submitted work. TH received compensation for advisory boards, speaker fees and research grants from Roche, Novartis and Biogen. US has served as a member of a scientific advisory board and data safety monitoring board for Biogen, Avexis and Novartis and received speaker fees from Biogen, Avexis, PTC and Sanofi-Aventis. VH received compensation for advisory boards from Avexis\/Novartis and Biogen. WMF has served as a member of a scientific advisory board for Biogen, Avexis, PTC, Sarepta, Sanofi-Aventis, Roche and Cytokinetics and received travel expenses and speaker fees from Biogen, Avexis, Novartis, PTC, Roche, Sarepta and Sanofi-Aventis.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"For the SMArtCARE registry, central ethics approval was obtained by the Ethics committee of the University of Freiburg (EK-Freiburg 56\/18), and local ethics approvals were obtained from all participating centers. SMArtCARE is registered in the German Clinical Trials Registry (DRKS00012699).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent for prospective follow-up and publication was obtained from the participating families.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}