{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:38:34Z","timestamp":1786451914250,"version":"build-2736575974"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004337","name":"Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of this study was to provide an overview of the clinical phenotypes associated with 4 <jats:italic>SMN2<\/jats:italic> copies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical phenotypes were analyzed in all the patients with 4 <jats:italic>SMN2<\/jats:italic> copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The cohort includes 169 patients (102 men and 67 women) with confirmed 4 <jats:italic>SMN2<\/jats:italic> copies (mean age at last follow\u2010up\u2009=\u200936.9\u2009\u00b1\u200919\u2009years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross\u2010sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age\u2009=\u200926.8\u2009years\u2009\u00b1\u200916.3 SD). The risk of loss of ambulation was significantly associated with SMA type (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (<jats:italic>p<\/jats:italic>\u2009=\u20090.009) but not in the pediatric cohort (<jats:italic>p<\/jats:italic>\u2009=\u20090.43).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our results expand the existing literature on natural history of 4 <jats:italic>SMN2<\/jats:italic> copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. 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