Loss of ambulation in SMA III at the time of disease-modifying treatments: an international study
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by survival motor neuron (SMN1) deletion. While loss of ambulation in SMA type III typically occurs at a median age of 13.4 years, outcomes in the treatment era remain unclear. This study aims to address that gap by investigating ambulation outcomes in individuals with type III receiving disease-modifying therapies. METHODS: This retrospective study analysed prospectively collected international data. Time-dependent Cox models assessed the association between treatment initiation and age at loss of ambulation, adjusting for age at onset, sex, SMN2 copies, birth year and country. Treatment was modelled as a time-dependent covariate to avoid immortal time bias. Descriptive analyses used Mann-Whitney U and χ² tests. RESULTS: Among 555 individuals with type III, treatment halved the risk of ambulation loss (HR=0.50), with median loss at 44 vs 32 years in treated and untreated groups. Later onset, ≥4 SMN2 copies and female sex were also protective. The treatment effect was significant in type IIIA (HR=0.34) but not IIIB, with no significant interactions by sex, country or SMN2, though effects remained directionally protective. CONCLUSIONS: Treatment in type III reduced the risk of ambulation loss by 50%, extending median ambulation by 12 years, with the greatest benefit in type IIIA. Later onset, female sex and higher SMN2 copy number were also protective but did not modify treatment effect. These findings underscore the value of early treatment and support its broad use to preserve ambulation across clinical subgroups.
Authors: Giorgia Coratti, Francesca Bovis, Valentina Franchino, Jacqueline Montes, Valeria Ada Sansone, Sally Dunaway Young, Chiara Cutrì, Amy Pasternak, Maria Carmela Pera, Marika Pane, Allan Glanzman, Elena Pegoraro, Tina Duong, Elena Sogus, Maria Sframeli, Sonia Messina, Elzo Cavalcante, Maria Cristina Scoto, Adele D’Amico, Rafael Rodriguez-Torres, Tiziana Mongini, Lorenzo Maggi, Michela Coccia, Massimiliano Filosto, Riccardo Zuccarino, Riccardo Masson, Giulia Ricci, Claudio Bruno, Lucia Ruggiero, Veria Vacchiano, Eustachio D’errico, Lorenzo Verriello, Vincenzo Nigro, Gaia Scarpini, Matteo Garibaldi, Mara Turri, Chiara Ticci, Angela Berardinelli, Caterina Agosto, Federica Ricci, Zarazuela Zolkipli-Cunningham, Basil T Darras, John Day, Michio Hirano, Francesco Muntoni, Richard S Finkel, Eugenio Mercuri
Institutions: Università Cattolica del Sacro Cuore, Agostino Gemelli University Polyclinic, University of Genoa, Centro Clinico Nemo, Columbia University, Stanford University, Boston Children's Hospital, University of Parma, Children's Hospital of Philadelphia, University of Padua, University of Messina, Great Ormond Street Hospital, National Institute for Health and Care Research, NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, University of Turin, Fondazione IRCCS Istituto Neurologico Carlo Besta, University of Brescia, University of Pisa, Istituto Giannina Gaslini, Federico II University Hospital, Istituto delle Scienze Neurologiche di Bologna, University of Bari Aldo Moro, University of Udine, Ospedale Santa Maria della Misericordia di Udine, University of Campania "Luigi Vanvitelli", Institut de Myologie, Sapienza University of Rome, Ospedale di Bolzano, Meyer Children's Hospital, Fondazione Istituto Neurologico Nazionale Casimiro Mondino, Azienda Ospedale - Università Padova, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, St. Jude Children's Research Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G296371341, G5062221813
OpenAlex ID: W7126187927