Loss of ambulation in SMA III at the time of disease-modifying treatments: an international study

Giorgia Coratti^{1

2}, Francesca Bovis³, Valentina Franchino⁴, Jacqueline Montes⁵, Valeria Ada Sansone⁴, Sally Dunaway Young⁶, Chiara Cutrì⁷, Amy Pasternak⁸, Maria Carmela Pera^{1

9}, Marika Pane¹⁰, Allan Glanzman¹¹, Elena Pegoraro¹², Tina Duong⁶, Elena Sogus¹², Maria Sframeli¹³, Sonia Messina¹³, Elzo Cavalcante^{14

15}, Maria Cristina Scoto^{14

15}, Adele D'Amico¹⁶, Rafael Rodriguez-Torres⁵, Tiziana Mongini¹⁷, Lorenzo Maggi¹⁸, Michela Coccia¹⁹, Massimiliano Filosto²⁰, Riccardo Zuccarino²¹, Riccardo Masson²², Giulia Ricci²³, Claudio Bruno²⁴, Lucia Ruggiero²⁵, Veria Vacchiano^{26

27}, Eustachio D'errico²⁸, Lorenzo Verriello²⁹, Vincenzo Nigro³⁰, Gaia Scarpini²⁶, Matteo Garibaldi^{31

32}, Mara Turri³³, Chiara Ticci³⁴, Angela Berardinelli³⁵, Caterina Agosto³⁶, Federica Ricci³⁷, Zarazuela Zolkipli-Cunningham³⁸, Basil T Darras⁸, John Day⁶, Michio Hirano³⁹, Francesco Muntoni^{14

15}, Richard S Finkel⁴⁰, Eugenio Mercuri^{41

2}; international SMA consortium (ISMAC)

Collaborators, Affiliations

Collaborators

international SMA consortium (ISMAC):
Emanuele Maria Costantini, Barbara Risi, Francesca Torri, Michela Catteruccia, Simone Morando, Dario Zoppi, Elena Briganti, Antonio Lauletta, Alice Gardani, Ilaria Cavallina, Giuliana Capece, Luca Bello, Francesca Benedetti, Antonio Trabacca, Teresa Vespino, Francesca Magri, Delia Gagliardi, Irene Bruno, Andrea Magnolato, Alberto Zambon, Stefano Previtali, Stefano Scarparo, Antonio Varone, Ilaria Bitetti, Maria Rosaria Manna, Filippo Brighina, Paolo Alonge, Grazia D'angelo, Sabrina Siliquini, Emer O'Reilly, Emilio Albamonte, Antonella Longo, Giulio Gadaleta, Enrica Rolle, Silvia Bonanno, Amanda Ferrero, Simona Damioli, Salvate Strano, Claudia Dosi, Gabriele Siciliano, Noemi Brolatti, Anna Russo, Rocco Liguori, Maria Elena Pessa, Esther Picillo, Chiara Bravetti, Sophia Paolucci, Matthew Civitello, Anna Capasso, Chiara Arpaia, Marianna Villa, Gianpaolo Cicala, Daniela Leone, Concetta Palermo, Beatrice Berti, Lavinia Fanelli, Sara Carnicella, Roberto De Sanctis, Giulia Norcia, Giulia Stanca, Nicola Forcina, Claire Fitzpatrick, Claudia Faini, Luca Teodani, Giovanni Baranello, Riccardo Not, Antonella Pini, Susan Matesanz, Michele Sacchini, Martina De Maria

Affiliations

¹ Pediatric Neurology, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy.
² Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.
³ University of Genoa, Genoa, Italy.
⁴ Centro Clinico NeMO, Milan, Italy.
⁵ Columbia University, New York, New York, USA.
⁶ Stanford University, Stanford, California, USA.
⁷ Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
⁸ Children's Hospital Boston, Boston, Massachusetts, USA.
⁹ Department of Medicine and Surgery, University of Parma, Parma, Italy.
¹⁰ Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy.
¹¹ Department of Physical Therapy, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹² Department of Neurosciences, University of Padua, Padua, Italy.
¹³ Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
¹⁴ Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK.
¹⁵ National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, London, UK.
¹⁶ Neurosciences, Bambino Gesu Pediatric Hospital IRCCS, Rome, Italy.
¹⁷ Department of Neurosciences, Università degli Studi di Torino, Turin, Italy.
¹⁸ Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy.
¹⁹ Centro Clinico NeMO, Ancona, Italy.
²⁰ Department of Clinical and Experimental Sciences, NeMO-Brescia Clinical Center for Neuromuscular Diseases, University of Brescia, Brescia, Italy.
²¹ Centro Clinico NeMO, Trento, Italy.
²² Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
²³ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
²⁴ Center of Translational and Experimental Myology and Department of Neuroscience, Rehabilitation, Ophthalmology Genetics, Maternal and Child Health, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²⁵ Department of Neurosciences and Reproductive and Odontostomatologic Sciences, Federico II University Hospital, Naples, Italy.
²⁶ IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy.
²⁷ Centro Clinico NeMO, Bologna, Italy.
²⁸ Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy.
²⁹ Neurology Unit, Department of Neurosciences, University Hospital Santa Maria della Misericordia, Udine, Italy.
³⁰ Department of Precision Medicine, University of Campania Luigi Vanvitelli, Caserta, Italy.
³¹ Neurology Mental Health and Sensory Organs (NESMOS), University of Rome La Sapienza, Rome, Italy.
³² Institut de Myologie, Paris, France.
³³ Department of Neurology/Stroke Unit, Ospedale di Bolzano, Bolzano, Italy.
³⁴ Ospedale Pediatrico Meyer, Florence, Italy.
³⁵ Department of Child Neuropsychiatry, Fondazione Istituto Neurologico Nazionale Casimiro Mondino, Pavia, Italy.
³⁶ Padua University Hospital, Padua, Italy.
³⁷ SC Neuropsichiatria Infantile, Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.
³⁸ The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁹ Neurology Department, Columbia University, New York, New York, USA.
⁴⁰ Pediatrics, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁴¹ Pediatric Neurology, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy eugeniomaria.mercuri@unicatt.it.

PMID: 41617535
DOI: 10.1136/jnnp-2025-337505

Free article

Loss of ambulation in SMA III at the time of disease-modifying treatments: an international study

Giorgia Coratti et al. J Neurol Neurosurg Psychiatry. 2026.

Free article

. 2026 Jan 30:jnnp-2025-337505.

doi: 10.1136/jnnp-2025-337505. Online ahead of print.

Authors

Collaborators

international SMA consortium (ISMAC):
Emanuele Maria Costantini, Barbara Risi, Francesca Torri, Michela Catteruccia, Simone Morando, Dario Zoppi, Elena Briganti, Antonio Lauletta, Alice Gardani, Ilaria Cavallina, Giuliana Capece, Luca Bello, Francesca Benedetti, Antonio Trabacca, Teresa Vespino, Francesca Magri, Delia Gagliardi, Irene Bruno, Andrea Magnolato, Alberto Zambon, Stefano Previtali, Stefano Scarparo, Antonio Varone, Ilaria Bitetti, Maria Rosaria Manna, Filippo Brighina, Paolo Alonge, Grazia D'angelo, Sabrina Siliquini, Emer O'Reilly, Emilio Albamonte, Antonella Longo, Giulio Gadaleta, Enrica Rolle, Silvia Bonanno, Amanda Ferrero, Simona Damioli, Salvate Strano, Claudia Dosi, Gabriele Siciliano, Noemi Brolatti, Anna Russo, Rocco Liguori, Maria Elena Pessa, Esther Picillo, Chiara Bravetti, Sophia Paolucci, Matthew Civitello, Anna Capasso, Chiara Arpaia, Marianna Villa, Gianpaolo Cicala, Daniela Leone, Concetta Palermo, Beatrice Berti, Lavinia Fanelli, Sara Carnicella, Roberto De Sanctis, Giulia Norcia, Giulia Stanca, Nicola Forcina, Claire Fitzpatrick, Claudia Faini, Luca Teodani, Giovanni Baranello, Riccardo Not, Antonella Pini, Susan Matesanz, Michele Sacchini, Martina De Maria

Affiliations

¹ Pediatric Neurology, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy.
² Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.
³ University of Genoa, Genoa, Italy.
⁴ Centro Clinico NeMO, Milan, Italy.
⁵ Columbia University, New York, New York, USA.
⁶ Stanford University, Stanford, California, USA.
⁷ Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
⁸ Children's Hospital Boston, Boston, Massachusetts, USA.
⁹ Department of Medicine and Surgery, University of Parma, Parma, Italy.
¹⁰ Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy.
¹¹ Department of Physical Therapy, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹² Department of Neurosciences, University of Padua, Padua, Italy.
¹³ Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
¹⁴ Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK.
¹⁵ National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, London, UK.
¹⁶ Neurosciences, Bambino Gesu Pediatric Hospital IRCCS, Rome, Italy.
¹⁷ Department of Neurosciences, Università degli Studi di Torino, Turin, Italy.
¹⁸ Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy.
¹⁹ Centro Clinico NeMO, Ancona, Italy.
²⁰ Department of Clinical and Experimental Sciences, NeMO-Brescia Clinical Center for Neuromuscular Diseases, University of Brescia, Brescia, Italy.
²¹ Centro Clinico NeMO, Trento, Italy.
²² Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
²³ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
²⁴ Center of Translational and Experimental Myology and Department of Neuroscience, Rehabilitation, Ophthalmology Genetics, Maternal and Child Health, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
²⁵ Department of Neurosciences and Reproductive and Odontostomatologic Sciences, Federico II University Hospital, Naples, Italy.
²⁶ IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy.
²⁷ Centro Clinico NeMO, Bologna, Italy.
²⁸ Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy.
²⁹ Neurology Unit, Department of Neurosciences, University Hospital Santa Maria della Misericordia, Udine, Italy.
³⁰ Department of Precision Medicine, University of Campania Luigi Vanvitelli, Caserta, Italy.
³¹ Neurology Mental Health and Sensory Organs (NESMOS), University of Rome La Sapienza, Rome, Italy.
³² Institut de Myologie, Paris, France.
³³ Department of Neurology/Stroke Unit, Ospedale di Bolzano, Bolzano, Italy.
³⁴ Ospedale Pediatrico Meyer, Florence, Italy.
³⁵ Department of Child Neuropsychiatry, Fondazione Istituto Neurologico Nazionale Casimiro Mondino, Pavia, Italy.
³⁶ Padua University Hospital, Padua, Italy.
³⁷ SC Neuropsichiatria Infantile, Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.
³⁸ The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁹ Neurology Department, Columbia University, New York, New York, USA.
⁴⁰ Pediatrics, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁴¹ Pediatric Neurology, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy eugeniomaria.mercuri@unicatt.it.

PMID: 41617535
DOI: 10.1136/jnnp-2025-337505

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.

Keywords: NEUROMUSCULAR; SPINAL MUSCULAR ATRO; TREATMENT OUTCOME.

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Conflict of interest statement

Competing interests: The authors declare the following competing interests outside the submitted work in the form of advisory board participation, steering committee membership, conference travel support or research grants. GC reports relationships with Biogen, Novartis, Roche and Avexis. JM reports relationships with Genentech/F. Hoffmann-La Roche, Scholar Rock, Biogen and Novartis Gene Therapies. VAS reports relationships with Biogen, Novartis, Roche and Lupin. SDY reports relationships with Genentech/F. Hoffmann-La Roche, Scholar Rock, Biogen and Cure SMA. AP reports relationships with Scholar Rock and Biogen. MCP and MP each report relationships with Biogen, Novartis and Roche. AG reports a relationship with Biogen. TD reports relationships with Genentech/F. Hoffmann-La Roche, Scholar Rock, Biogen, Cure SMA, ActiGraph, Novartis, Dyne, Trinds, Ned Pharma, Ionis, Sarepta, Pfizer, Duchenne UK and PPMD. SM reports relationships with Biogen, Novartis, Roche and Genzyme. EC reports relationships with Biogen and Roche. AD'A reports relationships with Astellas, Biogen, Sanofi, Amicus, Novartis, Roche, Biofen, Pfizer, PTC and Italfarmaco. RR-T reports relationships with Genentech/F. Hoffmann-La Roche, Scholar Rock, Biogen, Cure SMA and NMSG. LM reports relationships with Biogen, Alexion/AstraZeneca, Sanofi, Argenx, UCB and Roche. LM, MF and CB each report relationships with Biogen and Roche. CT reports relationships with Biogen, Roche and Novartis. FM reports relationships with Biogen, Novartis and Roche. RSF reports relationships with Biogen, Novartis, Roche, Scholar Rock and SMA Europe. EM reports relationships with Biogen, Novartis, Roche, Scholar Rock, SMA Europe, Empirion and Cytokinetics. All other authors declare no competing interests.

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Loss of ambulation in SMA III at the time of disease-modifying treatments: an international study

Collaborators

Affiliations

Loss of ambulation in SMA III at the time of disease-modifying treatments: an international study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources

Miscellaneous