Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

Martina Ricci, Gianpaolo Cicala, Anna Capasso, Giorgia Coratti, Simona Fiori, Costanza Cutrona, Adele D'Amico, Valeria A. Sansone, Claudio Bruno, Sonia Messina, Tiziana Mongini, Michela Coccia, Gabriele Siciliano, Giovanni Siciliano, Elena Pegoraro, Riccardo Masson, Massimiliano Filosto, Giacomo P. Comi, Stefania Corti, Serafino CortiDario Ronchi, Lorenzo Maggi, Maria G. D'Angelo, Michele Giovanni D'Angelo Bozzi, Veria Vacchiano, Chiara Ticci, Lucia Ruggiero, Lorenzo Verriello, Federica S. Ricci, Angela L. Berardinelli, Maria Antonietta Maioli, Matteo Garibaldi, Ida Marina Elisabetta Garibaldi, Vincenzo Nigro, Stefano C. Previtali, Maria Carmela Pera, Eduardo Tizzano, Marika Pane, Francesco Danilo Tiziano, Eugenio Maria Mercuri

Research output: Contribution to journalArticle


Objective: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies. Methods: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA). Results: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow-up = 36.9 ± 19 years). 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-sectional 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 = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), 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 (p = 0.009) but not in the pediatric cohort (p = 0.43). Interpretation: Our results expand the existing literature on natural history of 4 SMN2 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. ANN NEUROL 2023;94:1126–1135.
Original languageEnglish
Pages (from-to)1126-1135
Number of pages10
JournalAnnals of Neurology
Publication statusPublished - 2023


  • Spinal Muscular Atrophy


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