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Neuromuscular
Original research
Adults with spinal muscular atrophy: a large-scale natural history study shows gender effect on disease
  1. Lorenzo Maggi1,
  2. Luca Bello2,
  3. Silvia Bonanno1,
  4. Alessandra Govoni3,4,
  5. Claudia Caponnetto5,
  6. Luigia Passamano6,
  7. Marina Grandis5,7,
  8. Francesca Trojsi8,
  9. Federica Cerri9,
  10. Alice Gardani10,
  11. Manfredi Ferraro11,
  12. Giulio Gadaleta11,
  13. Vittoria Zangaro2,
  14. Luca Caumo2,
  15. Mariantonietta Maioli12,
  16. Raffaella Tanel13,
  17. Elena Saccani14,
  18. Megi Meneri3,
  19. Veria Vacchiano15,16,
  20. Giulia Ricci4,
  21. Gianni Sorarù2,
  22. Eustachio D'Errico17,
  23. Sara Bortolani11,
  24. Giovanni Pavesi18,
  25. Cinzia Gellera19,
  26. Riccardo Zanin20,
  27. Stefania Corti3,
  28. Mauro Silvestrini21,22,
  29. Luisa Politano6,
  30. Angelo Schenone5,7,
  31. Stefano Carlo Previtali9,
  32. Angela Berardinelli10,
  33. Mara Turri23,
  34. Lorenzo Verriello24,
  35. Michela Coccia21,
  36. Renato Mantegazza1,
  37. Rocco Liguori15,16,
  38. Massimiliano Filosto25,26,
  39. Gianni Marrosu12,
  40. Francesco Danilo Tiziano27,28,
  41. Gabriele Siciliano4,
  42. Isabella Laura Simone17,
  43. Tiziana Mongini11,
  44. Giacomo Comi3,29,
  45. Elena Pegoraro2
  1. 1 Neuroimmunology and Neuromuscular Disease Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  2. 2 Department of Neurosciences, University of Padova, Padova, Italy
  3. 3 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
  4. 4 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  5. 5 IRCCS Ospedale Policlinico San Martino, Genova, Italy
  6. 6 Cardiomyology and Medical Genetics Unit, University Hospital “L Vanvitelli”, Napoli, Italy
  7. 7 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Università di Genova, Genova, Italy
  8. 8 Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy
  9. 9 Department of Neurology, IRCCS Ospedale San Raffaele, Milano, Italy
  10. 10 IRCCS Mondino Foundation, Pavia, Italy
  11. 11 Department of Neurosciences Rita Levi Montalcini, University of Turin, Turin, Italy
  12. 12 Ospedale Binaghi, Cagliari, Italy
  13. 13 U.O. Neurologia, S. Chiara Hospital, Trento, Italy
  14. 14 Specialistic Medicine Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
  15. 15 IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy
  16. 16 Department of Biomedical and Neuromotor Sciences, Universita degli Studi di Bologna, Bologna, Italy
  17. 17 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
  18. 18 Department of Medicine and Surgery, University of Parma, Parma, Italy
  19. 19 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
  20. 20 Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  21. 21 Department of Neurological Sciences, Ospedali Riuniti di Ancona, Ancona, Italy
  22. 22 Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy
  23. 23 Department of Neurology/Stroke Unit, San Maurizio Hospital, Bolzano, Italy
  24. 24 Department of Neurosciences, Santa Maria della Misericordia University Hospital, Udine, Italy
  25. 25 Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
  26. 26 NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy
  27. 27 Department of Life Sciences and Public Health, Section of Genomic Medicine, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy
  28. 28 Department of Laboratory Science and Infectious Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
  29. 29 Department of Pathophysiology and Transplantation (DEPT), Dino Ferrari Centre, University of Milan, Milano, Italy
  1. Correspondence to Dr Lorenzo Maggi, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milano, Italy; lorenzo.maggi{at}istituto-besta.it

Abstract

Background Natural history of spinal muscular atrophy (SMA) in adult age has not been fully elucidated yet, including factors predicting disease progression and response to treatments. Aim of this retrospective, cross-sectional study, is to investigate motor function across different ages, disease patterns and gender in adult SMA untreated patients.

Methods Inclusion criteria were as follows: (1) clinical and molecular diagnosis of SMA2, SMA3 or SMA4 and (2) clinical assessments performed in adult age (>18 years).

Results We included 64 (38.8%) females and 101 (61.2%) males (p=0.0025), among which 21 (12.7%) SMA2, 141 (85.5%) SMA3 and 3 (1.8%) SMA4. Ratio of sitters/walkers within the SMA3 subgroup was significantly (p=0.016) higher in males (46/38) than in females (19/38). Median age at onset was significantly (p=0.0071) earlier in females (3 years; range 0–16) than in males (4 years; range 0.3–28), especially in patients carrying 4 SMN2 copies. Median Hammersmith Functional Rating Scale Expanded scores were significantly (p=0.0040) lower in males (16, range 0–64) than in females (40, range 0–62); median revised upper limb module scores were not significantly (p=0.059) different between males (24, 0-38) and females (33, range 0–38), although a trend towards worse performance in males was observed. In SMA3 patients carrying three or four SMN2 copies, an effect of female sex in prolonging ambulation was statistically significant (p=0.034).

Conclusions Our data showed a relevant gender effect on SMA motor function with higher disease severity in males especially in the young adult age and in SMA3 patients.

  • SPINAL MUSCULAR ATRO
  • NEUROMUSCULAR
  • MOTOR NEURON DISEASE

Data availability statement

Data are available on reasonable request. Data are available on reasonable request. All anonymised data from this study will be shared by request from any qualified investigator to the corresponding author. Data reuse is permitted only for academic purposes.

https://doi.org/10.1136/jnnp-2022-329320

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    Data availability statement

    Data are available on reasonable request. Data are available on reasonable request. All anonymised data from this study will be shared by request from any qualified investigator to the corresponding author. Data reuse is permitted only for academic purposes.

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    Footnotes

    • GC and EP are joint senior authors.

    • LM and LB contributed equally.

    • Correction notice Since this article was first published, figure 1 has been replaced to include a legend. This informs readers which colours relate to male and female results.

    • Contributors LM planned the study, performed data analysis and their interpretation, drafted the manuscript and submitted the manuscript. LB performed data analysis and their interpretation and drafted the manuscript. SB collected data, contributed to data interpretation and revised the manuscript. AG collected data and revised the manuscript. CC collected data and revised the manuscript. LP collected data and revised the manuscript. MG collected data and revised the manuscript. FT collected data and revised the manuscript. FC collected data and revised the manuscript. AG collected data and revised the manuscript. MF collected data and revised the manuscript. GG collected data and revised the manuscript. VZ collected data and revised the manuscript. LC collected data and revised the manuscript. MM collected data and revised the manuscript. RT collected data and revised the manuscript. ES collected data and revised the manuscript. MM collected data and revised the manuscript. VV collected data and revised the manuscript. GR collected data and revised the manuscript. GS collected data and revised the manuscript. collected data and revised the manuscript. ED'E collected data and revised the manuscript. SB collected data and revised the manuscript. GP contributed to data interpretation and revised the manuscript. CG collected data, contributed to data interpretation and revised the manuscript. RZ collected data, contributed to data interpretation and revised the manuscript. SC contributed to data interpretation and revised the manuscript. MS contributed to data interpretation and revised the manuscript. LP collected data, contributed to data interpretation and revised the manuscript. AS contributed to data interpretation and revised the manuscript. SCP collected data, contributed to data interpretation and revised the manuscript. AB collected data, contributed to data interpretation and revised the manuscript. MT collected data and revised the manuscript. LV collected data and revised the manuscript. MC collected data, contributed to data interpretation and revised the manuscript. RM contributed to data interpretation and revised the manuscript. RL contributed to data interpretation and revised the manuscript. MF collected data, contributed to data interpretation and revised the manuscript. GM contributed to data interpretation and revised the manuscript. FDT collected data, contributed to data interpretation and revised the manuscript. GS contributed to data interpretation and revised the manuscript. ILS contributed to data interpretation and revised the manuscript. TM contributed to data interpretation and revised the manuscript. GC planned the study, contributed to interpretation of data and drafted the manuscript. EP planned the study, contributed to interpretation of data and drafted the manuscript.

      LM acts as guarantoor.

    • Funding This work was supported/partially supported by the Italian Ministry of Health (RRC).

    • Competing interests LM has received honoraria for speaking, advisory boards and compensation for congress participations from Sanofi Genzyme, Roche and Biogen, outside the submitted work. LB participated in advisory boards for PTC Therapeutics, Sarepta Therapeutics, Edgewise Therapeutics, Epirium Bio and has received speaker honoraria from PTC Therapeutics and participated in research sponsored by Santhera Pharmaceuticals. SB has received funds for travel and congress participation from Sanofi Genzyme and Biogen. MG has received honoraria for speaking from Pfizer, Alnylam, Biogen and Sanofi-Aventis and has received financial support for research, not related to the study described in this manuscript, from Sanofi-Aventis. SCP has been Scientific board member for Esperare and Sarepta and PI of clinical trials for Esperare, FibroGen, Wave, Mallinckrodt, Dyne, Adienne. MT has received compensation for congress participations from Roche and Biogen. MC has received honoraria for speaking, advisory boards and compensation for congress participations from Roche and Biogen. RM has received funding for travel, meeting attendance or Advisory Board participation from Alexion, Argenx, Biomarin, Catalyst, SANOFI, Regeneron and UCB. RL reports personal fees from Biogen, Sanofi- Genzyme, Argon Healthcare s.r.l., Amicus Therapeutics s.r.l. and Alfasigma for Advisory Board consultancy and Lecture fees from Dynamicom Education, SIMG Service, Adnkronos salute unipersonale s.r.l. and DOC Congress s.r.l. outside the submitted work. ILS has received compensation for congress and honoraria for speaking from Biogen, Sanofi Genzyme, Roche, and Celgene Bristol Myers Squibb. TM has received honoraria for speaking, advisory boards and compensation for congress participations from Sanofi Genzyme, Roche and Biogen, outside the submitted work. GC has received compensation for participation ad advisory board for Roche, Sarepta and Italfarmaco. EP reports personal fees from Sarepta, grants and non-financial support from Santhera, personal fees and nonfinancial support from PTC Pharmaceuticals, non-financial support from Genzyme, personal fees from Roche, outside the submitted work.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.