Multicenter Study

. 2024 Dec;31(12):e16517.

doi: 10.1111/ene.16517. Epub 2024 Oct 11.

Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded

Giorgia Coratti^{1

2}, Francesca Bovis³, Maria Carmela Pera^{1

2}, Matthew Civitello⁴, Annemarie Rohwer^{5

6}, Francesca Salmin⁷, Allan M Glanzman⁸, Jacqueline Montes⁹, Amy Pasternak¹⁰, Roberto De Sanctis^{1

2}, Sally Dunaway Young¹¹, Tina Duong¹¹, Irene Mizzoni¹², Evelin Milev^{5

6}, Maria Sframeli¹³, Simone Morando¹⁴, Emilio Albamonte⁷, Adele D'Amico¹², Michela Catteruccia¹², Noemi Brolatti¹⁴, Marika Pane^{1

2}, Mariacristina Scoto^{5

6}, Sonia Messina¹³, Jesica Exposito Escudero^{15

16}, Liesbeth De Waele^{17

18}, Michio Hirano⁹, Zarazuela Zolkipli-Cunningham¹⁹, Basil T Darras¹⁰, Enrico Bertini¹², Andres Nascimiento Osorio^{15

16}, Claudio Bruno¹⁴, Natalie Goemans^{17

18}, Valeria A Sansone⁷, John Day¹¹, Giovanni Baranello^{5

6}, Francesco Muntoni^{5

6}, Richard Finkel³, Eugenio Mercuri^{1

2}; ISMAC/international SMA consortium

Collaborators, Affiliations

Collaborators

Affiliations

¹ Pediatric Neurology Unit, Catholic University, Rome, Italy.
² Centro Clinico Nemo, U.O.C. Neuropsichiatria Infantile Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
³ Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
⁴ St Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁵ Department of Developmental Neuroscience, Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK.
⁶ Neuromuscular Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁷ NEMO Center in Milan, Neurorehabilitation Unit, University of Milan, ASST Niguarda Hospital, Milan, Italy.
⁸ Department of Physical Therapy Rehabilitation, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁹ Columbia University Irving Medical Center, New York, New York, USA.
¹⁰ Neuromuscular Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹¹ Department of Neurology and Clinical Neurosciences, Stanford University, Palo Alto, California, USA.
¹² Unit of Neuromuscular and Neurodegenerative Disorders, Translational Paediatrics and Clinical Genetics, Bambino Gesù Children's Hospital, Rome, Italy.
¹³ Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
¹⁴ Center of Translational and Experimental Myology, Department of Neuroscience, Rehabilitation, Ophthalmology Genetics, Maternal and Child Health, IRCCS Istituto Giannina Gaslini and University of Genoa, Genoa, Italy.
¹⁵ Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, CIBERER - ISCIII, Barcelona, Spain.
¹⁶ Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
¹⁷ Department of Child Neurology, University Hospital Leuven, Leuven, Belgium.
¹⁸ Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
¹⁹ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 39392101
PMCID: PMC11555017
DOI: 10.1111/ene.16517

Multicenter Study

Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded

Giorgia Coratti et al. Eur J Neurol. 2024 Dec.

. 2024 Dec;31(12):e16517.

doi: 10.1111/ene.16517. Epub 2024 Oct 11.

Authors

Collaborators

Affiliations

¹ Pediatric Neurology Unit, Catholic University, Rome, Italy.
² Centro Clinico Nemo, U.O.C. Neuropsichiatria Infantile Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
³ Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.
⁴ St Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁵ Department of Developmental Neuroscience, Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK.
⁶ Neuromuscular Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁷ NEMO Center in Milan, Neurorehabilitation Unit, University of Milan, ASST Niguarda Hospital, Milan, Italy.
⁸ Department of Physical Therapy Rehabilitation, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁹ Columbia University Irving Medical Center, New York, New York, USA.
¹⁰ Neuromuscular Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹¹ Department of Neurology and Clinical Neurosciences, Stanford University, Palo Alto, California, USA.
¹² Unit of Neuromuscular and Neurodegenerative Disorders, Translational Paediatrics and Clinical Genetics, Bambino Gesù Children's Hospital, Rome, Italy.
¹³ Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
¹⁴ Center of Translational and Experimental Myology, Department of Neuroscience, Rehabilitation, Ophthalmology Genetics, Maternal and Child Health, IRCCS Istituto Giannina Gaslini and University of Genoa, Genoa, Italy.
¹⁵ Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, CIBERER - ISCIII, Barcelona, Spain.
¹⁶ Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
¹⁷ Department of Child Neurology, University Hospital Leuven, Leuven, Belgium.
¹⁸ Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
¹⁹ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 39392101
PMCID: PMC11555017
DOI: 10.1111/ene.16517

Abstract

Background and purpose: Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease-modifying treatments have reported their efficacy and safety, long-term natural history data are lacking for comparison. The aim of this prospective study was to report 4-year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number.

Methods: The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number.

Results: In SMA type II (n = 226), the 4-year mean change was -2.20 points. The largest mean changes were observed in sitters aged 5-14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4-year mean change was -2.75 points. The largest mean changes were in those aged 7-15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4-year changes.

Conclusions: Our findings provide natural history reference data for comparison with long-term follow-up of clinical trials or real-world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.

Keywords: Hammersmith Functional Motor Scale Expanded; long‐term results; motor function; spinal muscular atrophy.

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Conflict of interest statement

Coratti G, Pera MC, Glanzman A, Scoto M, Montes J, Pasternak A, De Sanctis R, Duong T, Dunaway Young S, Civitello M, Pane M, Albamonte E, Sansone AV, D'Amico A, Bruno C, Messina S, Bertini E, De Waele L, Baranello G, Day J, Muntoni F, Finkel R, Mercuri E report personal fees for advisory boards, steering committee, speaker fees or consultancies from Biogen S.R.L., Roche, Avexis and/or Novartis outside the submitted work; Zolkipli‐Cunningham Z reports support from Cure SMA outside the submitted work; Bovis F, Rohwer A, Goemans N, Darras BT, Nascimiento Osorio A, Hirano M, Sframeli M, Catteruccia M, Mizzoni I, Milev E, Morando S, Brolatti N, Exposito Escudero J, Salmin F have nothing to disclose.

Figures

**FIGURE 1**
Individual trajectories of SMA type II and III patients. (a) SMA type II, (b) SMA type II subdivided into non‐sitters (blue polynomial line) and sitters (dark red polynomial line), (c) SMA type III, (d) SMA type III subdivided into IIIa (black polynomial line) and IIIb (orange polynomial line), non‐sitters (red individual trajectories), sitters (green individual trajectories) and walkers (blue individual trajectories).

**FIGURE 2**
HFMSE 4‐year changes in SMA type II and SMA type III: (a) blue line, SMA type II; yellow line, SMA type III; (b) yellow dotted line, SMA type III; black line, SMA type IIIa; grey line, SMA type IIIb.

See this image and copyright information in PMC

References

1. Dubowitz V. Chaos in the classification of SMA: a possible resolution. Neuromuscul Disord. 1995;5:3‐5. - PubMed
1. Mercuri E, Sumner CJ, Muntoni F, Darras BT, Finkel RS. Spinal muscular atrophy. Nat Rev Dis Primers. 2022;8:52. - PubMed
1. Kolb SJ, Coffey CS, Yankey JW, et al. Natural history of infantile‐onset spinal muscular atrophy. Ann Neurol. 2017;82:883‐891. - PMC - PubMed
1. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83:810‐817. - PMC - PubMed
1. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile‐onset spinal muscular atrophy. N Engl J Med. 2017;377:1723‐1732. - PubMed

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Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded

Collaborators

Affiliations

Long-term natural history in type II and III spinal muscular atrophy: a 4-year international study on the Hammersmith Functional Motor Scale Expanded

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources