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. 2024;11(3):665-677.
doi: 10.3233/JND-230211.

Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3

Amy Wolfe  1   2   3 , Georgia Stimpson  1   3 , Danielle Ramsey  4 , Giorgia Coratti  5   6 , Sally Dunaway Young  7 , Anna Mayhew  8 , Marika Pane  5   6 , Annemarie Rohwer  1   3 , Robert Muni Lofra  8 , Tina Duong  7 , Emer O'Reilly  1   3 , Evelin Milev  1   3 , Matthew Civitello  9   10 , Valeria A Sansone  11 , Adele D'Amico  12 , Enrico Bertini  12 , Sonia Messina  13 , Claudio Bruno  14 , Emilio Albamonte  11 , Elena Mazzone  5   6 , Marion Main  1 , Jacqueline Montes  15 , Allan M Glanzman  16 , Zarazuela Zolkipli-Cunningham  16   17 , Amy Pasternak  18 , Chiara Marini-Bettolo  8 , John W Day  7 , Basil T Darras  18 , Darryl C De Vivo  15 , Giovanni Baranello  1   3 , Mariacristina Scoto  1   3 , Richard S Finkel  9   10 , Eugenio Mercuri  5   6 , Francesco Muntoni  1   3 ; international SMA consortium (iSMAc)
Affiliations

Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3

Amy Wolfe et al. J Neuromuscul Dis. 2024.

Abstract

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS).

Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019).

Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient.

Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex.

Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

Keywords: Spinal muscular atrophy; outcome measure; physical therapists; scoliosis.

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Conflict of interest statement

A.D. has received compensation as a consultant on advisory boards for Roche, Biogen, and AveXis. A.M. has served on medical/scientific advisory boards for Biogen and Roche, and has received fees for consulting and training services for Biogen, Roche, Novartis, and Biohaven. A.M.G. receives fees for consulting services for Biogen, Roche, and Audentes, and licensing fees for co-development of the CHOP INTEND. A.P. has served on medical/scientific advisory boards for AveXis, Biogen, and Roche, and has received fees for consulting services for Biogen, Roche, and Audentes. B.T.D. has served as an ad hoc scientific advisory board member for Audentes, AveXis/Novartis Gene Therapies, Biogen, Pfizer, Sarepta, Vertex, and Roche/Genentech; Steering Committee Chair for Roche FIREFISH and MANATEE studies, and DSMB member for Amicus Inc. and Lexeo Therapeutics; B.T.D. has no financial interests in these companies. B.T.D. has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund, and has received grants from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies; from Biogen for CS11; and from AveXis, Sarepta Pharmaceuticals, Novartis (AveXis), PTC Therapeutics, Roche, Scholar Rock, and Fibrogen. B.T.D. has also received royalties for books and online publications from Elsevier and UpToDate, Inc. C.B. has served as a consultant, speaker in sponsored symposiums, and principal investigator for Roche, and has received personal fees for AveXis and Roche. C.M. has received consultancy honoraria from Biogen, Roche, and Novartis for participation in educational activities/meetings. C.M. has also received research funding from Roche and Biogen to support Adult SMA REACH activity. D.C.D.V has served as an advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis, METAFORA, Roche, Sanofi, Sarepta, Scholar Rock, SMA Foundation, and Ultragenyx, with no financial interests in these companies; has received grants from Cure SMA, Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, National Institutes of Health, and SMA Foundation; has received research funding from Department of Defense, Glut1 Deficiency Foundation, Hope for Children Research Foundation, iSMAC initiative (Biogen), National Institutes of Health, Sanofi, and SMA Foundation; has received clinical trial funding from Ionis, Mallinckrodt, PTC, Santhera, Sarepta, Scholar Rock, and Ultragenyx; serves as the Data Safety Monitoring Committee Chair for Aspa Therapeutics; and is an inventor on a patent for Glut1DS gene therapy. D.R. reports participation to teaching initiatives for Roche. E.A. has served as a consultant and as a speaker in sponsored symposiums for Biogen. E.B. reports participation to Scientific Advisory Boards for Roche, Biogen, PTC Therapeutics, Pfizer, and Novartis. E.B. is involved in clinical trials with Roche, Biogen, Novartis, and PTC Therapeutics. E.Mercuri has participated in advisory boards for SMA studies for AveXis, Biogen, Ionis, Novartis, and Roche; has been a Principal Investigator for ongoing Biogen and Roche clinical trials; and has received research grants from Famiglie SMA Italy, Italian Telethon, Novartis, Scholar Rock, and SMA Europe. E.S.M. reports consultancy fees from Roche, Biogen, Scholar Rock, and Novartis. F.M. reports participation to scientific advisory boards and teaching initiatives for AveXis, Biogen, Roche, and Novartis. E.S.M. is a member of the Rare Disease Scientific Advisory Board for Pfizer. E.S.M. is involved as an investigator in clinical trials from AveXis, Biogen, and Roche. E.S.M. is the principal investigator of the SMA REACH UK clinical network, partially funded by Biogen and by SMA UK. G.B. is principal investigator of clinical trials sponsored by Pfizer, NS Pharma, and Reveragen; has received speaker and/or consulting fees from Sarepta, PTC Therapeutics, Biogen, Novartis Gene Therapies, Inc. (AveXis), and Roche; and has worked as principal investigator of SMA studies sponsored by Novartis Gene Therapies, Inc., and Roche. G.C. reports participation to scientific advisory boards and teaching initiatives for AveXis, Biogen, Roche, and Novartis. J.D. has received personal fees for AveXis, Biogen, Roche, and Novartis. J.M. serves on advisory boards for Biogen, Roche, Genentech, and Sarepta and as a consultant for Scholar Rock and Biogen. She receives grant support from the Muscular Dystrophy Association, Cure SMA, Genentech, and Novartis. M.P. has served as a consultant and as a speaker in sponsored symposiums for Biogen, and has received personal fees for AveXis. M.S. reports participation to scientific advisory boards and teaching initiatives for AveXis, Biogen, and Roche; M.S. is involved as an investigator in clinical trials from AveXis, Biogen, and Roche. R.M.L. has served in advisory boards for Biogen, Roche, and Novartis; has received consulting fees by Roche, Biogen, and Novartis; and research support by Roche and Biogen. R.S.F. has served on medical/scientific advisory boards on SMA-related topics for AveXis, Biogen, Capricor, Families of SMA, Genentech, Ionis Pharmaceuticals, Novartis, Roche, and ScholarRock; received research support from AveXis/Novartis, Biogen/Ionis, Capricor, Roche/Genentech, Scholar Rock, and NIH; and receives license fees for co-development of the CHOP INTEND. S.D.Y. serves on advisory boards for Biogen, Roche, and Scholar Rock, and as a consultant for Biogen, Roche, and Cure SMA. S.D.Y. receives grant support from Cure SMA. S.M. has received honoraria from Biogen, Roche, and Novartis for advisory boards and presentations. T.D. has served on scientific advisory boards for AveXis, Biogen, Roche, Scholar Rock, Novartis, CureSMA, Dyne, and Actigraph; and has received consulting fees Roche, Biogen, Biohaven, Dyne, Sarepta, Solid Bio, Tayjus, Astellas, ATOM, and Trinds. V.S. has served as a consultant and as a speaker in sponsored symposiums for Biogen, and has received personal fees for AveXis. A.W., E.O., E.Milev, G.S., A.R., M.C., M.M., and Z.Z.C. have no conflicting interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Fig. 1
Fig. 1
Average SMA 2 trajectories on the RHS and HFMSE by age and sex (average presented for participants who have not undergone scoliosis surgery) surgery).
Fig. 2
Fig. 2
Average SMA 2 trajectories on the RHS and RULM by age and sex (average presented for participants who have not undergone scoliosis surgery).
Fig. 3
Fig. 3
Average SMA 3a trajectory on the RHS and HFMSE by age and sex (average is presented for participants who have not undergone scoliosis surgery).
Fig. 4
Fig. 4
Average SMA 3a trajectories on the RHS and RULM by age and sex (average presented for participants who have not undergone scoliosis surgery).
Fig. 5
Fig. 5
Average SMA 3b trajectory on the RHS and HFMSE by age.
See this image and copyright information in PMC

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