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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., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The Revised upper limb module (RULM) has been increasingly used in clinical trials and in clinical settings. The aim of this study was to use the 'shift analysis' to assess the patterns of lost or gained abilities for each item on the RULM in an untreated cohort, stratified by SMA type, age, SMN2 copy number, and motor functional status. The analysis was performed on 222 12-month paired assessments from 129 individuals (115 assessment from type II and 107 from type III) who had at least two assessments at yearly intervals. There was a loss of one or more activities in 54% in type II and in 29% type III. A gain of one or more activities was found in 42% type II and in 22% type III. There were concomitant gains and losses in 27% in SMA II and in 9% in SMA III. Our results, measuring the number of abilities that are lost or gained, provide an additional method of detecting changes that can be used for the interpretation of the longitudinal data collected in treated SMA individuals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giorgia Coratti reports personal fees from BIOGEN S.R.L. ITALIA, ROCHE, GENESIS PHARMA, NOVARTIS, Biologix, outside the submitted work. Dr Coratti is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Roberto de Sanctis reports personal fees from BIOGEN S.R.L. ITALIA, ROCHE and NOVARTIS outside the submitted work. Dr De Sanctis is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Maria C Pera reports personal fees from ROCHE outside the submitted work. Dr Pera is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Jacqueline Montes reports personal fees from BIOGEN S.R.L. and ROCHE, outside the submitted work. Dr Montes is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Amy Pasternak reports grants from SMA FOUNDATION, during the conduct of the study. Dr Pasternak is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Allan M Glanzman received travel/lodging and compensation from Biogen to serve on an advisory board, received licensing fees from Children's Hospital of Philadelphia for the CHOP-INTEND motor scale, institutional support from NOVARTIS, Biogen and Roche for trial training and/or outcome measure review, and personal compensation from ATOM International (Mallinckrodt Pharmaceuticals, Catabasis Pharmaceuticals, ReveraGen Biopharma) for trial training; Aspa Theraputics for outcomes consulting; and Audentes Therapeutics for outcome review. Dr Glanman is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Sally Dunaway Young reports grants from Stanford Univesity and Columbia University, during the conduct of the study; personal fees from Biogen, Roche/Genentech, Scholar Rock, Cure SMA, grants from SMA Foundation, outside the submitted work. Dr Dunaway Young is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Marika Pane reports personal fees from BIOGEN S.R.L., PTC, NOVARTIS, SAREPTA, outside the submitted work. Dr Pane is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Mariacristina Scoto was CO-PI for SMA REACH UK, during the conduct of the study; received personal fees from ROCHE as PI (jewelfish) and member of advisory board, outside the submitted work. Dr Scoto is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Sonia Messina reports personal fees from BIOGEN S.R.L., NOVARTIS, PTC THERAPEUTICS, SANTHERA, outside the submitted work. Dr Messina is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Adele D'Amico reports personal fees from BIOGEN S.R.L., SAREPTA, NOVARTIS, outside the submitted work. Dr D'Amico is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Emilio Albamonte reports personal fees from BIOGEN S.R.L. outside the submitted work. Dr Albamonte is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Francesca Bovis reports personal fees from BIOGEN outside the submitted work. Basil T Darras reports personal fees from Biogen, NOVARTIS, Roche, Pfizer, Sarepta, PTC, outside the submitted work. Dr Darras is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Enrico Bertini reports personal fees from BIOGEN S.R.L., NOVARTIS, ROCHE, outside the submitted work. Dr Bertini is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Dr Bertini was supported by the Italian Ministry of Health with Current Research funds, Ministry of Health and by Ricerca Finalizzata RF-2019-12370334. Valeria A Sansone reports personal fees from BIOGEN S.R.L, NOVARTIS, SANTHERA, SAREPTA, PTC, outside the submitted work. Dr Sansone is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); John Day reports personal fees from NOVARTIS, ROCHE, BIOGEN S.R.L., Novartis, outside the submitted work. Dr Day is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Francesco Muntoni reports grants from Biogen, grants from Biogen, personal fees from Biogen, grants from NOVARTIS, personal fees from NOVARTIS, personal fees from Roche, during the conduct of the study; personal fees from Pfizer, grants from Sarepta, personal fees from Sarepta, personal fees from PTC, outside the submitted work. Dr Muntoni is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Dr Muntoni institutions receive registry funding (SMA REACH UK) from Biogen, Roche and Novartis; he also declares compensation for educational activities and advisory boards with Roche and Novartis; Darryl C. De Vivo reports personal fees from NOVARTIS, ROCHE, BIOGEN S.R.L., Cytokinetics Pharmaceuticals, outside the submitted work. Dr De Vivo is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Giovanni Baranello reports personal fees from NOVARTIS, ROCHE, BIOGEN S.R.L., Novartis, outside the submitted work. Dr Baranello is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Richard Finkel reports personal fees from NOVARTIS, ROCHE, BIOGEN S.R.L., Novartis, outside the submitted work. Dr Finkel is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Eugenio Mercuri reports personal fees from NOVARTIS, ROCHE, BIOGEN S.R.L., PTC THERAPEUTICS, SAREPTA, SANTHERA, SCHOLAR ROCK, outside the submitted work. Dr Mercuri is affiliated with an institution that receives funds for a SMA disease registry (ISMAR); Annemarie Rohwer, Irene Mizzoni, Simone Morando, Evelin Milev, Michela Catteruccia, Noemi Brolatti, Francesca Salmin, Matthew Civitello, Maria Sframeli, Zarazuela Zolkipli-Cunningham, Michio Hirano, Tina Duong, are affiliated with an institution that receives funding from BIOGEN, ROCHE and NOVARTIS for a SMA disease registry (ISMAR),, (Copyright © 2024. Published by Elsevier B.V.)

Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups., Competing Interests: Declaration of competing interest Authors’ declaration of financial interests/personal relationships statements are provided as supplementary material., (Copyright © 2024. Published by Elsevier B.V.)

Background and Purpose: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort., Methods: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire., Results: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type., Conclusions: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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.

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

The purpose of this study was to quantitate motor performance in 196 genetically confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate the test-retest reliability of measures of motor performance in young DMD boys, and to assess correlations among the different functional outcomes including timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a comparative effectiveness study of different steroid regimens in DMD. Eligible boys had to be able to rise from the floor independently and to perform pulmonary function testing consistently. The boys were evaluated with standardized assessments at the screening and baseline visits at 32 sites in 5 countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from floor, timed 10 m walk/run, six-minute walk distance, North Star Ambulatory Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9 years (range 4.1-8.1 years). Test-retest reliability was high for functional assessments, regardless of time lag between assessments (up to 90 days) and for the majority of age groups. Correlations were strong among the functional measures and timed tests, less so with FVC. Physiotherapy measures are reliable in a young, steroid-naïve population and rise from floor velocity appears to be a sensitive measure of strength in this population., Competing Interests: Declaration of Competing Interests Anna G. Mayhew has participated in SAB meetings for Roche, Regenxbio, Summit, PTC and Biogen and performs Consultancy work (training physiotherapists for trial in DMD) for Roche, Pfizer, PTC, Summit, Sarepta, Lysogene, Italfarmaco, Amicus, Biogen and Avexis. Dionne Moat provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd, Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd, Reveragen, Sarepta Therapeutics), outside the submitted work. Michael McDermott has been supported by a research grant from PTC Therapeutics, has received compensation for consulting from Fulcrum Therapeutics, Inc., and NeuroDerm, Ltd., and has served on Data and Safety Monitoring Boards (DSMBs) for AstraZeneca, Eli Lilly and Company, Catabasis Pharmaceuticals, Inc., Vaccinex, Inc., Cynapsus Therapeutics, Neurocrine Biosciences, Inc., Voyager Therapeutics, Prilenia Therapeutics Development, Ltd., ReveraGen BioPharma, Inc., and NS Pharma, Inc. Michelle Eagle is Managing Director at ATOM International Limited and is contracted with the following companies through ATOM: Amicus, Biomarin, Capricor, Catabasis, Denali, Dyne, Edgewise, Faraday, Fibrogen, Genethon, Italfarmaco, Lysogen, Modis, NSPharma, PTC, Sarepta, Solid, Referagen. Robert Griggs receives research support from the NIH, the Muscular Dystrophy Association, the Parent Project for Muscular Dystrophy, and from Sarepta Biopharma, PTC Therapeutics and Santhera Pharmaceuticals. He serves as a Consultant for Strongbridge and Stealth Pharmaceuticals. He is Chair of a DSMB for Solid Pharmaceuticals. He receives monies for editorial work from Elsevier as an Editor of Cecil Essentials and Cecil Textbook of Medicine. He serves as Chair of the Research Advisory Committee and is a Board Member of the American Brain Foundation. He is on the Executive Committee of the Muscle Study Group, which receives support for its activities from Pharmaceutical companies. Meredith K. James provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd, Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd, Reveragen, Sarepta Therapeutics), outside the submitted work. MKJ has received payment for participation on advisory boards for F. Hoffman La Roche AG, PTC Therapeutics and fee support for PhD studies from the Jain Foundation, outside the submitted work. Robert Muni-Lofra has participated in the advisory board for Biogen and Roche and performs consultancy work (training physiotherapists for trial in DMD and SMA) for Roche, Pfizer, PTC, Summit, Sarepta, Italfarmaco, Amicus, Biogen and Avexis. Lindsey Pallant has performed consultancy work (workshops and training physiotherapists in trials for DMD) for PTC and Sarepta. Katy Eichinger has received personal compensation for serving on advisory boards and/or as a consultant for Ionis, Biogen, Acceleron, Fulcrum, Avidity, PTC and the Myotonic Dystrophy Foundation. Dr. Eichinger has received personal compensation for serving as a speaker from Cure SMA, FSH Society, and Ology. She has received research/grant support from the CMTA. Heather McMurchie has received financial support from PTC and Biogen to access and provide training. Marina DiMarco attended a World Muscle Society conference sponsored by PTC Therapeutics and is a Consultant Physiotherapist presenting at PTC workshops. Lindsay N. Alfano provides consultancy services through ATOM International, Ltd for the following companies: Amicus Therapeutics Pty Ltd, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics); reports royalties and other support from Sarepta Therapeutics; royalties for licensed technologies; other support from Novartis Gene Therapies; advisory board for Biogen. Linda P. Lowes provides consultancy services through ATOM International, Ltd for the following companies: Amicus Therapeutics Pty Ltd, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics); reports royalties and other support from Sarepta Therapeutics; royalties for licensed technologies; other support from Novartis Gene Therapies; advisory board for Biogen. Amy Pasternak has participated in advisory boards for Roche, Biogen, Avexis, Scholar Rock and Audentes. Victoria Kern has received an honorarium from the MDA USA for a presentation. Cheryl Scholtes has sat on advisor panels for Biogen Canada and Roche Canada, and has been provided education on behalf of Biogen Canada and Roche Canada. Catherine Lacroix has acted as a consultant and advisory board participant to Biogen. Katherine Kundrat has participated in an advisory board for Biogen. Michela Guglieri is the study chair for a ReveraGen study. MG has research collaborations with ReveraGen and Sarepta. MG is (has been over the past 5 years) PI for clinical trials sponsored by Pfizer, Italfarmaco, Santhera, ReveraGen, Dynacure, Roche, PTC, Summit. MG has been participating in advisory boards for Pfizer, NS Pharma, Dyne (consultancies through Newcastle University). MG has performed consultancy work (speaker) for Sarepta. Declarations of interest: none for remaining authors, (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches., Competing Interests: Declarations of Competing Interest Giorgia Coratti reports personal fees from BIOGEN S.R.L. ITALIA, ROCHE, GENESIS PHARMA, AVEXIS, Biologix, outside the submitted work; Roberto de Sanctis reports personal fees from BIOGEN S.R.L. ITALIA and AVEXIS outside the submitted work; Maria C Pera reports personal fees from ROCHE outside the submitted work; Jacqueline Montes reports personal fees from BIOGEN S.R.L. and ROCHE, outside the submitted work Amy Pasternak reports grants from SMA FOUNDATION, during the conduct of the study; Elena Stacy Mazzone reports personal fees from BIOGEN S.R.L., ROCHE, AVEXIS, SCHOLAR ROCK, outside the submitted work; Allan M Glanzman received travel/lodging and compensation from Biogen to serve on an advisory board, received licensing fees from Children's Hospital of Philadelphia for the CHOP-INTEND motor scale, institutional support from AveXis, Biogen and Roche for trial training and/or outcome measure review, and personal compensation from ATOM International (Mallinckrodt Pharmaceuticals, Catabasis Pharmaceuticals, ReveraGen Biopharma) for trial training; Aspa Theraputics for outcomes consulting; and Audentes Therapeutics for outcome review. Sally Dunaway Young reports grants from Stanford Univesity and Columbia University, during the conduct of the study; personal fees from Biogen, Roche/Genentech, Scholar Rock, Cure SMA, grants from SMA Foundation, outside the submitted work; Marika Pane reports personal fees from BIOGEN S.R.L., PTC, AVEXIS, SAREPTA, outside the submitted work; Mariacristina Scoto was CO-PI for SMA REACH UK, during the conduct of the study; received personal fees from ROCHE as PI (jewelfish) and member of advisory board, outside the submitted work; Sonia Messina reports personal fees from BIOGEN S.R.L., AVEXIS, PTC THERAPEUTICS, SANTHERA, outside the submitted work; Adele D'Amico reports personal fees from BIOGEN S.R.L., SAREPTA, NOVARTIS, outside the submitted work; Emilio Albamonte reports personal fees from BIOGEN S.R.L. outside the submitted work; Basil T Darras reports personal fees from Biogen, Avexis, Roche, Pfizer, Sarepta, PTC, outside the submitted work; Enrico Bertini reports personal fees from BIOGEN S.R.L., AVEXIS, ROCHE, outside the submitted work; Valeria A Sansone reports personal fees from BIOGEN S.R.L, AVEXIS, SANTHERA, SAREPTA, PTC, outside the submitted work; John Day reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., Novartis, outside the submitted work Claudio Bruno reports personal fees from Biogen, from Avexis, from Roche, outside the submitted work; Francesco Muntoni reports grants from Biogen, personal fees from Biogen, grants from Avexis, personal fees from Avexis, personal fees from Roche, during the conduct of the study; personal fees from Pfizer, grants from Sarepta, personal fees from Sarepta, personal fees from PTC, outside the submitted work; Darryl C. De Vivo reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., Cytokinetics Pharmaceuticals, outside the submitted work; Richard Finkel reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., Novartis, outside the submitted work; Eugenio Mercuri reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., PTC THERAPEUTICS, SAREPTA, SANTHERA, outside the submitted work; Evelin Milev, Laura Antonaci, Annalia Frongia, Matthew Civitello, Maria Sframeli, Massimo Russo, Tina Duong, have nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 mo., Methods: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-mo changes also included the analysis of concordance between scales with changes grouped as stable (±2 points), improved (>+2) or declined (>-2)., Results: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2, the point of slope change was 4.1 y for the HFMSE and 5.8 for the RULM, while for type 3, it was 6 y for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least two assessments at 12 mo. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups., Discussion: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3., (© 2021 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Objective: We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort., Methods: Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment., Results: Over 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT., Interpretation: Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study., Competing Interests: Declaration of Competing Interest GC, RDS, JM, AMG, SDY, MP, SM, ADA, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees BIOGEN S.R.L. outside the submitted work; GC, MCP, RDS, JM, AMG, SDY, MS, BTD, EB, JD, FM, DCDV, RF, CB, EM reports personal fees ROCHE outside the submitted work; GC reports personal fees GENESIS PHARMA and Biologix outside the submitted work; GC, RDS, AMG, MP, SM, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees AVEXIS outside the submitted work; AP, SDY, reports personal fees SMA FOUNDATION outside the submitted work; SDY reports personal fees SCHOLAR ROCK outside the submitted work; ADA, JD, RF reports personal fees NOVARTIS outside the submitted work; SL, SC, LA, AF, FS, PT, MC, TD, have nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status., Methods: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments., Results: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (β = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (β = -1.15, p < 0.0001) and IIIB (β = -0.69, p = 0.002)., Interpretation: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117., (© 2020 American Neurological Association.)

Background: Previous research suggests that artificial agents may be a promising source of social support for humans. However, the bulk of this research has been conducted in the context of social support interventions that specifically address stressful situations or health improvements. Little research has examined social support received from artificial agents in everyday contexts., Objective: Considering that social support manifests in not only crises but also everyday situations and that everyday social support forms the basis of support received during more stressful events, we aimed to investigate the types of everyday social support that can be received from artificial agents., Methods: In Study 1, we examined publicly available user reviews (N=1854) of Replika, a popular companion chatbot. In Study 2, a sample (n=66) of Replika users provided detailed open-ended responses regarding their experiences of using Replika. We conducted thematic analysis on both datasets to gain insight into the kind of everyday social support that users receive through interactions with Replika., Results: Replika provides some level of companionship that can help curtail loneliness, provide a "safe space" in which users can discuss any topic without the fear of judgment or retaliation, increase positive affect through uplifting and nurturing messages, and provide helpful information/advice when normal sources of informational support are not available., Conclusions: Artificial agents may be a promising source of everyday social support, particularly companionship, emotional, informational, and appraisal support, but not as tangible support. Future studies are needed to determine who might benefit from these types of everyday social support the most and why. These results could potentially be used to help address global health issues or other crises early on in everyday situations before they potentially manifest into larger issues., (©Vivian Ta, Caroline Griffith, Carolynn Boatfield, Xinyu Wang, Maria Civitello, Haley Bader, Esther DeCero, Alexia Loggarakis. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 06.03.2020.)

The positive outcome of different therapeutic approaches for spinal muscular atrophy (SMA) in clinical trials and in clinical practice have highlighted the need to establish if functional changes are associated with possible changes of patient health-related quality of life or have an effect on activities of daily living and caregiver burden. The aim of this paper is to provide a critical review of the tools previously or currently used to measure quality of life, activity of daily living, and caregiver burden in SMA. We identified 36 measures. Only 6 tools were specifically developed for SMA while the others had been used and at least partially validated in wider groups of neuromuscular disorders including SMA. Twelve of the 36 focused on health-related quality of life, 5 on activities of daily living and 9 on caregiver burden. Ten included a combination of items. The review provides a roadmap of the different tools indicating their suitability for different SMA types or age groups. Scales assessing activities of daily living and care burden can provide patients and carers perspective on functional changes over time that should be added to the observer rated scales used in clinic., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We report the development of a new disease registry on SMA as the result of a collaboration among three national networks in United States, Italy, and United Kingdom in partnership with a biotechnology company and with the support of advocacy groups. The aim of establishing a large collaborative registry within academic centers was to establish a structured but flexible system for collection of prospective, highly curated data that will deeply phenotype all patients with SMA and follow them longitudinally over several years. This paper describes the process leading to the development of the registry including the identification of the relevant data elements, the design of an electronic CRF with a shared data dictionary, the piloting of the first version and the definition of the final version. The registry will provide a central structure for conducting academic studies based on a much larger cohort of patients than those available in the individual networks. Due to the quality control of the data collected the registry can also be used for postmarketing purposes, allowing to share, in a transparent and controlled way, real-world data with pharmaceutical partners, drug regulatory agencies, and advocacy groups for better understanding of safety and effectiveness of new treatments., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures., Methods: Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded., Results: A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive., Conclusions: Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 --2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6-10: -7.9 m/year; 11-19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To characterize the use of physical therapy (PT) and occupational therapy (OT) consultation in our pediatric intensive care unit (PICU)., Materials and Methods: We studied children aged 1week-18years admitted to a tertiary care PICU for ≥3days. Patient characteristics, details of PT and OT sessions and adverse events were collected. A multivariable logistic regression was performed to determine factors associated with receipt of PT and OT consultation with propensity analysis followed by a regression for factors associated with outcome., Results: Of 138 children studied, 40 (29%) received PT and OT consultation. Services were initiated 6.9±10.0 (mean±standard deviation) days after PICU admission. Range of motion (83%) was the most common therapy provided and 28% of patients were ambulated. Sixty-four of 297 (21.5%) sessions were deferred and 7 (2.4%) sessions were terminated early due to physiologic instability with no serious adverse events. Children who received PT and OT were older, more likely to require neuromuscular blocking agents, and had lower pre-PICU POPC scores (all p<0.05)., Conclusions: Data are needed to inform on the efficacy of rehabilitative therapies initiated in the ICU to improve outcome for critically ill children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients., Methods: An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale., Results: Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups., Conclusions: The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi-center clinical research. Muscle Nerve 55: 869-874, 2017., (© 2016 Wiley Periodicals, Inc.)

Background: Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients' and caregivers' views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE)., Methods: First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE., Results: Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2., Conclusions: Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers.

Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.