Publications

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder that is caused by a mutation in the dystrophin gene. The disease is characterized by progressive weakness of skeletal muscle, resulting in loss of ambulation and eventually respiratory insufficiency. Cardiac muscle is also involved, and cardiomyopathy is a prominent feature of DMD. The care of patients with DMD has changed in important ways over the past 15 years, with the use of chronic steroid therapy combined with noninvasive respiratory support such as continuous positive airway pressure for home use. More recently, therapies targeting specific genetic mutations in DMD have been approved, using gene-skipping oligonucleotides, and many other novel therapies are being evaluated in clinical trials, including mini-dystrophin genes delivered by viral vectors. In view of this new era in care and outcomes, it is appropriate to review the role of advanced cardiac therapies such as ventricular assist devices and heart transplantation in the care of this population. In September 2024, a group of healthcare professionals with expertise in DMD and heart failure convened to review this topic; the consensus opinion of this group (DMD Cardiac Care Consortium) is presented in this manuscript.

View details for DOI 10.1111/petr.70253

View details for PubMedID 41424087

Abstract

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and severely affects multiple organ systems, including the brain, heart, skeletal muscle, and gastrointestinal (GI) tract. Despite 80% of individuals with DM1 experiencing GI dysfunction that affects their daily life, the mechanisms of GI dysmotility in DM1 remain an understudied aspect of the disease. DM1 is caused by a CTG repeat expansion in the DMPK gene that, when expressed as an expanded CUG repeat RNA, sequesters and reduces the activity of the muscleblind-like (MBNL) RNA-binding protein family. We developed a mouse line with conditional, smooth muscle-specific knockout of Mbnl1 and Mbnl2 to model and investigate myogenic mechanisms contributing to GI dysmotility in DM1. Mice with Mbnl knockout exhibited delayed GI transit of small and large bowel in vivo and increased smooth muscle contractile tone of jejunum and colon segments ex vivo. Smooth muscle from the jejunum and colon showed no histopathology suggesting an intrinsic defect and contained increased phosphorylation of the 20 kDa myosin light chain (Mlc20), consistent with increased contraction. RNA sequencing of mouse and human DM1 GI samples enriched for smooth muscle revealed conserved misregulated alternative splicing of transcripts associated with the regulation of Mlc20 phosphorylation and smooth muscle contraction. These findings demonstrate that Mbnl knockout disrupts the regulation of contraction dynamics and causes GI smooth muscle hyperactivity, suggesting that therapeutics that reduce GI contractile activity may improve DM1 GI symptoms.

View details for DOI 10.1073/pnas.2522788122

View details for PubMedID 41379996

Abstract

Myotonic dystrophy (DM), the most common adult-onset muscular dystrophy, affects not only motor function and muscle integrity but also leads to debilitating cardiopulmonary, gastrointestinal, and multisystem complications. Central nervous system (CNS) involvement is increasingly recognized, manifesting as impairments in working memory, executive function, sleep regulation, and mood and behavior. These interrelated, multisystemic features contribute to multifaceted symptoms that significantly reduce quality of life for patients and their families. To identify potential biomarkers of CNS disease activity in DM1, we performed the first exploratory cerebrospinal fluid (CSF) proteomic profiling study.CSF samples from patients with DM1 (n = 11) and healthy controls (n = 5) were analyzed using Olink monoclonal antibody panels, quantifying 1,072 proteins. LASSO (Least Absolute Shrinkage and Selection Operator) regression identified proteins discriminating between DM1 and controls. Pathway enrichment analysis was performed using the Reactome database to assess biological significance.Six candidate biomarker proteins were differentially expressed between between DM1 patients and controls: CKAP4, SCARF1, NCAM1, CD59, PTH1R, and CA4. LASSO analysis further identified 15 proteins discriminating DM1 and controls, implicating pathways related to neuronal health, neuroinflammation, cognitive impairment, skeletal abnormalities, motor control, neuromuscular junction integrity, and cytoskeletal regulation. Dysregulated pathways included IGF transport, MAPK signaling, NCAM signaling, and broader signal transduction cascades pathways also implicated in other neurodevelopmental, neurodegenerative, and neuromuscular disorders.This first exploratory CSF proteomic analysis in DM1 identified dysregulated protein networks that may underlie CNS dysfunction in this multisystemic disease. These findings provide novel insights into DM1 pathophysiology and support the potential of CSF proteomic signatures as candidate diagnostic tools, indicators of disease activity, and measures of therapeutic response, pending validation in larger, independent cohorts.

View details for DOI 10.3389/fnins.2025.1709678

View details for Web of Science ID 001634262100001

View details for PubMedID 41383381

View details for PubMedCentralID PMC12689921

View details for DOI 10.1016/j.nmd.2025.105549

View details for Web of Science ID 001603113300119

View details for DOI 10.1016/j.nmd.2025.105735

View details for Web of Science ID 001603281100002

View details for DOI 10.1016/j.nmd.2025.105982

View details for Web of Science ID 001641126100161

View details for DOI 10.1016/j.nmd.2025.105938

View details for Web of Science ID 001641126100030

View details for DOI 10.1016/j.nmd.2025.106032

View details for Web of Science ID 001641126100179

View details for DOI 10.1016/j.nmd.2025.105983

View details for Web of Science ID 001641126100061

Abstract

Assessing human movement is essential for diagnosing and monitoring movement-related conditions like neuromuscular disorders. Timed function tests (TFTs) are among the most widespread types of assessments due to their speed and simplicity, but they cannot capture disease-specific movement patterns. Conversely, biomechanical analysis can produce sensitive disease-specific biomarkers, but it is traditionally confined to laboratory settings. Recent advances in smartphone video-based biomechanical analysis enable the quantification of three-dimensional movement with the ease and speed required for clinical settings. However, the potential of this technology to offer more sensitive assessments of human function than TFTs remains untested.To compare video-based analysis with TFTs, we collected an observational dataset from 129 individuals: 28 with facioscapulohumeral muscular dystrophy, 58 with myotonic dystrophy, and 43 controls with no diagnosed neuromuscular condition. We used OpenCap, a free open-source software tool, to capture smartphone video-based biomechanics of nine different movements in a median time of 16 minutes per participant. From these recordings, we extracted 34 interpretable movement features. Using these features, we evaluated the ability of video-based biomechanics to reproduce four TFTs (10-meter walk, 10-meter run, timed up-and-go, and 5-times sit-to-stand) while capturing additional disease-specific signatures of movement.Video-based biomechanical analysis reproduced all four TFTs (r>0.98) with similar test-retest reliability. In addition, video metrics outperformed TFTs at disease classification (P=0.021). Unlike TFTs, video-based biomechanical analysis identified disease-specific signatures of movement, such as differences in gait kinematics, that are not evident in TFTs.Video-based biomechanical analysis can complement existing functional movement assessments by capturing more sensitive, disease-specific outcomes from human movement. This technology enables digital health solutions for assessing and monitoring motor function, complementing traditional clinical outcome measures to enhance care, management, and clinical trial design for movement-related conditions. (Funded by the Wu Tsai Human Performance Alliance and others.).

View details for DOI 10.1056/aioa2401137

View details for PubMedID 40926960

View details for PubMedCentralID PMC12416922

View details for DOI 10.1016/j.nmd.2025.106033

View details for Web of Science ID 001641126100117

View details for DOI 10.1016/j.nmd.2025.105600

View details for Web of Science ID 001603113300193

View details for DOI 10.1016/j.nmd.2025.105529

View details for Web of Science ID 001603113300174

View details for DOI 10.1016/j.nmd.2025.105609

View details for Web of Science ID 001603113300195

Abstract

Gene transfer therapy represents a major advancement in the treatment of patients with Duchenne muscular dystrophy (DMD). As clinical use expands, there is an urgent need for standardized, evidence and practice-informed guidelines to ensure safe and equitable delivery of this and similar products. A group of clinicians and researchers, coordinated by the Muscular Dystrophy Association and Parent Project Muscular Dystrophy, developed these consensus guidelines to outline recommendations for patient selection, institutional readiness, monitoring, and adverse event management, particularly in the first three months after treatment. This document emphasizes the importance of experienced multidisciplinary teams, real-time safety surveillance, and transparent reporting to support patient safety and clinician decision-making after treatment. While the Food and Drug Administration has approved only one gene therapy product for the treatment of patients with DMD, these recommendations may potentially apply to other products in clinical development. Currently, significant knowledge gaps remain regarding long-term safety, durability, and optimal timing of dosing, particularly for patients with advanced disease. Researchers do not fully understand how combination therapies and genetic background may impact the response to gene therapy. To address these gaps, ongoing real-world data collection, cross-center collaboration, and flexible adaptation of clinical protocols are essential. While these guidelines are based primarily on clinical expertise rather than well-established evidence, the guideline provides a foundation to support administration of gene therapy for patients with DMD. As the field evolves, continued refinement will be essential to maximize benefit, reduce risk, and inform future standards of care.

View details for DOI 10.1016/j.nmd.2025.106208

View details for PubMedID 41005046

Abstract

In the COMET trial, avalglucosidase alfa treatment for late-onset Pompe disease was safe, tolerable and associated with stabilization or improvement in disease parameters through 97 weeks. We report outcomes in the trial extension through 145 weeks of treatment.In this phase 3, double-blind, randomized trial, participants with previously untreated late-onset Pompe disease were randomly assigned to receive 20 mg/kg avalglucosidase alfa or alglucosidase alfa every other week for 49 weeks; thereafter, all patients received 20 mg/kg avalglucosidase alfa every other week. For this analysis, efficacy was assessed at 145 weeks and safety to last follow-up (data cutoff: March 11, 2022).Of 100 participants in the double-blind treatment period, 95 entered the open-label extension, and 88 completed ≥ 145 weeks of treatment. At study start, the mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 145, the LS mean (SE) FVC percent predicted increased by 1.38 (1.22) in the avalglucosidase alfa arm and 1.25 (1.34) in the switch arm. The LS mean (SE) 6MWT distance walked increased by 20.65 (9.60) m and 0.29 (10.42) m, respectively. Potentially treatment-related adverse events were reported in 27 patients (53%) in the avalglucosidase alfa arm and 25 patients (57%) in the switch arm. Anti-drug antibodies declined over time in both arms.In this randomized clinical trial extension, positive clinical outcomes were maintained for patients taking avalglucosidase alfa for up to 145 weeks with no new safety concerns.ClinicalTrials.gov, NCT02782741, https://clinicaltrials.gov/ct2/show/NCT02782741 . Registration date: 2016-05-23; Date of first patient enrolled: 2016-11-02.

View details for DOI 10.1007/s00415-025-13266-y

View details for PubMedID 40817977

View details for PubMedCentralID 6642938

Abstract

BACKGROUND: Limb-girdle muscular dystrophy (MD) type R2 (LGMDR2, formerly LGMD2B) is an autosomal recessive form of MD caused by variants in the dysferlin gene, DYSF. It leads to slow proximal and distal muscle weakening that generally results in loss of ambulation around early adulthood but without the lethal cardiorespiratory dysfunction observed in the more severe Duchenne MD. How loss of dysferlin causes muscle fibre death is poorly understood, but recent evidence suggests a link between muscle wasting and loss of muscle cholesterol homeostasis with circulating lipoprotein abnormalities in many forms of MD.METHODS: Cross-sectional circulating total cholesterol (CHOL), high-density lipoprotein-associated cholesterol (HDL-C), non-HDL-C, creatine kinase (CK), transaminase levels and bilirubin were collected as part of the Jain Clinical Outcomes Study of Dysferlinopathy, a large multicentre LGMDR2 patient cohort (N=188), along with ambulatory function values.RESULTS: We report that 43%, 49% and 50% of male patients were found to have abnormal circulating CHOL, HDL-C and non-HDL-C levels, respectively, whereas in female patients 39%, 37% and 30% of values were in the abnormal range. Overall, 68% of the total cohort had at least one abnormal cholesterol value (78% of males and 60% of females) and 89% of male CHOL/HDL-C ratios were in the suboptimal range (above 3.5). Although most patients were ambulant, the severity of circulating lipid abnormalities did not correlate with early loss of ambulation. Transaminase levels were lower in late-stage LGMDR2 samples, whereas bilirubin remained unchanged, suggesting a low muscular mass rather than hepatic origin and the absence of major liver damage.CONCLUSIONS: Data from the largest natural history cohort of LGMDR2 patients support the concept that dyslipidemia is a comorbidity of LGMDR2, and the causal role of cholesterol abnormalities in muscle death should be further investigated.

View details for DOI 10.1002/jcsm.70042

View details for PubMedID 40814795

Abstract

Limb-girdle muscular dystrophy R2 (LGMDR2) is characterized by progressive muscle weakness usually leading to severe disability. The rate of progression and disease severity is variable among patients, although factors influencing this variability are not completely understood. The Dysferlinopathy Clinical Outcome Study is a natural history study that followed patients with LGMDR2 for 3 consecutive years using functional outcome measures and skeletal muscle MRI.The aim of our study was to develop statistical models able to describe fat fraction (FF) progression of the lower limbs in patients with LGMDR2 using clinical and radiologic variables to better understand which factors influence disease progression and improve the design of future clinical trials.We used linear-mixed modeling to analyze changes in FF over time according to patients' age. We calculated the average FF trajectory for each muscle of the lower limbs. We built 2 multivariate models for each segment adding other clinical factors and using likelihood ratio test and residuals' analysis to determine whether they better fitted observed FF values.Muscles that participated in the same joint movement progressed similarly over time. FF was expected to be higher the older patients were and the earlier the age at symptom onset. Women had absolute FF values 8.8% higher than men in the lower leg. No differences in FF trajectory were seen based on ethnic groups (White, Asian, Black, or Hispanic), genetic variants, or residual dysferlin expression. Although multivariate models showed a better global fit to the data, there was no improvement in representing individual patient variability.In conclusion, this study provides a better understanding of skeletal muscle fat replacement progression in the lower limb muscles of patients with LGMDR2, highlighting the influence of age at symptom onset, sex, and baseline motor function, which should be considered in the design and analysis of clinical trials. Although complex models improved the overall data fit, they did not improve the accuracy in identifying changes at a patient level, underlying the need for further research and validation and the fact that other variables we have not measured are probably influencing progression.

View details for DOI 10.1212/NXG.0000000000200283

View details for PubMedID 40740171

View details for PubMedCentralID PMC12310143

Abstract

Assessing human movement is essential for diagnosing and monitoring movement-related conditions like neuromuscular disorders. Timed function tests (TFTs) are among the most widespread assessments due to their speed and simplicity, but they cannot capture disease-specific movement patterns. Conversely, biomechanical analysis can produce sensitive disease-specific biomarkers but is traditionally confined to laboratory settings. Recent advances in smartphone video-based biomechanical analysis enable quantification of 3D movement with the ease and speed required for clinical settings. However, the potential of this technology to offer more sensitive assessments of human function than TFTs remains untested.To compare video-based analysis against TFTs, we collected an observational dataset from 129 individuals: 28 with facioscapulohumeral muscular dystrophy, 58 with myotonic dystrophy, and 43 controls with no diagnosed neuromuscular condition. We used OpenCap, a free open-source software tool, to capture smartphone video-based biomechanics of nine different movements in a median time of 16 minutes per participant. From these recordings we extracted 34 interpretable movement features. Using these features, we evaluated the ability of video-based biomechanics to reproduce four TFTs (10-meter walk, 10-meter run, timed up-and-go, and 5-time sit-to-stand) while capturing additional disease-specific signatures of movement.Video-based biomechanical analysis reproduced all four TFTs (r > 0.98) with similar test-retest reliability. In addition, video metrics outperformed TFTs at disease classification (p = 0.021). Unlike TFTs, video-based biomechanical analysis identified disease-specific signatures of movement such as differences in gait kinematics that are not evident in TFTs.Video-based biomechanical analysis can complement existing functional movement assessments by capturing more sensitive, disease-specific outcomes from human movement. This technology enables digital health solutions for assessing and monitoring motor function, complementing traditional clinical outcome measures to enhance care, management, and clinical trial design for movement-related conditions.

View details for DOI 10.1101/2024.09.26.613967

View details for PubMedID 40766489

View details for PubMedCentralID PMC12324206

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a genetically complex condition marked by progressive skeletal muscle weakness, primarily affecting the face, shoulders, and upper arms. Here, we generated human induced pluripotent stem cell (iPSC) lines from two clinically diagnosed FSHD patients and characterized their pluripotency and germline markers. Both lines exhibited pluripotency markers, maintained normal karyotypes, and were capable of differentiating into all three germ layers. These iPSC lines are valuable resources for studying FSHD mechanisms and potential drug discovery applications.

View details for DOI 10.1016/j.scr.2025.103794

View details for PubMedID 40773824

Abstract

The Spinal Muscular Atrophy Functional Composite (SMA-FC) combines scores from the Hammersmith Functional Motor Scale Expanded (HFMSE), Upper Limb Module (ULM), and Six-Minute Walk Test (6MWT) into a single score and removes the floor and ceiling effects of the HFMSE. Our objective was to evaluate a revised version of the SMA-FC (SMA-FCR) by including the Revised ULM (RULM) in untreated and nusinersen-treated SMA.We included participants with HFMSE, RULM, and 6MWT data at the same visit. The SMA-FCR represented the average of the 3 test scores, each expressed as the percentage of the maximum possible score (HFMSE and RULM) or the percent of predicted normative performance (6MWT). Mean annual rates of change were calculated in participants who had SMA-FCR data at 2 or more visits while untreated and/or while treated.There were 580 participants (49.6% female) with a mean (SD) age of 19.2 (15.5) years (range 1.3-70.6 years). The median (interquartile range) SMA-FCR scores were 3.6 (0.0-8.1) for nonsitters, 22.3 (16.3-31.2) for sitters, and 75.1 (63.7-86.6) for walkers. The SMA-FCR score reduced the ceiling effect seen with the RULM in walkers and the floor effect seen with the HFMSE in nonsitters. The mean annual rate of change in the SMA-FCR was -0.62 (95% CI -1.15 to -0.08, p = 0.02) in untreated participants and 0.15 (95% CI -0.12 to 0.42, p = 0.28) in treated participants (difference = 0.77, 95% CI 0.19-1.34, p = 0.009). The mean annual rate of change in the HFMSE was -0.19 (95% CI -0.63 to 0.25, p = 0.40) in untreated participants and -0.21 (95% CI -0.43 to 0.01, p = 0.06) in treated participants (difference = -0.02, 95% CI -0.49 to 0.46, p = 0.94).The SMA-FCR broadens the spectrum of abilities captured in SMA. Analyses of the treated-untreated differences in mean annual rate of change suggest that the SMA-FCR may be more sensitive to change than the HFMSE. The use of the SMA-FCR in clinical trials might allow for study designs with broader eligibility criteria including weaker individuals who score minimally on the HFMSE and stronger individuals who score maximally on the RULM.

View details for DOI 10.1212/WNL.0000000000213839

View details for PubMedID 40577678

View details for DOI 10.1161/CIRCRESAHA.124.325931

View details for PubMedID 40654082

Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

View details for DOI 10.1101/2025.07.11.664426

View details for PubMedID 40672150

View details for PubMedCentralID PMC12265700

Abstract

The aim of this international retrospective study was to assess 4-year change using the Hammersmith Functional Motor Scale Expanded (HFMSE) in individuals with type II and III spinal muscular atrophy (SMA) treated with nusinersen and to establish predictors of HFMSE changes.Individuals with type II or III SMA, and at least 4 years of nusinersen-only treatment were included. All were assessed using the HFMSE. Age at baseline, sex, motor function, SMN2 copy number, and age of onset were also retrospectively collected. Linear mixed effect models were used to calculate yearly changes and trajectory predictors.We included 73 individuals with SMA type II (mean age 8.58 years, SD 7.91, IQR 3.04-10.70) and 111 type III (mean age 7.91 years, SD 17.83, IQR 8.15-34.42). Over 4 years, mean changes were + 4.18 (95% CI: 2.85-5.50) for SMA II and + 1.08 (95% CI: 0.12-2.04) for SMA III. Age (SMA II: -0.34\[-0.51 to -0.17]; SMA III: -0.13\[-0.20 to -0.06], p < 0.001) and baseline HFMSE (SMA II: 1.02\[0.70-1.34]; SMA III: 0.79\[0.71-0.87], p < 0.001) were the strongest predictors of progression, with younger age and higher baseline scores associated with better outcomes. Functional status was only predictive for type III (6.96\[4.26-9.66]).Our results confirm that, given a follow up of 4 years, there is a persistent impact of nusinersen on clinical progression that is better observed in younger patients with higher HFMSE scores at baseline, especially during the first 2 years of treatment.

View details for DOI 10.1111/ene.70268

View details for PubMedID 40576143

Abstract

Background: Individuals with neuromuscular diseases (NMDs) have low physical activity levels and an increased risk of cardiovascular and pulmonary diseases. Respiratory gas kinetics obtained during cardiopulmonary exercise testing (CPET) may provide valuable insights into disease mechanisms and cardiorespiratory fitness in individuals with NMD. Recovery from exercise is an important marker of exercise performance and overall physical health, and impaired recovery is strongly associated with poor health outcomes. This study evaluates recovery metrics in individuals with NMD after performing maximal exertion during CPET. Methods: A total of 34 individuals with NMD and 15 healthy volunteers were recruited for the study. CPET was performed using a wearable metabolic system and a wheelchair-accessible total body trainer to peak exertion. Recovery metrics assessed were (i) the time to reach 50% O2 recovery compared with peak exercise and (ii) the ratios of ventilation and respiratory gases between peak exercise and the highest values observed during recovery (overshoot). Results: The NMD group had a significantly longer time to reach 50% O2 recovery (T1/2 VO2: 105 ± 43.4 vs. 76 ± 36.4 s, p = 0.02), lower respiratory overshoot (17.1 ± 13.0% vs. 28.8 ± 9.03%), and lower ventilation/VO2 (31.9 ± 28.3 vs. 52.2 ± 23.5) compared to the control group. Conclusions: This study observes significantly impaired recovery metrics following peak exercise in individuals with NMD compared to controls. These insights may improve the understanding of exercise recovery and mechanics, thus improving prognostication and optimizing exercise prescriptions for individuals with NMD.

View details for DOI 10.3390/jcm14124190

View details for PubMedID 40565934

View details for DOI 10.1136/annrheumdis-2025-eular.B1260

View details for Web of Science ID 001527945100054

View details for Web of Science ID 001521601100190

View details for Web of Science ID 001587763700017

View details for Web of Science ID 001521601100188

View details for Web of Science ID 001521601100226

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 5-14years 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 7-15years, 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.

View details for DOI 10.1111/ene.16517

View details for PubMedID 39392101

View details for Web of Science ID 001315123204328

View details for Web of Science ID 001330908100296

View details for DOI 10.1016/j.nmd.2024.07.185

View details for Web of Science ID 001330908100177

View details for DOI 10.1016/j.nmd.2024.07.264

View details for Web of Science ID 001330908100256

View details for DOI 10.1016/j.nmd.2024.07.276

View details for Web of Science ID 001330908100268

View details for DOI 10.1016/j.nmd.2024.07.045

View details for Web of Science ID 001330908100037

View details for DOI 10.1016/j.nmd.2024.07.528

View details for Web of Science ID 001330908100520

View details for Web of Science ID 001330908100615

View details for DOI 10.1016/j.nmd.2024.07.077

View details for Web of Science ID 001330908100069

View details for DOI 10.1016/j.nmd.2024.07.094

View details for Web of Science ID 001330908100086

View details for DOI 10.1016/j.nmd.2024.07.093

View details for Web of Science ID 001330908100085

View details for DOI 10.1016/j.nmd.2024.07.454

View details for Web of Science ID 001330908100446

View details for Web of Science ID 001315123203148

Abstract

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.

View details for DOI 10.1016/j.nmd.2024.08.006

View details for PubMedID 39299818

View details for Web of Science ID 001319566000386

Abstract

Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020.This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected.Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up.This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned.This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.

View details for DOI 10.1212/CPJ.0000000000200298

View details for PubMedID 38932995

View details for PubMedCentralID PMC11196214

Abstract

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.

View details for DOI 10.1016/j.nmd.2024.05.003

View details for PubMedID 38936290

Abstract

Background: The natural history of spinal muscular atrophy (SMA) is well understood, with progressive muscle weakness resulting in declines in function. The development of contractures is common and negatively impacts function. Clinically, joint hypermobility (JH) is observed but is poorly described, and its relationship with function is unknown. Methods: Lower-limb ROM (range of motion) assessments of extension and flexion at the hip, knee, and ankle were performed. ROMs exceeding the published norms were included in the analysis. The functional assessments performed included the six-minute walk test (6 MWT) and the Hammersmith Functional Motor Scale-Expanded (HFMSE). Results: Of the 143 participants, 86% (n = 123) had at least one ROM measure that was hypermobile, and 22% (n = 32) had three or more. The HFMSE scores were inversely correlated with hip extension JH (r = -0.60, p = 0.21; n = 6) and positively correlated with knee flexion JH (r = 0.24, p = 0.02, n = 89). There was a moderate, inverse relationship between the 6 MWT distance and ankle plantar flexion JH (r = -0.73, p = 0.002; n = 15). Conclusions: JH was identified in nearly all participants in at least one joint in this study. Hip extension, knee flexion and ankle plantar flexion JH was associated with function. A further understanding of the trajectory of lower-limb joint ROM is needed to improve future rehabilitation strategies.

View details for DOI 10.3390/jcm13092634

View details for PubMedID 38731167

View details for PubMedCentralID PMC11084694

Abstract

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.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.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.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.

View details for DOI 10.1111/ene.16309

View details for PubMedID 38656662