Pub Date : 2026-03-01Epub Date: 2026-01-15DOI: 10.1016/j.nmd.2026.106337
Matthew G. Birkbeck , Ian S. Schofield , Ian Wilson , James Bashford , Julie Hall , Chiara Marini-Bettolo , Volker Straub , Roger G. Whittaker , Andrew M. Blamire
Motor unit MRI (MUMRI) non-invasively detects fasciculation, a common symptom of SMA and potential biomarker for clinical trials. We applied MUMRI in ten SMA III patients and ten controls comparing fasciculation rates. Images of the tongue, upper arm, paraspinal and thighs & lower legs were acquired using MUMRI and 3-point Dixon (fat fraction) sequences. Fasciculation rate (cm−3min−1) was significantly higher in SMA than controls for: paraspinal 0.15 ± 0.20 vs. 0.003 ± 0.006, p = 0.001, thighs 1.28 ± 1.76 vs. 0.008 ± 0.005, p = 0.002 and lower legs 0.53 ± 0.85 vs. 0.02 ± 0.02, p = 0.001, but not for the tongue 0.20 ± 0.20 vs. 0.06 ± 0.09, p = 0.082 or upper arm 0.45 ± 0.95 vs. 0.002 ± 0.004, p = 0.014. Fat fraction %, was significantly higher in SMA than controls for: upper arm 35.0 ± 25.4 vs. 4.2 ± 1.1, p<<0.001, paraspinal 41.4 ± 31.0 vs. 7.4 ± 4.5, p = 0.002, thighs 54.8 ± 23.8 vs. 5.7 ± 1.0, p<<0.001 and lower legs 29.6 ± 23.5 vs. 4.4 ± 0.9, p = 0.0003, but not for the tongue 13.9 ± 3.2 vs. 13.0 ± 3.3, p = 0.393. MUMRI is an attractive non-invasive biomarker, which could be used to monitor progression & response in SMA clinical trials.
{"title":"Motor unit magnetic resonance imaging (MUMRI) as a novel biomarker of muscle activity in spinal muscular atrophy","authors":"Matthew G. Birkbeck , Ian S. Schofield , Ian Wilson , James Bashford , Julie Hall , Chiara Marini-Bettolo , Volker Straub , Roger G. Whittaker , Andrew M. Blamire","doi":"10.1016/j.nmd.2026.106337","DOIUrl":"10.1016/j.nmd.2026.106337","url":null,"abstract":"<div><div>Motor unit MRI (MUMRI) non-invasively detects fasciculation, a common symptom of SMA and potential biomarker for clinical trials. We applied MUMRI in ten SMA III patients and ten controls comparing fasciculation rates. Images of the tongue, upper arm, paraspinal and thighs & lower legs were acquired using MUMRI and 3-point Dixon (fat fraction) sequences. Fasciculation rate (cm<sup>−3</sup>min<sup>−1</sup>) was significantly higher in SMA than controls for: paraspinal 0.15 ± 0.20 <em>vs.</em> 0.003 ± 0.006, <em>p</em> = 0.001, thighs 1.28 ± 1.76 <em>vs.</em> 0.008 ± 0.005, <em>p</em> = 0.002 and lower legs 0.53 ± 0.85 <em>vs.</em> 0.02 ± 0.02, <em>p</em> = 0.001, but not for the tongue 0.20 ± 0.20 <em>vs.</em> 0.06 ± 0.09, <em>p</em> = 0.082 or upper arm 0.45 ± 0.95 <em>vs.</em> 0.002 ± 0.004, <em>p</em> = 0.014. Fat fraction %, was significantly higher in SMA than controls for: upper arm 35.0 ± 25.4 <em>vs.</em> 4.2 ± 1.1, <em>p</em><<0.001, paraspinal 41.4 ± 31.0 <em>vs.</em> 7.4 ± 4.5, <em>p</em> = 0.002, thighs 54.8 ± 23.8 <em>vs.</em> 5.7 ± 1.0, <em>p</em><<0.001 and lower legs 29.6 ± 23.5 <em>vs.</em> 4.4 ± 0.9, <em>p</em> = 0.0003, but not for the tongue 13.9 ± 3.2 <em>vs.</em> 13.0 ± 3.3, <em>p</em> = 0.393. MUMRI is an attractive non-invasive biomarker, which could be used to monitor progression & response in SMA clinical trials.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"60 ","pages":"Article 106337"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-28DOI: 10.1016/j.nmd.2026.106360
Stephan Wenninger , Hani Kushlaf , Noemi Hummel , Brian Fox , Birgit Gloeckner , Fred Holdbrook , Vipul Jain , Markus Peceny , Benedikt Schoser , Kristl G. Claeys
We determined the proportion of adults with late-onset Pompe disease (LOPD) with clinically important changes in 6-minute walk distance (6MWD) and/or forced vital capacity (FVC) after switching from alglucosidase alfa (alg) to cipaglucosidase alfa plus miglustat (cipa+mig) in PROPEL (NCT03729362). This post hoc analysis (95 patients) used published anchor- and distribution-based minimal clinically important differences for 6MWD (in meters for anchor-based; % predicted for distribution-based) and a 3 % threshold for FVC (% predicted). For 6MWD, a higher percentage of patients improved after switching to cipa+mig versus alg plus placebo (alg+pbo) (anchor-based: 29.2 % versus 13.3 %; distribution-based: 33.8 % versus 13.3 %), fewer patients worsened (anchor-based: 12.3 % versus 26.7 %; distribution-based: 7.7 % versus 13.3 %). For FVC, 27.7 % versus 0.0 % improved for cipa+mig versus alg+pbo, 27.7 % versus 53.3 % worsened. Overall, 50.8 % versus 13.3 % of patients experienced improvements in 6MWD (% predicted) and/or FVC with cipa+mig versus alg+pbo, 30.8 % versus 56.7 % worsened. For combined responses from 6MWD (% predicted) and FVC (% predicted), the odds of a better versus a lower response category (improvement > stability > worsening) were 4.05 (95 % confidence interval 1.73–9.51) times higher for cipa+mig than alg+pbo (P = 0.0013). Adults with LOPD switching from alg to cipa+mig have greater chances of clinically relevant motor and lung function improvements than those remaining on alg.
我们确定了在PROPEL （NCT03729362）中，从α葡萄糖苷酶（alg）切换到α葡萄糖苷酶加米卢司他（cipa+mig）后，6分钟步行距离（6MWD）和/或强制肺活量（FVC）发生临床重要变化的迟发性Pompe病（LOPD）成人的比例。这项事后分析（95例患者）使用了已公布的基于锚点和基于分布的最小临床重要差异的6MWD（基于锚点的以米为单位；基于分布的预测百分比）和3%的FVC阈值（预测百分比）。对于6MWD，切换到cipa+mig与alg+安慰剂（alg+pbo）后改善的患者比例更高（锚定型：29.2% vs 13.3%；分布型：33.8% vs 13.3%），更少的患者恶化（锚定型：12.3% vs 26.7%；分布型：7.7% vs 13.3%）。对于FVC， cipa+mig和alg+pbo分别有27.7%和0.0%的改善，27.7%和53.3%的恶化。总体而言，50.8%比13.3%的患者在6MWD（预期百分比）和/或FVC （cipa+mig vs alg+pbo）中得到改善，30.8%比56.7%恶化。对于6MWD（%预测）和FVC（%预测）的联合反应，cipa+mig的较好与较低反应类别（改善b>稳定b>恶化）的几率是alg+pbo的4.05（95%置信区间1.73-9.51）倍（P = 0.0013）。成年LOPD患者从alg切换到cipa+可能比继续使用alg的患者有更大的临床相关运动和肺功能改善的机会。
{"title":"Clinically important improvements in 6-minute walk distance and forced vital capacity in adults with late-onset Pompe disease switching from alglucosidase alfa to cipaglucosidase alfa plus miglustat in the PROPEL study","authors":"Stephan Wenninger , Hani Kushlaf , Noemi Hummel , Brian Fox , Birgit Gloeckner , Fred Holdbrook , Vipul Jain , Markus Peceny , Benedikt Schoser , Kristl G. Claeys","doi":"10.1016/j.nmd.2026.106360","DOIUrl":"10.1016/j.nmd.2026.106360","url":null,"abstract":"<div><div>We determined the proportion of adults with late-onset Pompe disease (LOPD) with clinically important changes in 6-minute walk distance (6MWD) and/or forced vital capacity (FVC) after switching from alglucosidase alfa (alg) to cipaglucosidase alfa plus miglustat (cipa+mig) in PROPEL (NCT03729362). This <em>post hoc</em> analysis (95 patients) used published anchor- and distribution-based minimal clinically important differences for 6MWD (in meters for anchor-based; % predicted for distribution-based) and a 3 % threshold for FVC (% predicted). For 6MWD, a higher percentage of patients improved after switching to cipa+mig versus alg plus placebo (alg+pbo) (anchor-based: 29.2 % versus 13.3 %; distribution-based: 33.8 % versus 13.3 %), fewer patients worsened (anchor-based: 12.3 % versus 26.7 %; distribution-based: 7.7 % versus 13.3 %). For FVC, 27.7 % versus 0.0 % improved for cipa+mig versus alg+pbo, 27.7 % versus 53.3 % worsened. Overall, 50.8 % versus 13.3 % of patients experienced improvements in 6MWD (% predicted) and/or FVC with cipa+mig versus alg+pbo, 30.8 % versus 56.7 % worsened. For combined responses from 6MWD (% predicted) and FVC (% predicted), the odds of a better versus a lower response category (improvement > stability > worsening) were 4.05 (95 % confidence interval 1.73–9.51) times higher for cipa+mig than alg+pbo (<em>P</em> = 0.0013). Adults with LOPD switching from alg to cipa+mig have greater chances of clinically relevant motor and lung function improvements than those remaining on alg.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"60 ","pages":"Article 106360"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-08DOI: 10.1016/j.nmd.2025.106304
Jodi Warman-Chardon , Volker Straub , John Vissing , Sarah Schlaeger , Hermien E. Kan
Quantitative muscle MRI (qMRI) has emerged as a promising non-invasive biomarker for assessing neuromuscular diseases (NMDs). However, clinical implementation is limited by the significant time required for manual muscle segmentation, which restricts analysis to limited muscle regions rather than comprehensive whole-muscle assessment. The 286th European NeuroMuscular Centre (ENMC) workshop brought together 18 international participants from 10 countries to establish consensus on optimal qMRI acquisition protocols and automated analysis tools, revealing that while most centers utilize qMRI techniques, barriers to manual segmentation include limited expertise and excessive time requirements. Automated segmentation methods using machine learning architectures, particularly 3D U-Net models, have demonstrated promising results for individual muscle segmentation. Multi-center studies are starting to implement standardized protocols, while machine learning approaches can distinguish among many NMDs with higher accuracy than human experts. Data sharing platforms and federated learning approaches address the need for larger NMD cohorts with standardized and vendor-agnostic data formats, while maintaining patient privacy. The integration of automated 3D muscle segmentation tools integrated into clinical workflows represents a transformative advancement to revolutionize diagnosis, disease monitoring, and therapeutic assessment in NMDs. This consensus workshop provides a roadmap for accelerating the translation of qMRI from research tools to clinically implemented biomarkers for NMD management.
{"title":"286th ENMC international workshop: Muscle imaging: artificial intelligence, automatic segmentation and imaging data sharing in neuromuscular disease. Hoofddorp, The Netherlands, 7-9 March 2025","authors":"Jodi Warman-Chardon , Volker Straub , John Vissing , Sarah Schlaeger , Hermien E. Kan","doi":"10.1016/j.nmd.2025.106304","DOIUrl":"10.1016/j.nmd.2025.106304","url":null,"abstract":"<div><div>Quantitative muscle MRI (qMRI) has emerged as a promising non-invasive biomarker for assessing neuromuscular diseases (NMDs). However, clinical implementation is limited by the significant time required for manual muscle segmentation, which restricts analysis to limited muscle regions rather than comprehensive whole-muscle assessment. The 286th European NeuroMuscular Centre (ENMC) workshop brought together 18 international participants from 10 countries to establish consensus on optimal qMRI acquisition protocols and automated analysis tools, revealing that while most centers utilize qMRI techniques, barriers to manual segmentation include limited expertise and excessive time requirements. Automated segmentation methods using machine learning architectures, particularly 3D U-Net models, have demonstrated promising results for individual muscle segmentation. Multi-center studies are starting to implement standardized protocols, while machine learning approaches can distinguish among many NMDs with higher accuracy than human experts. Data sharing platforms and federated learning approaches address the need for larger NMD cohorts with standardized and vendor-agnostic data formats, while maintaining patient privacy. The integration of automated 3D muscle segmentation tools integrated into clinical workflows represents a transformative advancement to revolutionize diagnosis, disease monitoring, and therapeutic assessment in NMDs. This consensus workshop provides a roadmap for accelerating the translation of qMRI from research tools to clinically implemented biomarkers for NMD management.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"60 ","pages":"Article 106304"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-13DOI: 10.1016/j.nmd.2025.106310
Sara L. Cook , Tyller Mensa , Henry Noma , Maya Jahnke , Noemi Vidal-Folch , Christian Stout , Ron F. Hrstka , Sybil C.L. Hrstka , Lindsey Kirkeby , Devin Oglesbee , Linda Hasadsri , Duygu Selcen , Nathan P. Staff
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by homozygous loss of the SMN1 gene. Copy number of the nearly identical paralog, SMN2, correlates with disease severity. SMN2 is the primary modifier of SMA, with only a few other modifiers reported. We reviewed the literature of rare siblings affected by SMA that show discordance in clinical presentation despite having the same number of SMN2 copies, which predicts the presence of genetic modifiers. We further recruited a sibling pair with discordant clinical presentations and performed detailed characterization. We utilized droplet digital PCR for deletion duplication testing and Sanger sequencing for analysis of the SMN2 exons 1–7 which confirmed zero copies of SMN1, four copies of SMN2, and no SMN2 modifying variants. Skin fibroblasts from each sibling were collected, reprogrammed into iPSCs, and differentiated to motor neurons. Patient-specific motor neurons revealed similar levels of SMN protein between the two siblings. Patient-specific iPSC-derived motor neurons collected from discordant siblings reported here may represent a powerful model for the discovery of SMN-independent modifiers.
{"title":"Clinically discordant siblings with spinal muscular atrophy: insights from their patient-specific iPSC-derived motor neurons and literature review","authors":"Sara L. Cook , Tyller Mensa , Henry Noma , Maya Jahnke , Noemi Vidal-Folch , Christian Stout , Ron F. Hrstka , Sybil C.L. Hrstka , Lindsey Kirkeby , Devin Oglesbee , Linda Hasadsri , Duygu Selcen , Nathan P. Staff","doi":"10.1016/j.nmd.2025.106310","DOIUrl":"10.1016/j.nmd.2025.106310","url":null,"abstract":"<div><div>Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by homozygous loss of the <em>SMN1</em> gene. Copy number of the nearly identical paralog, <em>SMN2</em>, correlates with disease severity. <em>SMN2</em> is the primary modifier of SMA, with only a few other modifiers reported. We reviewed the literature of rare siblings affected by SMA that show discordance in clinical presentation despite having the same number of <em>SMN2</em> copies, which predicts the presence of genetic modifiers. We further recruited a sibling pair with discordant clinical presentations and performed detailed characterization. We utilized droplet digital PCR for deletion duplication testing and Sanger sequencing for analysis of the <em>SMN2</em> exons 1–7 which confirmed zero copies of <em>SMN1</em>, four copies of <em>SMN2</em>, and no <em>SMN2</em> modifying variants. Skin fibroblasts from each sibling were collected, reprogrammed into iPSCs, and differentiated to motor neurons. Patient-specific motor neurons revealed similar levels of SMN protein between the two siblings. Patient-specific iPSC-derived motor neurons collected from discordant siblings reported here may represent a powerful model for the discovery of SMN-independent modifiers.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"59 ","pages":"Article 106310"},"PeriodicalIF":2.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-13DOI: 10.1016/j.nmd.2025.106281
Wolfram Kress , Ute Hehr , Berthold Schalke , Clemens R. Mueller , Tiemo Grimm
Becker muscular dystrophy, BMD (#300,324) was first described by Becker and Kiener in 1955 and later recognised as a clinically milder allelic form of Duchenne muscular dystrophy (DMD). In muscle biopsies, BMD is characterized by the residual expression of dystrophin protein resulting in an apparently partial function. The mutations underlying BMD belong to the milder end of the wide spectrum of dystrophin mutations. We had the opportunity to study the mutation in a recent offspring of the original family of Becker and Kiener and identified a single amino acid substitution in exon 3 of the dystrophin gene: c.136G>T, p.(Asp46Tyr), a missense mutation which has already been described in another BMD family from Italy.
{"title":"Becker muscular dystrophy (BMD) is caused by a dystrophin missense mutation in the original family of Becker and Kiener","authors":"Wolfram Kress , Ute Hehr , Berthold Schalke , Clemens R. Mueller , Tiemo Grimm","doi":"10.1016/j.nmd.2025.106281","DOIUrl":"10.1016/j.nmd.2025.106281","url":null,"abstract":"<div><div>Becker muscular dystrophy, BMD (#300,324) was first described by Becker and Kiener in 1955 and later recognised as a clinically milder allelic form of Duchenne muscular dystrophy (DMD). In muscle biopsies, BMD is characterized by the residual expression of dystrophin protein resulting in an apparently partial function. The mutations underlying BMD belong to the milder end of the wide spectrum of <em>dystrophin</em> mutations. We had the opportunity to study the mutation in a recent offspring of the original family of Becker and Kiener and identified a single amino acid substitution in exon 3 of the dystrophin gene: c.136G><em>T</em>, p.(Asp46Tyr), a missense mutation which has already been described in another BMD family from Italy.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"59 ","pages":"Article 106281"},"PeriodicalIF":2.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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