Introduction/aims: Spinal muscular atrophy (SMA) manifests with progressive motor neuron degeneration, leading to muscle weakness. Onasemnogene abeparvovec is a US Food and Drug Administration-approved gene replacement therapy for SMA. This study aimed to present short-term data of children in the United Arab Emirates (UAE) treated with onasemnogene abeparvovec, particularly in the context of children requiring invasive ventilatory support via tracheostomy.
Methods: A retrospective analysis was performed on 60 children who received onasemnogene abeparvovec. All these children received corticosteroids. They were followed up for up to 3 months. Motor function assessments were performed before and after the gene therapy. Comprehensive clinical evaluations, including pulmonary functions, were performed at baseline and the 3-month mark.
Results: Forty-three percent were male, and the mean age at the time of infusion was 29.6 months (SD ± 17.2). The mean weight was 10.1 kg (SD 2.6). All children demonstrated marked improvements in motor function within 3 months of gene therapy administration. No adverse effects attributable to corticosteroid therapy were observed. Positive clinical outcomes, including increased ventilator-free intervals, reduced antibiotic dependency, and fewer hospital admissions, were reported among children with invasive ventilation via tracheostomy.
Discussion: This study demonstrates the favorable tolerability and promising responses to onasemnogene abeparvovec in invasively ventilated pediatric patients. Early improvements in motor function, as observed within 3 months post-treatment, suggest its potential as a viable therapeutic option for this vulnerable patient population.
{"title":"Onasemnogene abeparvovec gene therapy for spinal muscular atrophy: A cohort study from the United Arab Emirates.","authors":"Vivek Mundada, Omendra Narayan, Siddharth Arora, Nidhi Beri, Rania Abusamra, Deepak Mullasery, Deepak Parashar","doi":"10.1002/mus.28222","DOIUrl":"10.1002/mus.28222","url":null,"abstract":"<p><strong>Introduction/aims: </strong>Spinal muscular atrophy (SMA) manifests with progressive motor neuron degeneration, leading to muscle weakness. Onasemnogene abeparvovec is a US Food and Drug Administration-approved gene replacement therapy for SMA. This study aimed to present short-term data of children in the United Arab Emirates (UAE) treated with onasemnogene abeparvovec, particularly in the context of children requiring invasive ventilatory support via tracheostomy.</p><p><strong>Methods: </strong>A retrospective analysis was performed on 60 children who received onasemnogene abeparvovec. All these children received corticosteroids. They were followed up for up to 3 months. Motor function assessments were performed before and after the gene therapy. Comprehensive clinical evaluations, including pulmonary functions, were performed at baseline and the 3-month mark.</p><p><strong>Results: </strong>Forty-three percent were male, and the mean age at the time of infusion was 29.6 months (SD ± 17.2). The mean weight was 10.1 kg (SD 2.6). All children demonstrated marked improvements in motor function within 3 months of gene therapy administration. No adverse effects attributable to corticosteroid therapy were observed. Positive clinical outcomes, including increased ventilator-free intervals, reduced antibiotic dependency, and fewer hospital admissions, were reported among children with invasive ventilation via tracheostomy.</p><p><strong>Discussion: </strong>This study demonstrates the favorable tolerability and promising responses to onasemnogene abeparvovec in invasively ventilated pediatric patients. Early improvements in motor function, as observed within 3 months post-treatment, suggest its potential as a viable therapeutic option for this vulnerable patient population.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":" ","pages":"808-815"},"PeriodicalIF":2.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-08DOI: 10.1002/mus.28227
Yu-Fang Huang, Kerstin Sandholm, Barbro Persson, Bo Nilsson, Anna Rostedt Punga
Introduction/aims: There are no blood biomarkers to monitor treatment effects in myasthenia gravis (MG) or studies visualizing the acetylcholine receptor (AChR) antibody-induced membrane attack complex (MAC) at the human muscle membrane. This study aimed to compare levels of complement activation products and native complement components in MG patients and healthy controls (HCs) and to model the AChR antibody-mediated attacks in human muscle cells.
Methods: We assessed the complement components and activation product levels with enzyme-linked immunosorbent assay and magnetic bead-based sandwich assays in plasma and sera of 23 MG patients and matched HCs. Receiver operator characteristic (ROC) curve analysis evaluated the diagnostic accuracy. Complement levels were correlated with the myasthenia gravis composite (MGC) scores. AChR+ MG modeling in human muscle cells used sera from nine MG patients and three HCs.
Results: MG patients had significantly higher plasma levels of C3a (p < .0001), C5 (p = .0003), and soluble C5b-9 (sC5b-9; p < .0001) than HCs. The ROC curve analysis showed a clear separation between MG patients and HCs for plasma C3a (AUC = 0.9720; p < .0001) and sC5b-9 (AUC = 0.8917, p < .0001). MG patients had higher levels of plasma complement Factor I (FI; p = .0002) and lower properdin levels (p < .0001). The MGC had moderate correlations with plasma Factor B (FB), FI, and Factor H. AChR+ MG patient sera triggered the deposition of MAC and reduced AChRs.
Discussion: We suggest validating plasma C3a and sC5b-9 as blood biomarkers for complement activation in MG. Further, the in vitro study allowed visualization of MAC deposition after applying AChR+ MG sera on human muscle cells.
{"title":"Visualization and characterization of complement activation in acetylcholine receptor antibody seropositive myasthenia gravis.","authors":"Yu-Fang Huang, Kerstin Sandholm, Barbro Persson, Bo Nilsson, Anna Rostedt Punga","doi":"10.1002/mus.28227","DOIUrl":"10.1002/mus.28227","url":null,"abstract":"<p><strong>Introduction/aims: </strong>There are no blood biomarkers to monitor treatment effects in myasthenia gravis (MG) or studies visualizing the acetylcholine receptor (AChR) antibody-induced membrane attack complex (MAC) at the human muscle membrane. This study aimed to compare levels of complement activation products and native complement components in MG patients and healthy controls (HCs) and to model the AChR antibody-mediated attacks in human muscle cells.</p><p><strong>Methods: </strong>We assessed the complement components and activation product levels with enzyme-linked immunosorbent assay and magnetic bead-based sandwich assays in plasma and sera of 23 MG patients and matched HCs. Receiver operator characteristic (ROC) curve analysis evaluated the diagnostic accuracy. Complement levels were correlated with the myasthenia gravis composite (MGC) scores. AChR+ MG modeling in human muscle cells used sera from nine MG patients and three HCs.</p><p><strong>Results: </strong>MG patients had significantly higher plasma levels of C3a (p < .0001), C5 (p = .0003), and soluble C5b-9 (sC5b-9; p < .0001) than HCs. The ROC curve analysis showed a clear separation between MG patients and HCs for plasma C3a (AUC = 0.9720; p < .0001) and sC5b-9 (AUC = 0.8917, p < .0001). MG patients had higher levels of plasma complement Factor I (FI; p = .0002) and lower properdin levels (p < .0001). The MGC had moderate correlations with plasma Factor B (FB), FI, and Factor H. AChR+ MG patient sera triggered the deposition of MAC and reduced AChRs.</p><p><strong>Discussion: </strong>We suggest validating plasma C3a and sC5b-9 as blood biomarkers for complement activation in MG. Further, the in vitro study allowed visualization of MAC deposition after applying AChR+ MG sera on human muscle cells.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":" ","pages":"851-861"},"PeriodicalIF":2.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elisa Mamino,Ségolène Lithfous,Thierry Pebayle,André Dufour,Olivier Després
INTRODUCTION/AIMSLimitations exist in evaluating mechanical detection thresholds (MDTs) due to a lack of dependable electronic instruments designed to assess Aβ fibers and measure MDTs across different body areas. This study aims to evaluate the test-retest and inter-rater reliability of the cutaneous mechanical stimulator (CMS), an electronic tactile stimulator, in quantifying MDTs.METHODSUsing a test-retest design, participants underwent assessments of MDTs using Semmes-Weinstein monofilaments (SWM) and the CMS. This study included 27 healthy volunteers (mean age 24.07 ± 3.76 years). Two raters assessed MDTs using SWM and the CMS at two stimulation sites (the left hand and foot) in two experimental sessions approximately 2 weeks apart.RESULTSMDTs using SWM and the CMS showed excellent reliability on the hand (intraclass correlation coefficient [ICC] = .84) and foot (ICC = .90). A comparison of results obtained at the two sessions showed that MDTs on the hand displayed good reliability for both SWM (ICC = .63) and the CMS (ICC = .73), whereas MDTs on the foot displayed fair reliability for SWM (ICC = .50) and the CMS (ICC = .42). MDTs exhibited good inter-rater reliability with SWM (ICC = .66) and excellent inter-rater reliability with the CMS (ICC = .82) on the hand, as well as showing fair inter-rater reliability with SWM (ICC = .53) and good inter-rater reliability with the CMS (ICC = .60) on the foot.DISCUSSIONThe CMS showed superior inter-rater reliability, indicating its potential as a valuable tool for assessing tactile sensitivity in research and clinical settings.
{"title":"Test-retest and inter-rater reliability of two devices measuring tactile mechanical detection thresholds in healthy adults: Semmes-Weinstein monofilaments and the cutaneous mechanical stimulator.","authors":"Elisa Mamino,Ségolène Lithfous,Thierry Pebayle,André Dufour,Olivier Després","doi":"10.1002/mus.28258","DOIUrl":"https://doi.org/10.1002/mus.28258","url":null,"abstract":"INTRODUCTION/AIMSLimitations exist in evaluating mechanical detection thresholds (MDTs) due to a lack of dependable electronic instruments designed to assess Aβ fibers and measure MDTs across different body areas. This study aims to evaluate the test-retest and inter-rater reliability of the cutaneous mechanical stimulator (CMS), an electronic tactile stimulator, in quantifying MDTs.METHODSUsing a test-retest design, participants underwent assessments of MDTs using Semmes-Weinstein monofilaments (SWM) and the CMS. This study included 27 healthy volunteers (mean age 24.07 ± 3.76 years). Two raters assessed MDTs using SWM and the CMS at two stimulation sites (the left hand and foot) in two experimental sessions approximately 2 weeks apart.RESULTSMDTs using SWM and the CMS showed excellent reliability on the hand (intraclass correlation coefficient [ICC] = .84) and foot (ICC = .90). A comparison of results obtained at the two sessions showed that MDTs on the hand displayed good reliability for both SWM (ICC = .63) and the CMS (ICC = .73), whereas MDTs on the foot displayed fair reliability for SWM (ICC = .50) and the CMS (ICC = .42). MDTs exhibited good inter-rater reliability with SWM (ICC = .66) and excellent inter-rater reliability with the CMS (ICC = .82) on the hand, as well as showing fair inter-rater reliability with SWM (ICC = .53) and good inter-rater reliability with the CMS (ICC = .60) on the foot.DISCUSSIONThe CMS showed superior inter-rater reliability, indicating its potential as a valuable tool for assessing tactile sensitivity in research and clinical settings.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"94 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
INTRODUCTION/AIMSIn a recent study, we showed that nerve ultrasound of the upper limbs could distinguish inherited sensory neuronopathy from inherited axonopathy; surprisingly, no differences were found in the lower limb nerves. In this study, we compared lower limb nerve ultrasound measurements in inherited neuronopathy, inherited axonopathy, and acquired axonopathy.METHODSTibial and sural nerve ultrasound cross-sectional areas (CSAs) of 34 healthy controls were retrospectively compared with those of three patient groups: 17 with cerebellar ataxia with neuronopathy and vestibular areflexia syndrome (CANVAS), 18 with Charcot-Marie-Tooth type 2 (CMT2), and 18 with acquired length-dependent sensorimotor axonal neuropathy, using ANOVA with post-hoc Tukey honestly significance difference (HSD) (significance level set at p < .05).RESULTSThe nerve CSAs of CANVAS and CMT2 patients were not significantly different. Both the tibial and the sural nerve CSAs were significantly smaller in CANVAS and CMT2 compared with the acquired axonal neuropathy group. Tibial nerve CSAs of CANVAS and CMT2 were significantly smaller than controls. Tibial and sural nerve CSAs of the acquired axonal neuropathy group were also significantly larger than the controls'.DISCUSSIONUltrasound of the lower limb nerves distinguished inherited from acquired axonopathy with the nerve size respectively reduced and increased in these two groups. This has potential implication for the differential diagnosis of these diseases in clinical practice.
{"title":"Lower limb nerve ultrasound: A four-way comparison of acquired and inherited axonopathy, inherited neuronopathy and healthy controls.","authors":"Luciana Pelosi,Daniele Coraci,Eoin Mulroy,Ruth Leadbetter,Luca Padua,Richard Roxburgh","doi":"10.1002/mus.28260","DOIUrl":"https://doi.org/10.1002/mus.28260","url":null,"abstract":"INTRODUCTION/AIMSIn a recent study, we showed that nerve ultrasound of the upper limbs could distinguish inherited sensory neuronopathy from inherited axonopathy; surprisingly, no differences were found in the lower limb nerves. In this study, we compared lower limb nerve ultrasound measurements in inherited neuronopathy, inherited axonopathy, and acquired axonopathy.METHODSTibial and sural nerve ultrasound cross-sectional areas (CSAs) of 34 healthy controls were retrospectively compared with those of three patient groups: 17 with cerebellar ataxia with neuronopathy and vestibular areflexia syndrome (CANVAS), 18 with Charcot-Marie-Tooth type 2 (CMT2), and 18 with acquired length-dependent sensorimotor axonal neuropathy, using ANOVA with post-hoc Tukey honestly significance difference (HSD) (significance level set at p < .05).RESULTSThe nerve CSAs of CANVAS and CMT2 patients were not significantly different. Both the tibial and the sural nerve CSAs were significantly smaller in CANVAS and CMT2 compared with the acquired axonal neuropathy group. Tibial nerve CSAs of CANVAS and CMT2 were significantly smaller than controls. Tibial and sural nerve CSAs of the acquired axonal neuropathy group were also significantly larger than the controls'.DISCUSSIONUltrasound of the lower limb nerves distinguished inherited from acquired axonopathy with the nerve size respectively reduced and increased in these two groups. This has potential implication for the differential diagnosis of these diseases in clinical practice.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"50 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Floris V Raasveld,Daniel T Weigel,Wen-Chih Liu,Maximilian Mayrhofer-Schmid,Barbara Gomez-Eslava,Vlad Tereshenko,Charles D Hwang,Brian J Wainger,William Renthal,Mark Fleming,Ian L Valerio,Kyle R Eberlin
INTRODUCTION/AIMSNeuromas come in different shapes and sizes; yet the correlation between neuroma morphology and symptomatology is unknown. Therefore, we aim to investigate macroscopic traits of excised human neuromas and assess the validity of a morphological classification system and its potential clinical implications.METHODSEnd-neuroma specimens were collected from prospectively enrolled patients undergoing symptomatic neuroma surgery. Protocolized images of the specimens were obtained intraoperatively. Pain data (Numeric rating scale, 0-10) were prospectively collected during preoperative interview, patient demographic and comorbidity factors were collected from chart review. A morphological classification is proposed, and the inter-rater reliability (IRR) was assessed. Distribution of neuroma morphology with patient factors, was described.RESULTSForty-five terminal neuroma specimens from 27 patients were included. Residual limb patients comprised 93% of the population, of which 2 were upper (8.0%) and 23 (92.0%) were lower extremity residual limb patients. The proposed morphological classification, consisting of three groups (bulbous, fusiform, atypical), demonstrated a strong IRR (Cohen's kappa = 0.8). Atypical neuromas demonstrated higher preoperative pain, compared with bulbous and fusiform. Atypical morphology was more prevalent in patients with diabetes and peripheral vascular disease.DISCUSSIONA validated morphological classification of neuroma is introduced. These findings may assist surgeons and researchers with better understanding of symptomatic neuroma development and their clinical implications. The potential relationship of neuroma morphology with the vascular and metabolic microenvironment requires further investigation.
{"title":"Neuroma morphology: A macroscopic classification system.","authors":"Floris V Raasveld,Daniel T Weigel,Wen-Chih Liu,Maximilian Mayrhofer-Schmid,Barbara Gomez-Eslava,Vlad Tereshenko,Charles D Hwang,Brian J Wainger,William Renthal,Mark Fleming,Ian L Valerio,Kyle R Eberlin","doi":"10.1002/mus.28261","DOIUrl":"https://doi.org/10.1002/mus.28261","url":null,"abstract":"INTRODUCTION/AIMSNeuromas come in different shapes and sizes; yet the correlation between neuroma morphology and symptomatology is unknown. Therefore, we aim to investigate macroscopic traits of excised human neuromas and assess the validity of a morphological classification system and its potential clinical implications.METHODSEnd-neuroma specimens were collected from prospectively enrolled patients undergoing symptomatic neuroma surgery. Protocolized images of the specimens were obtained intraoperatively. Pain data (Numeric rating scale, 0-10) were prospectively collected during preoperative interview, patient demographic and comorbidity factors were collected from chart review. A morphological classification is proposed, and the inter-rater reliability (IRR) was assessed. Distribution of neuroma morphology with patient factors, was described.RESULTSForty-five terminal neuroma specimens from 27 patients were included. Residual limb patients comprised 93% of the population, of which 2 were upper (8.0%) and 23 (92.0%) were lower extremity residual limb patients. The proposed morphological classification, consisting of three groups (bulbous, fusiform, atypical), demonstrated a strong IRR (Cohen's kappa = 0.8). Atypical neuromas demonstrated higher preoperative pain, compared with bulbous and fusiform. Atypical morphology was more prevalent in patients with diabetes and peripheral vascular disease.DISCUSSIONA validated morphological classification of neuroma is introduced. These findings may assist surgeons and researchers with better understanding of symptomatic neuroma development and their clinical implications. The potential relationship of neuroma morphology with the vascular and metabolic microenvironment requires further investigation.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"9 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
James D Berry,Sabrina Paganoni,Matthew B Harms,Neil Shneider,Jinsy Andrews,Timothy M Miller,Suma Babu,Alex V Sherman,Brent T Harris,Frank A Provenzano,Hemali P Phatnani,Jeremy Shefner,Mark A Garret,Shaffeeq S Ladha,Amy Y Tsou,Praveena Mohan,Courtney Igne,,Robert Bowser
Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.
肌萎缩性脊髓侧索硬化症（ALS）治疗方面的最新进展推动了该领域的发展，并为该领域带来了取得更多突破的希望，但科学上的巨大差距依然存在。这一尚未满足的需求仍在严峻地提醒我们，需要创新的范式来振兴 ALS 研究。为了实现更多信息、更有针对性和更个性化的药物开发，美国国立卫生研究院（NIH）成立了一个名为 "Access for ALL in ALS (ALL ALS) "的全国 ALS 临床研究联盟。这一新联盟由多个机构组成，旨在组织美国的 ALS 临床研究工作。ALL ALS 正在与多个利益相关方合作，以落实《加速 ALS 关键疗法获取法案》（ACT for ALS）公私合作项目的建议。ALL ALS 将为 ALS 患者（有症状人群）或有可能患 ALS 的人群（无症状 ALS 基因携带者）提供大规模、集中化和随时可用的基础设施，用于收集和存储各种数据。重要的是，ALL ALS 的设计旨在鼓励社区参与、平等和包容。该联盟优先考虑招募在地域、种族文化和社会经济方面具有多样性的参与者。收集的数据包括纵向临床数据以及生物流体、基因组和数字生物标记物，这些数据将被统一并链接到加速 ALS 药物合作组织 (AMP ALS) 的中央门户网站，以便与研究界共享。ALL ALS 的目标是提供一个全面、包容、开放的科学数据集，帮助研究人员回答 ALS 临床相关的重要科学问题。
{"title":"Access for ALL in ALS: A large-scale, inclusive, collaborative consortium to unlock the molecular and genetic mechanisms of amyotrophic lateral sclerosis.","authors":"James D Berry,Sabrina Paganoni,Matthew B Harms,Neil Shneider,Jinsy Andrews,Timothy M Miller,Suma Babu,Alex V Sherman,Brent T Harris,Frank A Provenzano,Hemali P Phatnani,Jeremy Shefner,Mark A Garret,Shaffeeq S Ladha,Amy Y Tsou,Praveena Mohan,Courtney Igne,,Robert Bowser","doi":"10.1002/mus.28244","DOIUrl":"https://doi.org/10.1002/mus.28244","url":null,"abstract":"Recent progress in therapeutics for amyotrophic lateral sclerosis (ALS) has spurred development and imbued the field of ALS with hope for more breakthroughs, yet substantial scientific gaps persist. This unmet need remains a stark reminder that innovative paradigms are needed to invigorate ALS research. To move toward more informative, targeted, and personalized drug development, the National Institutes of Health (NIH) established a national ALS clinical research consortium called Access for ALL in ALS (ALL ALS). This new consortium is a multi-institutional effort that aims to organize the ALS clinical research landscape in the United States. ALL ALS is operating in partnership with several stakeholders to operationalize the recommendations of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) Public Private Partnership. ALL ALS will provide a large-scale, centralized, and readily accessible infrastructure for the collection and storage of a wide range of data from people living with ALS (symptomatic cohort) or who may be at risk of developing ALS (asymptomatic ALS gene carriers). Importantly, ALL ALS is designed to encourage community engagement, equity, and inclusion. The consortium is prioritizing the enrollment of geographically, ethnoculturally, and socioeconomically diverse participants. Collected data include longitudinal clinical data and biofluids, genomic, and digital biomarkers that will be harmonized and linked to the central Accelerating Medicines Partnership for ALS (AMP ALS) portal for sharing with the research community. The aim of ALL ALS is to deliver a comprehensive, inclusive, open-science dataset to help researchers answer important scientific questions of clinical relevance in ALS.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"22 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexander Zygmunt, Brenda Wong, David Moon, Paul Horn, Richard Rathbun, Joshua Lambert, Jean Bange, Irina Rybalsky, Lisa Reebals, Cuixia Tian
Introduction/AimsStudies have demonstrated that certain genotypes in Duchenne muscular dystrophy (DMD) have milder or more severe phenotypes. These studies included individuals treated and not treated with corticosteroids and multiple sites with potentially varying standards of care. We aimed to assess genotype–phenotype correlations for age at loss of ambulation (LoA) in a large cohort of individuals with DMD treated with corticosteroids at one center.MethodsIn this retrospective review of medical records, encounters were included for individuals diagnosed with DMD if prescribed corticosteroids, defined as daily deflazacort or prednisone or high‐dose weekend prednisone, for 12 consecutive months. Encounters were excluded if the participants were taking disease‐modifying therapy. Data were analyzed using survival analysis for LoA and Fisher's exact tests to assess the percentage of late ambulatory (>14 years old) individuals for selected genotypes.ResultsOverall, 3948 encounters from 555 individuals were included. Survival analysis showed later age at LoA for exon 44 skip amenable (p = .004), deletion exons 3–7 (p < .001) and duplication exon 2 (p = .043) cohorts and earlier age at LoA for the exon 51 skip amenable cohort (p < .001) when compared with the rest of the cohort. Individuals with deletions of exons 3–7 had significantly more late ambulatory individuals than other cohorts (75%), while those with exon 51 skip amenable deletions had significantly fewer (11.9%) compared with other cohorts.DiscussionThis confirms previous observations of genotype–phenotype correlations in DMD and enhances information for trial design and clinical management.
{"title":"The impact of genotype on age at loss of ambulation in individuals with Duchenne muscular dystrophy treated with corticosteroids: A single‐center study of 555 patients","authors":"Alexander Zygmunt, Brenda Wong, David Moon, Paul Horn, Richard Rathbun, Joshua Lambert, Jean Bange, Irina Rybalsky, Lisa Reebals, Cuixia Tian","doi":"10.1002/mus.28255","DOIUrl":"https://doi.org/10.1002/mus.28255","url":null,"abstract":"Introduction/AimsStudies have demonstrated that certain genotypes in Duchenne muscular dystrophy (DMD) have milder or more severe phenotypes. These studies included individuals treated and not treated with corticosteroids and multiple sites with potentially varying standards of care. We aimed to assess genotype–phenotype correlations for age at loss of ambulation (LoA) in a large cohort of individuals with DMD treated with corticosteroids at one center.MethodsIn this retrospective review of medical records, encounters were included for individuals diagnosed with DMD if prescribed corticosteroids, defined as daily deflazacort or prednisone or high‐dose weekend prednisone, for 12 consecutive months. Encounters were excluded if the participants were taking disease‐modifying therapy. Data were analyzed using survival analysis for LoA and Fisher's exact tests to assess the percentage of late ambulatory (>14 years old) individuals for selected genotypes.ResultsOverall, 3948 encounters from 555 individuals were included. Survival analysis showed later age at LoA for exon 44 skip amenable (<jats:italic>p</jats:italic> = .004), deletion exons 3–7 (<jats:italic>p</jats:italic> < .001) and duplication exon 2 (<jats:italic>p</jats:italic> = .043) cohorts and earlier age at LoA for the exon 51 skip amenable cohort (<jats:italic>p</jats:italic> < .001) when compared with the rest of the cohort. Individuals with deletions of exons 3–7 had significantly more late ambulatory individuals than other cohorts (75%), while those with exon 51 skip amenable deletions had significantly fewer (11.9%) compared with other cohorts.DiscussionThis confirms previous observations of genotype–phenotype correlations in DMD and enhances information for trial design and clinical management.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"36 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction/AimsCerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is caused by RFC1 expansions. Sensory neuronopathy, polyneuropathy, and involvement of motor, autonomic, and cranial nerves have all been described with RFC1 expansions. We aimed to describe the electrodiagnostic features of patients with RFC1 expansions through multimodal electrophysiological investigations.MethodsThirty‐five patients, with a median age of 70 years, and pathologic biallelic repeat expansions in the RFC1 gene, were tested for motor and sensory nerve conduction, flexor carpi radialis (FCR) and soleus H‐reflexes, blink reflex, electrochemical skin conductance, sympathetic skin response (SSR), and heart rate variability with deep breathing (HRV).ResultsOnly 16 patients (46%) exhibited the full clinical CANVAS spectrum. Distal motor amplitudes were normal in 30 patients and reduced in the legs of five patients. Distal sensory amplitudes were bilaterally reduced in a non‐length dependent manner in 30 patients. Conduction velocities were normal. Soleus H‐reflexes were abnormal in 19/20 patients of whom seven had preserved Achilles reflexes. FCR H‐reflexes were absent or decreased in amplitude in 13/14 patients. Blink reflex was abnormal in 4/19 patients: R1 latencies for two patients and R2 latencies for two others. Fourteen out of 31 patients (45%) had abnormal results in at least one autonomic nervous system test, either for ESC (12/31), SSR (5/14), or HRV (6/19).DiscussionLess than half of the patients with RFC1 expansions exhibited the full clinical CANVAS spectrum, but nearly all exhibited typical sensory neuronopathy and abnormal H‐reflexes. Involvement of small nerve fibers and brainstem neurons was less common.
{"title":"Electrophysiological features of the peripheral neuropathy in patients with pathologic biallelic RFC1 repeat expansions","authors":"Calezis Claudia, Bonello‐Palot Nathalie, Verschueren Annie, Azulay Jean‐Philippe, Fortanier Etienne, Grapperon Aude‐Marie, Kouton Ludivine, Gallard Julien, Salort‐Campana Emmanuelle, Attarian Shahram, Delmont Emilien","doi":"10.1002/mus.28257","DOIUrl":"https://doi.org/10.1002/mus.28257","url":null,"abstract":"Introduction/AimsCerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is caused by <jats:italic>RFC1</jats:italic> expansions. Sensory neuronopathy, polyneuropathy, and involvement of motor, autonomic, and cranial nerves have all been described with <jats:italic>RFC1</jats:italic> expansions. We aimed to describe the electrodiagnostic features of patients with <jats:italic>RFC1</jats:italic> expansions through multimodal electrophysiological investigations.MethodsThirty‐five patients, with a median age of 70 years, and pathologic biallelic repeat expansions in the <jats:italic>RFC1</jats:italic> gene, were tested for motor and sensory nerve conduction, flexor carpi radialis (FCR) and soleus H‐reflexes, blink reflex, electrochemical skin conductance, sympathetic skin response (SSR), and heart rate variability with deep breathing (HRV).ResultsOnly 16 patients (46%) exhibited the full clinical CANVAS spectrum. Distal motor amplitudes were normal in 30 patients and reduced in the legs of five patients. Distal sensory amplitudes were bilaterally reduced in a non‐length dependent manner in 30 patients. Conduction velocities were normal. Soleus H‐reflexes were abnormal in 19/20 patients of whom seven had preserved Achilles reflexes. FCR H‐reflexes were absent or decreased in amplitude in 13/14 patients. Blink reflex was abnormal in 4/19 patients: R1 latencies for two patients and R2 latencies for two others. Fourteen out of 31 patients (45%) had abnormal results in at least one autonomic nervous system test, either for ESC (12/31), SSR (5/14), or HRV (6/19).DiscussionLess than half of the patients with <jats:italic>RFC1</jats:italic> expansions exhibited the full clinical CANVAS spectrum, but nearly all exhibited typical sensory neuronopathy and abnormal H‐reflexes. Involvement of small nerve fibers and brainstem neurons was less common.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"9 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mansoureh Mamarabadi, Sarah Mauney, Yuebing Li, Loutfi S. Aboussouan
Dyspnea is a common symptom in neuromuscular disorders and, although multifactorial, it is usually due to respiratory muscle involvement, associated musculoskeletal changes such as scoliosis or, in certain neuromuscular conditions, cardiomyopathy. Clinical history can elicit symptoms such as orthopnea, trepopnea, sleep disruption, dysphagia, weak cough, and difficulty with secretion clearance. The examination is essential to assist with the diagnosis of an underlying neurologic disorder and determine whether dyspnea is from a cardiac or pulmonary origin. Specific attention should be given to possible muscle loss, use of accessory muscles of breathing, difficulty with neck flexion/extension, presence of thoraco‐abdominal paradox, conversational dyspnea, cardiac examination, and should include a detailed neurological examination directed at the suspected differential diagnosis. Pulmonary function testing including sitting and supine spirometry, measures of inspiratory and expiratory muscle strength, cough peak flow, sniff nasal inspiratory pressure, pulse oximetry, transcutaneous CO2, and arterial blood gases will help determine the extent of the respiratory muscle involvement, assess for hypercapnic or hypoxemic respiratory failure, and qualify the patient for noninvasive ventilation when appropriate. Additional testing includes dynamic imaging with sniff fluoroscopy or diaphragm ultrasound, and diaphragm electromyography. Polysomnography is indicated for sleep related symptoms that are not otherwise explained. Noninvasive ventilation alleviates dyspnea and nocturnal symptoms, improves quality of life, and prolongs survival. Therapy targeted at neuromuscular disorders may help control the disease or favorably modify its course. For patients who have difficulty with secretion clearance, support of expiratory function with mechanical insufflation‐exsufflation, oscillatory devices can reduce the aspiration risk.
{"title":"Evaluation and management of dyspnea as the dominant presenting feature in neuromuscular disorders","authors":"Mansoureh Mamarabadi, Sarah Mauney, Yuebing Li, Loutfi S. Aboussouan","doi":"10.1002/mus.28243","DOIUrl":"https://doi.org/10.1002/mus.28243","url":null,"abstract":"Dyspnea is a common symptom in neuromuscular disorders and, although multifactorial, it is usually due to respiratory muscle involvement, associated musculoskeletal changes such as scoliosis or, in certain neuromuscular conditions, cardiomyopathy. Clinical history can elicit symptoms such as orthopnea, trepopnea, sleep disruption, dysphagia, weak cough, and difficulty with secretion clearance. The examination is essential to assist with the diagnosis of an underlying neurologic disorder and determine whether dyspnea is from a cardiac or pulmonary origin. Specific attention should be given to possible muscle loss, use of accessory muscles of breathing, difficulty with neck flexion/extension, presence of thoraco‐abdominal paradox, conversational dyspnea, cardiac examination, and should include a detailed neurological examination directed at the suspected differential diagnosis. Pulmonary function testing including sitting and supine spirometry, measures of inspiratory and expiratory muscle strength, cough peak flow, sniff nasal inspiratory pressure, pulse oximetry, transcutaneous CO<jats:sub>2</jats:sub>, and arterial blood gases will help determine the extent of the respiratory muscle involvement, assess for hypercapnic or hypoxemic respiratory failure, and qualify the patient for noninvasive ventilation when appropriate. Additional testing includes dynamic imaging with sniff fluoroscopy or diaphragm ultrasound, and diaphragm electromyography. Polysomnography is indicated for sleep related symptoms that are not otherwise explained. Noninvasive ventilation alleviates dyspnea and nocturnal symptoms, improves quality of life, and prolongs survival. Therapy targeted at neuromuscular disorders may help control the disease or favorably modify its course. For patients who have difficulty with secretion clearance, support of expiratory function with mechanical insufflation‐exsufflation, oscillatory devices can reduce the aspiration risk.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"64 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction/AimsIntravenous immune globulin (IVIG) has been used as early treatment for autoimmune neuromuscular diseases, but due to cost and frequency, may be switched to rituximab. Rituximab and other B‐cell‐depleting medications require screening of hepatitis B virus (HBV) serologies given the risk of HBV reactivation (HBVr). We aimed to describe the incidence and characteristics of passively transferred antiviral serologies from IVIG and how to differentiate between passive antibody transfer and resolved HBV infection.MethodsThis was a single‐center descriptive study of neurology patients prescribed rituximab and IVIG. Retrospective medical record reviews were performed and patient‐specific variables were collected.ResultsTwelve patients had reactive anti‐HBc results after starting IVIG, but only 9 were confirmed to have reactive anti‐HBc from passive transfer. Whether reactive anti‐HBc in the remaining three patients was from passive IVIG transfer could not be confirmed. Five patients with reactive anti‐HBc results during rituximab screening did not have pre‐IVIG anti‐HBc results for comparison and were started on antiviral prophylaxis. Reactive anti‐HBc serologies changed to nonreactive after IVIG discontinuation 44–321 days after the last IVIG infusion.DiscussionThis study confirms IVIG can passively transfer anti‐HBc serologies in a neurologic cohort. Ideally, HBV serologies would be checked before starting IVIG to help later determine if passive transfer occurred. With the increasing use of B‐cell‐depleting medications for neuromuscular conditions, it is important for providers to be knowledgeable on the interpretation of HBV serologies for patients on IVIG and to ensure implementation of an HBVr prophylaxis management strategy for patients when appropriate.
{"title":"Assessing hepatitis B virus serologies when transitioning patients from intravenous immune globulin therapy to rituximab for the treatment of autoimmune neuromuscular diseases","authors":"Nicole M. Hahn, Lara W. Katzin","doi":"10.1002/mus.28253","DOIUrl":"https://doi.org/10.1002/mus.28253","url":null,"abstract":"Introduction/AimsIntravenous immune globulin (IVIG) has been used as early treatment for autoimmune neuromuscular diseases, but due to cost and frequency, may be switched to rituximab. Rituximab and other B‐cell‐depleting medications require screening of hepatitis B virus (HBV) serologies given the risk of HBV reactivation (HBVr). We aimed to describe the incidence and characteristics of passively transferred antiviral serologies from IVIG and how to differentiate between passive antibody transfer and resolved HBV infection.MethodsThis was a single‐center descriptive study of neurology patients prescribed rituximab and IVIG. Retrospective medical record reviews were performed and patient‐specific variables were collected.ResultsTwelve patients had reactive anti‐HBc results after starting IVIG, but only 9 were confirmed to have reactive anti‐HBc from passive transfer. Whether reactive anti‐HBc in the remaining three patients was from passive IVIG transfer could not be confirmed. Five patients with reactive anti‐HBc results during rituximab screening did not have pre‐IVIG anti‐HBc results for comparison and were started on antiviral prophylaxis. Reactive anti‐HBc serologies changed to nonreactive after IVIG discontinuation 44–321 days after the last IVIG infusion.DiscussionThis study confirms IVIG can passively transfer anti‐HBc serologies in a neurologic cohort. Ideally, HBV serologies would be checked before starting IVIG to help later determine if passive transfer occurred. With the increasing use of B‐cell‐depleting medications for neuromuscular conditions, it is important for providers to be knowledgeable on the interpretation of HBV serologies for patients on IVIG and to ensure implementation of an HBVr prophylaxis management strategy for patients when appropriate.","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":"5 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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