Pub Date : 2024-08-01Epub Date: 2024-06-06DOI: 10.1002/mus.28169
Dylan V Neel, Clara Baselga-Garriga, Molly Benson, Mackenzie Keegan, Marianne Chase, Derek D'Agostino, Kristin Drake, Jennifer Linn Hagar, Meredith Gibbons Hasenoehrl, Jennifer Kulesa-Kelley, Alex Leite, Silpa Mohapatra, Susanna Marie Portaro, Lindsay M Pothier, Jesse Rosenthal, Alexander V Sherman, Hong Yu, Alexandra McCaffrey, Doreen Ho, Sarah Luppino, Richard Bedlack, Daragh Heitzman, Senda Ajroud-Driss, Jonathan Katz, Kevin Felice, Charles Whitaker, Shafeeq Ladha, Gustavo Alameda, Eduardo Locatelli, Irfan A Qureshi, Michael T Hotchkin, Michael R Hayden, Merit E Cudkowicz, Suma Babu, James D Berry, Sabrina Paganoni
Introduction/aims: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers.
Methods: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration.
Results: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing.
Discussion: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.
导言/目的:扩大准入(EA)是由美国食品和药物管理局(Food and Drug Administration)监管的一种途径,旨在为不符合临床试验条件的严重疾病患者提供研究用产品(IP)。本报告旨在分享美国九个中心针对肌萎缩侧索硬化症(ALS)的多中心、多药物 EA 项目的设计和运作情况:方法:建立了一个中央协调中心来设计和实施该计划。方法:成立了一个中央协调中心来设计和实施该计划,并制定了模板化的文件和流程,以简化研究设计、监管提交和不同方案的临床操作。该计划包括三个方案,并提供了在 HEALEY ALS 平台试验的各个方案中进行测试的 IPs(verdiperstat、CNM-Au8 和 pridopidine)。所有 EA 方案(EAP)都收集了临床和安全性数据。项目队列由不符合平台试验条件的参与者组成,包括处于疾病进展晚期和病程较长的参与者:从 2021 年 7 月到 2022 年 9 月,3 个 EAP 共筛查了 85 名参与者。筛查失败率为 3.5%。平台试验方案的入组工作已按计划完成,并根据结果确定了相应 EAP 的持续时间。韦迪哌司坦 EAP 于 2022 年 12 月结束。参与verdiperstat EAP的平均时间为5.8±4.1个月。CNM-Au8和普利多哌啶EAP正在进行中:讨论:与 ALS 随机临床试验同时进行的多中心 EAP 可成功招募不符合临床试验条件的参与者。
{"title":"Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.","authors":"Dylan V Neel, Clara Baselga-Garriga, Molly Benson, Mackenzie Keegan, Marianne Chase, Derek D'Agostino, Kristin Drake, Jennifer Linn Hagar, Meredith Gibbons Hasenoehrl, Jennifer Kulesa-Kelley, Alex Leite, Silpa Mohapatra, Susanna Marie Portaro, Lindsay M Pothier, Jesse Rosenthal, Alexander V Sherman, Hong Yu, Alexandra McCaffrey, Doreen Ho, Sarah Luppino, Richard Bedlack, Daragh Heitzman, Senda Ajroud-Driss, Jonathan Katz, Kevin Felice, Charles Whitaker, Shafeeq Ladha, Gustavo Alameda, Eduardo Locatelli, Irfan A Qureshi, Michael T Hotchkin, Michael R Hayden, Merit E Cudkowicz, Suma Babu, James D Berry, Sabrina Paganoni","doi":"10.1002/mus.28169","DOIUrl":"10.1002/mus.28169","url":null,"abstract":"<p><strong>Introduction/aims: </strong>Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers.</p><p><strong>Methods: </strong>A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration.</p><p><strong>Results: </strong>A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing.</p><p><strong>Discussion: </strong>Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262452","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 : 2024-08-01Epub Date: 2024-06-14DOI: 10.1002/mus.28179
Leonardo Barzaghi, Matteo Paoletti, Mauro Monforte, Sara Bortolani, Chiara Bonizzoni, Feiweier Thorsten, Niels Bergsland, Francesco Santini, Xeni Deligianni, Giorgio Tasca, Elena Ballante, Silvia Figini, Enzo Ricci, Anna Pichiecchio
Introduction/aims: Muscle diffusion tensor imaging has not yet been explored in facioscapulohumeral muscular dystrophy (FSHD). We assessed diffusivity parameters in FSHD subjects compared with healthy controls (HCs), with regard to their ability to precede any fat replacement or edema.
Methods: Fat fraction (FF), water T2 (wT2), mean, radial, axial diffusivity (MD, RD, AD), and fractional anisotropy (FA) of thigh muscles were calculated in 10 FSHD subjects and 15 HCs. All parameters were compared between FSHD and controls, also exploring their gradient along the main axis of the muscle. Diffusivity parameters were tested in a subgroup analysis as predictors of disease involvement in muscle compartments with different degrees of FF and wT2 and were also correlated with clinical severity scores.
Results: We found that MD, RD, and AD were significantly lower in FSHD subjects than in controls, whereas we failed to find a difference for FA. In contrast, we found a significant positive correlation between FF and FA and a negative correlation between MD, RD, and AD and FF. No correlation was found with wT2. In our subgroup analysis we found that muscle compartments with no significant fat replacement or edema (FF < 10% and wT2 < 41 ms) showed a reduced AD and FA compared with controls. Less involved compartments showed different diffusivity parameters than more involved compartments.
Discussion: Our exploratory study was able to demonstrate diffusivity parameter abnormalities even in muscles with no significant fat replacement or edema. Larger cohorts are needed to confirm these preliminary findings.
{"title":"Muscle diffusion tensor imaging in facioscapulohumeral muscular dystrophy.","authors":"Leonardo Barzaghi, Matteo Paoletti, Mauro Monforte, Sara Bortolani, Chiara Bonizzoni, Feiweier Thorsten, Niels Bergsland, Francesco Santini, Xeni Deligianni, Giorgio Tasca, Elena Ballante, Silvia Figini, Enzo Ricci, Anna Pichiecchio","doi":"10.1002/mus.28179","DOIUrl":"10.1002/mus.28179","url":null,"abstract":"<p><strong>Introduction/aims: </strong>Muscle diffusion tensor imaging has not yet been explored in facioscapulohumeral muscular dystrophy (FSHD). We assessed diffusivity parameters in FSHD subjects compared with healthy controls (HCs), with regard to their ability to precede any fat replacement or edema.</p><p><strong>Methods: </strong>Fat fraction (FF), water T2 (wT2), mean, radial, axial diffusivity (MD, RD, AD), and fractional anisotropy (FA) of thigh muscles were calculated in 10 FSHD subjects and 15 HCs. All parameters were compared between FSHD and controls, also exploring their gradient along the main axis of the muscle. Diffusivity parameters were tested in a subgroup analysis as predictors of disease involvement in muscle compartments with different degrees of FF and wT2 and were also correlated with clinical severity scores.</p><p><strong>Results: </strong>We found that MD, RD, and AD were significantly lower in FSHD subjects than in controls, whereas we failed to find a difference for FA. In contrast, we found a significant positive correlation between FF and FA and a negative correlation between MD, RD, and AD and FF. No correlation was found with wT2. In our subgroup analysis we found that muscle compartments with no significant fat replacement or edema (FF < 10% and wT2 < 41 ms) showed a reduced AD and FA compared with controls. Less involved compartments showed different diffusivity parameters than more involved compartments.</p><p><strong>Discussion: </strong>Our exploratory study was able to demonstrate diffusivity parameter abnormalities even in muscles with no significant fat replacement or edema. Larger cohorts are needed to confirm these preliminary findings.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317842","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 : 2024-08-01Epub Date: 2024-06-10DOI: 10.1002/mus.28177
Yu-Fang Huang, Amol K Bhandage, Lisa Diaz-Pintado Adeström, Anna Rostedt Punga
Introduction/aims: The circulating microRNAs (miRNAs) miR-150-5p, miR-30e-5p, and miR-21-5p have been suggested as potential biomarkers for myasthenia gravis (MG); however, the relationships between short-term natural changes of the miRNAs and patient-reported MG outcome scores have not been well-studied. We assessed the short-term fluctuations in miRNA levels and patient-reported outcome measures in MG.
Methods: This prospective cohort study included 39 MG patients with regular follow-ups and unchanged medications at the Neurology outpatient clinic at Uppsala University Hospital. Patients had weekly follow-up visits for 1 month, at which blood samples were drawn, and scores from MG activities of daily living (MG-ADL), MG quality-of-life-15 (MG-QoL15), and Fatigue Severity Scale (FSS) were assessed. Serum levels of miRNA miR-150-5p, miR-30e-5p, and miR-21-5p were analyzed using quantitative real-time PCR.
Results: Intra-individual levels of miR-30e-5p and miR-150-5p were stable, whereas a significant reduction in miR-21-5p was observed from week 1 to week 2 (p = .0024) and from week 2 to week 3 (p < .0001). There were intra-individual differences over a short time in MG-ADL, with higher scores in female patients (p = .0281) and a significant reduction from the first to the second weeks (p = .0281), whereas MG-QoL15 and FSS scores were stable.
Discussion: The suggested MG biomarkers miR-30e-5p and miR-150-5p were more stable than miR-21-5p over a short time, indicating their short-term stability as biomarkers. Prospective multi-center studies with longer periods of follow-up and matched controls are needed to validate these miRNAs as biomarkers in MG.
{"title":"Short-term changes in serum miRNA levels and patient-reported clinical outcomes in myasthenia gravis.","authors":"Yu-Fang Huang, Amol K Bhandage, Lisa Diaz-Pintado Adeström, Anna Rostedt Punga","doi":"10.1002/mus.28177","DOIUrl":"10.1002/mus.28177","url":null,"abstract":"<p><strong>Introduction/aims: </strong>The circulating microRNAs (miRNAs) miR-150-5p, miR-30e-5p, and miR-21-5p have been suggested as potential biomarkers for myasthenia gravis (MG); however, the relationships between short-term natural changes of the miRNAs and patient-reported MG outcome scores have not been well-studied. We assessed the short-term fluctuations in miRNA levels and patient-reported outcome measures in MG.</p><p><strong>Methods: </strong>This prospective cohort study included 39 MG patients with regular follow-ups and unchanged medications at the Neurology outpatient clinic at Uppsala University Hospital. Patients had weekly follow-up visits for 1 month, at which blood samples were drawn, and scores from MG activities of daily living (MG-ADL), MG quality-of-life-15 (MG-QoL15), and Fatigue Severity Scale (FSS) were assessed. Serum levels of miRNA miR-150-5p, miR-30e-5p, and miR-21-5p were analyzed using quantitative real-time PCR.</p><p><strong>Results: </strong>Intra-individual levels of miR-30e-5p and miR-150-5p were stable, whereas a significant reduction in miR-21-5p was observed from week 1 to week 2 (p = .0024) and from week 2 to week 3 (p < .0001). There were intra-individual differences over a short time in MG-ADL, with higher scores in female patients (p = .0281) and a significant reduction from the first to the second weeks (p = .0281), whereas MG-QoL15 and FSS scores were stable.</p><p><strong>Discussion: </strong>The suggested MG biomarkers miR-30e-5p and miR-150-5p were more stable than miR-21-5p over a short time, indicating their short-term stability as biomarkers. Prospective multi-center studies with longer periods of follow-up and matched controls are needed to validate these miRNAs as biomarkers in MG.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296448","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 : 2024-08-01Epub Date: 2024-06-04DOI: 10.1002/mus.28170
Kathryn P Connaghan, Jordan R Green, Marziye Eshghi, Abigail E Haenssler, Zoe A Scheier, Alison Clark, Amrita Iyer, Brian D Richburg, Hannah P Rowe, June Okada, Stephen A Johnson, Jukka-Pekka Onnela, Katherine M Burke, James D Berry
Introduction/aims: Many people living with amyotrophic lateral sclerosis (PALS) report restrictions in their day-to-day communication (communicative participation). However, little is known about which speech features contribute to these restrictions. This study evaluated the effects of common speech symptoms in PALS (reduced overall speaking rate, slowed articulation rate, and increased pausing) on communicative participation restrictions.
Methods: Participants completed surveys (the Communicative Participation Item Bank-short form; the self-entry version of the ALS Functional Rating Scale-Revised) and recorded themselves reading the Bamboo Passage aloud using a smartphone app. Rate and pause measures were extracted from the recordings. The association of various demographic, clinical, self-reported, and acoustic speech features with communicative participation was evaluated with bivariate correlations. The contribution of salient rate and pause measures to communicative participation was assessed using multiple linear regression.
Results: Fifty seven people living with ALS participated in the study (mean age = 61.1 years). Acoustic and self-report measures of speech and bulbar function were moderately to highly associated with communicative participation (Spearman rho coefficients ranged from rs = 0.48 to rs = 0.77). A regression model including participant age, sex, articulation rate, and percent pause time accounted for 57% of the variance of communicative participation ratings.
Discussion: Even though PALS with slowed articulation rate and increased pausing may convey their message clearly, these speech features predict communicative participation restrictions. The identification of quantitative speech features, such as articulation rate and percent pause time, is critical to facilitating early and targeted intervention and for monitoring bulbar decline in ALS.
{"title":"The relationship of rate and pause features to the communicative participation of people living with ALS.","authors":"Kathryn P Connaghan, Jordan R Green, Marziye Eshghi, Abigail E Haenssler, Zoe A Scheier, Alison Clark, Amrita Iyer, Brian D Richburg, Hannah P Rowe, June Okada, Stephen A Johnson, Jukka-Pekka Onnela, Katherine M Burke, James D Berry","doi":"10.1002/mus.28170","DOIUrl":"10.1002/mus.28170","url":null,"abstract":"<p><strong>Introduction/aims: </strong>Many people living with amyotrophic lateral sclerosis (PALS) report restrictions in their day-to-day communication (communicative participation). However, little is known about which speech features contribute to these restrictions. This study evaluated the effects of common speech symptoms in PALS (reduced overall speaking rate, slowed articulation rate, and increased pausing) on communicative participation restrictions.</p><p><strong>Methods: </strong>Participants completed surveys (the Communicative Participation Item Bank-short form; the self-entry version of the ALS Functional Rating Scale-Revised) and recorded themselves reading the Bamboo Passage aloud using a smartphone app. Rate and pause measures were extracted from the recordings. The association of various demographic, clinical, self-reported, and acoustic speech features with communicative participation was evaluated with bivariate correlations. The contribution of salient rate and pause measures to communicative participation was assessed using multiple linear regression.</p><p><strong>Results: </strong>Fifty seven people living with ALS participated in the study (mean age = 61.1 years). Acoustic and self-report measures of speech and bulbar function were moderately to highly associated with communicative participation (Spearman rho coefficients ranged from r<sub>s</sub> = 0.48 to r<sub>s</sub> = 0.77). A regression model including participant age, sex, articulation rate, and percent pause time accounted for 57% of the variance of communicative participation ratings.</p><p><strong>Discussion: </strong>Even though PALS with slowed articulation rate and increased pausing may convey their message clearly, these speech features predict communicative participation restrictions. The identification of quantitative speech features, such as articulation rate and percent pause time, is critical to facilitating early and targeted intervention and for monitoring bulbar decline in ALS.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-03-27DOI: 10.1002/mus.28087
Michael P Skolka, Margherita Milone, William J Litchy, Ruple S Laughlin, Devon I Rubin, Teerin Liewluck
Introduction/aims: Rhabdomyolysis is an etiologically heterogeneous, acute necrosis of myofibers characterized by transient marked creatine kinase (CK) elevation associated with myalgia, muscle edema, and/or weakness. The study aimed to determine the role of electrodiagnostic (EDX) testing relative to genetic testing and muscle biopsy in patients with unprovoked rhabdomyolysis in identifying an underlying myopathy.
Methods: EDX database was reviewed to identify unprovoked rhabdomyolysis patients who underwent EDX testing between January 2012 and January 2022. Each patient's clinical profile, EDX findings, muscle pathology, laboratory, and genetic testing results were analyzed.
Results: Of 66 patients identified, 32 had myopathic electromyography (EMG). Muscle biopsy and genetic testing were performed in 41 and 37 patients, respectively. A definitive diagnosis was achieved in 15 patients (11 myopathic EMG and 4 nonmyopathic EMG; p = .04) based on abnormal muscle biopsy (4/11 patients) or genetic testing (12/12 patients, encompassing 5 patients with normal muscle biopsy and 3 patients with nonmyopathic EMG). These included seven metabolic and eight nonmetabolic myopathies (five muscular dystrophies and three ryanodine receptor 1 [RYR1]-myopathies). Patients were more likely to have baseline weakness (p < .01), elevated baseline CK (p < .01), and nonmetabolic myopathies (p = .03) when myopathic EMG was identified.
Discussion: Myopathic EMG occurred in approximately half of patients with unprovoked rhabdomyolysis, more likely in patients with weakness and elevated CK at baseline. Although patients with myopathic EMG were more likely to have nonmetabolic myopathies, nonmyopathic EMG did not exclude myopathy, and genetic testing was primarily helpful to identify an underlying myopathy. Genetic testing should likely be first-tier diagnostic testing following unprovoked rhabdomyolysis.
{"title":"The utility of electrodiagnostic testing in unprovoked rhabdomyolysis in the era of next-generation sequencing.","authors":"Michael P Skolka, Margherita Milone, William J Litchy, Ruple S Laughlin, Devon I Rubin, Teerin Liewluck","doi":"10.1002/mus.28087","DOIUrl":"10.1002/mus.28087","url":null,"abstract":"<p><strong>Introduction/aims: </strong>Rhabdomyolysis is an etiologically heterogeneous, acute necrosis of myofibers characterized by transient marked creatine kinase (CK) elevation associated with myalgia, muscle edema, and/or weakness. The study aimed to determine the role of electrodiagnostic (EDX) testing relative to genetic testing and muscle biopsy in patients with unprovoked rhabdomyolysis in identifying an underlying myopathy.</p><p><strong>Methods: </strong>EDX database was reviewed to identify unprovoked rhabdomyolysis patients who underwent EDX testing between January 2012 and January 2022. Each patient's clinical profile, EDX findings, muscle pathology, laboratory, and genetic testing results were analyzed.</p><p><strong>Results: </strong>Of 66 patients identified, 32 had myopathic electromyography (EMG). Muscle biopsy and genetic testing were performed in 41 and 37 patients, respectively. A definitive diagnosis was achieved in 15 patients (11 myopathic EMG and 4 nonmyopathic EMG; p = .04) based on abnormal muscle biopsy (4/11 patients) or genetic testing (12/12 patients, encompassing 5 patients with normal muscle biopsy and 3 patients with nonmyopathic EMG). These included seven metabolic and eight nonmetabolic myopathies (five muscular dystrophies and three ryanodine receptor 1 [RYR1]-myopathies). Patients were more likely to have baseline weakness (p < .01), elevated baseline CK (p < .01), and nonmetabolic myopathies (p = .03) when myopathic EMG was identified.</p><p><strong>Discussion: </strong>Myopathic EMG occurred in approximately half of patients with unprovoked rhabdomyolysis, more likely in patients with weakness and elevated CK at baseline. Although patients with myopathic EMG were more likely to have nonmetabolic myopathies, nonmyopathic EMG did not exclude myopathy, and genetic testing was primarily helpful to identify an underlying myopathy. Genetic testing should likely be first-tier diagnostic testing following unprovoked rhabdomyolysis.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140294063","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 : 2024-08-01Epub Date: 2024-06-10DOI: 10.1002/mus.28180
Nikolaos M Marinakis, Maria Svingou, Giorgos-Konstantinos Papadimas, Constantinos Papadopoulos, Elisabeth Chroni, Roser Pons, Evangelos Pavlou, Ioannis Sarmas, Konstantina Kosma, Paraskevi Apostolou, Christalena Sofocleous, Joanne Traeger-Synodinos, Kyriaki Kekou
Introduction/aims: Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant (Thomsen) or a recessive (Becker) disorder. MC is caused by variants in the voltage-gated chloride channel 1 (CLCN1) gene, important for the normal repolarization of the muscle action potential. More than 250 disease-causing variants in the CLCN1 gene have been reported. This study provides an MC genotype-phenotype spectrum in a large cohort of Greek patients and focuses on novel variants and disease epidemiology, including additional insights for the variant CLCN1:c.501C > G.
Methods: Sanger sequencing for the entire coding region of the CLCN1 gene was performed. Targeted segregation analysis of likely candidate variants in additional family members was performed. Variant classification was based on American College of Medical Genetics (ACMG) guidelines.
Results: Sixty-one patients from 47 unrelated families were identified, consisting of 51 probands with Becker MC (84%) and 10 with Thomsen MC (16%). Among the different variants detected, 11 were novel and 16 were previously reported. The three most prevalent variants were c.501C > G, c.2680C > T, and c.1649C > G. Additionally, c.501C > G was detected in seven Becker cases in-cis with the c.1649C > G.
Discussion: The large number of patients in whom a diagnosis was established allowed the characterization of genotype-phenotype correlations with respect to both previously reported and novel findings. For the c.501C > G (p.Phe167Leu) variant a likely nonpathogenic property is suggested, as it only seems to act as an aggravating modifying factor in cases in which a pathogenic variant triggers phenotypic expression.
导言/目的:先天性肌强直(MC)是人类最常见的遗传性通道病。先天性肌强直以肌肉僵硬为特征,可通过常染色体显性(汤姆森)或隐性(贝克尔)遗传。MC 由电压门控氯离子通道 1(CLCN1)基因变异引起,该基因对肌肉动作电位的正常复极化非常重要。目前已报道的 CLCN1 基因致病变体超过 250 个。本研究提供了一大批希腊患者的 MC 基因型-表型谱,并重点研究了新型变异和疾病流行病学,包括对变异 CLCN1:c.501C > G 的进一步了解:方法:对 CLCN1 基因的整个编码区进行了桑格测序。方法:对 CLCN1 基因的整个编码区进行了 Sanger 测序,并对其他家庭成员中可能存在的候选变异进行了有针对性的分离分析。变异分类基于美国医学遗传学会(ACMG)指南:结果:从47个无血缘关系的家族中鉴定出61名患者,其中51名患者为贝克型MC(84%),10名患者为汤姆森型MC(16%)。在检测到的不同变异中,11个是新变异,16个是以前报道过的变异。最常见的三个变异为 c.501C > G、c.2680C > T 和 c.1649C > G。此外,在七个贝克尔病例中还检测到 c.501C > G 与 c.1649C > G 顺式变异:讨论:大量已确诊患者的基因型与表型之间的相关性,既有以前报道的,也有新发现的。c.501C > G (p.Phe167Leu)变异可能不具有致病性,因为它似乎只在致病变异引发表型表达的病例中充当加重病情的修饰因素。
{"title":"Myotonia congenita in a Greek cohort: Genotype spectrum and impact of the CLCN1:c.501C > G variant as a genetic modifier.","authors":"Nikolaos M Marinakis, Maria Svingou, Giorgos-Konstantinos Papadimas, Constantinos Papadopoulos, Elisabeth Chroni, Roser Pons, Evangelos Pavlou, Ioannis Sarmas, Konstantina Kosma, Paraskevi Apostolou, Christalena Sofocleous, Joanne Traeger-Synodinos, Kyriaki Kekou","doi":"10.1002/mus.28180","DOIUrl":"10.1002/mus.28180","url":null,"abstract":"<p><strong>Introduction/aims: </strong>Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant (Thomsen) or a recessive (Becker) disorder. MC is caused by variants in the voltage-gated chloride channel 1 (CLCN1) gene, important for the normal repolarization of the muscle action potential. More than 250 disease-causing variants in the CLCN1 gene have been reported. This study provides an MC genotype-phenotype spectrum in a large cohort of Greek patients and focuses on novel variants and disease epidemiology, including additional insights for the variant CLCN1:c.501C > G.</p><p><strong>Methods: </strong>Sanger sequencing for the entire coding region of the CLCN1 gene was performed. Targeted segregation analysis of likely candidate variants in additional family members was performed. Variant classification was based on American College of Medical Genetics (ACMG) guidelines.</p><p><strong>Results: </strong>Sixty-one patients from 47 unrelated families were identified, consisting of 51 probands with Becker MC (84%) and 10 with Thomsen MC (16%). Among the different variants detected, 11 were novel and 16 were previously reported. The three most prevalent variants were c.501C > G, c.2680C > T, and c.1649C > G. Additionally, c.501C > G was detected in seven Becker cases in-cis with the c.1649C > G.</p><p><strong>Discussion: </strong>The large number of patients in whom a diagnosis was established allowed the characterization of genotype-phenotype correlations with respect to both previously reported and novel findings. For the c.501C > G (p.Phe167Leu) variant a likely nonpathogenic property is suggested, as it only seems to act as an aggravating modifying factor in cases in which a pathogenic variant triggers phenotypic expression.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296447","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 : 2024-08-01Epub Date: 2024-05-30DOI: 10.1002/mus.28164
Rebecca Traub, Taha Qarni, Adam D Cohen, Chafic Karam
The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.
外周神经病变的诊断评估包括检测是否存在单克隆丙种球蛋白病,约有 10% 的外周神经病变患者会出现这种情况。作为医生,我们的职责是确定神经病变是否与单克隆抗体病直接相关,或者这两种疾病的并发是否纯属偶然。评估医生需要熟悉与单克隆丙种球蛋白病相关的不同类型的神经病变、其临床和电诊断特征,以及适当的诊断评估和管理。单克隆蛋白病的检测包括血清蛋白电泳(SPEP)和血液免疫固定,有时也包括尿液免疫固定,以及游离轻链和定量免疫球蛋白的测定。特异性抗体检测以副蛋白类型和神经病变表型为导向。游离轻链异常并伴有感觉和自主神经病变的患者应进行 AL 淀粉样变性评估。当发现λ单克隆蛋白同时伴有慢性炎症性脱髓鞘神经病(CIDP)的临床表型时,应考虑诊断为多发性神经病、器官肥大、内分泌病、单克隆浆细胞紊乱、皮肤改变(POEMS)综合征。IgM副蛋白相关性神经病患者应评估是否患有远端获得性脱髓鞘感觉运动(DADS)神经病,伴或不伴有抗髓鞘相关糖蛋白(MAG)抗体或CANOMAD综合征。在许多病例中,意义不明的单克隆丙种球蛋白病(MGUS)是偶然出现的,与神经病变无关。在对单克隆蛋白患者进行评估时,与肿瘤科的合作至关重要,以评估是否存在潜在的浆细胞瘤或 B 细胞淋巴瘤。
{"title":"Paraproteinemic neuropathies.","authors":"Rebecca Traub, Taha Qarni, Adam D Cohen, Chafic Karam","doi":"10.1002/mus.28164","DOIUrl":"10.1002/mus.28164","url":null,"abstract":"<p><p>The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179482","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 : 2024-08-01Epub Date: 2024-06-03DOI: 10.1002/mus.28171
Yao Zhang, Wei-Yao Liu, Wei-Li Xue, Han Wu, Yan Yuan, Xin-Yuan Ma, Hong Wang, Xian-Li Zhou
Introduction/aims: The current diagnosis of ulnar neuropathy at the elbow (UNE) relies mainly on the clinical presentation and nerve electrodiagnostic (EDX) testing, which can be uncomfortable and yield false negatives. The aim of this study was to investigate the diagnostic value of conventional ultrasound, shear wave elastography (SWE), and superb microvascular imaging (SMI) in diagnosing UNE.
Methods: We enrolled 40 patients (48 elbows) with UNE and 48 healthy volunteers (48 elbows). The patients were categorized as having mild, moderate or severe UNE based on the findings of EDX testing. The cross-sectional area (CSA) was measured using conventional ultrasound. Ulnar nerve (UN) shear wave velocity (SWV) and SMI were performed in a longitudinal plane.
Results: Based on the EDX findings, UNE severity was graded as mild in 4, moderate in 10, and severe in 34. The patient group showed increased ulnar nerve CSA and stiffness at the site of maximal enlargement (CSA mean at the site of max enlargement [CSAmax] and SWV mean at the site of max enlargement [SWVmax]), ulnar nerve CSA ratio, and stiffness ratio (elbow-to-upper arm), compared with the control group (p < .001). Furthermore, the severe UNE group showed higher ulnar nerve CSAmax and SWVmax compared with the mild and moderate UNE groups (p < .001). The cutoff values for diagnosis of UNE were 9.5 mm2 for CSAmax, 3.06 m/s for SWVmax, 2.00 for CSA ratio, 1.36 for stiffness ratio, and grade 1 for SMI.
Discussion: Our findings suggest that SWE and SMI are valuable diagnostic tools for the diagnosis and assessment of severity of UNE.
简介/目的:目前,肘部尺神经病变(UNE)的诊断主要依赖于临床表现和神经电诊断(EDX)测试,这可能会让人感到不适,并产生假阴性结果。本研究旨在探讨传统超声、剪切波弹性成像(SWE)和超微血管成像(SMI)在诊断 UNE 方面的诊断价值:我们招募了 40 名 UNE 患者(48 个肘部)和 48 名健康志愿者(48 个肘部)。根据 EDX 检测结果将患者分为轻度、中度和重度 UNE。横截面积(CSA)用传统超声波测量。在纵向平面上测量了尺神经(UN)剪切波速度(SWV)和SMI:根据 EDX 检查结果,4 例患者的 UNE 严重程度为轻度,10 例为中度,34 例为重度。与对照组相比,患者组的尺神经CSA和最大增大部位的僵硬度(最大增大部位的CSA平均值[CSAmax]和最大增大部位的SWV平均值[SWVmax])、尺神经CSA比率和僵硬度比率(肘部与上臂)均有所增加(与轻度和中度UNE组相比,患者组的尺神经CSA最大值和SWVmax最大值分别为3.06 m/s和3.06 m/s)。讨论:我们的研究结果表明,SWE 和 SMI 是诊断和评估 UNE 严重程度的重要诊断工具。
{"title":"Diagnostic efficiency of conventional ultrasound, shear wave elastography, and superb microvascular imaging in evaluating ulnar neuropathy at the elbow.","authors":"Yao Zhang, Wei-Yao Liu, Wei-Li Xue, Han Wu, Yan Yuan, Xin-Yuan Ma, Hong Wang, Xian-Li Zhou","doi":"10.1002/mus.28171","DOIUrl":"10.1002/mus.28171","url":null,"abstract":"<p><strong>Introduction/aims: </strong>The current diagnosis of ulnar neuropathy at the elbow (UNE) relies mainly on the clinical presentation and nerve electrodiagnostic (EDX) testing, which can be uncomfortable and yield false negatives. The aim of this study was to investigate the diagnostic value of conventional ultrasound, shear wave elastography (SWE), and superb microvascular imaging (SMI) in diagnosing UNE.</p><p><strong>Methods: </strong>We enrolled 40 patients (48 elbows) with UNE and 48 healthy volunteers (48 elbows). The patients were categorized as having mild, moderate or severe UNE based on the findings of EDX testing. The cross-sectional area (CSA) was measured using conventional ultrasound. Ulnar nerve (UN) shear wave velocity (SWV) and SMI were performed in a longitudinal plane.</p><p><strong>Results: </strong>Based on the EDX findings, UNE severity was graded as mild in 4, moderate in 10, and severe in 34. The patient group showed increased ulnar nerve CSA and stiffness at the site of maximal enlargement (CSA mean at the site of max enlargement [CSA<sub>max</sub>] and SWV mean at the site of max enlargement [SWV<sub>max</sub>]), ulnar nerve CSA ratio, and stiffness ratio (elbow-to-upper arm), compared with the control group (p < .001). Furthermore, the severe UNE group showed higher ulnar nerve CSA<sub>max</sub> and SWV<sub>max</sub> compared with the mild and moderate UNE groups (p < .001). The cutoff values for diagnosis of UNE were 9.5 mm2 for CSA<sub>max</sub>, 3.06 m/s for SWV<sub>max</sub>, 2.00 for CSA ratio, 1.36 for stiffness ratio, and grade 1 for SMI.</p><p><strong>Discussion: </strong>Our findings suggest that SWE and SMI are valuable diagnostic tools for the diagnosis and assessment of severity of UNE.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199729","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 : 2024-08-01Epub Date: 2024-06-05DOI: 10.1002/mus.28173
Michael Kiefer, Elise Townsend, Celina Goncalves, K Courtney Shellenbarger, Perman Gochyyev, Brenda L Wong
Introduction/aims: Appendicular lean mass index (ALMI) has been linked to motor function in patients with Duchenne muscular dystrophy (DMD). However, quantification of the relationship between ALMI and disease-specific clinical outcome assessment trajectories is needed. The purpose of this study was to determine associations between dual-energy x-ray absorptiometry (DXA) derived estimates of ALMI and motor function in ambulatory patients with DMD.
Methods: A retrospective analysis of longitudinal clinical visit data from 137 glucocorticoid-treated patients with DMD collected via structured motor assessment protocol evaluated associations between ALMI and motor function indexed by the North Star Ambulatory Assessment (NSAA) and 10 Meter Walk/run Test (10MWT). Body composition was assessed using DXA. ALMI was calculated by dividing arm and leg lean mass by height in m2; fat mass index (FMI) was calculated by dividing whole body fat mass by height in m2. Linear mixed-effects models were used to estimate associations between ALMI and motor function, controlling for age and FMI.
Results: The full prediction model (age, age,2 ALMI, and FMI) explained 57% of the variance in NSAA scores and 63% of the variance in 10MWT speed. A 1 kg/m2 higher ALMI value predicted a 5.4-point higher NSAA score (p < .001) and 0.45 m/s faster 10MWT speed (p < .001). A 1 kg/m2 higher FMI value predicted a 1.5-point lower NSAA score (p < .001) and 0.14 meters/second slower 10MWT speed (p < .001).
Discussion: DXA-derived estimates of ALMI and FMI are associated with motor function in DMD and may explain variation in DMD disease progression.
{"title":"Appendicular lean mass index and motor function in ambulatory patients with Duchenne muscular dystrophy.","authors":"Michael Kiefer, Elise Townsend, Celina Goncalves, K Courtney Shellenbarger, Perman Gochyyev, Brenda L Wong","doi":"10.1002/mus.28173","DOIUrl":"10.1002/mus.28173","url":null,"abstract":"<p><strong>Introduction/aims: </strong>Appendicular lean mass index (ALMI) has been linked to motor function in patients with Duchenne muscular dystrophy (DMD). However, quantification of the relationship between ALMI and disease-specific clinical outcome assessment trajectories is needed. The purpose of this study was to determine associations between dual-energy x-ray absorptiometry (DXA) derived estimates of ALMI and motor function in ambulatory patients with DMD.</p><p><strong>Methods: </strong>A retrospective analysis of longitudinal clinical visit data from 137 glucocorticoid-treated patients with DMD collected via structured motor assessment protocol evaluated associations between ALMI and motor function indexed by the North Star Ambulatory Assessment (NSAA) and 10 Meter Walk/run Test (10MWT). Body composition was assessed using DXA. ALMI was calculated by dividing arm and leg lean mass by height in m<sup>2</sup>; fat mass index (FMI) was calculated by dividing whole body fat mass by height in m<sup>2</sup>. Linear mixed-effects models were used to estimate associations between ALMI and motor function, controlling for age and FMI.</p><p><strong>Results: </strong>The full prediction model (age, age,<sup>2</sup> ALMI, and FMI) explained 57% of the variance in NSAA scores and 63% of the variance in 10MWT speed. A 1 kg/m<sup>2</sup> higher ALMI value predicted a 5.4-point higher NSAA score (p < .001) and 0.45 m/s faster 10MWT speed (p < .001). A 1 kg/m<sup>2</sup> higher FMI value predicted a 1.5-point lower NSAA score (p < .001) and 0.14 meters/second slower 10MWT speed (p < .001).</p><p><strong>Discussion: </strong>DXA-derived estimates of ALMI and FMI are associated with motor function in DMD and may explain variation in DMD disease progression.</p>","PeriodicalId":18968,"journal":{"name":"Muscle & Nerve","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262449","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}