IGHMBP2-related disorders comprise a clinical spectrum from spinal muscular atrophy with respiratory distress type 1 (SMARD1) to Charcot-Marie-Tooth disease type 2S, with increasingly recognized atypical and overlapping phenotypes. We report four pediatric cases from three unrelated families with biallelic pathogenic variants in IGHMBP2. Case 1, a premature infant represents SMARD1. Case 2 had infantile-onset neuropathy without respiratory symptoms. Case 3 and 4, two siblings, presented with a Guillain-Barré syndrome-like phenotype, cauda equina enhancement on spinal neuroimaging, elevated cerebrospinal fluid protein, and electromyography revealing acute motor and sensory axonal neuropathy. Despite an initial response to intravenous immunoglobulin, previous symptoms in Case 3 led to consideration of an immune-mediated neuropathy superimposed on a genetic background. Genetic analysis identified a homozygous nonsense variant in Cases 1 and 2, and novel compound heterozygous missense variants in Case 3 and 4. Thus, the list of overlapping genetic and acquired neuropathies now also includes IGHMBP2-related CMT2S.
{"title":"Phenotypic continuum in IGHMBP2-related disorders: a portfolio of cases from typical to Guillain-Barré syndrome-like presentation","authors":"Hatice Bektaş , Nagihan Şener , Neslihan Bilgin , Gizem Ürel Demir , İbrahim Öncel , Ülkühan Öztoprak , Çağrı Mesut Temuçin , Pelin Özlem Şimşek Kiper , Gülen Eda Utine , Göknur Haliloğlu","doi":"10.1016/j.nmd.2025.106309","DOIUrl":"10.1016/j.nmd.2025.106309","url":null,"abstract":"<div><div><em>IGHMBP2</em>-related disorders comprise a clinical spectrum from spinal muscular atrophy with respiratory distress type 1 (SMARD1) to Charcot-Marie-Tooth disease type 2S, with increasingly recognized atypical and overlapping phenotypes. We report four pediatric cases from three unrelated families with biallelic pathogenic variants in <em>IGHMBP2</em>. Case 1, a premature infant represents SMARD1. Case 2 had infantile-onset neuropathy without respiratory symptoms. Case 3 and 4, two siblings, presented with a Guillain-Barré syndrome-like phenotype, cauda equina enhancement on spinal neuroimaging, elevated cerebrospinal fluid protein, and electromyography revealing acute motor and sensory axonal neuropathy. Despite an initial response to intravenous immunoglobulin, previous symptoms in Case 3 led to consideration of an immune-mediated neuropathy superimposed on a genetic background. Genetic analysis identified a homozygous nonsense variant in Cases 1 and 2, and novel compound heterozygous missense variants in Case 3 and 4. Thus, the list of overlapping genetic and acquired neuropathies now also includes <em>IGHMBP2</em>-related CMT2S.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"59 ","pages":"Article 106309"},"PeriodicalIF":2.8,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864217","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 : 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":"2025-12-13","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 : 2025-12-13DOI: 10.1016/j.nmd.2025.106306
Rachele Rossi , Annemieke Aartsma-Rus , Francesco Muntoni , Aurelie Goyenvalle , Pietro Spitali
Duchenne muscular dystrophy (DMD) is a rare genetic disorder affecting male children, characterized by progressive muscle wasting and weakness. It is a fatal disease, typically leading to death between the ages of 20 and 40, and currently, there is no effective cure. DMD is caused by mutations, most commonly large deletions, in the DMD gene, one of the largest genes in the human genome. This gene also exhibits a distinctive feature known as transcript imbalance, which refers to the unbalance expression of the transcript along its length, with the 5′ end being more abundantly expressed than the 3′ end. Although transcript imbalance was first described in 1995, it remains a poorly understood phenomenon with many unanswered questions. This review highlights the need for a deeper investigation into transcript imbalance, which has not yet received sufficient attention from the scientific community or from sponsors involved in DMD translational research. Understanding and addressing this phenomenon is critical not only for refining antisense oligonucleotide (AON) therapies and enhancing their therapeutic efficacy, but also for developing innovative strategies that improve DMD transcript targeting and muscle delivery.
{"title":"The complexity of dystrophin transcription and processing: implications of transcript imbalance on dystrophin gene targeting strategies","authors":"Rachele Rossi , Annemieke Aartsma-Rus , Francesco Muntoni , Aurelie Goyenvalle , Pietro Spitali","doi":"10.1016/j.nmd.2025.106306","DOIUrl":"10.1016/j.nmd.2025.106306","url":null,"abstract":"<div><div>Duchenne muscular dystrophy (DMD) is a rare genetic disorder affecting male children, characterized by progressive muscle wasting and weakness. It is a fatal disease, typically leading to death between the ages of 20 and 40, and currently, there is no effective cure. DMD is caused by mutations, most commonly large deletions, in the <em>DMD</em> gene, one of the largest genes in the human genome. This gene also exhibits a distinctive feature known as transcript imbalance, which refers to the unbalance expression of the transcript along its length, with the 5′ end being more abundantly expressed than the 3′ end. Although transcript imbalance was first described in 1995, it remains a poorly understood phenomenon with many unanswered questions. This review highlights the need for a deeper investigation into transcript imbalance, which has not yet received sufficient attention from the scientific community or from sponsors involved in DMD translational research. Understanding and addressing this phenomenon is critical not only for refining antisense oligonucleotide (AON) therapies and enhancing their therapeutic efficacy, but also for developing innovative strategies that improve <em>DMD</em> transcript targeting and muscle delivery.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"59 ","pages":"Article 106306"},"PeriodicalIF":2.8,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885695","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 : 2025-12-12DOI: 10.1016/j.nmd.2025.106307
Bochen Zhu , Kexin Jiao , Darrel Sou Li , Jialong Zhang , Ning Zhu , Xingyu Xia , Lingchun Liu , Mingshi Gao , Nachuan Cheng , Ningning Wang , Sushan Luo , Jianying Xi , Chongbo Zhao , Shengqing Li , Wenhua Zhu
Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is a muscular dystrophy associated with pathogenic variants in MEGF10, with previous studies suggesting a potential genotype-phenotype correlation. In this report, we present three patients from two unrelated families finally diagnosed with a milder phenotype of EMARDD. All patients presented with adulthood-onset disease, featuring progressive limb weakness, dysphagia, and severe respiratory difficulties. Muscle pathology was characterized by rimmed vacuoles, and abnormal protein aggregates rather than minicores. Four novel heterozygous variants in MEGF10 were identified: c.1A>T, p.(Met1?); c.370T>C, p.(Cys124Arg); c.2087G>T, p.(Gly696Val); and c.2484T>G, p.(Cys828Trp). This report enriches the genetic and phenotypic landscape of EMARDD and further advances our understanding of MEGF10-related myopathies.
{"title":"Expanded spectrum of MEGF10 related myopathies: late-onset myofibrillar myopathy-like phenotype with novel variants","authors":"Bochen Zhu , Kexin Jiao , Darrel Sou Li , Jialong Zhang , Ning Zhu , Xingyu Xia , Lingchun Liu , Mingshi Gao , Nachuan Cheng , Ningning Wang , Sushan Luo , Jianying Xi , Chongbo Zhao , Shengqing Li , Wenhua Zhu","doi":"10.1016/j.nmd.2025.106307","DOIUrl":"10.1016/j.nmd.2025.106307","url":null,"abstract":"<div><div>Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is a muscular dystrophy associated with pathogenic variants in <em>MEGF10</em>, with previous studies suggesting a potential genotype-phenotype correlation. In this report, we present three patients from two unrelated families finally diagnosed with a milder phenotype of EMARDD. All patients presented with adulthood-onset disease, featuring progressive limb weakness, dysphagia, and severe respiratory difficulties. Muscle pathology was characterized by rimmed vacuoles, and abnormal protein aggregates rather than minicores. Four novel heterozygous variants in <em>MEGF10</em> were identified: c.1A>T, p.(Met1?); c.370T>C, p.(Cys124Arg); c.2087G>T, p.(Gly696Val); and c.2484T>G, p.(Cys828Trp). This report enriches the genetic and phenotypic landscape of EMARDD and further advances our understanding of <em>MEGF10</em>-related myopathies.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"59 ","pages":"Article 106307"},"PeriodicalIF":2.8,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878628","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 : 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":"2025-12-08","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}
Primary desminopathies often present as myofibrillar myopathy with predominant dominant inheritance. There are only few reports of recessive desminopathies. Distinct muscle MRI features with predominant involvement of gluteus maximus, semitendinosus, sartorius, gracilis and peroneal muscles have been described in dominant desminopathies. We report five patients with recessive desminopathies carrying novel homozygous DES variants (c.1023+5G>A and c.958delG). All presented with features of congenital myasthenic syndrome since early childhood. Novel MRI features with fatty infiltration of gluteus medius/ minimus, adductor magnus, quadriceps femoris and hamstrings were noted. Gracilis and short head of biceps femoris were consistently spared. In the leg, in addition to peroneal muscle involvement, there was severe fatty atrophy of anterior leg muscles. There was also myoedema posterior leg compartment. Thus, this study expands the imaging features of desminopathies with myasthenic syndrome.
{"title":"Novel muscle MRI features in Desmin related myasthenic myopathy","authors":"Dipti Baskar , Seetam Kumar Tumulu , Kiran Polavarapu , Akshata Huddar , Gopikrishnan Unnikrishnan , Seena Vengalil , Saraswati Nashi , Vidya Nittur , Gautham Arunachal , Jitender Saini , Hanns Lochmuller , Atchayaram Nalini","doi":"10.1016/j.nmd.2025.106302","DOIUrl":"10.1016/j.nmd.2025.106302","url":null,"abstract":"<div><div>Primary desminopathies often present as myofibrillar myopathy with predominant dominant inheritance. There are only few reports of recessive desminopathies. Distinct muscle MRI features with predominant involvement of gluteus maximus, semitendinosus, sartorius, gracilis and peroneal muscles have been described in dominant desminopathies. We report five patients with recessive desminopathies carrying novel homozygous <em>DES</em> variants (c.1023+5G><em>A</em> and c.958delG). All presented with features of congenital myasthenic syndrome since early childhood. Novel MRI features with fatty infiltration of gluteus medius/ minimus, adductor magnus, quadriceps femoris and hamstrings were noted. Gracilis and short head of biceps femoris were consistently spared. In the leg, in addition to peroneal muscle involvement, there was severe fatty atrophy of anterior leg muscles. There was also myoedema posterior leg compartment. Thus, this study expands the imaging features of desminopathies with myasthenic syndrome.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106302"},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775141","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}
Striated muscles are fundamental components of the human body, playing a central role in motor function. Since antiquity, muscle structure and function have been subjects of inquiry, initially grounded in descriptive anatomical observations. Only with scientific progress and the development of new investigative tools—particularly microscopy—did the histological study of muscle begin to evolve into its current form. The histological examination of normal striated muscle has been instrumental in identifying key pathological features of neuromuscular disorders. Beginning with pivotal discoveries in the 19th century, followed by significant advances throughout the 20th century, our present understanding of myopathology has been shaped by this cumulative progress. Notably, muscle biopsy—now a routine diagnostic procedure in suspected myopathies—has played a critical role in these developments. This review presents a systematic approach that effectively illustrates the key steps in the histological analysis of normal and pathological striated muscle.
{"title":"A historical perspective on the morphology of normal and pathological striated muscle","authors":"Mégane Le Quang , Jean-Michel Vallat , Marie-Laure Martin-Négrier , Stéphane Mathis","doi":"10.1016/j.nmd.2025.106301","DOIUrl":"10.1016/j.nmd.2025.106301","url":null,"abstract":"<div><div>Striated muscles are fundamental components of the human body, playing a central role in motor function. Since antiquity, muscle structure and function have been subjects of inquiry, initially grounded in descriptive anatomical observations. Only with scientific progress and the development of new investigative tools—particularly microscopy—did the histological study of muscle begin to evolve into its current form. The histological examination of normal striated muscle has been instrumental in identifying key pathological features of neuromuscular disorders. Beginning with pivotal discoveries in the 19th century, followed by significant advances throughout the 20th century, our present understanding of myopathology has been shaped by this cumulative progress. Notably, muscle biopsy—now a routine diagnostic procedure in suspected myopathies—has played a critical role in these developments. This review presents a systematic approach that effectively illustrates the key steps in the histological analysis of normal and pathological striated muscle.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106301"},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734002","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 : 2025-11-27DOI: 10.1016/j.nmd.2025.106300
Samna Haider , Ahmed Daud Siddiqui , Muhammad Asad , Marium Amjad , Nidal Bin Kamran , Hoor Ul Ain , Ayesha Khan , Hussain Haider Shah , Shahreena Athar Siddiqui , Amama Anis , Elsa Khan , Radeyah Waseem
Primary periodic paralysis (PPP) comprises inherited ion channelopathies, marked by episodic or sustained muscle weakness. Dichlorphenamide has been investigated as a treatment option, however existing studies report inconsistent and variable findings regarding its efficacy. To clarify these inconsistencies, we conducted a meta-analysis and systematic review evaluating its effectiveness in managing PPP. A comprehensive literature exploration was undertaken across multiple databases encompassing studies disseminated up to July 2025, assessing efficacy of dichlorphenamide in PPP. Primary outcomes encompassed mean changes in weekly attack frequency and severity-weighted scores. Meta-analysis was performed using RevMan, reporting mean differences (MD), statistical significance was ascribed to p-values < 0.05. Evidence certainty was evaluated using the GRADE framework. Clinically significant reductions in the frequency of weekly periodic paralytic attacks were observed in both the hyperkalemic and hypokalemic subgroups (MD -1.72, P-value: 0.01), as well as across the age subgroups, adolescents and adults (MD -0.95, P-value: <0.00001). Analysis of severity-weighted attack scores also revealed significant improvements across both etiological hyperkalemic and hypokalemic categories (MD -1.37, P-value: 0.002), and age-based subgroups (MD -1.28, P-value: <0.00001). Along with therapeutic benefits, some adverse effects were also associated with dichlorphenamide, such as paresthesias (p < 0.00001), cognitive disturbances (p: 0.008), dysgeusia (p: 0.01), and rash (p: 0.006). The GRADE analysis confirmed high-certainty evidence for primary outcomes, supporting dichlorphenamide’s consistent efficacy across etiologies and ages, though its side effects necessitate careful monitoring and counseling.
{"title":"Safety and efficacy of dichlorphenamide in patients with periodic paralysis: A systematic review and meta-analysis","authors":"Samna Haider , Ahmed Daud Siddiqui , Muhammad Asad , Marium Amjad , Nidal Bin Kamran , Hoor Ul Ain , Ayesha Khan , Hussain Haider Shah , Shahreena Athar Siddiqui , Amama Anis , Elsa Khan , Radeyah Waseem","doi":"10.1016/j.nmd.2025.106300","DOIUrl":"10.1016/j.nmd.2025.106300","url":null,"abstract":"<div><div>Primary periodic paralysis (PPP) comprises inherited ion channelopathies, marked by episodic or sustained muscle weakness. Dichlorphenamide has been investigated as a treatment option, however existing studies report inconsistent and variable findings regarding its efficacy. To clarify these inconsistencies, we conducted a meta-analysis and systematic review evaluating its effectiveness in managing PPP. A comprehensive literature exploration was undertaken across multiple databases encompassing studies disseminated up to July 2025, assessing efficacy of dichlorphenamide in PPP. Primary outcomes encompassed mean changes in weekly attack frequency and severity-weighted scores. Meta-analysis was performed using RevMan, reporting mean differences (MD), statistical significance was ascribed to p-values < 0.05. Evidence certainty was evaluated using the GRADE framework. Clinically significant reductions in the frequency of weekly periodic paralytic attacks were observed in both the hyperkalemic and hypokalemic subgroups (MD -1.72, P-value: 0.01), as well as across the age subgroups, adolescents and adults (MD -0.95, P-value: <0.00001). Analysis of severity-weighted attack scores also revealed significant improvements across both etiological hyperkalemic and hypokalemic categories (MD -1.37, P-value: 0.002), and age-based subgroups (MD -1.28, P-value: <0.00001). Along with therapeutic benefits, some adverse effects were also associated with dichlorphenamide, such as paresthesias (<em>p</em> < 0.00001), cognitive disturbances (p: 0.008), dysgeusia (p: 0.01), and rash (p: 0.006). The GRADE analysis confirmed high-certainty evidence for primary outcomes, supporting dichlorphenamide’s consistent efficacy across etiologies and ages, though its side effects necessitate careful monitoring and counseling.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106300"},"PeriodicalIF":2.8,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724898","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}
We report a case of HMGCR-related limb-girdle muscular dystrophy (LGMD) with neonatal onset and early lethality. The patient, homozygous for the p.Arg641Cys variant in HMGCR, presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK). This case stands out among the 17 previously reported patients for its extremely early onset and rapid clinical deterioration. Functional studies confirmed the pathogenicity of the variant: in vitro assays showed severely impaired HMGCR enzymatic activity, and in vivo modeling using homozygous knock-in mice resulted in embryonic lethality, underscoring its deleterious effect on essential metabolic processes. The patient’s early death highlights the urgent need for targeted therapies and early diagnosis. This case expands the clinical and molecular spectrum of HMGCR-related LGMD and supports refining phenotype classification based on genotype–phenotype correlations and age of onset to improve diagnostic precision.
{"title":"HMGCR-related muscular dystrophy: a case of severe neonatal-onset form","authors":"Jariya Upadia , Yuwen Li , Yoshinori Osaki , Seiya Mizuno , Satoru Takahashi , Hitoshi Shimano","doi":"10.1016/j.nmd.2025.106299","DOIUrl":"10.1016/j.nmd.2025.106299","url":null,"abstract":"<div><div>We report a case of <em>HMGCR</em>-related limb-girdle muscular dystrophy (LGMD) with neonatal onset and early lethality. The patient, homozygous for the p.Arg641Cys variant in <em>HMGCR</em>, presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK). This case stands out among the 17 previously reported patients for its extremely early onset and rapid clinical deterioration. Functional studies confirmed the pathogenicity of the variant: <em>in vitro</em> assays showed severely impaired HMGCR enzymatic activity, and <em>in vivo</em> modeling using homozygous knock-in mice resulted in embryonic lethality, underscoring its deleterious effect on essential metabolic processes. The patient’s early death highlights the urgent need for targeted therapies and early diagnosis. This case expands the clinical and molecular spectrum of <em>HMGCR</em>-related LGMD and supports refining phenotype classification based on genotype–phenotype correlations and age of onset to improve diagnostic precision.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106299"},"PeriodicalIF":2.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678250","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}
Malignant Hyperthermia Susceptibility (MHS) is a pharmacogenetic disorder triggered by volatile anesthetics and muscle relaxants, leading to a hypermetabolic reaction in skeletal muscle that can be fatal if untreated. Diagnosis relies on an in vitro contracture test (IVCT) on muscle biopsy and/or genetic testing for pathogenic variants in the RYR1 gene, which accounts for most cases; less frequently, variants are found in CACNA1S and STAC3. However, unlike the IVCT, genetic testing is limited by the large number of RYR1 variants classified as of uncertain significance (VUS), preventing it from fully replacing the IVCT.
We report data from 250 MHS individuals followed over 20 years, in whom 100 RYR1 and 3 CACNA1S variants were identified. Among the RYR1 variants, 81 were previously reported and 19 were novel, all classified as VUS according to European Malignant Hyperthermia Group (EMHG) and Variant Curation Expert Panel (VCEP) criteria. Similarly, of the 3 CACNA1S variants, 1 was previously reported and 2 were classified as VUS.
The reporting of novel variants is crucial for improving the accuracy and consistency of variant classification, thereby supporting a more precise interpretation of their clinical significance.
{"title":"Identification of novel potentially causative RYR1 variants in individuals with malignant hyperthermia susceptibility","authors":"Daniela Rossi , Carlotta Pranzo , Sara Roccabianca , Lucia Galli , Alfredo Orrico , Giovanna Sorbello , Vincenzo Tegazzin , Pasquale D’Onofrio , Armando Fucci , Salvatore Quarta , Stefano Perni , Egidio Maria Rubino , Matteo Serano , Gianna Berti , Diego Lopergolo , Alessandro Malandrini , Filip Van Petegem , Vincenzo Sorrentino","doi":"10.1016/j.nmd.2025.106296","DOIUrl":"10.1016/j.nmd.2025.106296","url":null,"abstract":"<div><div>Malignant Hyperthermia Susceptibility (MHS) is a pharmacogenetic disorder triggered by volatile anesthetics and muscle relaxants, leading to a hypermetabolic reaction in skeletal muscle that can be fatal if untreated. Diagnosis relies on an <em>in vitro</em> contracture test (IVCT) on muscle biopsy and/or genetic testing for pathogenic variants in the <em>RYR1</em> gene, which accounts for most cases; less frequently, variants are found in <em>CACNA1S</em> and <em>STAC3</em>. However, unlike the IVCT, genetic testing is limited by the large number of <em>RYR1</em> variants classified as of uncertain significance (VUS), preventing it from fully replacing the IVCT.</div><div>We report data from 250 MHS individuals followed over 20 years, in whom 100 <em>RYR1</em> and 3 <em>CACNA1S</em> variants were identified. Among the <em>RYR1</em> variants, 81 were previously reported and 19 were novel, all classified as VUS according to European Malignant Hyperthermia Group (EMHG) and Variant Curation Expert Panel (VCEP) criteria. Similarly, of the 3 <em>CACNA1S</em> variants, 1 was previously reported and 2 were classified as VUS.</div><div>The reporting of novel variants is crucial for improving the accuracy and consistency of variant classification, thereby supporting a more precise interpretation of their clinical significance.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"58 ","pages":"Article 106296"},"PeriodicalIF":2.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786660","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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