Journal of neuromuscular diseases最新文献

{"title":"Smartphone-Based Assessment of Mobility and Manual Dexterity in Adult People with Spinal Muscular Atrophy.","authors":"Eduardo Arteaga-Bracho, Gautier Cosne, Christoph Kanzler, Angelos Karatsidis, Claudia Mazzà, Joaquin Penalver-Andres, Cong Zhu, Changyu Shen, Kelley Erb M, Maren Freigang, Hanna-Sophie Lapp, Simone Thiele, Stephan Wenninger, Erik Jung, Susanne Petri, Markus Weiler, Christoph Kleinschnitz, Maggie C Walter, René Günther, Nolan Campbell, Shibeshih Belachew, Tim Hagenacker","doi":"10.3233/JND-240004","DOIUrl":"10.3233/JND-240004","url":null,"abstract":"<p><strong>Background: </strong>More responsive, reliable, and clinically valid endpoints of disability are essential to reduce size, duration, and burden of clinical trials in adult persons with spinal muscular atrophy (aPwSMA).</p><p><strong>Objective: </strong>The aim is to investigate the feasibility of smartphone-based assessments in aPwSMA and provide evidence on the reliability and construct validity of sensor-derived measures (SDMs) of mobility and manual dexterity collected remotely in aPwSMA.</p><p><strong>Methods: </strong>Data were collected from 59 aPwSMA (23 walkers, 20 sitters and 16 non-sitters) and 30 age-matched healthy controls (HC). SDMs were extracted from five smartphone-based tests capturing mobility and manual dexterity, which were administered in-clinic and remotely in daily life for four weeks. Reliability (Intraclass Correlation Coefficients, ICC) and construct validity (ability to discriminate between HC and aPwSMA and correlations with Revised Upper Limb Module, RULM and Hammersmith Functional Scale - Expanded HFMSE) were quantified for all SDMs.</p><p><strong>Results: </strong>The smartphone-based assessments proved feasible, with 92.1% average adherence in aPwSMA. The SDMs allowed to reliably assess both mobility and dexterity (ICC > 0.75 for 14/22 SDMs). Twenty-one out of 22 SDMs significantly discriminated between HC and aPwSMA. The highest correlations with the RULM were observed for SDMs from the manual dexterity tests in both non-sitters (Typing, ρ= 0.78) and sitters (Pinching, ρ= 0.75). In walkers, the highest correlation was between mobility tests and HFMSE (5 U-Turns, ρ= 0.79).</p><p><strong>Conclusions: </strong>This exploratory study provides preliminary evidence for the usability of smartphone-based assessments of mobility and manual dexterity in aPwSMA when deployed remotely in participants' daily life. Reliability and construct validity of SDMs remotely collected in real-life was demonstrated, which is a pre-requisite for their use in longitudinal trials. Additionally, three novel smartphone-based performance outcome assessments were successfully established for aPwSMA. Upon further validation of responsiveness to interventions, this technology holds potential to increase the efficiency of clinical trials in aPwSMA.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"1049-1065"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in Physiopathological Markers in Myotonic Dystrophy Type 1 Skeletal Muscle: A 3-Year Follow-up Study.","authors":"Marie-Pier Roussel, Aymeric Ravel-Chapuis, Jonathan Gobin, Bernard J Jasmin, Jean-Philippe Leduc-Gaudet, Cynthia Gagnon, Elise Duchesne","doi":"10.3233/JND-230139","DOIUrl":"10.3233/JND-230139","url":null,"abstract":"<p><strong>Background: </strong>Myotonic dystrophy type 1 (DM1) is a slowly progressive disease caused by abnormal CTG repetitions on the dystrophia myotonica protein kinase (DMPK) gene. Long mRNA from CTG repetitions stabilizes in nuclear foci and sequester muscleblind-like splicing regulator 1 (MBNL1). Cardinal signs of DM1 include muscle wasting and weakness. The impacts of DM1 progression on skeletal muscle are under-researched.</p><p><strong>Objective: </strong>Identifying physiopathological markers related to maximal strength loss over time in DM1.</p><p><strong>Methods: </strong>Twenty-two individuals with DM1 participated in two maximal isometric muscle strength (MIMS) evaluations of their knee extensors and two vastus lateralis muscle biopsies, 3 years apart. Muscle fiber typing, size (including minimal Feret's diameter [MFD] and atrophy/hypertrophy factors [AF/HF]), and nuclear foci and MBNL1 colocalization (foci/MBNL1+) were evaluated. Immunoblotting was used to measure glycogen synthase kinase-3 beta (GSK3β), p62, LC3BI, LC3BII, and oxidative phosphorylation proteins.</p><p><strong>Results: </strong>There are significant correlations between the fold changes of MIMS with type 1 fiber MFD (ρ= 0.483) and AF (ρ= -0.514). Regression analysis shows that baseline percentage of foci/MBNL1+ nuclei and strength training explain 44.1% of foci/MBNL1+ nuclei percentage variation over time. There are fair to excellent correlations between the fold changes of MIMS and GSK3β (ρ= 0.327), p62 (ρ= 0.473), LC3BI (ρ= 0.518), LC3BII (ρ= -0.391) and LC3BII/LC3BI (ρ= -0.773).</p><p><strong>Conclusion: </strong>Type 1 MFD decrease and AF increase are correlated with MIMS loss. There seems to be a plateau effect in foci/MBNL1+ nuclei accumulation and strength training helps decrease this accumulation. Autophagy marker LC3BII/LC3BI ratio has a good biomarker potential of MIMS loss, but more investigations are needed.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"981-995"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.","authors":"Stefan Nicolau, Jyoti Malhotra, Maryann Kaler, Pamela Magistrado-Coxen, Megan A Iammarino, Natalie F Reash, Emma C Frair, Saranga Wijeratne, Benjamin J Kelly, Peter White, Linda P Lowes, Megan A Waldrop, Kevin M Flanigan","doi":"10.3233/JND-230107","DOIUrl":"10.3233/JND-230107","url":null,"abstract":"<p><p>Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"679-685"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140094232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health-Related Quality of Life in FKRP-Related Limb-Girdle Muscular Dystrophy R9.","authors":"Synnøve M Jensen, Oddgeir Friborg, Svein Ivar Mellgren, Kai Ivar Müller, Svein Bergvik, Kjell Arne Arntzen","doi":"10.3233/JND-221629","DOIUrl":"10.3233/JND-221629","url":null,"abstract":"<p><strong>Background: </strong>Limb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care.</p><p><strong>Objective: </strong>To investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality.</p><p><strong>Methods: </strong>Participants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i.e., Individualized Neuromuscular Quality of Life questionnaire (INQoL) and the 36-item Short Form (SF-36) at baseline, 8, and 14 months and measures of fatigue and sleep quality at 9 months.</p><p><strong>Results: </strong>HRQoL response rate was 84/90 (75 c.826 C > A homozygotes and nine c.826 C > A compound heterozygotes). Compared to Norwegian normative data, all SF-36 domain scores were impaired (p≤0.006) except mental health in males (p = 0.05) and pain scores. During 14 months, perceived muscle weakness and the INQoL index (disease burden) worsened in c.826 C > A homozygotes. Compound heterozygotes reported more dysphagia and physical difficulties than homozygotes and showed a tendency towards worsening in weakness over time but some improvement on the INQoL index. Homozygous females reported generally poorer HRQoL and a higher burden than males. The INQoL index was related to perceived muscle weakness and fatigue, and fatigue to myalgia and mental distress. The prevalence of fatigue and poor sleep was 40% and 49%, respectively.</p><p><strong>Conclusions: </strong>The 14-month follow-up period shows a worsening of perceived weakness and burden in c.826 C > A homozygotes, which can then be expected. The prevalence and impact of fatigue indicate a need for awareness and treatment of fatigue. Myalgia and mental distress are potential targets in the treatment of fatigue, which future studies need to establish. Sleep issues and gender-specific care needs also require attention in LGMDR9.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"59-74"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10789334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71482625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review.","authors":"Elisabetta Pupillo, Ammar Al-Chalabi, Serena Sassi, Emilio Arippol, Lorenzo Tinti, Eugenio Vitelli, Massimiliano Copetti, Maurizio A Leone, Elisa Bianchi","doi":"10.3233/JND-230217","DOIUrl":"10.3233/JND-230217","url":null,"abstract":"<p><strong>Background: </strong>More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found.</p><p><strong>Objective: </strong>To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022.</p><p><strong>Methods: </strong>We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses.</p><p><strong>Results: </strong>213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%.</p><p><strong>Conclusion: </strong>The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"749-765"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Break Down of the Complexity and Inconsistency Between Levels of Matriglycan and Disease Phenotype in FKRP-Related Dystroglycanopathies: A Review and Model of Interpretation.","authors":"Qi L Lu, Molly C Holbrook, Marcela P Cataldi, Anthony Blaeser","doi":"10.3233/JND-230205","DOIUrl":"10.3233/JND-230205","url":null,"abstract":"<p><p>Dystroglycanopathies are a group of muscle degenerative diseases characterized with significant reduction in matriglycan expression critical in disease pathogenesis. Missense point mutations in the Fukutin-related protein (FKRP) gene cause variable reduction in the synthesis of matriglycan on alpha-dystroglycan (α-DG) and a wide range of disease severity. Data analyses of muscle biopsies from patients fail to show consistent correlation between the levels of matriglycan and clinical phenotypes. By reviewing clinical reports in conjunction with analysis of clinically relevant mouse models, we identify likely causes for the confusion. Nearly all missense FKRP mutations retain variable, but sufficient function for the synthesis of matriglycan during the later stage of muscle development and periods of muscle regeneration. These factors lead to a highly heterogenous pattern of matriglycan expression in diseased muscles, depending on age and stages of muscle regeneration. The limited size in clinical biopsy samples from different parts of even a single muscle tissue at different time points of disease progression may well mis-represent the residual function (base-levels) of the mutated FKRPs and phenotypes. We propose to use a simple Multi Point tool from ImageJ to more accurately measure the signal intensity of matriglycan expression on fiber membrane for assessing mutant FKRP function and therapeutic efficacy. A robust and sensitive immunohistochemical protocol would further improve reliability and comparability for the detection of matriglycan.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"275-284"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10977439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nociceptive Pain in Patients with Neuromuscular Disorders: A Cross-Sectional Clinical Study.","authors":"Elena Sagerer, Corinna Wirner-Piotrowski, Marko Mijic, Marcela Arndt, Natalia Garcia-Angarita, Benedikt Schoser, Stephan Wenninger","doi":"10.3233/JND-240068","DOIUrl":"10.3233/JND-240068","url":null,"abstract":"<p><strong>Background: </strong>Muscle pain is a common symptom in patients with neuromuscular disorders (NMD) and accounts for severely reduced quality of life. OBJECTIVE: This clinical study aimed to observe possible differences in pain prevalence among distinct NMDs and to determine whether the patients' nociceptive pain is influenced by gender, muscle strength and psychological factors and to examine potential pain-associated alterations in muscle properties.</p><p><strong>Methods: </strong>The cross-sectional study on nociceptive pain in various NMDs involved patient-reported outcomes, muscle strength evaluations (dynamometry and quick motor function test (QMFT)), nociceptive pain evaluations (muscular pressure pain threshold (PPT)), and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, and creep (myotonometry).</p><p><strong>Results: </strong>Involving 81 NMD patients and a control group, the study found high variability in pain prevalence among the subgroups. Patients with DM2 and FSHD had significantly higher levels of pain prevalence compared to other examined NMD subgroups and the control group. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in the arm and leg region. As assessed by myotonometry, less pain is experienced in neck muscles with a high muscle tone, high stiffness, and a short relaxation time highlighting the importance of intrinsic muscular tone for their pressure pain sensitivity.</p><p><strong>Conclusion: </strong>Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs, especially in women, should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"1111-1122"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative muscle MRI in sporadic inclusion body myositis (sIBM): A prospective cohort study.","authors":"Lara Schlaffke, Robert Rehmann, Martijn Froeling, Anne-Katrin Güttsches, Matthias Vorgerd, Elena Enax-Krumova, Johannes Forsting","doi":"10.3233/JND-240053","DOIUrl":"10.3233/JND-240053","url":null,"abstract":"<p><strong>Background: </strong>Sporadic inclusion body myositis (sIBM) is the predominant idiopathic inflammatory myopathy (IIM) in older people. Limitations of classical clinical assessments have been discussed as possible explanations for failed clinical trials, underlining the need for more sensitive outcome measures. Quantitative muscle MRI (qMRI) is a promising candidate for evaluating and monitoring sIBM.</p><p><strong>Objective: </strong>Longitudinal assessment of qMRI in sIBM patients.</p><p><strong>Methods: </strong>We evaluated fifteen lower extremity muscles of 12 sIBM patients (5 females, mean age 69.6, BMI 27.8) and 12 healthy age- and gender-matched controls. Seven patients and matched controls underwent a follow-up evaluation after one year. Clinical assessment included testing for muscle strength with Quick Motor Function Measure (QMFM), IBM functional rating scale (IBM-FRS), and gait analysis (6-minute walking distance). 3T-MRI scans of the lower extremities were performed, including a Dixon-based sequence, T2 mapping and Diffusion Tensor Imaging. The qMRI-values fat-fraction (FF), water T2 relaxation time (wT2), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ1), and radial diffusivity (RD) were analysed.</p><p><strong>Results: </strong>Compared to healthy controls, significant differences for all qMRI parameters averaged over all muscles were found in sIBM using a MANOVA (p < 0.001). In low-fat muscles (FF < 10%), a significant increase of wT2 and FA with an accompanying decrease of MD, λ1, and RD was observed (p≤0.020). The highest correlation with clinical assessments was found for wT2 values in thigh muscles (r≤-0.634). Significant changes of FF (+3.0%), wT2 (+0.6 ms), MD (-0.04 10-3mm2/s), λ1 (-0.05 10-3mm2/s), and RD (-0.03 10-3mm2/s) were observed in the longitudinal evaluation of sIBM patients (p≤0.001). FA showed no significant change (p = 0.242).</p><p><strong>Conclusion: </strong>qMRI metrics correlate with clinical findings and can reflect different ongoing pathophysiological mechanisms. While wT2 is an emerging marker of disease activity, the role of diffusion metrics, possibly reflecting changes in fibre size and intracellular deposits, remains subject to further investigations.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"997-1009"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GNE Myopathy: Genotype - Phenotype Correlation and Disease Progression in an Indian Cohort.","authors":"Dipti Baskar, Nishanth Reddy, Veeramani Preethish-Kumar, Kiran Polavarapu, Vikas Nishadham, Seena Vengalil, Saraswati Nashi, Sai Bhargava Sanka, Mainak Bardhan, Akshata Huddar, Gopikrishnan Unnikrishnan, Ganaraja Valakunja Harikrishna, Swetha Gunasekaran, Priya Treesa Thomas, Muddasu Suhasini Keerthipriya, Manu Santhappan Girija, Gautham Arunachal, Ram Murthy Anjanappa, Ichizo Nishino, Oksana Pogoryelova, Hanns Lochmuller, Atchayaram Nalini","doi":"10.3233/JND-230130","DOIUrl":"10.3233/JND-230130","url":null,"abstract":"<p><strong>Introduction: </strong>GNE myopathy is a rare slowly progressive adult-onset distal myopathy with autosomal recessive inheritance. It has distinctive features of quadriceps sparing with preferential anterior tibial involvement. Most patients eventually become wheelchair bound by 10-20 years after onset. This study analyzes the phenotype-genotype characteristics and disease progression in a large cohort of GNEM patients from India.</p><p><strong>Materials and methods: </strong>Retrospective observational study on GNEM from a quaternary neurology referral hospital in southern India. Data was collected from clinical phenotyping, serum creatine kinase levels, muscle biopsy histopathology, genetic analysis and functional assessment scales - IBMFRS and MDFRS.</p><p><strong>Results: </strong>157 patients were included with mean age at onset and diagnosis: 26.5±6.2 years and 32.8±7.8 years, respectively. M:F ratio was 25 : 13. Most common presenting symptom: foot drop (46.5%) and limb girdle weakness (19.1%). Wasting and weakness of small muscles of hand and finger flexors seen in 66.2% and as an initial symptoms in 5.2%. Though tibialis anterior involvement was most common (89.2%), early quadriceps weakness was noted in 3.2% and Beevor's sign in 59.2%. Rimmed vacuoles were present in 75% of patients with muscle biopsy. Most common variant was the Indian Founder variant identified in 129 patients (c.2179 G>A, p.Val727Met - 82.2%) and most common zygosity being compound heterozygous state (n = 115, 87.5%). Biallelic kinase domain variations predisposed to a more severe phenotype. Wheelchair bound state noted in 8.9% with a mean age and duration of 32.0±7.1 and 6.3±4.9 years respectively, earlier than previous studies on other ethnic groups.</p><p><strong>Conclusion: </strong>This is the largest GNEM cohort reported from South Asia. The p.Val727Met variant in compound heterozygous state is noted in majority (82.2%) of the cases. Observed relationships between genotype and clinical parameters shows that severity of the disease might be attributable to specific GNE genotype and thus could aid in predicting the disease progression.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"959-968"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antisense Oligonucleotide-Mediated Downregulation of IGFBPs Enhances IGF-1 Signaling.","authors":"Alper Yavas, Maaike van Putten, Annemieke Aartsma-Rus","doi":"10.3233/JND-230118","DOIUrl":"10.3233/JND-230118","url":null,"abstract":"<p><p>Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have been conducted to show the therapeutic potential of IGF-1, however, delivery issues, short half-life and isoform complexity have impose challenges. Antisense oligonucleotides (AONs) are able to downregulate target proteins by interfering with their transcripts. Here, we investigated the feasibility of enhancing IGF-1 signaling by downregulation of IGF-binding proteins. We observed that out of frame exon skipping of Igfbp1 and Igfbp3 downregulated their protein expression, which increased Akt phosphorylation on the downstream IGF-1 signaling in vitro. 3'RNA sequencing analysis revealed the related transcriptome in C2C12 cells in response to IGFBP3 downregulation. The AONs did however not induce any exon skipping or protein knockdown in mdx mice after 6 weeks of systemic treatment. We conclude that IGFBP downregulation could be a good strategy to increase IGF-1 signaling but alternative tools are needed for efficient delivery and knockdown in vivo.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"299-314"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10977368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}