Neuromuscular Disorders最新文献

{"title":"01O Response to rozanolixizumab across treatment cycles in patients with generalised myasthenia gravis: a post hoc analysis","authors":"J. Vissing ,&nbsp;J. Grosskreutz ,&nbsp;A. Habib ,&nbsp;Z. Mahuwala ,&nbsp;R. Mantegazza ,&nbsp;R. Pascuzzi ,&nbsp;S. Sacconi ,&nbsp;T. Vu ,&nbsp;R. Beau Lejdstrom ,&nbsp;B. Greve ,&nbsp;F. Grimson ,&nbsp;T. Tarancón ,&nbsp;V. Bril","doi":"10.1016/j.nmd.2024.07.012","DOIUrl":"10.1016/j.nmd.2024.07.012","url":null,"abstract":"<div><div>In the Phase 3 MycarinG (NCT03971422) study, one cycle (six once-weekly subcutaneous infusions) of rozanolixizumab 7mg/kg or 10mg/kg significantly improved myasthenia Gravis (MG)-specific outcomes versus placebo. After MycarinG, patients could enrol in open-label extensions (OLEs) MG0004 (NCT04124965) then MG0007 (NCT04650854), or MG0007 directly. We evaluate response to rozanolixizumab over multiple treatment cycles in patients with generalised MG based on Cycle 1 response. MG0004 was a ≤52-week OLE of chronic, once-weekly rozanolixizumab 7mg/kg or 10mg/kg. In MG0007, after one six-week cycle (rozanolixizumab 7mg/kg or 10mg/kg), subsequent cycles were administered upon symptom worsening. Data were pooled across MycarinG, MG0004 (first 6 weeks) and MG0007 (interim analysis; data cut-off: 08 July 2022) for patients with ≥2 symptom-driven cycles. MG-Activities of Daily Living (MG-ADL) and Quantitative MG (QMG) response rate (≥2.0- and ≥3.0-point improvement from baseline, respectively) at Day 43 in each cycle was analysed. Post hoc analyses of response rates were conducted based on Cycle 1 response. Overall, 127 patients had ≥2 symptom-driven cycles. In Cycle 1, 74.0% (94/127) and 68.5% (87/127) of patients were MG-ADL and QMG responders, respectively, at Day 43. Among MG-ADL Cycle 1 responders, MG-ADL response rates remained high over subsequent cycles (Cycle 2: 78.7% [74/94]; Cycle 3: 77.1% [54/70]; Cycle 4: 78.0% [46/59]). Similar patterns were observed for QMG response among QMG Cycle 1 responders (Cycle 2: 67.4% [58/86]; Cycle 3: 76.2% [48/63]; Cycle 4: 69.2% [36/52]). Of 33 (26.0%) MG-ADL non-responders at Cycle 1, 63.6% (21/33) were responders at Cycle 2. Of 40 (31.5%) QMG non-responders at Cycle 1, 51.3% (20/39) were responders at Cycle 2. Patients receiving rozanolixizumab demonstrated a high response rate over multiple cycles irrespective of initial response. Initial non-responders may benefit from additional rozanolixizumab treatment cycles.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.3"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423643","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}

{"title":"03O Identification of Class I HLA genetic predispositions and prediction of autoantigenic epitopes in dermatomyositis patients of Indian origin","authors":"B. Jassal ,&nbsp;R. Deepak ,&nbsp;YV. Venugopalan ,&nbsp;V. Suri ,&nbsp;M. Sharma","doi":"10.1016/j.nmd.2024.07.016","DOIUrl":"10.1016/j.nmd.2024.07.016","url":null,"abstract":"<div><div>The discovery of dermatomyositis (DM)-specific autoantibodies has led to a more refined categorization of DM patients into homogenous subgroups. While previous studies have demonstrated the association of Human Leucocyte Antigen (HLA) alleles with DM-specific autoantibodies, the specific epitopes involved in these associations remain unexplored. We aimed to genotype Class-I MHC alleles and to examine specific HLA genetic variants associated with DM patients and to finally predict autoantigenic epitopes. HLA-A, HLA-B, and HLA-C alleles were directly genotyped in Indian cohort of 71 DM patients and 114 ethnically matched controls by next generation sequencing, sequence-specific primer PCR assay, or multiplex assay using the blood genomic DNA. Allele frequency analysis and amino acid alignments were performed using the Genentech/MiDAS bioinformatics package. T-cell epitope prediction was performed using Immune Epitope Database and Tools (IEDB). HLA-A*33:03 allele (Pa= 0.010, OR= 12.024 [3.652 – 54.452]) was more frequently detected in DM-specific autoantibody positive patients (12.26%) than healthy controls (1.32%). Out of all the DM-specific autoantibodies, this Class-I HLA allele showed significant positive association with Mi-2 autoantibody (Pa= 0.006, OR= 15.136 [4.150 – 72.444]) only, which retained its significance after the stepwise conditioning analysis as well. Its association with rest of the autoantibody positive (anti-MDA5 (n=9), anti-NXP2 (n=8), and anti-TIF1g (n=5)) subgroups did not reach statistical significance. Based on Class-I MHC binding, processing, and immunogenicity prediction scores, 15 out of 7,614 peptides of 8 to 11 amino acid residues were predicted to be epitope of Mi-2 autoantigen. High-resolution HLA sequencing more precisely characterised the allele associated with Mi2 autoantibody. Prediction of Mi-2 autoantigenic epitopes presents promising candidates for experimental validation which could pave the way for peptide immunotherapy in Mi2-positive DM subgroup in future.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.7"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423647","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}

{"title":"364P Gross motor delays in boys with Duchenne muscular dystrophy are seen in infancy","authors":"L. Lowes ,&nbsp;N. Reash ,&nbsp;M. Iammarino ,&nbsp;A. Connolly ,&nbsp;L. Pietruszewski ,&nbsp;M. Smith ,&nbsp;J. Peng ,&nbsp;C. Steiner ,&nbsp;C. Tsao ,&nbsp;M. Waldrop ,&nbsp;K. Flanigan ,&nbsp;S. Chagat ,&nbsp;A. Meyer ,&nbsp;J. Mendell ,&nbsp;L. Alfano","doi":"10.1016/j.nmd.2024.07.101","DOIUrl":"10.1016/j.nmd.2024.07.101","url":null,"abstract":"<div><div>There is an increased focus on the developmental abilities of infants and young boys with Duchenne Muscular Dystrophy as clinical trials are increasingly enrolling younger cohorts. Normal maturational gains in gross motor skills, however, makes clinical trials challenging as it is difficult to determine if post-treatment improvement is attributable to the therapeutic or simply to maturation. While there is some understanding of the natural history of infants and toddlers with DMD, there is an urgent need to objectively quantify motor function in this young cohort using a normative-referenced scale to enable data-driven decision-making in these early years. Several countries have now implemented newborn screening for DMD which will allow for diagnosis within the first few weeks of life. Families will likely have questions about trial participation or initiating approved therapies. This submission reports on the prevalence of gross motor delay and documents the trajectory of gross motor skill acquisition in boys with Duchenne muscular dystrophy using the Bayley Scales of Infant &amp; Toddler Development, Third Edition (Bayley 3). Ninety boys (2 months – 5.8 years at their first visit) were evaluated during regularly scheduled clinic visits. Deletion was the most common genetic variant (69%), but the sample included duplications, nonsense, splice site and INDEL variants. We report on longitudinal assessments for 47 boys, with two to six follow up visits, resulting in 128 total assessments. All boys had a delay in gross motor skills when compared with normative controls at least one visit. Although the Bayley 3 was designed for use in children under the age of 42.5 months, none of the older boys in this cohort achieved a perfect score suggesting it could be used until age 6 years. Raw scores increased with age; however, a plateau was noted at 5 years. The average scaled score (which compares a boy's performance to age matched peers; mean=10; SD= 3) was 5 which indicates a significant delay and is 1.6 standard deviations below the mean. Five out of the 90 boys (5.5%) received a scaled score within the normal range at one visit, but this was not maintained over time. The minimum detectable change for this cohort was 4.8 raw points and 1.01 scaled points. Interestingly, there were several items that presented more difficulty than would be expected for their age. These included jumping forward, jumping down from a step, heel-toe walking, standing on one foot for 8 seconds and using a reciprocal pattern to climb stairs. With newborn screening and interventional trials recruiting younger cohorts it is imperative that we understand the typical developmental trajectory of infants and young boys with DMD. A well-documented developmental natural history study could be used to determine if the rate of change in gross motor development following an intervention falls outside of expectations for DMD.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.92"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423995","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}

{"title":"146P Investigation of bone health in a large cohort of naïve SMA patients","authors":"C. Panicucci ,&nbsp;N. Brolatti ,&nbsp;S. Casalini ,&nbsp;G. Coratti ,&nbsp;M. Pedemonte ,&nbsp;F. Ricci ,&nbsp;T. Mongini ,&nbsp;V. Sansone ,&nbsp;M. Filosto ,&nbsp;L. Bello ,&nbsp;E. Pegoraro ,&nbsp;I. Bruno ,&nbsp;L. Verriello ,&nbsp;G. Ricci ,&nbsp;A. D'Amico ,&nbsp;E. Mercuri ,&nbsp;M. Maghnie ,&nbsp;N. Di Iorgi ,&nbsp;C. Bruno ,&nbsp;working group ITASMAC","doi":"10.1016/j.nmd.2024.07.053","DOIUrl":"10.1016/j.nmd.2024.07.053","url":null,"abstract":"<div><div>SMA patients have a high risk of osteoporosis although limited data are available, and bone fragility management is not fully integrated in the standard of care. This multicenter, retrospective, cross-sectional study aims to evaluate fracture prevalence and bone mineral density (BMD Z-score) in naïve SMA patients included in the ITASMAC registry data, by using hospital charts and dual-energy X-ray absorptiometry (DXA) measurements. Data were available in 148 SMA patients from 11 National referral center for SMA (6.1% SMA1, 42.6% SMA2, and 51.3% SMA3). Overall, 46/148 (31.1%) patients presented at least 1 fragility fracture, 2/9 SMA1 (22.2%), 20/63 SMA2 (32.3%), and 24/76 SMA3 (31.6%), at a mean age of 12 years for SMA1 and SMA2, and 31 for SMA3. Long bone fractures were the most prevalent (93%), and only 4/46 (9%) of fractured patients were treated with bisphosphonates. DXA scans before the first fracture were available in 82 patients, performed at median age of 5 years for SMA1 (n= 3), 15 for SMA2 (n=37), and 27 for SMA3 (n=42). Pathologic BMD Z-scores were observed in 3/3 (100%) SMA1, 35/37 (95%) SMA2, and 21/42 (50%) SMA3. The lowest median BMD Z-scores were registered at femur (-2.9), followed by total body (-2.5) and lumbar spine (-2.2). In conclusion, we detected an overall fractures prevalence of 30%, without significant differences between SMA types. BMD Z-scores were significantly lower in SMA1 and SMA2 compared to SMA3. This baseline analysis of bone health in naïve SMA patients, provides a starting point for longitudinal studies to determine SMA treatment effects on bone in this condition.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.44"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423382","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}

{"title":"204P A phase 1 study of antisense oligonucleotide NS-035 in patients with Fukuyama congenital muscular dystrophy","authors":"G. Fujino ,&nbsp;A. Kitamura ,&nbsp;A. Takahashi ,&nbsp;M. Maeda ,&nbsp;A. Kubota ,&nbsp;Y. Tokuyama ,&nbsp;I. Wada ,&nbsp;K. Kobayashi ,&nbsp;H. Komaki ,&nbsp;M. Taniguchi-Ikeda ,&nbsp;K. Ishigaki ,&nbsp;T. Toda","doi":"10.1016/j.nmd.2024.07.055","DOIUrl":"10.1016/j.nmd.2024.07.055","url":null,"abstract":"<div><div>Fukuyama congenital muscular dystrophy (FCMD) is an autosomal recessive disease that primarily affects the skeletal muscles, brain, and eyes. FCMD is most commonly caused by a 3-kb retrotransposal insertion into the 3′ untranslated region of the fukutin gene, resulting in aberrant mRNA splicing (exon-trapping). In collaboration with Nippon Shinyaku, we discovered an antisense oligonucleotide, NS-035, that can prevent this exon-trapping, recovering normal fukutin mRNA expression and protein function in both mouse models and cells of FCMD patients. To obtain regulatory approval for NS-035, we initiated the first-in-human phase 1 study of NS-035 in patients with FCMD. This was a two-center, open-label, uncontrolled, dose-escalation clinical trial comprising four cohorts. Twelve patients with FCMD (aged 5–10 years) carrying homozygous or compound heterozygous variants in the fukutin gene were included, with three patients in each cohort. The study was initiated in cohort 1. D-mannitol alone was administered intravenously once during the premedication phase, followed by simultaneous doses of NS-035 and D-mannitol administered intravenously once weekly for 12 weeks during the treatment phase. The dose of D-mannitol was fixed at 500 mg/kg in all cohorts, while NS-035 was increased stepwise from cohorts 1 to 4 (1.6, 6.0, 20, and 40 mg/kg). The primary endpoint was safety, and the secondary endpoints were pharmacokinetics and efficacy (glycosylation rate of alpha-dystroglycan [DG], expression of glycosylated alpha-DG, exon-trapping inhibition efficiency, evaluation of gross motor function, and changes in blood CK value). Following institutional review board approval in June 2021, the trial was initiated in August 2021. This study is currently in progress with the final patient (patient 12). This study is progressing smoothly and is scheduled for completion in 2024.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.46"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423385","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}

{"title":"Table of Contents for the Main Abstracts","authors":"","doi":"10.1016/S0960-8966(24)00951-9","DOIUrl":"10.1016/S0960-8966(24)00951-9","url":null,"abstract":"","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104455"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423579","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}

{"title":"231P Efficacy of tranilast in preventing exacerbating cardiac function and death from heart failure in muscular dystrophy patients with advanced-stage heart failure: a single-arm, open-label, multicenter study","authors":"T. Matsumura ,&nbsp;T. Fukudome ,&nbsp;Y. Motoyoshi ,&nbsp;A. Nakamura ,&nbsp;S. Kuru ,&nbsp;K. Segawa ,&nbsp;R. Kitao ,&nbsp;C. Watanabe ,&nbsp;T. Tamura ,&nbsp;T. Takahashi ,&nbsp;H. Hashimoto ,&nbsp;M. Sekimizu ,&nbsp;A. Saito ,&nbsp;M. Asakura ,&nbsp;K. Kimura ,&nbsp;Y. Iwata","doi":"10.1016/j.nmd.2024.07.082","DOIUrl":"10.1016/j.nmd.2024.07.082","url":null,"abstract":"<div><div>Transient receptor potential cation channel subfamily V member 2 (TRPV2) functions as a stretch-sensitive calcium channel, with overexpression in the sarcolemma of skeletal and cardiac myocytes leading to detrimental calcium influx, triggering muscle degeneration. In our previous pilot study, we showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two patients with muscular dystrophy (MD) and advanced heart failure. Building on this, we performed a single-arm, open-label, multicenter study herein to evaluate the safety and efficacy of tranilast in the treatment of advanced heart failure in MD patients. This study involved 18 MD patients with BNP levels &gt; 100 pg/mL, despite receiving standard cardioprotective therapy. Tranilast was administered orally at a dose of 100 mg, three times daily. We published earlier the primary endpoint, the change in the logarithm of BNP level from baseline to 28 weeks (short-term treatment). All 15 patients who completed the short-term treatment consented to be enrolled in long-term therapy for an additional 116 weeks. After all participants completed the long-term treatment, we assessed TRPV2 expression on the peripheral blood mononuclear cell surfaces, cardiac events, total mortality, left ventricular fractional shortening, BNP, human atrial natriuretic peptide, cardiac troponin T, creatine kinase, pinch strength, and quality of life. Two patients died, and one withdrew during the long-term period. The survival rate was 80.7%, and no cardiac deaths were reported. Despite the presence of progressive disease, the cardiac indices remained stable, and only BNP levels at 144 weeks showed significant changes. Notably, TRPV2 expression decreased throughout the study period. The findings suggest that tranilast can inhibit TRPV2 expression for an extended period and is effective in preventing the worsening of cardiac function and subsequent death from heart failure.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.73"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423585","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}

{"title":"217P Comparing IBMFRS and sIFA as progression indicators in inclusion body myositis patients from the INSPIRE-IBM trial","authors":"P. Gaid ,&nbsp;M. Wencel ,&nbsp;I. Hernandez ,&nbsp;N. Goyal ,&nbsp;M. Dimachkie ,&nbsp;T. Lloyd ,&nbsp;P. Mohassel ,&nbsp;C. Weihl ,&nbsp;M. Freimer ,&nbsp;A. Shaibani ,&nbsp;M. Wicklund ,&nbsp;S. Dixon ,&nbsp;N. Chahin ,&nbsp;L. Wang ,&nbsp;P. Shieh ,&nbsp;A. Amato ,&nbsp;C. Quinn ,&nbsp;O. Carbunar ,&nbsp;T. Mozaffar ,&nbsp;INSPIRE IBM Study Group","doi":"10.1016/j.nmd.2024.07.068","DOIUrl":"10.1016/j.nmd.2024.07.068","url":null,"abstract":"<div><div>Inclusion body myositis (IBM) is a common muscular disorder in individuals over the age of 40 years, characterized by atrophy and progressive muscle weakness. Patient-reported outcomes such as the IBMFRS or the sIFA questionnaire provide valuable insights into disease impact from the patient's perspective on their symptoms, functional limitations, and quality of life. However, it remains a topic of further investigation to determine which of these questionnaires exhibits stronger correlations with disease progression. The INSPIRE-IBM is a natural history study involving 150 IBM patients across 13 different US sites. Evaluations are conducted biannually over two years and patients complete IBMFRS, sIFA, EAT-10, Sydney Swallow Questionnaire, PROMIS, along with manual muscle testing and pulmonary functions tests. This abstract analyzes correlations between IBMFRS and sIFA with the other assessments by regression analysis to identify which is a stronger correlator with disease progression. Preliminary analysis, involving 87 patients who completed three time points, revealed a strong correlation between IBMFRS and sIFA (R2=0.7, p=3.21E-96). Both outcomes show moderate correlation with PFTs (R2 between 0.5-0.7), with no significant difference in strength of correlation. IBMFRS and sIFA exhibit similar correlation with MMTs (R2=0.43, p=0.93). As the study is ongoing, more timepoints will be available per patient closer to the conference date and will be included in the analysis.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.59"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423595","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}

{"title":"02O Characterization of a mouse model for Jo-1, PL-7 and PL-12 associated anti-synthetase syndrome","authors":"D. Cengiz ,&nbsp;C. Preusse ,&nbsp;S. Lichtenberg ,&nbsp;K. Koch-Hölsken ,&nbsp;V. Umathum ,&nbsp;A. Herrmann ,&nbsp;A. Schaenzer ,&nbsp;S. Meuth ,&nbsp;W. Stenzel ,&nbsp;T. Ruck","doi":"10.1016/j.nmd.2024.07.013","DOIUrl":"10.1016/j.nmd.2024.07.013","url":null,"abstract":"<div><div>Anti-synthetase syndrome (ASyS) is an autoimmune condition, characterized by the presence of autoantibodies directed against an aminoacyl-tRNA synthetase (anti-ARS). Patients present clinical symptoms such as myositis, interstitial lung disease, Raynaud's phenomenon, and arthritis. Anti-Jo-1, anti-PL-7 and anti-PL-12 are the most frequent anti-ARS. However, their role in ASyS pathogenesis remains incompletely understood. Therefore, robust animal models are essential to gain a detailed insight into the underlying pathophysiology. Aiming to characterize these pathophysiological features, we established and studied a mouse model for Jo-1, PL-7 and PL-12 associated ASyS. ASyS was induced in NOD.Idd 3/5 mice by injection of 200 µg Jo-1, PL-7 or PL-12 recombinant protein emulsified in Complete Freund's Adjuvant (CFA) in combination with OX86. Controls received CFA and Phosphate Buffered Saline only. Muscle strength was assessed by rotarod tests and the effects on the peripheral immune system were investigated by flow cytometry in spleen and lymph nodes. Morphological characteristics of skeletal muscle and lung tissue of immunized mice and the tissue infiltrating immune cells were validated using histology and immunohistochemistry. Immunization of mice led to clinical symptoms including muscle weakness and demonstrated variations in the immune cell response between the ARS subtypes. Histological analysis of skeletal muscle tissues showed infiltration by immune cells in the epimysium, spreading into the adjacent perifascicular area with progressing disease. Analysis of lung specimens by immunohistological staining demonstrated peribronchial accentuated accumulation of lymphocyte aggregates. We present a mouse model, which recapitulates features of the human phenotype of ASyS, to study the molecular pathogenesis and provide new insights into the pathomechanisms.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.4"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423644","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}

{"title":"270P Single nucleus RNA sequencing reveals unique myonuclei populations in late-onset myopathy","authors":"T. Soule ,&nbsp;C. Pontifex ,&nbsp;N. Rosin ,&nbsp;M. Joel ,&nbsp;S. Lee ,&nbsp;M. Nguyen ,&nbsp;S. Chhibber ,&nbsp;G. Pfeffer","doi":"10.1016/j.nmd.2024.07.088","DOIUrl":"10.1016/j.nmd.2024.07.088","url":null,"abstract":"<div><div>Genetic myopathies represent a large, heterogeneous group of diseases. Typical outcomes include progressive weakness over time, painful joints, and even deteriorating heart and respiratory function. There is tremendous variation in which muscles are affected, disease severity, and curiously, the age of onset. Mutations in a muscle specific protein would be expected to cause immediate consequences to muscular function. However, some patients remain unaffected until after normal muscle development has completed, only experiencing weakness starting in their 20s or later in life. The mechanisms behind the delay in onset of these diseases remain obscure. Single-cell technologies are a powerful method to obtain quantitative, cell-specific transcriptional information. This is a promising approach to studying skeletal muscle disease because it provides a high-resolution look at the many cell types regulating muscle homeostasis and repair. Our goal was to use single nucleus RNA sequencing to find transcriptional similarities between late-onset myopathy patients. To this end, we developed a novel nuclei isolation approach from frozen human skeletal muscle biopsies. We isolated nuclei from the muscle of 10 patients with a diverse range of myopathies and 4 age and sex matched controls. After processing, this yielded over 100,000 nuclei with quality control metrics in line with literature values. We identified 12 cell types, and interestingly, a unique population of differentiating myonuclei derived almost entirely from myopathic patients. These myonuclei express markers of senescence, aging, and impaired differentiation potential. Very few control nuclei were present in this population, implying a cell state that is specific to disease. Overall, our findings suggest that myogenic progenitors in late-onset myopathic muscle may be aging prematurely.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.79"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423232","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}