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In the Phase 3 RAISE study (NCT04115293), zilucoplan significantly improved Myasthenia Gravis (MG)-specific outcomes in patients with acetylcholine receptor autoantibody-positive generalised MG. After the first 12 weeks of the ongoing, open-label extension study, RAISE-XT (NCT04225871), corticosteroid dose could be changed per the investigator's discretion. Here, we evaluate changes in corticosteroid dose during zilucoplan treatment in RAISE-XT. In RAISE-XT, adults who completed a qualifying double-blind study (NCT03315130/NCT04115293) self-administered daily subcutaneous zilucoplan 0.3mg/kg, either continuing previous zilucoplan treatment or switching from placebo. Primary outcome was incidence of treatment-emergent adverse events (TEAEs). This post hoc analysis assessed proportions of patients who discontinued/reduced or increased their corticosteroid dose relative to double-blind baseline and change from baseline (CFB) in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at Week 60. 200 patients enrolled. At week 60, 30% (n=18/60) and 22% (n=12/54) of patients receiving corticosteroids in the zilucoplan and placebo-switch groups, respectively, had reduced or discontinued corticosteroids. Among these patients, mean dose reductions were 14mg and 16mg; mean (standard deviation [SD]) CFB in MG-ADL score was −5.00 (3.96) and −5.67 (6.89), respectively. At week 60, 12% (n=7/60) and 7% (n=4/54) of patients in the zilucoplan and placebo-switch groups, respectively, had increased corticosteroid dose (∼12mg mean dose increase in both groups) with mean (SD) CFB in MG-ADL score of −4.86 (2.55) and −9.75 (4.57). TEAEs occurred in 188 (94.0%) patients (data cut-off: 08 September 2022). While receiving zilucoplan, discontinuation or reduction of concomitant corticosteroids was possible with maintained efficacy. [ABSTRACT FROM AUTHOR]

The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information about myotonic dystrophy type 1 (DM1) and type 2 (DM2). Established in May 2012 by Newcastle University and supported by Muscular Dystrophy UK, Cure-DM and the Myotonic Dystrophy Support Group, the registry facilitates academic and clinical research, enables better characterisation and understanding of DM and disseminates information relating to upcoming studies and research advancements to participants. The registry is used to capture longitudinal, self-reported data through an online portal available to patients and clinicians. Where specialised clinical or genetic information is available, the neuromuscular specialist involved in the patient's care can provide some additional data. The registry is a Core Member of the TREAT- NMD Global Registries Network for DM1, collecting the standardised dataset and contributing to global data enquiries. The registry has successfully assisted with recruitment to clinical trials and has supported over 30 research enquiries to date. These include anonymised data reports to industry, and academic research surveys into topics including COVID-19, dysphagia, pregnancy, patient preferences for future treatments and the patient/caregiver experience. The registry continues to be a versatile, cost-effective research tool to facilitate and advance a range of DM research. Additional work continues to be done to improve reporting of genetic information on the registry and to overcome perceived boundaries to registration and participation. [ABSTRACT FROM AUTHOR]

Background: We report our experience of patients with generalised myasthenia gravis (gMG) treated with efgartigimod, an neonatal Fc receptor antagonist, under the Early Access to Medicine Scheme (EAMS) in the UK., Methods: Data from all UK patients treated with efgartigimod under the EAMS July 2022 to July 2023 were collected retrospectively. Efgartigimod was administered as per the ADAPT protocol (consisting of a treatment cycle of four infusions at weekly intervals with further cycles given according to clinical need)., Results: 48 patients with acetylcholine receptor antibody-positive gMG were treated in 12 centres. Most (75%) were female and most had a disease duration of over 10 years. The average MG-Activities of Daily Living (ADL) score at baseline was 11.2. Most (72.9%) patients had undergone thymectomy. 77.0% were taking prednisolone at baseline. All patients had used non-steroidal immunosuppressant treatments, the average number tried was 2.6 (range 1-6). 51% had received rituximab. 54.2% of patients required regular intravenous immunoglobulin/plasma exchange.75% of patients had a mean reduction in the MG-ADL of≥2 points in the first cycle and this remained stable throughout the study. The mean intracycle reduction in the MG-ADL score in the first, second, third and fourth cycles were -4.6 to -3.9, -3.4 and -4.2, respectively. Side effects were generally mild. No rescue treatments were required. At the end of the study, 96% of patients remained on efgartigimod., Conclusion: Efgartigimod is a safe and effective treatment for patients with refractory, treatment-resistant gMG., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP., Methods: ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed., Findings: Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group)., Interpretation: ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options., Funding: argenx., Competing Interests: Declaration of interests JAA reports consulting fees from Akcea Therapeutics, Alexion, Alnylam, Annexon Biosciences, argenx, CSL Behring, Grifols, Immunovant, ImmuPharma, Johnson & Johnson, and Takeda, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alnylam, Annexon Biosciences, argenx, CSL Behring, and Takeda. TD reports participation on a data safety monitoring board or advisory board for Dianthus Therapeutics. CE reports grants or contracts from argenx; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from argenx; support for attending meetings and travel from argenx; and stock or stock options from argenx. AT was an employee of argenx, and reports stock or stock options at the time of the study completion. JTG is an employee of argenx; reports support for attending meetings and travel from argenx; and reports stock or stock options from argenx. BVH is an employee of argenx. PU is an employee of argenx; reports patents planned, issued, or pending from argenx; reports stock or stock options from argenx; and reports other financial or non-financial interests from argenx. EH is an employee of argenx; reports patents planned, issued, or pending from argenx; and reports stock or stock options from argenx. KGG reports consulting fees from Alexion, and UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alexion, argenx, and Xeris Pharmaceuticals; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for Myasthenia Gravis Foundation of America. FL reports grants or contracts from German Ministry of Education and Research, German Research Society DFG, HORIZON MSCA 2022 Doctoral Network, and Stiftung Pathobiochemie of the German Society for Laboratory Medicine; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Biogen, Fresenius, Grifols, Novartis, Roche, and Teva Pharmaceuticals; support for attending meetings and travel from Bayer, Grifols, and Merck; and participation on a data safety monitoring board or advisory board for argenx, Alexion, Biogen, and Roche. MLi reports grants or contracts from Kedrion Biopharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CSL Behring, Kedrion Biopharma, and Takeda; support for attending meetings and travel from CSL Behring, Kedrion Biopharma, and Takeda; and other financial or non-financial interests from argenx. MLo was an employee of argenx at the time of the study completion. LQ reports grants or contracts from argenx, CIBERER, Instituto de Salud Carlos III–Ministry of Economy and Innovation (Spain), and UCB; consulting fees from Annexon Biosciences, Alnylam, argenx, Avilar Therapeutics, CSL Behring, Dianthus Therapeutics, Janssen, LFB, Novartis, Nuvig Therapeutics, Roche, Sanofi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam, argenx, CSL Behring, Novartis, Roche, and Sanofi; support for attending meetings and travel from Alnylam and Sanofi; participation on a data safety monitoring board or advisory board for argenx, CSL Behring, Sanofi, and UCB; and a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Inflammatory Neuropathy Consortium and Peripheral Nerve Society. NS reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam, and participation on a data safety monitoring board or advisory board for Takeda. RY reports consulting fees from Japan Tobacco and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alnylam Japan, CSL Behring, FP Pharm, Kyowa Kirin, Ono Pharmaceutical, and Takeda Pharmaceutical. RAL reports royalties or licenses from UpToDate; consulting fees from Annexon Biosciences, argenx, CSL Behring, Dianthus Therapeutics, Grifols, Immunovant, Janssen, Nuvig Therapeutics, Sanofi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from argenx, CSL Behring, Medscape, and Sanofi; participation on a data safety monitoring board or advisory board for Boehringer Ingelheim and Novartis; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Peripheral Nerve Society and GBS-CIDP Foundation International. PAvD reports support for attending meetings and travel from argenx and participation on a data safety monitoring board or advisory board for argenx. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene resulting in reduced levels of SMN protein. SMN protein is produced by cells throughout the body, and evidence suggests that low SMN protein can have systemic implications, including in male reproductive organs. However, a paucity of research exists on this important topic. This article will discuss findings from non-clinical studies on the role of SMN in the male reproductive system; additionally, real-world observational reports of individuals with SMA will be examined. Furthermore, we will review the non-clinical reproductive findings of risdiplam, a small-molecule SMN2 splicing modifier approved for the treatment of SMA, which has widespread distribution in both the central nervous system and peripheral organs. Specifically, the available non-clinical evidence of the effect of risdiplam on male reproductive organs and spermatogenesis is examined. Lastly, the article will highlight available capabilities to assess male fertility as well as the advanced reproductive technologies utilized to treat male infertility. This article demonstrates the need for further research to better understand the impacts of SMA on male fertility and reproduction., (© 2024. The Author(s).)

Neuromuscular disorders are a group of conditions that can result in weakness of skeletal muscles. Examples include fatal diseases such as amyotrophic lateral sclerosis and conditions associated with high morbidity such as myopathies (muscle diseases). Many of these disorders are known to have abnormal protein folding and protein aggregates. Thus, easy to apply methods for the detection of such changes may prove useful diagnostic biomarkers. Raman spectroscopy has shown early promise in the detection of muscle pathology in neuromuscular disorders and is well suited to characterising the conformational profiles relating to protein secondary structure. In this work, we assess if Raman spectroscopy can detect differences in protein structure in muscle in the setting of neuromuscular disease. We utilise in vivo Raman spectroscopy measurements from preclinical models of amyotrophic lateral sclerosis and the myopathy Duchenne muscular dystrophy, together with ex vivo measurements of human muscle samples from individuals with and without myopathy. Using quantitative conformation profiling and matrix factorisation we demonstrate that quantitative 'conformational fingerprinting' can be used to identify changes in protein folding in muscle. Notably, myopathic conditions in both preclinical models and human samples manifested a significant reduction in α-helix structures, with concomitant increases in β-sheet and, to a lesser extent, nonregular configurations. Spectral patterns derived through non-negative matrix factorisation were able to identify myopathy with a high accuracy (79% in mouse, 78% in human tissue). This work demonstrates the potential of conformational fingerprinting as an interpretable biomarker for neuromuscular disorders.

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments., Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population., Design: Ongoing, multicenter, phase III open-label extension (OLE) study., Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score., Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening ( n  = 52, 26%) and COVID-19 ( n  = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints., Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses., Trial Registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871)., (© The Author(s), 2024.)

Hereditary spastic paraplegia (HSP) is characterised by progressive lower-limb spasticity and weakness resulting in ambulation difficulties. During clinical practice, walking is observed and/or assessed by timed 10-metre walk tests; time, feasibility, and methodological reliability are barriers to detailed characterisation of patients' walking abilities when instrumenting this test. Wearable sensors have the potential to overcome such drawbacks once a validated approach is available for patients with HSP. Therefore, while limiting patients' and assessors' burdens, this study aims to validate the adoption of a single lower-back wearable inertial sensor approach for step detection in HSP patients; this is the first essential algorithmic step in quantifying most gait temporal metrics. After filtering the 3D acceleration signal based on its smoothness and enhancing the step-related peaks, initial contacts (ICs) were identified as positive zero-crossings of the processed signal. The proposed approach was validated on thirteen individuals with HSP while they performed three 10-metre tests and wore pressure insoles used as a gold standard. Overall, the single-sensor approach detected 794 ICs (87% correctly identified) with high accuracy (median absolute errors ( mae ): 0.05 s) and excellent reliability (ICC = 1.00). Although about 12% of the ICs were missed and the use of walking aids introduced extra ICs, a minor impact was observed on the step time quantifications ( mae 0.03 s (5.1%), ICC = 0.89); the use of walking aids caused no significant differences in the average step time quantifications. Therefore, the proposed single-sensor approach provides a reliable methodology for step identification in HSP, augmenting the gait information that can be accurately and objectively extracted from patients with HSP during their clinical assessment., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Specifically, all the opinions are those of the authors and not the funders. The content in this publication reflects the authors&rsquo; views, and neither IMI nor the European Union, EFPIA, NHS, NIHR, or any associated partners are responsible for any use that may be made of the information contained herein.

Background: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis., Methods: RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18-74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II-IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293. An open-label extension study is ongoing (NCT04225871)., Findings: Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change -4·39 [95% CI -5·28 to -3·50] vs -2·30 [-3·17 to -1·43]; least squares mean difference -2·09 [-3·24 to -0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug., Interpretation: Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study., Funding: UCB Pharma., Competing Interests: Declaration of interests JFH has received research support (paid to his institution) from Alexion Pharmaceuticals, argenx BVBA, Cartesian Therapeutics, the US Centers for Disease Control and Prevention, the Myasthenia Gravis Foundation of America, the Muscular Dystrophy Association, the US National Institutes of Health (including the National Institute of Neurological Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Diseases), PCORI, Ra Pharmaceuticals (now UCB Biosciences), and Takeda Pharmaceuticals; honoraria from Alexion Pharmaceuticals, argenx BVBA, F Hoffman-LaRoche, Immunovant, Ra Pharmaceuticals (now UCB Biosciences), Regeneron Pharmaceuticals, Sanofi US, and Viela Bio (now Horizon Therapeutics); and non-financial support from Alexion Pharmaceuticals, argenx BVBA, Ra Pharmaceuticals (now UCB Biosciences), and Toleranzia. SB has served as a paid consultant for Sanofi Genzyme, Merck, Alexion, UCB, Biogen, and Bristol Myers Squibb. AG has served as a paid consultant for Medtronic, Atlantic Research Group, Calico, Apellis, Anexon, ALS Pharmaceuticals, QurAlis, Orion, Sanofi Genzyme, Ionis, Wave Life Therapies, Anelixis, Roche, Cytokinetics, Mitsubishi Tanabe Pharma, Amylyx, Alexion, UCB, Ra Pharmaceuticals (now UCB Biosciences), Biogen, Eli Lilly, and Amicus Therapeutics. CH has received funding for consultancy on scientific or educational advisory boards for UCB Pharma, argenx, Lupin, Roche and Biogen. HJK is a consultant for Roche, Cabaletta Bio, Lincoln Therapeutics, Takeda, and UCB Pharmaceuticals; and is chief executive officer and chief marketing office of ARC Biotechnology, based on US Patent 8,961,98. He is principal investigator of the Rare Disease Network for Myasthenia Gravis National Institute of Neurological Disorders & Stroke, and Targeted Therapy for Myasthenia Gravis. AM received funding for travel, meeting attendance, or advisory board participation from CSL Behring and UCB. RM received funding for travel, meeting attendance, or advisory board participation from Alexion, argenx, BioMarin, Catalyst, Sanofi, Regeneron, and UCB. MM has served as a paid consultant for argenx and Alexion Pharmaceuticals, and has received speaker honoraria from Asahi Kasei Medical, argenx and Alexion Pharmaceuticals. KU has served as a paid consultant for UCB Pharma, argenx, Janssen Pharma, Viela Bio, Chugai Pharma, Hanall BioPharma, and Mitsubishi Tanabe Pharma; and has received speaker honoraria from argenx, Alexion Pharmaceuticals, and the Japan Blood Products Organization. TV is the USF Site Principal Investigator for myasthenia gravis clinical trials sponsored by Alexion/AstraZeneca, argenx, Ra/UCB, Horizon/Viela Bio, Janssen/Momenta, Sanofi, Regeneron, and Cartesian Therapeutics; and has received speaking or consulting honoraria from Alexion, argenx, and UCB. MDW has received honoraria for serving on scientific advisory boards for Alexion, UCB-Ra, argenx, Biogen, Mitsubishi Tanabe Pharma, and Amylyx; consulting honoraria from Cytokinetics and CSL Behring; and speaker honoraria from Soleo Health. He also serves as a special government employee for the US Food and Drug Administration. MZ has served as a paid consultant for Signant Health. MZ was an employee of Medical University of Warsaw, Warsaw, Poland, during the conduct of the study, but is currently employed by MTZ Clinical Research powered by Pratia. BB, Melissa Brock, GdlB, PWD, and MV are employees and shareholders of UCB Pharma. RL was a Veramed consultant for UCB Pharma during the conduct of the study. Veramed are a full-service provider for UCB Pharma. RL is employed by ONO Pharma UK. MIL is funded by the UK National Health Service (Myasthenia and Related Disorders Service and National Specialised Commissioning Group for Neuromyelitis Optica, UK) and by the University of Oxford, Oxford, UK. She has been awarded research grants from the UK association for patients with myasthenia, Myaware, and the University of Oxford. She has received speaker honoraria or travel grants from Biogen Idec, Novartis, argenx, UCB, and the Guthy-Jackson Charitable Foundation. MIL serves on scientific or educational advisory boards for UCB Pharma, argenx, and Viela/Horizon. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses., Methods: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics., Results: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts., Conclusion: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Background: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations., Methods: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene., Results: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death., Conclusion: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The diagnosis of muscle disorders ("myopathies") can be challenging and new biomarkers of disease are required to enhance clinical practice and research. Despite advances in areas such as imaging and genomic medicine, muscle biopsy remains an important but time-consuming investigation. Raman spectroscopy is a vibrational spectroscopy application that could provide a rapid analysis of muscle tissue, as it requires no sample preparation and is simple to perform. Here, we investigated the feasibility of using a miniaturised, portable fibre optic Raman system for the rapid identification of muscle disease. Samples were assessed from 27 patients with a final clinico-pathological diagnosis of a myopathy and 17 patients in whom investigations and clinical follow-up excluded myopathy. Multivariate classification techniques achieved accuracies ranging between 71-77%. To explore the potential of Raman spectroscopy to identify different myopathies, patients were subdivided into mitochondrial and non-mitochondrial myopathy groups. Classification accuracies were between 74-89%. Observed spectral changes were related to changes in protein structure. These data indicate fibre optic Raman spectroscopy is a promising technique for the rapid identification of muscle disease that could provide real time diagnostic information. The application of fibre optic Raman technology raises the prospect of in vivo bedside testing for muscle diseases which would significantly streamline the diagnostic pathway of these disorders.