Neuromuscular Disorders最新文献

{"title":"362P Whole-body MRI reveals common and distinctive muscle involvement in “clinically asymptomatic” female carriers of pathogenic DMD variants","authors":"F. Giliberto ,&nbsp;A. Vigliano ,&nbsp;L. Luce ,&nbsp;J. Pastor Rueda ,&nbsp;H. Chaves ,&nbsp;L. Mesa ,&nbsp;M. Carcione ,&nbsp;C. Mazzanti ,&nbsp;C. Llames Massini ,&nbsp;P. Radic ,&nbsp;C. Cejas","doi":"10.1016/j.nmd.2024.07.099","DOIUrl":"10.1016/j.nmd.2024.07.099","url":null,"abstract":"<div><div>DMD-carriers were traditionally considered asymptomatic given the X-linked recessive inheritance pattern of these diseases. Yet, it has recently been discovered that they exhibit different levels of muscle involvement.</div><div>This study aimed to characterize and compare the muscle structure on MRI of DMD-carriers and a control group. Secondly, we pursue a correlation between levels of muscle involvement and clinical manifestations, creatine kinase (CK) levels, DMD molecular alteration and X-chromosome inactivation (XCI) patterns. We enrolled 30 genetically confirmed DMD female carriers and 30 healthy non-carrier controls, BMI and age matched. All individuals underwent whole-body MRI, where semi-quantitative scales were used to assess muscle edema, trophism and fatty infiltration. Neurological examination, Serum CK measurement, DMD genetic screening, and XCI studies were only performed on the DMD-carriers. Statistically significant differences in muscle involvement were observed between DMD-carriers and the control group. Female carriers exhibited muscle affection in 33% of the 48 muscle groups analyzed, while the control group presented only the 10% affected. Most of the DMD-carriers’ implicated muscles showed mild atrophy and mild to moderate fatty infiltration. The muscles more frequently affected were gastrocnemius, gluteus maximus and soleus. No statistical correlation was found between the levels or pattern of muscle involvement on MRI and the neurological examination, CK values, type of genetic variant and XCI patterns. DMD-carriers exhibit frequent and distinctive muscle involvement patterns on MRI, questioning the conception of “asymptomatic” DMD-Carriers. These results, together with findings in other X-linked disorders, lead to a revision of the concept of asymptomatic carriers of X-linked recessive diseases and raise awareness of the need to develop best practice guidelines for the evaluation and management of these females.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.90"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423993","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":"Welcome to the 29th World Muscle Society Congress in Prague, Czechia, 2024","authors":"","doi":"10.1016/j.nmd.2024.08.002","DOIUrl":"10.1016/j.nmd.2024.08.002","url":null,"abstract":"","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104445"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423269","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":"147VP Efficacy and safety of Nusinersen in the treatment of spinal muscular atrophy in adolescents and adults","authors":"W. Ningning ,&nbsp;Y. Hu ,&nbsp;L. Yu ,&nbsp;W. Zhu","doi":"10.1016/j.nmd.2024.07.054","DOIUrl":"10.1016/j.nmd.2024.07.054","url":null,"abstract":"&lt;div&gt;&lt;div&gt;We aimed to explore the efficacy and safety of Nusinersen treatment in terms of motor function and electrophysiological indicators in Chinese adolescents and adults with SMA. The study included adolescent and adult SMA patients diagnosed at Huashan Hospital affiliated with Fudan University, The First Affiliated Hospital of Soochow University, and The First Affiliated Hospital of Anhui Medical University from October 2022 to December 2023, who received at least 4 doses of Nusinersen. Assessments of motor scales and pulmonary function, including the Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), 6-Minute Walk Test (6MWT), and forced vital capacity (FVC%), were conducted the day before the 1st, 4th, 5th, and 6th treatments (V1, V4, V5, V6). Electrophysiological indicators, including compound muscle action potential (CMAP) and motor unit number index (MUNIX) for upper and lower limb nerves, were also collected to compare improvements in these metrics before and after treatment. A total of 54 patients were included in the study and divided into two groups: those able to walk independently (ambulatory group) and those unable to walk independently but able to sit independently (non-ambulatory group). The average age of the patients was 27.03 years (range 13-53 years), with 64.81% being male. Type II accounted for 16.67% (9/54), and Type III for 79.63% (43/54). Changes in HFMSE scores were statistically significant in both the non-ambulatory and ambulatory subgroups. In the ambulatory subgroup, HFMSE scores improved from baseline to V4 (mean +2.3 points, P=0.004), V5 (+3.0 points, P=0.004), and V6 (+4.2 points, P=0.005), with the ambulatory group showing more pronounced improvements compared to the non-ambulatory group. There was no statistically significant change in the average RULM score from baseline to V4, V5, and V6, but a positive trend was observed, with more marked improvements in the non-ambulatory group. The 6MWT showed significant improvement, with 33.33% (5/15), 66.67% (9/15), and 80.00% (12/15) of patients demonstrating clinically meaningful improvements at V4, V5, and V6, respectively. The CMAP and MUNIX values of upper and lower limb muscles showed a positive correlation with SMN2 copy numbers, motor function status, and baseline motor function scores. After treatment, the most significant increases were observed in the abductor digiti minimi (+0.92mV, P&lt;0.001), trapezius (+0.86mV, P&lt;0.001), and abductor pollicis brevis (+0.81mV, P&lt;0.001) muscles, and lower limb muscles (tibialis anterior +0.44mV, P=0.017). The MUNIX results were similar to CMAP values, with upper limb improvements being superior to lower limbs. A CMAP value of the trapezius muscle ≥ 1.76 mV suggested that patients were more likely to respond to treatment by day 300 (sensitivity 84.6%, specificity 85.7%). With the extension of treatment duration, the incidence rate of adverse reactions remained stable, mainly pres","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.45"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423384","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":"129P Newborn screening for spinal muscular atrophy in Poland – a summary of 3-year experience","authors":"M. Gos ,&nbsp;J. Wasiluk ,&nbsp;A. Landowska ,&nbsp;M. Jurzyk ,&nbsp;W. Wawer ,&nbsp;P. Kubiszyn ,&nbsp;J. Wieczorek ,&nbsp;O. Kordowska ,&nbsp;L. Nosarieva ,&nbsp;K. Durda ,&nbsp;M. Fraczyk ,&nbsp;M. Jedrzejowska ,&nbsp;M. Ołtarzewski","doi":"10.1016/j.nmd.2024.07.036","DOIUrl":"10.1016/j.nmd.2024.07.036","url":null,"abstract":"<div><div>Spinal muscular atrophy (SMA) is a rare disorder that affects about 1/7000-8000 people in Poland.</div><div>The disease can be successfully treated with available targeted drugs such as nusinersen, onasemnogene abeparvovec and risdiplam that are available from public funds for every SMA patient. The newborn screening for SMA has been implemented in March 2022 and since then it was implemented in whole country as a part of National Newborn Screening Programme. Herein, we present our three-year experience with SMA as a routine part of NBS. Newborn screening for SMA as a genetic test is not obligatory and parents have to consent for molecular testing (opt-in). Standard dried blood spots are used for DNA extraction and a PCR-HRM based test (SALSA MC002 SMA Newborn Screen test, MRC-Holland) is used for screening. After the positive result of first-tier test, we perform follow-up testing with MLPA technique (P021 kit, MRC-Holland). During 3 years, over 750 000 newborns were screened and SMA has been confirmed in 101 children that were admitted to regional children neurological clinics. The results of the first-tier test and MLPA verification from blood spot were ready on the 8th day of life (mean: 8.5±3.7; 3 days since registration in the central database). On the day 14th (mean 14.7±5.0; 9 days since registration), the results of the verification test were available. About 70% of diagnosed patients were asymptomatic, others presented mild symptoms of the disease. Three children with 1 SMN2 copy presented with SMA0. The treatment was implemented as soon as possible if patients were carrying from 1 to 3 SMN2 copies (2, 27 and 39 children, respectively). On average, therapy was started at 22nd day of life. The newborn screening for SMA was successfully implemented in Poland and became a part of the routine screening. Our procedure allows for quick identification of SMA patients that would benefit from targeted therapies. Based on the population data, the prevalence of SMA can be estimated at ≈1/7500.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.27"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423492","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":"230P Physiotherapy for rare hereditary NMDs- an open and free e-learning course for physiotherapists. Results after 18 months online at sjelden.no","authors":"A. Rosenberger ,&nbsp;R. Schandy ,&nbsp;S. Lysne ,&nbsp;H. Hæstad","doi":"10.1016/j.nmd.2024.07.081","DOIUrl":"10.1016/j.nmd.2024.07.081","url":null,"abstract":"<div><div>Physiotherapy is an important modality for patients with neuromuscular disorders, as individually targeted physiotherapy approaches may enhance functions in daily life, and thereby affect quality of life. In Norway, there is scarce knowledge of physiotherapy for neuromuscular patients among physiotherapists (PTs). The PTs at the National Neuromuscular Centre, Norway (NMK), saw the need for the development of free and easily attainable learning resources to empower PTs at hospitals and in communities in their clinical reasoning process. A service development project was conducted, resulting in an e-learning course published at the Norwegian learning platform sjelden.no. The e-learning course was developed in close collaboration with sjelden.no, a learning platform for rare diseases funded by Norwegian National Advisory Unit on Rare Disorders (NKSD). The project period ran from 2018-2022. The course is presented in written and spoken Norwegian and consists of five modules. 1) Introduction 2) Human movement- from healthy to muscle disease 3) Examples of movement analysis of patients 4) Intervention examples 5) Course test with 15 multiple choice questions. The course was published in Sep.2022. Information and advertisement has been provided from NMK at national and international conferences, on NMK's SoMe-platforms and website, and at clinical courses for PTs in Norway. From September 2022-March 2024, the e-learning course has had 2209 users and 3772 views based on statistics from Google Analytics. This is the 3rd most visited learning resource at sjelden.no. The introductory video has 400 full-length finishes, while 120 PTs has passed the course-test. The e-learning course has good statistics of use by Norwegian PTs when looking at users, views and completion of the course test. To enhance the sharing of evidence-based physiotherapy for NMD-patients to PTs, a digital course thus seems to be a cost-effective and potent tool. To enable availability for an international audience, translation to English with publishing through sjelden.no and ERN Euro-NMD is planned for 2024-2025.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.72"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423584","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":"211P Following patient mobility in daily life: the EJP-DT4RD project","authors":"J. Hogrel ,&nbsp;R. Muni-Lofra ,&nbsp;P. Santmarty ,&nbsp;V. Decostre ,&nbsp;T. Marques ,&nbsp;E. Haf Davies ,&nbsp;V. Straub ,&nbsp;the DT4RD Project Group","doi":"10.1016/j.nmd.2024.07.062","DOIUrl":"10.1016/j.nmd.2024.07.062","url":null,"abstract":"<div><div>The DT4RD (Digital Tools 4 Rare Diseases) project is dedicated to the development of a non-invasive toolbox that measures patient mobility in daily life. Although tremendous progress has been made in this regard in the last few years, there is still a strong need to obtain disease-related information that generates fundamental clinical and patient-relevant outcomes accepted by regulators. Such data can be harnessed through digitised means using tools such as wearable devices, sensors, videos and smartphone apps. For example, movement sensors in the patient's home, worn on the body, or mobility aid can assess general movements whilst distinguishing between the patient's voluntary and involuntary actions. The development of novel clinical outcome assessments (COA) has the potential to facilitate the drug development process across rare diseases and support the improvement of the quality of life for patient care, clinical outcomes and ability to collect information in the home environment. The remote evaluation of patient movements can also reduce indirect costs, such as travel to study sites and lost wages, thereby increasing the accessibility of research studies for patients. The aim of this study is to compare hospital-based COAs with home-based COAs to validate their use for remote monitoring of patients. The recruitment target is 40 patients with confirmed diagnosis of a neuromuscular condition. Participants will be followed for one year with three hospital visits and regular recordings at home. We will present preliminary results obtained from 12 patients followed for six months. This project gives the possibility to question the classical ways of obtaining information from patients and creates new opportunities for acquiring patient-centred real data in daily life. Home monitoring provides a scientifically advanced approach to mobility assessment in clinical trials. By offering objective, continuous, and real-world monitoring of mobility parameters, it enhances data quality, ecological validity, and patient engagement. The integration of home monitoring technologies in clinical trial designs can revolutionise the assessment of mobility outcomes, leading to more accurate and meaningful insights into patients' mobility abilities, changes, and responses to interventions. The DT4RD program is funded by a grant from the European Joint Programme on Rare Diseases and co-funded by Chiesi and CSL Behring.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.53"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423717","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":"213P Sensitivity to change of the motor function measure (MFM) in myotonic dystrophy type 1","authors":"S. Ribault ,&nbsp;P. Rippert ,&nbsp;G. Bassez ,&nbsp;T. Duong ,&nbsp;C. Vuilllerot","doi":"10.1016/j.nmd.2024.07.064","DOIUrl":"10.1016/j.nmd.2024.07.064","url":null,"abstract":"<div><div>Myotonic dystrophy type 1 (DM1) is a hereditary multisystemic disease characterized by progressive muscle wasting, heart conduction abnormalities, early-onset cataract, and endocrinological disorders. It is caused by a non-coding CTG repeat expansion in the DMPK gene. With new therapeutic advancements and ongoing clinical trials focusing on siRNA, antisense oligonucleotides or gene therapy, there is an imperative to identify a suitable clinical outcome to assess motor function in DM1. The Motor Function Measure is a 3-dimensional quantitative scale (D1: standing/transfers, D2: Proximal/axial, D3: Distal) designed to monitor motor function in patients with neuromuscular diseases encompassing the spectrum of the disease regardless disease severity or functional level. This is a multicentric retrospective review of adults and children with a genetic diagnosis of DM1. Included subject were male or female DM1 patients with the availability of at least 2 MFM32 scores at 1 year. MFM32’s mean slope of change and standard response mean (SRM) were calculated. 343 subjects were included. At the first MFM mean age was 36.3 years (+/- 16.1, min: 6.1yo; max: 71.8yo), and mean MFM32 scores were 69.1%+/-25.1, 91.9%+/-9.1, 90.8.1%+/-8.4, and 82.4%+/-13.8 for D1, D2, D3 and Total score respectively. Average time between first and last assessments was 5.1 years (+/- 3.6, min: 1 y; max: 15.9yo). MFM32’s yearly mean slope of change was -2.25% (+/-3.86) for D1, -1.09% (+/-3.50) for D2, -0.54% (+/-2.95) for D3, -1.44 (+/-2.46) for total score. SRM was -0.58 for D1, -0.31 for D2, -0.18 for D3, -0.59 for total score. Understanding the change over time in a natural history cohort is important to understand the impact of change against a changing disease landscape. We showed MFM32’s responsiveness to change most relevant in the standing and transfer domain (D1) and MFM total score than the more proximal or distal domains.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.55"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423719","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":"363P A cross-sectional survey upper limb functional using PUL 2.0 at large clinical centers and registries in patients with Duchenne muscular dystrophy","authors":"G. Coratti ,&nbsp;E. Niks ,&nbsp;M. van der Holst ,&nbsp;C. Tian ,&nbsp;E. Mercuri ,&nbsp;F. Muntoni ,&nbsp;L. Servais ,&nbsp;S. Ward","doi":"10.1016/j.nmd.2024.07.100","DOIUrl":"10.1016/j.nmd.2024.07.100","url":null,"abstract":"<div><div>Upper limb function is a critical determinant of quality of life for patients with Duchenne Muscular Dystrophy (DMD) who have lost the ability to walk. However, the majority of clinical trials assessing new therapeutic agents have focused on ambulant patients with DMD. The reasons for this gap are multi-fold but are due in part to the consensus for using the PUL 2.0 assessment as a primary endpoint being more recent. This study is a cross-functional survey of upper limb functional assessments focused on the large clinical centers and clinical registries led by cTAP collaborators and determined i) the number of patients with PUL 2.0 assessments, ii) frequency of evaluation, iii) functional characteristics of patients at baseline, and iv) the trigger for initiating PUL 2.0 evaluation. Most centers assessed upper limb function at 6-month intervals. The number of patients and patient visits at each center were, respectively: Italian Group (341,1628), CCHMC (256, 1145), GOSH (84, ∼240), Leiden University Medical Center (LUMC)(81, 278) and NMCL (25, &gt;100). Mean PUL 2.0 entry score was 29.9 (SD 12.5) and 30.93 (SD 5.1) in the Italian Group and LUMC respectively; corresponding age at entry was (12.2 (SD 6.23) and 11.75 (SD 12.1). The number of patients with 5 or more follow-up assessments was 88 at 6 monthly intervals for the Italian Group and 28 at 12-month intervals for LUMC. Assessment of ambulatory function across centers was largely coherent, while protocols to assess bone health, cardiac function, and pulmonary function were less consistent. The results of this study will aid drug developers in better understanding the characteristics of this patient population, a pre-requisite step to designing clinical trials that can yield definitive assessment and therapeutic efficacy. It also highlights the importance of collecting consistent and high-quality real-world data in rare diseases.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.91"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423994","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":"365P Duchenne video assessment 2.0 scorecard performance: evaluation of inter-item and inter-scorecard relationships","authors":"M. Contesse ,&nbsp;A. Sapp ,&nbsp;C. Zigler ,&nbsp;W. Chen ,&nbsp;J. Marshall ,&nbsp;G. Gensler ,&nbsp;C. Brown ,&nbsp;R. Barnes ,&nbsp;D. King ,&nbsp;S. Wilson ,&nbsp;M. Leffler","doi":"10.1016/j.nmd.2024.07.102","DOIUrl":"10.1016/j.nmd.2024.07.102","url":null,"abstract":"<div><div>People with Duchenne muscular dystrophy (DMD) compensate for muscle weakness by changing their movement patterns. The Duchenne Video Assessment (DVA) is a home-based tool that measures ease of movement through identification of movement compensations. The DVA directs caregivers to video record patients attempting specific movement tasks (e.g., Climb 5 Stairs) at home using a mobile application. DVA 2.0 comprises 18 movement tasks and assesses patients at any disease stage through a subset of tasks relevant to their functional group. DVA-certified physical therapists rate the videos using validated scorecards with clinically meaningful compensatory movement criteria (“items”). ARISE is a longitudinal, observational study of 150 participants with DMD aged 2 and older to evaluate the measurement properties of DVA 2.0 over 24 months. Using baseline data, we evaluated the relationships among DVA 2.0 scorecards and criteria to confirm that they contribute distinct information to the outcome. We assessed the correlation between each criteria pair, and correlation type (polychoric, rank-biserial, Phi) was determined by number of levels within compared criteria. We assessed inter-scorecard relationships using a Spearman correlation matrix. Criteria and scorecards with very strong correlations (&gt;|0.9|) were explored for content overlap and considered for removal. All scorecards and all but one pair of criteria had correlations below the threshold. One pair of criteria for Reach Across the Table to Grab a Cell Phone was above the threshold (rpc = 0.971), but 15% of the study population differed in severity level for the two criteria. Since expert consensus previously established the clinical meaningfulness of each criterion and maintaining both criteria provides additional information for 15% of the study population, both were retained. The results confirm that all DVA 2.0 criteria and scorecards contribute distinct information about the ease of movement of people with DMD.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.93"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423996","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":"278P Mapping human skeletal muscle enhancers to increase rates of genetic diagnosis","authors":"R. Taylor ,&nbsp;J. Taylor ,&nbsp;E. Denisenko ,&nbsp;M. Jones ,&nbsp;J. Clayton ,&nbsp;N. Laing ,&nbsp;A. Forrest ,&nbsp;H. Alinejad-Rokny ,&nbsp;G. Ravenscroft","doi":"10.1016/j.nmd.2024.07.096","DOIUrl":"10.1016/j.nmd.2024.07.096","url":null,"abstract":"<div><div>Despite the identification of almost 600 disease genes for neuromuscular disorders, only 30-50% of affected individuals receive a genetic diagnosis following diagnostic screening via targeted gene panels or clinical exomes. For a subset of those patients who do not receive a genetic diagnosis, the disease causing variant may be located in the 98% of the human genome that is non-coding. Approximately 20-40% of the non-coding genome has a regulatory function, dictating when in development, in which tissues, and at what level our coding genes are expressed. Genetic variation in regulatory regions has been shown to cause Mendelian disease by reducing or abolishing the expression of the corresponding coding gene. However, regulatory regions are not routinely screened because we do not know where these regions are in the genome. In order to differentiate the functional non-coding variants from the vast number of benign non-coding variants we need to know which regions of the genome regulate gene expression in the tissues relevant to the disease. We have approached this systematically with a focus on identifying the distal regulatory elements involved in expression of skeletal muscle disease genes. We have mapped enhancer-promoter interactions in healthy adult human skeletal muscle tissue (n=3 unrelated donors) by creating genome-wide chromatin conformation capture libraries at 5kb resolution using the Dovetail Genomics OMNI-C workflow. We also profiled human skeletal muscle regulatory regions (n=3 donors) by performing ChIP-seq for histone modifications associated with enhancers (H3K4me1) and promoters (H3K4me3), as well as the chromatin architecture protein CTCF. These data were integrated with human skeletal muscle snRNA-seq (n=4 donors) and various public datasets associated with skeletal muscle relevant phenotypes. We have created a high-quality map of human skeletal muscle enhancers and their linked promoters and show that this map is capable of identifying statistically significant interactions between key muscle gene promoters with both known and novel distal regulatory elements. Our hope is that this map can now be used as a screening tool to prioritise non-coding sequence variants that are likely to be causal for Mendelian muscle diseases.</div></div>","PeriodicalId":19135,"journal":{"name":"Neuromuscular Disorders","volume":"43 ","pages":"Article 104441.87"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142424006","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}