Journal of neuromuscular diseases最新文献

{"title":"Phenotypic intrafamilial variability of 5q-associated spinal muscular atrophy: A systematic multicentre sibling study.","authors":"Benedikt Becker, Isabell Cordts, Jutta Becker, Rene Günther, Matthias Baumann, Günther Bernert, Astrid Eisenkölbl, Barbara Fiedler, Marina Flotats-Bastardas, Martin Fleger, Tim Hagenacker, Andreas Hahn, Elke Hobbiebrunken, Andrea Bevot, Jörg Jahnel, Jessika Johannsen, Christoph Kamm, Jan Christoph Koch, Cornelia Köhler, Heike Kölbel, Wolfgang Müller-Felber, Christoph Neuwirth, Barbara Plecko, Christian Stadler, Martin Smitka, Arpad Von Moers, Regina Trollmann, Markus Weiler, Andreas Ziegler, Susanne Goldbach, Kristina Probst-Schendzielorz, Hanns Lochmüller, Ulrike Schara-Schmidt, Maggie C Walter, Janbernd Kirschner, Brunhilde Wirth, Astrid Pechmann, Marcus Deschauer","doi":"10.1177/22143602251370577","DOIUrl":"https://doi.org/10.1177/22143602251370577","url":null,"abstract":"<p><p>Background and objectivesThe severity of the phenotype of spinal muscular atrophy (SMA) is highly variable, yet little is known about the phenotypic variation among siblings. We systematically investigated the phenotypic variability of therapy-naïve 5q-SMA siblings leveraging a large multicentre cohort from the SMArtCARE registry.ResultsClinical information was available from 132 siblings of 65 families. There were 24 (18.2%) type 1, 38 (28.7%) type 2, 54 (40.9%) type 3 patients, and 16 (12.1%) presymptomatic individuals. In 17 families (32.1%), there was discordance in the type of SMA among symptomatic siblings. We found no influence of gender on discordance in SMA type among siblings (p = 0.528). The median age at disease onset within all sibships varied by 6 months (interquartile range (IQR) = 1-30). There was no correlation in age of onset among siblings (r = 0.405; p = 0.052). Among siblings who lost ambulation, the median interval between the start of wheelchair use was 12 months, but the maximal interval was 18 years. In one pair of siblings, one sibling lost the ability to walk at the age of 13, whereas the other sibling was still ambulatory at the age of 54. In 6 sibling pairs (9.5%), only one of both siblings had a history of scoliosis surgery. Analysing <i>SMN2</i> copy numbers, in one sibling pair (1.8%) 1 <i>SMN2</i> gene copy was detected, while 10 (17.5%) had 2 copies, 23 (40.4%) had 3 copies, and 17 (29.8%) had 4 copies. Concordance in <i>SMN2</i> copy numbers across siblings was observed in 90% of families. With increasing <i>SMN2</i> copy number, the median differences in age of onset among siblings increased without reaching statistical significance.ConclusionThis study reports considerable phenotypic variability in therapy-naïve SMA sibships that cannot solely be explained by differences in <i>SMN2</i> copy numbers.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"22143602251370577"},"PeriodicalIF":3.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040471","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":"State of the art: Pregnancy in spinal muscular atrophy in the treatment era.","authors":"Maggie C Walter, Bernert Günther, Blaschek Astrid, Deschauer Marcus, Günther René, Hiebeler Miriam, Hahn Andreas, Kamm Christoph, Kirschner Janbernd, Lochmüller Hanns, Löscher Wolfgang, Müller-Felber Wolfgang, Rudnik-Schöneborn Sabine, Schara-Schmidt Ulrike, Thiele Simone, Uzelac Zeljko, Vill Katharina, Weiler Markus, Hagenacker Tim","doi":"10.1177/22143602251370414","DOIUrl":"https://doi.org/10.1177/22143602251370414","url":null,"abstract":"<p><p>An increasing number of adults with spinal muscular atrophy (SMA) wish to become parents. New disease-modifying therapies (DMT) have improved health outcomes and are expected to reduce disability in adults with SMA, but their current label prevents their use in pregnancy. While there is some information on pregnancy outcomes in the pre-DMT era, little has been published recently, and no ubiquitously accepted guidelines exist. Nonetheless, it is crucial to provide knowledgeable and open counselling, ideally in the context of treatments. Counseling for both adolescent and adult patients should include the subject of 'reproductive choices' when discussing the selection of DMTs for those considering parenthood. A multi-disciplinary team, including gynecologists and neurologists with expertise in neuromuscular disorders must closely monitor pregnant patients with SMA, preferably within disease registries, to detect potential complications early and ensure optimal treatment options are available. Real-world data in so far three patients with SMA showed a beneficial pregnancy outcome with nusinersen. It is anticipated that forthcoming real-world data will finally clarify the safety of administering Nusinersen during pregnancy, particularly in relation to child health and for preserving muscle function and preventing motor deterioration in the affected mother.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"22143602251370414"},"PeriodicalIF":3.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040439","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":"Electrical impedance myography captures features of muscle structure measured by MRI and transcriptomic analysis in facioscapulohumeral muscular dystrophy.","authors":"Leo H Wang, Buket Sonbas Cobb, Lara Riem, Olivia DuCharme, Dennis Ww Shaw, Michaela Walker, Katy Eichinger, Leann Lewis, Rabi Tawil, Johanna I Hamel, Karlien Mul, Silvia S Blemker, Stephen J Tapscott, Seth D Friedman, Seward B Rutkove, Jeffrey M Statland","doi":"10.1177/22143602251369246","DOIUrl":"https://doi.org/10.1177/22143602251369246","url":null,"abstract":"<p><strong>Background: </strong>Electrical impedance myography (EIM) has been proposed as an efficient, non-invasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD).</p><p><strong>Objective: </strong>We investigate whether EIM parameters are associated with muscle structure measured by magnetic resonance imaging (MRI), muscle histology, and transcriptomic analysis as well as strength at the individual leg muscle level.</p><p><strong>Methods: </strong>We performed a multi-center cross-sectional study enrolling 33 patients with FSHD. EIM measurements were recorded from bilateral vastus lateralis, tibialis anterior (TA), and medial gastrocnemius muscles and compared to quantitative muscle volume measures by MRI as well as knee extension and ankle dorsiflexion strength by quantitative muscle testing. EIM measurements of the bilateral TA were further compared to histology and transcriptomic analysis (RNAseq) of muscle and fat content.</p><p><strong>Results: </strong>EIM phase at multiple frequencies was positively associated to the amount of muscle measured by MRI (ρ = 0.48 to 0.70, <i>p </i><math><mo>≤</mo></math> 0.001) and negatively associated to the amount of fat replacement of muscle (ρ = -0.53 to -0.73, <i>p </i><math><mo>≤</mo></math> 0.001). EIM phase of the vastus lateralis and TA was positively associated with knee extension and ankle dorsiflexion strength normalized to age and sex (ρ = 0.45 to 0.60, <i>p</i> < 0.0001). The bilateral TA muscles were analyzed at the histopathological and molecular (transcriptomic) levels and showed that EIM phase was positively associated with amount of muscle (ρ = 0.33 to 0.35, <i>p</i> < .01) and negatively associated with amount of fat (ρ = -0.36 to -0.56, <i>p</i> < .001) by transcriptomic analysis.</p><p><strong>Conclusions: </strong>This study supports the hypothesis that the amount and quality of muscle tissue as assessed by EIM is associated with the amount and quality of muscle tissues as assessed by MRI and muscle biopsy, with all measures ultimately being strongly associated with muscle strength. These data provide further convergent validity for the use of EIM as a potential non-invasive biomarker to assess muscle health in FSHD.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"22143602251369246"},"PeriodicalIF":3.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015644","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":"AlphaMissense prediction for the evaluation of missense variants in the diagnostic setting of neuromuscular disorders.","authors":"Martin Krenn, Axel Schmidt, Matias Wagner, Margot Ernst, Elisabeth Graf, Gudrun Zulehner, Hakan Cetin, Fritz Zimprich, Jakob Rath","doi":"10.1177/22143602251370957","DOIUrl":"https://doi.org/10.1177/22143602251370957","url":null,"abstract":"<p><p>Next-generation sequencing has improved diagnostic outcomes for neuromuscular disorders, but interpreting rare missense variants remains challenging. We evaluated AlphaMissense, a recently developed machine learning tool, for predicting missense variant pathogenicity, using 45 (likely) pathogenic variants and 21 variants of uncertain significance from 58 deeply phenotyped patients. AlphaMissense predicted 69% of pathogenic variants correctly, but also classified 62% of variants of uncertain significance as pathogenic. Median AlphaMissense scores were not significantly different between pathogenic and uncertain variants. Overall, AlphaMissense accurately predicted the pathogenicity of most missense variants, but may be limited in certain functional contexts, highlighting the need for disease-specific interpretation approaches.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"22143602251370957"},"PeriodicalIF":3.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000720","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":"Disease-modifying therapies for spinal muscular atrophy: Family experience, ethical considerations, and the role of social determinants of health.","authors":"Lena Xiao, Djurdja Djordjevic, Sohee Kang, Hernan Gonorazky, Jackie Chiang, Munazzah Ambreen, Elisa Nigro, Eugenia Law, Lauren Weinstock, Reshma Amin, Melissa D McCradden","doi":"10.1177/22143602251375561","DOIUrl":"https://doi.org/10.1177/22143602251375561","url":null,"abstract":"<p><strong>Objectives: </strong>Spinal muscular atrophy is a progressive neuromuscular condition associated with a complex chronic disease course. An in-depth understanding of the ethical issues and social determinants of health impacting the experiences of families and children living with this condition is critical to improving care delivery. We identified the ethical tensions faced by families caring for children with spinal muscular atrophy as well as the influence of social determinants of health in relation to their perception of novel disease-modifying therapies.</p><p><strong>Design: </strong>Qualitative study including semi-structured interviews with caregivers of children with spinal muscular atrophy who received disease-modifying therapies. Interviews were audio recorded, transcribed verbatim, and coded. Thematic analysis was utilized to identify ethically salient themes.</p><p><strong>Setting: </strong>The Hospital for Sick Children (Toronto, Canada)Results:Fifteen family caregivers of children with spinal muscular atrophy type 1 (n = 5), type 2 (n = 5), and type 3 (n = 5) participated. There were three core themes highlighted including (1) best interests of the child, (2) burden of care and associated moral distress, and (3) parent agency. These experiences were impacted by resources and social determinants of health.</p><p><strong>Conclusion: </strong>This study provides important insights into the ethical tensions and relevant social determinants of health impacting the caregiver experience. Understanding the experiences of diverse families will allow more appropriate resource distribution, better counselling and supports for families facing unique psychosocial challenges and treatment burdens, and overall improved delivery of patient and family-centered care.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"22143602251375561"},"PeriodicalIF":3.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957613","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":"Pain in adult and adolescent patients with 5q-associated Spinal Muscular Atrophy - an often underrated phenomenon.","authors":"Lisa M Keipert, Claudia D Wurster, Zeljko Uzelac, Johannes Dorst, Joachim Schuster, Kurt Wollinsky, Albert Ludolph, Dorothée Lulé","doi":"10.1177/22143602251325773","DOIUrl":"10.1177/22143602251325773","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is a genetic disorder leading to progressive muscle weakness and atrophy. Pain in SMA may be the consequence of the underlying neuromuscular disease but has hardly been investigated so far.</p><p><strong>Objective: </strong>To assess pain in SMA and its interaction with patient's wellbeing.</p><p><strong>Methods: </strong>In a prospective, cross-sectional study design, 70 adult and adolescent SMA patients (median age 30 years, IQR 21-49 years, types I-IV) were assessed at the Department of Neurology, Ulm University hospital. Pain was evaluated with a self-adapted Pain Scale, depressiveness with the ALS-Depression-Inventory-12-Items (ADI-12) and global Quality of Life (gQoL) with the Anamnestic Comparative Self-Assessment (ACSA).</p><p><strong>Results: </strong>We found an intermittent frequency of pain in 80% in SMA patients with more than half of the patients experience pain at least once a week. The mean pain intensity score estimated by pain frequency and strength was 24 on a scale of 0 to 240, indicating a frequently appearing mild to moderate pain. Pain was mostly located in the lumbar spine, hip, and thoracic spine. The pain intensity score was independent from demographics (age, gender) or clinical parameters (SMA type, physical state), but, instead, it was associated to depressiveness. Depressiveness was more prevalent in older SMA patients. gQoL was rather independent from pain intensity or physical state.</p><p><strong>Conclusions: </strong>The study provides evidence for a prevalence of mild to moderate pain in 80% of adult and adolescent SMA patients. Pain was not simply caused by physical deficits and did not severely interfere with patients' quality of life, but, instead, was closely interrelated with patients' affective state.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"662-669"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111067","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":"Calpainopathy (limb-girdle muscular dystrophy type R1): clinical features, diagnostic approaches, and biotechnological treatment methods.","authors":"Sergey N Bardakov, Irina Sorochanu, Lilit A Mkrtchyan, Yana S Slesarenko, Vadim A Tsargush, Igor S Limaev, Artur A Isaev, Ivan A Yakovlev, Roman V Deev","doi":"10.1177/22143602251345967","DOIUrl":"10.1177/22143602251345967","url":null,"abstract":"<p><p>Calpainopathy, or limb-girdle muscular dystrophy type R1/2A (LGMDR1/2A), is the most prevalent form of LGMD, comprising about 32% of all cases. The disease is caused by mutations in the <i>CAPN3</i> gene, leading to dysfunction of the corresponding protein-an enzyme critical for muscle fiber cytoskeleton remodeling and protein signaling regulation through selective proteolysis. Clinical manifestations demonstrate significant phenotypic polymorphisms, ranging from oligosymptomatic forms to severe early-onset cases, with the loss of ambulation occurring 10-25 years after disease onset. A characteristic feature is predominantly symmetrical involvement of limb and trunk muscles, leading to early mobility loss, disability, and reduced work capacity. Noninvasive imaging can suggest dystrophic muscle disease but requires differentiation from other myopathies. Confirming the diagnosis involves histological, immunological, and molecular genetic studies to identify calpain-3 activity or <i>CAPN3</i> gene expression alterations. Currently, no targeted or etiological therapies are available for calpainopathy. Treatment focuses on symptom management, complication prevention, and slowing disease progression. Preclinical research demands the development of an appropriate animal model that displays disease phenotypes mirroring those observed in humans. Preclinical and clinical research are also investigating therapeutic options, including the use of drugs that have proven effective in other myopathies and genome editing via transgenic <i>CAPN3</i> delivery to restore protein activity. Gene therapy has shown promise in murine models, but safety concerns, particularly systemic toxicity affecting the heart and other organs, remain significant. This review comprehensively analyzes the clinical features, diagnostic approaches, and advancements in modeling and therapeutic development for calpainopathy.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"594-618"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199411","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":"A homozygous single-nucleotide variant in <i>TNNT1</i> causes abnormal troponin T isoform expression in a patient with severe nemaline myopathy: A case report.","authors":"Milla Laarne, Ali Oghabian, Jenni Laitila, Pirjo Isohanni, Olli Tynninen, Fang Zhao, Fanny Rostedt, Jaakko Sarparanta, Lydia Sagath, Michael W Lawlor, Carina Wallgren-Pettersson, Vilma-Lotta Lehtokari, Katarina Pelin","doi":"10.1177/22143602251339569","DOIUrl":"10.1177/22143602251339569","url":null,"abstract":"<p><strong>Background: </strong>Slow skeletal troponin T (ssTnT, <i>TNNT1</i>) is the tropomyosin-binding subunit of the troponin complex in the slow-twitch fibers of skeletal muscle. Exon 5 of <i>TNNT1</i> is alternatively spliced, and retention of the 3' region of intron 11 (exon 12') has also been described. Variants in <i>TNNT1</i> are known to cause nemaline myopathy (NM).</p><p><strong>Objective: </strong>To identify and further investigate the disease-causing variant in a patient with lethal NM.</p><p><strong>Methods: </strong>The genetic analyses included a gene panel, Sanger sequencing, whole-exome sequencing, and targeted array-CGH. Muscle biopsy was analyzed using routine histopathological methods. The alternative splicing of <i>TNNT1</i> exon 12 in patient muscle was quantified from RNA sequencing data, and the protein expression was confirmed by western blot. Expression of ssTnT in patient muscle was studied by immunohistology.</p><p><strong>Results: </strong>The patient presented with arthrogryposis, stiffness, respiratory insufficiency, and minimal spontaneous movements. Histopathology showed hypotrophy and predominance of type II fibers, perimysial connective tissue accumulation, and nemaline bodies. The patient was homozygous for the <i>TNNT1</i> missense variant (NM_003283.6:c.653C > G, p.(Pro218Arg), NM_ 001126132.3:c.612-7C > G), predicted to disrupt splicing. RNA-seq revealed inclusion of exon 12' in 49.85% of transcripts, whereas in controls exon 12' was not expressed. Exon 12' expression on the protein level was confirmed by western blot. Immunohistology showed strong ssTnT expression in remaining type I fibers, and low expression in type IIA fibers.</p><p><strong>Conclusions: </strong>The c.653C > G variant was shown to alter <i>TNNT1</i> splicing. The results suggest a novel pathogenetic mechanism involving abnormal expression of a troponin T isoform.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"689-698"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111064","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":"Systematic review for economic evaluations on newborn screening for spinal muscular atrophy.","authors":"Alexander C Pace, Corrina Poon, Pranesh Chakraborty, Maryam Oskoui, Hugh McMillan, Alex Mackenzie, Jeff Round","doi":"10.1177/22143602251336862","DOIUrl":"10.1177/22143602251336862","url":null,"abstract":"<p><p>ObjectiveEvaluate the quality and cost-effectiveness of economic evaluations of newborn screening (NBS) for Spinal Muscular Atrophy (SMA).MethodsA systematic review was conducted following Cochrane Handbook guidelines and PRISMA-S checklist. From 146 identified papers, 22 were screened for full-text, and 5 were included. Studies were evaluated for quality of reporting and transparency using the CHEERs and QHES checklists. Data was extracted to inform the review.ResultsFour economic evaluations on NBS for SMA with high reporting quality were identified. Each study employed a cost-utility analysis with similar model structures, using a decision tree for screening and a Markov model for treatment outcomes. They each compared NBS with treatment vs clinical diagnosis (no screening) with treatment. Although treatment protocols of each study varied due to differences in the strategies considered and availability of treatment. All studies included a societal perspective in their analysis and considered a lifetime horizon ranging from 30 months to 100 years. Early NBS with treatment was found to be more cost-effective than late treatment in all studies with ICER values ranging from £-117,541 to $714,000 per QALY. The wide range of ICER values are due to assumptions of long-term outcomes which are still largely unknown.ConclusionNBS with treatment was found to be cost-effective by all studies when compared to no NBS and late treatment. Although there is uncertainty around long term outcomes. Future research should focus on collecting long-term efficacy and safety data and evaluating the cost-effectiveness of pre-symptomatic treatment.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"619-629"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119626","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":"The evolving genetic landscape of neuromuscular fetal akinesias.","authors":"Göknur Haliloğlu, Gianina Ravenscroft","doi":"10.1177/22143602251339357","DOIUrl":"10.1177/22143602251339357","url":null,"abstract":"<p><p>Fetal akinesia is a broad term used to describe absent (or reduced, fetal hypokinesia) fetal movements, and it can be detected as early as the first trimester. Depending on the developmental age of onset, anything that interferes or limits the normal <i>in utero</i> movement results in a range of deformations affecting multiple organs and organ systems. Arthrogryposis, also termed arthrogryposis multiplex congenita (AMC), is a definitive terminology for multiple congenital contractures, with two major subgroups; amyoplasia and distal arthrogryposis (DA). The spectrum includes fetal akinesia deformation sequence (FADS), lethal congenital contracture syndrome (LCCS), and multiple pterygium syndrome (MPS). Variants in more than >400 genes are known to cause AMC, and it is increasingly recognized that variants in genes encoding critical components (including ventral horn cell, peripheral nerve, neuromuscular junction, skeletal muscle) of the extended motor unit underlie ∼40% of presentations. With unbiased screening approaches, including sequencing of comprehensive disease gene panels, exomes and genomes, novel genes and phenotypic expansions associated with known human disease genes have been uncovered in the setting of fetal akinesia. Autosomal-recessive titinopathy is the most frequent genetic cause of AMC. Accurate genetic diagnosis is critical to genetic counseling and informing family planning. Around 50% remain undiagnosed following comprehensive prenatal, diagnostic or research screening. Comprehensive phenotyping and periodic reanalysis with appropriate genomic tools are valuable strategies when faced with initial inconclusive results. There are likely many novel causative genes still to identify, which will inform our understanding of the molecular pathways underlying early human development and <i>in utero</i> movement.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"577-593"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986731","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}