Journal of neuromuscular diseases最新文献

{"title":"A Likely Pathogenic variant in the KBTBD13 Gene: A Case Series of Three Patients with Nemaline Myopathy Type 6.","authors":"Esmee S B van Kleef, Karlijn Bouman, Joery P F Molenaar, Josine M de Winter, Floor A M Duijkers, Filip Eftimov, Corien C Verschuuren-Bemelmans, Tineke van der Laan, Benno Küsters, Edoardo Malfatti, Erik-Jan Kamsteeg, Baziel G M van Engelen, Coen A C Ottenheijm, Jonne Doorduin, Nicol C Voermans","doi":"10.3233/JND-230196","DOIUrl":"https://doi.org/10.3233/JND-230196","url":null,"abstract":"<p><strong>Background: </strong>Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13 gene, also called the Dutch founder variant.</p><p><strong>Objective: </strong>To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13 gene.</p><p><strong>Results: </strong>We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivo functional tests was observed. This was confirmed by in vitro functional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier.</p><p><strong>Conclusions: </strong>The c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene is a likely pathogenic variant causing NEM6.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140352","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":"An International Retrospective Early Natural History Study of LAMA2-Related Dystrophies.","authors":"Lauren Hinkley, Rotem Orbach, Justin Park, Rachel Alvarez, Gustavo Dziewczapolski, Carsten G Bönnemann, A Reghan Foley","doi":"10.3233/JND-240048","DOIUrl":"https://doi.org/10.3233/JND-240048","url":null,"abstract":"<p><strong>Background: </strong>LAMA2-related dystrophies (LAMA2-RDs) represent one of the most common forms of congenital muscular dystrophy and have historically been classified into two subtypes: complete or partial deficiency of laminin-211 (merosin). Patients with LAMA2-RD with the typical congenital phenotype manifest severe muscle weakness, delayed motor milestones, joint contractures, failure to thrive, and progressive respiratory insufficiency.</p><p><strong>Objective: </strong>While a comprehensive prospective natural history study has been performed in LAMA2-RD patients over 5 years of age, the early natural history of patients with LAMA2-RD 5 years and younger has not been comprehensively characterized.</p><p><strong>Methods: </strong>We extracted retrospective data for patients with LAMA2-RD ages birth through 5 years via the Congenital Muscle Disease International Registry (CMDIR). We analyzed the data using a phenotypic classification based on maximal motor milestones to divide patients into two phenotypic groups: \"Sit\" for those patients who attained that ability to remain seated and \"Walk\" for those patients who attained the ability to walk independently by 3.5 years of age.</p><p><strong>Results: </strong>Sixty patients with LAMA2-RD from 10 countries fulfilled the inclusion criteria. Twenty-four patients had initiated non-invasive ventilation by age 5 years. Hospitalizations during the first years of life were often related to respiratory insufficiency. Feeding/nutritional difficulties and orthopedic issues were commonly reported. Significant elevations of creatine kinase (CK) observed during the neonatal period declined rapidly within the first few months of life.</p><p><strong>Conclusions: </strong>This is the largest international retrospective early natural history study of LAMA2-RD to date, contributing essential data for understanding early clinical findings in LAMA2-RD which, along with the data being collected in international, prospective early natural history studies, will help to establish clinical trial readiness. Our proposed nomenclature of LAMA2-RD1 for patients who attain the ability to sit (remain seated) and LAMA2-RD2 for patients who attain the ability to walk independently is aimed at further improving LAMA2-RD classification.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036079","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":"Life Expectancy and Causes of Death in Patients with Myotonic Dystrophy Type 2.","authors":"Manon J Damen, Otto G Muilwijk, Tom B G Olde Dubbelink, Baziel G M van Engelen, Nicol C Voermans, Alide A Tieleman","doi":"10.3233/JND-240089","DOIUrl":"https://doi.org/10.3233/JND-240089","url":null,"abstract":"<p><strong>Background: </strong>Myotonic Dystrophy type 2 (DM2) is a dominantly inherited multisystem disease caused by a CCTG repeat expansion in intron 1 of the CNBP gene. Although in the last two decades over 1500 patients with DM2 have been diagnosed worldwide, our clinical impression of a reduced life expectancy in DM2 has not been investigated previously.</p><p><strong>Objective: </strong>The aim of this observational study was to determine the life expectancy and the causes of death in patients with genetically confirmed DM2.</p><p><strong>Methods: </strong>We identified the data of all deceased patients with DM2 in the Dutch neuromuscular database between 2000 and 2023. Ages and causes of death and the patients' clinical features during lifetime were determined. Age of death in DM2 was compared to the general population by using life tables with prognostic cohort life expectancy (CLE) and period life expectancy (PLE) data of the Dutch electronic database of statistics (CBS StatLine).</p><p><strong>Results: </strong>Twenty-six deceased patients were identified in the Dutch DM2 cohort (n = 125). Median age of death in DM2 (70.9 years) was significantly lower compared to sex- and age-matched CLE (78.1 years) and PLE (82.1 years) in the Netherlands. Main causes of death were cardiac diseases (31%) and pneumonia (27%). Seven patients (27%) had a malignancy at the time of death.</p><p><strong>Conclusion: </strong>These results provide new insights into the phenotype of DM2. Life expectancy in patients with DM2 is reduced, possibly attributable to multiple causes including increased risk of cardiac disease, pneumonia, and malignancies. The occurrence of a significantly reduced life expectancy has implications for clinical practice and may form a basis for advanced care planning, including end-of-life care, to optimize quality of life for patients with DM2 and their family. Research in larger cohorts should be done to confirm these findings and to ascertain more about the natural course in DM2.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140353","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":"E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 3rd eNMD Congress: Pisa, Italy, 29-30 October 2021.","authors":"Erika Schirinzi, Mario Alessandro Bochicchio, Hanns Lochmüller, John Vissing, Jordie-Diaz-Manerae, Teresinha Evangelista, Jean-Philippe Plançon, Luca Fanucci, Marco Marini, Alessandro Tonacci, Michelangelo Mancuso, Sandrine Segovia-Kueny, Antonio Toscano, Corrado Angelini, Benedikt Schoser, Sabrina Sacconi, Gabriele Siciliano","doi":"10.3233/JND-230091","DOIUrl":"https://doi.org/10.3233/JND-230091","url":null,"abstract":"<p><p>Neuromuscular diseases (NMDs), in their phenotypic heterogeneity, share quite invariably common issues that involve several clinical and socio-economical aspects, needing a deep critical analysis to develop better management strategies. From diagnosis to treatment and follow-up, the development of technological solutions can improve the detection of several critical aspects related to the diseases, addressing both the met and unmet needs of clinicians and patients. Among several aspects of the digital transformation of health and care, this congress expands what has been learned from previous congresses editions on applicability and usefulness of technological solutions in NMDs. In particular the focus on new solutions for remote monitoring provide valuable insights to increase disease-specific knowledge and trigger prompt decision-making. In doing that, several perspectives from different areas of expertise were shared and discussed, pointing out strengths and weaknesses on the current state of the art on topic, suggesting new research lines to advance technology in this specific clinical field.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904787","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 NDUFS6 Variant Associated with Neuropathy and Optic Atrophy","authors":"A. Gangfuss, Philipp Rating, Tomas Ferreira, A. Hentschel, A. D. Marina, Heike Kölbel, A. Sickmann, A. Abicht, Florian Kraft, Tobias Ruck, Johann Böhm, Anne Schänzer, Ulrike Schara-Schmidt, Teresa M. Neuhann, Rita Horvath, Andreas Roos","doi":"10.3233/jnd-230181","DOIUrl":"https://doi.org/10.3233/jnd-230181","url":null,"abstract":"Background: The NADH dehydrogenase [ubiquinone] iron-sulfur protein 6 (NDUFS6) gene encodes for an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Bi-allelic NDUFS6 variants have been linked with a severe disorder mostly reported as a lethal infantile mitochondrial disease (LMID) or Leigh syndrome (LS). Objective: Here, we identified a homozygous variant (c.309 + 5 G >  A) in NDUFS6 in one male patient with axonal neuropathy accompanied by loss of small fibers in skin biopsy and further complicated by optic atrophy and borderline intellectual disability. Methods: To address the pathogenicity of the variant, biochemical studies (mtDNA copy number quantification, ELISA, Proteomic profiling) of patient-derived leukocytes were performed. Results: The analyses revealed loss of NDUFS6 protein associated with a decrease of three further mitochondrial NADH dehydrogenase subunit/assembly proteins (NDUFA12, NDUFS4 and NDUFV1). Mitochondrial copy number is not altered in leukocytes and the mitochondrial biomarker GDF15 is not significantly changed in serum. Conclusions: Hence, our combined clinical and biochemical data strengthen the concept of NDUFS6 being causative for a very rare form of axonal neuropathy associated with optic atrophy and borderline intellectual disability, and thus expand (i) the molecular genetic landscape of neuropathies and (ii) the clinical spectrum of NDUFS6-associated phenotypes.","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":"10 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139447000","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":"Post-hoc Nonparametric Analysis of Forced Vital Capacity in the COMET Trial Demonstrates Superiority of Avalglucosidase Alfa vs Alglucosidase Alfa.","authors":"Matthias Boentert, Emmanuelle Salort Campana, Shahram Attarian, Jordi Diaz-Manera, Mazen M Dimachkie, Magali Periquet, Nathan Thibault, Patrick Miossec, Tianyue Zhou, Kenneth I Berger","doi":"10.3233/JND-230175","DOIUrl":"10.3233/JND-230175","url":null,"abstract":"<p><p>In the COMET trial of patients with late-onset Pompe disease, greater improvement in upright forced vital capacity (FVC) % predicted was observed with avalglucosidase alfa (AVA) vs alglucosidase alfa (ALGLU) (estimated treatment difference: 2.43%). The pre-specified mixed model repeated measures (MMRM) analysis demonstrated non-inferiority of AVA (P = 0.0074) and narrowly missed superiority (P = 0.063; 95% CI: -0.13-4.99). We report superiority of AVA in two post-hoc analyses that account for an extreme outlier participant with low FVC and severe chronic obstructive pulmonary disease at baseline: MMRM excluding the outlier (P = 0.013) and non-parametric analysis of all data with repeated measures analysis of covariance (P = 0.019).</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"369-374"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10977360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139074348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A c.1775C > T Point Mutation of Sodium Channel Alfa Subunit Gene (SCN4A) in a Three-Generation Sardinian Family with Sodium Channel Myotonia.","authors":"Carmen Campanale, Paola Laghetti, Ilaria Saltarella, Concetta Altamura, Eleonora Canioni, Emanuele Iosa, Lorenzo Maggi, Raffaella Brugnoni, Paolo Tacconi, Jean-François Desaphy","doi":"10.3233/JND-230134","DOIUrl":"10.3233/JND-230134","url":null,"abstract":"<p><strong>Background: </strong>The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation.</p><p><strong>Methods: </strong>Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro electrophysiology, site-directed mutagenesis and heterologous expression were collected.</p><p><strong>Results: </strong>A heterozygous point mutation (c.1775C > T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude.</p><p><strong>Conclusions: </strong>The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"725-734"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3.","authors":"Amy Wolfe, Georgia Stimpson, Danielle Ramsey, Giorgia Coratti, Sally Dunaway Young, Anna Mayhew, Marika Pane, Annemarie Rohwer, Robert Muni Lofra, Tina Duong, Emer O'Reilly, Evelin Milev, Matthew Civitello, Valeria A Sansone, Adele D'Amico, Enrico Bertini, Sonia Messina, Claudio Bruno, Emilio Albamonte, Elena Mazzone, Marion Main, Jacqueline Montes, Allan M Glanzman, Zarazuela Zolkipli-Cunningham, Amy Pasternak, Chiara Marini-Bettolo, John W Day, Basil T Darras, Darryl C De Vivo, Giovanni Baranello, Mariacristina Scoto, Richard S Finkel, Eugenio Mercuri, Francesco Muntoni","doi":"10.3233/JND-230211","DOIUrl":"10.3233/JND-230211","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS).</p><p><strong>Objective: </strong>In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019).</p><p><strong>Methods: </strong>We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient.</p><p><strong>Results: </strong>RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex.</p><p><strong>Conclusions: </strong>This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"665-677"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expert Insights from a Delphi-driven Neurologists' Panel: Real-world Mexiletine use in Patients with Myotonic Disorders in Italy.","authors":"Dario Lidonnici, Pietro Brambilla, Roberto Ravasio, Alla Zozulya-Weidenfeller, Annette Beiderbeck, Mariska van Aswegen, Rosa Oliveira, Valeria A Sansone","doi":"10.3233/JND-230115","DOIUrl":"10.3233/JND-230115","url":null,"abstract":"<p><strong>Background: </strong>Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented.</p><p><strong>Objective: </strong>Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic.</p><p><strong>Methods: </strong>A panel of 8 Italian neurologists took part in a two-round Delphi panel between June and October 2022, analyzing the current use of mexiletine in Italian clinical practice.</p><p><strong>Results: </strong>The panelists assist 1126 patients (69% DM type1, 18% NDM and 13% DM type2). Adult NDM patients receive, on average, 400-600 mg of mexiletine hydrochloride (HCl) while adult DM patients receive 100-600 mg, per day in the long-term. The severity of symptoms is considered the main reason to start mexiletine treatment for both NDM and DM patients. Mexiletine is reckoned to have a clinical impact for both NDM and DM patients, but currently drug access is problematic.</p><p><strong>Conclusions: </strong>Mexiletine treatment is recognized to have a role in the reduction of the symptomatic burden for NDM and DM patients. Patient management could be improved by facilitating access to therapy and developing new drug formulations.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"411-423"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10977357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139671996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.","authors":"Catarina Olimpio, Ida Paramonov, Leslie Matalonga, Steven Laurie, Katherine Schon, Kiran Polavarapu, Janbernd Kirschner, Ulrike Schara-Schmidt, Hanns Lochmüller, Patrick F Chinnery, Rita Horvath","doi":"10.3233/JND-240020","DOIUrl":"10.3233/JND-240020","url":null,"abstract":"<p><strong>Background: </strong>The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed.</p><p><strong>Objective: </strong>We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders.</p><p><strong>Methods: </strong>The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP.</p><p><strong>Results: </strong>Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n = 1, MT-TN), nuclear encoded mitochondrial genes (n = 2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n = 5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data.</p><p><strong>Conclusions: </strong>In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":" ","pages":"767-775"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}