Article
Biochemistry & Molecular Biology
Johan Lindqvist, Henk Granzier
Summary: Nemaline myopathy is a common congenital myopathy with no approved treatments. Inhibiting myostatin can mitigate muscle deficits in this disease, potentially serving as a therapeutic option.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Lauren E. Schultz, Mert Colpan, Garry E. Smith Jr, Rachel M. Mayfield, Tania M. Larrinaga, Alla S. Kostyukova, Carol C. Gregorio
Summary: Actin, a highly expressed protein in eukaryotic cells, plays a vital role in cellular processes. This study found that a mutation in the Lmod3 protein disrupts its structure and function, leading to the development of muscle diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Zhexin Wang, Michael Grange, Sabrina Pospich, Thorsten Wagner, Ay Lin Kho, Mathias Gautel, Stefan Raunser
Summary: This study reveals the structure of nebulin bound to thin filaments and demonstrates its stabilizing role. It also highlights the different interactions of nebulin with actin and myosin, as well as its interaction with a troponin T linker, explaining its regulatory function.
Article
Neurosciences
Natasha Ranu, Jenni Laitila, Hannah F. Dugdale, Jennifer Mariano, Justin S. Kolb, Carina Wallgren-Pettersson, Nanna Witting, John Vissing, Juan Jesus Vilchez, Chiara Fiorillo, Edmar Zanoteli, Mari Auranen, Manu Jokela, Giorgio Tasca, Kristl G. Claeys, Nicol C. Voermans, Johanna Palmio, Sanna Huovinen, Maurizio Moggio, Thomas Nyegaard Beck, Aikaterini Kontrogianni-Konstantopoulos, Henk Granzier, Julien Ochala
Summary: Nemaline myopathy (NM) is a common genetic muscle disorder associated with mutations in the NEB gene. This study revealed that the myosin stabilizing state, known as super-relaxed state, is impaired in NM patients, leading to increased energy consumption in resting muscle fibers. Proteomics analysis also showed metabolic changes in a nebulin-deficient mouse model. These findings provide insights into the pathophysiology of NM and suggest potential therapeutic targets for NEB-NM.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Genetics & Heredity
Cristina Skrypnyk, Aseel Ahmed Husain, Hisham Y. Hassan, Jameel Ahmed, Abdulla Darwish, Latifa Almusalam, Noureddine Ben Khalaf, Fahad Al Qashar
Summary: This study reports two Arab patients from consanguineous families diagnosed with different severities of nemaline myopathy. The clinical phenotype was linked to homozygous variants in NEB and KLHL40 genes. The study highlights the importance of detailed assessment in prenatal, neonatal, and infancy stages for accurate diagnosis and intervention of nemaline myopathy.
FRONTIERS IN GENETICS
(2023)
Article
Clinical Neurology
Paulo Ribeiro Nobrega, Jorge Luiz de Brito de Souza, Rebeca Bessa Mauricio, Anderson Rodrigues Brandao de Paiva, Daniel Aguiar Dias, Clara Gontijo Camelo, Edmar Zanotelli, David Schlesinger, Pedro Braga-Neto, Cristiane Araujo Martins Moreno
Summary: We report two cases of nemaline myopathy with pronounced central nervous system involvement and novel facial and skeletal dysmorphic findings, possibly expanding the disease phenotype.
NEUROLOGICAL SCIENCES
(2023)
Article
Neurosciences
Stefan Nicolau, Aneesha Dasgupta, Surendra Dasari, M. Cristine Charlesworth, Kenneth L. Johnson, Akhilesh Pandey, Jason D. Doles, Margherita Milone
Summary: Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both involve the accumulation of nemaline rods in muscle fibers. However, SLONM can be treated while iNM cannot. The distinction between these disorders is crucial for accurate diagnosis and the development of effective treatments. Through histological, proteomic, and transcriptomic analysis, we identified unique pathological and molecular signatures associated with SLONM and iNM, suggesting different underlying mechanisms. These findings provide valuable insights for enhancing diagnostic tools and developing treatments for SLONM.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Article
Clinical Neurology
Nathalie Laflamme, Baiba Lace, Samarth Thonta Setty, Nadie Rioux, Yvan Labrie, Arnaud Droit, Nicolas Chrestian, Serge Rivest
Summary: A 6-year-old boy with nemaline myopathy was found to have a causative mutation in the NEB gene, which could alter protein splicing levels and affect muscle function. This discovery contributes to a better understanding of the role of nebulin in neuromuscular diseases.
FRONTIERS IN NEUROLOGY
(2021)
Review
Biochemistry & Molecular Biology
Szilard Szikora, Peter Gorog, Jozsef Mihaly
Summary: Actin-containing tropomyosin and troponin decorated thin filaments are crucial components of the contractile apparatus in muscles. The optimal length of these filaments is critical for efficient muscle activity and can be regulated by various mechanisms. Mutations affecting these factors can alter thin filament length and are associated with certain diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Clinical Neurology
Briana Christophers, Michael A. Lopez, Vandana A. Gupta, Hannes Vogel, Mary Baylies
Summary: This review provides a narrative synthesis of case descriptions of pediatric patients with nemaline myopathy (NM). It analyzes the findings from genetic, histopathologic, and disease presentation studies, highlighting the wide spectrum of disease seen in children with NM despite sharing the same mutation. The review also discusses clinical considerations relevant to the care of patients with NM.
JOURNAL OF CHILD NEUROLOGY
(2022)
Article
Clinical Neurology
Adnan A. Mubaraki
Summary: Generalized weakness in pediatric and adolescent population can be caused by various disorders affecting the neuromuscular axis. Next-generation sequencing plays a crucial role in diagnosing muscle diseases, especially in cases with a family history of consanguinity. Clinicians need to be aware of congenital diseases affecting the muscles and the importance of NGS in reaching a correct diagnosis.
CASE REPORTS IN NEUROLOGY
(2021)
Review
Biochemistry & Molecular Biology
Paul Dowling, Stephen Gargan, Dieter Swandulla, Kay Ohlendieck
Summary: The loss of skeletal muscle mass and strength is the main cause of frailty syndrome, which is closely associated with sarcopenia in the elderly. Mass spectrometry-based proteomic surveys have improved our understanding of the molecular and cellular changes during muscle atrophy and age-related fiber-type shifting. Proteomic analysis suggests that contractile proteins can be used as markers of fiber-type transitions during aging.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Juliana Gurgel-Giannetti, Lucas Santos Souza, Guilherme L. Yamamoto, Marina Belisario, Monize Lazar, Wilson Campos, Rita de Cassia M. Pavanello, Mayana Zatz, Umbertina Reed, Edmar Zanoteli, Acary Bulle Oliveira, Vilma-Lotta Lehtokari, Erasmo B. Casella, Marcela C. Machado-Costa, Carina Wallgren-Pettersson, Nigel G. Laing, Vincenzo Nigro, Mariz Vainzof
Summary: Nemaline myopathy in Brazilian patients shows significant clinical and genetic heterogeneity, with a high frequency of NEB gene mutations. There is noticeable variability in clinical presentation and MRI patterns, with respiratory involvement often being severe.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Clinical Neurology
Kiran Polavarapu, Mainak Bardhan, Ram Murthy Anjanappa, Seena Vengalil, Veeramani Preethish-Kumar, Leena Shingavi, Tanushree Chawl, Saraswati Nashi, Dhaarini Mohan, Gautham Arunachal, Thenral S. Geetha, Vedam Ramprasad, Atchayaram Nalini
Summary: This study describes two adult patients with MYPN-related cap myopathy, presenting with early-onset, insidiously progressive, and minimally disabling proximodistal weakness. Both patients had no cardiac symptoms, and muscle MRI revealed specific muscle involvement. Whole-exome sequencing identified significant homozygous splicesite variants in both patients.
JOURNAL OF CLINICAL NEUROLOGY
(2021)
Review
Oncology
Hongbin Yu, Du He, Qing Zhang, Bei Cao, Weiping Liu, Yu Wu
Summary: MGCS-associated myopathy is a rare muscular disorder that is often misdiagnosed or diagnosed late. Comprehensive screening for MGCS is crucial to prevent misdiagnosis or delayed diagnosis.
FRONTIERS IN ONCOLOGY
(2022)
Article
Psychology, Developmental
Anita K. Chisholm, Francesca Lami, Kristina M. Haebich, Alex Ure, Amanda Brignell, Tiba Maloof, Natalie A. Pride, Karin S. Walsh, Alice Maier, Melissa Rouel, Yael Granader, Belinda Barton, Hayley Darke, Ian Fuelscher, Gabriel Dabscheck, Vicki A. Anderson, Katrina Williams, Kathryn N. North, Jonathan M. Payne
Summary: This study investigated sex and age differences in autistic behaviors in children with NF1. Males exhibited greater social communication deficits compared to females, and age-related improvement of social communication difficulties was observed in males but not females. No sex differences were found for restricted/repetitive behaviors, which were stable over time for both males and females.
JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS
(2023)
Article
Clinical Neurology
Conrad C. Weihl, Ana Topf, Rocio Bengoechea, Jennifer Duff, Richard Charlton, Solange Kapetanovic Garcia, Cristina Dominguez-Gonzalez, Abdulaziz Alsaman, Aurelio Hernandez-Lain, Luis Varona Franco, Monica Elizabeth Ponce Sanchez, Sarah J. Beecroft, Hayley Goullee, Jil Daw, Ankan Bhadra, Heather True, Michio Inoue, Andrew R. Findlay, Nigel Laing, Montse Olive, Gianina Ravenscroft, Volker Straub
Summary: This article reports a novel chaperonopathy associated with the DNAJB4 gene, causing muscle weakness and early respiratory failure. Loss of DNAJB4 function may lead to the accumulation of its client proteins, resulting in muscle dysfunction and degeneration.
ACTA NEUROPATHOLOGICA
(2023)
Article
Biochemistry & Molecular Biology
Lein N. H. Dofash, Gavin Monahan, Emilia Servian-Morilla, Eloy Rivas, Fathimath Faiz, Patricia Sullivan, Emily Oates, Joshua Clayton, Rhonda L. Taylor, Mark R. Davis, Traude Beilharz, Nigel G. Laing, Macarena Cabrera-Serrano, Gianina Ravenscroft
Summary: Nemaline myopathy 8 (NEM8) is a severe autosomal recessive disorder caused by variants in the KLHL40 gene. This study reports a case of a 26-year-old man with mild NEM8, characterized by hypotonia, fractures, and contractures. Genetic analysis identified compound heterozygous variants in KLHL40, including a truncating deletion and a likely pathogenic variant in the 3' UTR. Functional analysis revealed that the 3' UTR variant induced aberrant splicing and decreased expression of KLHL40 mRNA and protein. This study highlights the importance of considering abnormal 3' UTR splicing in variant curation for Mendelian diseases.
HUMAN MOLECULAR GENETICS
(2023)
Article
Clinical Neurology
Pedro M. Rodriguez Cruz, Gianina Ravenscroft, Daniel Natera, Aisling Carr, Adnan Manzur, Wei Wei Liu, Norbert R. Vella, Ivonne Jerico, Lidia Gonzalez-Quereda, Pia Gallano, Simon Attard Montalto, Mark R. Davis, Phillipa J. Lamont, Nigel G. Laing, Pierre Bourque, Andres Nascimento, Francesco Muntoni, Kiran Polavarapu, Hanns Lochmueller, Jacqueline Palace, David Beeson
Summary: This study reports the clinical and molecular features of 13 patients with acetylcholine receptor deficiency. The patients were found to carry the CHRNA1 variant NM_001039523.3:c.257G > A (p.Arg86His), which resulted in a non-functional acetylcholine receptor α-subunit. The study also emphasizes the importance of including alternative exons in variant analysis.
NEUROMUSCULAR DISORDERS
(2023)
Article
Medicine, General & Internal
D. Pellerin, M. C. Danzi, C. Wilke, M. Renaud, S. Fazal, M. -J Dicaire, C. K. Scriba, C. Ashton, C. Yanick, D. Beijer, A. Rebelo, C. Rocca, Z. Jaunmuktane, J. A. Sonnen, R. Lariviere, D. Genis, L. Molina Porcel, K. Choquet, R. Sakalla, S. Provost, R. Robertson, X. Allard-Chamard, M. Tetreault, S. J. Reiling, S. Nagy, V Nishadham, M. Purushottam, S. Vengalil, M. Bardhan, A. Nalini, Z. Chen, J. Mathieu, R. Massie, C. H. Chalk, A. -L Lafontaine, F. Evoy, M. -F Rioux, J. Ragoussis, K. M. Boycott, M. -P Dube, A. Duquette, H. Houlden, G. Ravenscroft, N. G. Laing, P. J. Lamont, M. A. Saporta, R. Schuele, L. Schoels, R. La Piana, M. Synofzik, S. Zuchner, B. Brais
Summary: A repeat expansion in the FGF14 gene was found to be associated with late-onset cerebellar ataxias (LOCAs) in French Canadian and German populations as well as in Australian and Indian patients. This discovery provides important insights for further research and diagnosis of LOCAs.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Nikhil Shri Sahajpal, Alex R. R. Hastie, Maximilian Schieck, Ashis K. K. Mondal, Marc Felde, Caspar I. I. van der Made, Janet S. S. Chou, Adrienne G. G. Randolph, Thomas Illig, Michael C. C. Zody, Catherine A. A. Brownstein, Alan H. H. Beggs, Alexander Hoischen, Alka Chaubey, Ravindra Kolhe
Summary: Several studies have found genetic variants associated with severe COVID-19, but none have reported genetic determinants for neurological complications. This report identifies rare/unique structural variants implicated in neurological functions in two individuals with neurological manifestations of COVID-19. It highlights the potential genetic link to neurological symptoms and calls for collective efforts to study these cohorts for possible genetic factors.
Article
Genetics & Heredity
Zornitza Stark, Tiffany Boughtwood, Matilda Haas, Jeffrey Braithwaite, Clara L. Gaff, Ilias Goranitis, Amanda B. Spurdle, David P. Hansen, Oliver Hofmann, Nigel Laing, Sylvia Metcalfe, Ainsley J. Newson, Hamish S. Scott, Natalie Thorne, Robyn L. Ward, Marcel E. Dinger, Stephanie Best, Janet C. Long, Sean M. Grimmond, John Pearson, Nicola Waddell, Christopher P. Barnett, Matthew Cook, Michael Field, David Fielding, Stephen B. Fox, Jozef Gecz, Adam Jaffe, Richard J. Leventer, Paul J. Lockhart, Sebastian Lunke, Andrew J. Mallett, Julie McGaughran, Linda Mileshkin, Katia Nones, Tony Roscioli, Ingrid E. Scheffer, Christopher Semsarian, Cas Simons, David M. Thomas, David R. Thorburn, Richard Tothill, Deborah White, Sally Dunwoodie, Peter T. Simpson, Peta Phillips, Marie-Jo Brion, Keri Finlay, Michael CJ. Quinn, Tessa Mattiske, Emma Tudini, Kirsten Boggs, Sean Murray, Kathy Wells, John Cannings, Andrew H. Sinclair, John Christodoulou, Kathryn N. North
Summary: Australian Genomics is a national collaborative partnership that aims to integrate genomics into healthcare through a whole-of-system approach. It has evaluated genomic testing outcomes in over 5,200 individuals across rare disease and cancer studies and provided evidence-based changes in policy and practice, resulting in government funding and access to genomic tests. It has also developed national skills, infrastructure, policy, and data resources to support data sharing and improve clinical genomic delivery.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Deborah Schofield, Evelyn Lee, Jayamala Parmar, Simon Kelly, Matthew Hobbs, Nigel Laing, Jan Mumford, Rupendra Shrestha
Summary: The purpose of this study was to evaluate the cost effectiveness of population-based, expanded reproductive carrier screening. The results showed that expanded screening was cost effective and could avert a significant number of affected births and save healthcare resources.
GENETICS IN MEDICINE
(2023)
Article
Clinical Neurology
Roula Ghaoui, Thuong T. Ha, Jennifer Kerkhof, Haley McConkey, Song Gao, Milena Babic, Rob King, Gianina Ravenscroft, Barbara Koszyca, Sophia Otto, Nigel G. Laing, Hamish Scott, Bekim Sadikovic, Karin S. Kassahn
Summary: This study reports a patient with a pathogenic variant in the DNMT3A gene who presented to the neuromuscular clinic with congenital myopathy, rhabdomyolysis, severe myalgias, and chest pain, along with phenotypic features associated with TBRS. Muscle biopsy showed minor myopathic features, and cardiac investigations revealed mildly impaired bi-ventricular systolic function. The study highlights the phenotypic overlap in patients with syndromic disorders presenting to neuromuscular clinics and the limitations of gene panels in establishing a molecular diagnosis.
NEUROMUSCULAR DISORDERS
(2023)
Article
Genetics & Heredity
Robert J. Graham, Basil T. Darras, Tmirah Haselkorn, Dan Fisher, Casie A. Genetti, Weston Miller, Alan H. Beggs
Summary: This study analyzed healthcare resource utilization in XLMTM patients within a US medical claims database. The results showed a significant increase in healthcare resource use among XLMTM patients over the past five years. Most patients required respiratory and feeding support and had multiple hospitalizations throughout childhood and beyond.
ORPHANET JOURNAL OF RARE DISEASES
(2023)
Article
Clinical Neurology
Katarina Pelin, Lydia Sagath, Johanna Lehtonen, Kirsi Kiiski, Olli Tynninen, Anders Paetau, Mridul Johari, Marco Savarese, Carina Wallgren-Pettersson, Vilma-Lotta Lehtokari
Summary: The study identified novel biallelic splice-site variants in the TPM3 gene which significantly reduce TPM3 protein expression, leading to the development of nemaline myopathy.
JOURNAL OF NEUROMUSCULAR DISEASES
(2023)
Article
Biotechnology & Applied Microbiology
Patricia J. Sullivan, Velimir Gayevskiy, Ryan L. Davis, Marie Wong, Chelsea Mayoh, Amali Mallawaarachchi, Yvonne Hort, Mark J. McCabe, Sarah Beecroft, Matilda R. Jackson, Peer Arts, Andrew Dubowsky, Nigel Laing, Marcel E. Dinger, Hamish S. Scott, Emily Oates, Mark Pinese, Mark J. Cowley
Summary: Introme is a tool that uses machine learning to comprehensively evaluate the likelihood of a variant impacting splicing by integrating predictions from multiple splice detection tools, additional splicing rules, and gene architecture features. Through extensive benchmarking, Introme outperformed other tools in detecting clinically significant splice variants.
Article
Genetics & Heredity
Vilma-Lotta Lehtokari, Minna Simila, Marianne Tammepuu, Carina Wallgren-Pettersson, Sonja Strang-Karlsson, Sinikka Hiekkala
Summary: This pilot study is the first comprehensive survey-based study of the physical, psychological, and social functioning of adult persons with nemaline myopathy or related disorders. The results indicate that non-ambulatory patients face more challenges in all areas of functioning compared to ambulatory patients, and the COVID-19 pandemic has a greater impact on non-ambulatory patients. The study provides directions for improving future research.
ORPHANET JOURNAL OF RARE DISEASES
(2023)
Article
Genetics & Heredity
Aurelien Perrin, Corinne Metay, Marco Savarese, Rabah Ben Yaou, German Demidov, Isabelle Nelson, Guilhem Sole, Yann Pereon, Enrico Silvio Bertini, Fabiana Fattori, Adele D'Amico, Federica Ricci, Mira Ginsberg, Andreea Seferian, Odile Boespflug-Tanguy, Laurent Servais, Francoise Chapon, Emmeline Lagrange, Karen Gaudon, Adrien Bloch, Robin Ghanem, Lucie Guyant-Marechal, Mridul Johari, Charles Van Goethem, Michel Fardeau, Raul Juntas Morales, Casie A. Genetti, Minttu Marttila, Michel Koenig, Alan Beggs, Bjarne Udd, Gisele Bonne, Mireille Cossee
Summary: Titinopathies are complex neuromuscular pathologies caused by mutations in the titin gene (TTN). A study identified multiple deletion-type CNVs in the TTN gene in several families, revealing new genotype-phenotype associations, mainly distal myopathy.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Clinical Neurology
Carolin K. Scriba, Igor Stevanovski, Sanjog R. Chintalaphani, Hasindu Gamaarachchi, Roula Ghaoui, Darshan Ghia, Robert D. Henderson, Nerissa Jordan, Antony Winkel, Phillipa J. Lamont, Miriam J. Rodrigues, Richard H. Roxburgh, Ben Weisburd, Nigel G. Laing, Ira W. Deveson, Mark R. Davis, Gianina Ravenscroft
Summary: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome is a neurological disorder associated with biallelic pentanucleotide expansions in the RFC1 gene. In an Australasian cohort, known pathogenic expansions were detected in 15.3% of patients, along with the identification of novel repeat motifs. This study demonstrates the substantial contribution of RFC1 pathogenic expansions to neurological disease in the Australasian population and highlights the heterogeneity of the locus.
BRAIN COMMUNICATIONS
(2023)