Article
Cell Biology
Karla G. Espinosa, Salma Geissah, Linda Groom, Jonathan Volpatti, Ian C. Scott, Robert T. Dirksen, Mo Zhao, James J. Dowling
Summary: This study reported a new zebrafish model, zebrafish speg-DKO, of centronuclear myopathy (CNM), and demonstrated its ability to accurately recapitulate multiple phenotypes associated with CNM. This model provides a potential platform for investigating disease mechanisms and evaluating potential therapies for CNM.
DISEASE MODELS & MECHANISMS
(2022)
Article
Biochemistry & Molecular Biology
Yukari Endo, Linda Groom, Sabrina M. Wang, Emanuela Pannia, Nigel W. Griffiths, Jenica L. M. Van Gennip, Brian Ciruna, Jocelyn Laporte, Robert T. Dirksen, James J. Dowling
Summary: CACNA1S-related myopathy is a congenital muscle disease with no effective therapies available. The lack of suitable animal models has hindered its study. Researchers have successfully generated zebrafish models that mimic key aspects of the severe and mild forms of the disease, providing a basis for future mechanistic studies and therapy development.
HUMAN MOLECULAR GENETICS
(2023)
Review
Clinical Neurology
Kun Huang, Fang-Fang Bi, Huan Yang
Summary: This study estimated the prevalence of congenital myopathy through a systematic review and meta-analysis. The prevalence varied among different subtypes and populations. The overall quality of studies on this disease is generally moderate, emphasizing the need for higher-quality research on orphan diseases.
FRONTIERS IN NEUROLOGY
(2021)
Article
Clinical Neurology
Charlotte Gineste, Alix Simon, Marie Braun, David Reiss, Jocelyn Laporte
Summary: The study shows that tamoxifen can improve muscle function and structure in mouse models of BIN1 and DNM2-related centronuclear myopathies, likely by reducing dynamin 2 levels. This suggests the potential repurposing of tamoxifen for the treatment of autosomal forms of centronuclear myopathies.
Review
Biochemistry & Molecular Biology
Raquel Gomez-Oca, Belinda S. Cowling, Jocelyn Laporte
Summary: Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects caused by mutations in genes encoding proteins involved in membrane remodeling, trafficking, and excitation-contraction coupling. Animal models have confirmed shared pathological anomalies in T-tubule remodeling, organelle mispositioning, and protein homeostasis, supporting the development of common therapeutic targets for CNM forms. Promising preclinical results have led to ongoing clinical trials for CNM treatment, including gene therapy and repurposing of existing drugs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Suzie Buono, Arnaud Monseur, Alexia Menuet, Anne Robe, Catherine Koch, Jocelyn Laporte, Leen Thielemans, Marion Depla, Belinda S. Cowling
Summary: Generating reliable preclinical data in animal models of disease is crucial for therapy development. In this study, statistical analysis and modeling were conducted to predict disease progression, which was then validated using data from a new colony of mice, demonstrating the reproducibility of disease phenotype. Furthermore, the refined phenotypic parameters were used to test the therapeutic efficacy of Dnm2 targeting, showing a significant improvement in disease progression.
DISEASE MODELS & MECHANISMS
(2022)
Review
Biochemistry & Molecular Biology
Shiyu Luo, Samantha M. Rosen, Qifei Li, Pankaj B. Agrawal
Summary: Mutations in SPEG gene are associated with centronuclear myopathy, cardiomyopathy, or a combination of both, playing critical roles in skeletal and cardiac muscle development, maintenance, and function. Understanding the basic mechanisms of SPEG in regulating muscle development will provide insights into therapeutic targets for SPEG-related disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
Jonathan R. Volpatti, Mehdi M. Ghahramani-Seno, Melanie Mansat, Nesrin Sabha, Ege Sarikaya, Sarah J. Goodman, Eric Chater-Diehl, Alper Celik, Emanuela Pannia, Carine Froment, Lucie Combes-Soia, Nika Maani, Kyoko E. Yuki, Gaetan Chicanne, Liis Uuskula-Reimand, Simon Monis, Sana Akhtar Alvi, Casie A. Genetti, Bernard Payrastre, Alan H. Beggs, Carsten G. Bonnemann, Francesco Muntoni, Michael D. Wilson, Rosanna Weksberg, Julien Viaud, James J. Dowling
Summary: In this study, we identified valproic acid as a potential therapy for XLMTM through drug screening in zebrafish and mouse models. We found that valproic acid suppresses the disease phenotype by inhibiting HDAC and normalizing DNA methylation. Additionally, we discovered a unique DNA methylation signature in XLMTM patients, suggesting that epigenetic alterations could be targeted for therapeutic intervention.
ACTA NEUROPATHOLOGICA
(2022)
Article
Neurosciences
Valerie Biancalana, John Rendu, Annabelle Chaussenot, Helen Mecili, Eric Bieth, Melanie Fradin, Sandra Mercier, Maud Michaud, Marie-Christine Nougues, Laurent Pasquier, Sabrina Sacconi, Norma B. Romero, Pascale Marcorelles, Francois Jerome Authier, Antoinette Gelot Bernabe, Emmanuelle Uro-Coste, Claude Cances, Bertrand Isidor, Armelle Magot, Marie-Christine Minot-Myhie, Yann Pereon, Julie Perrier-Boeswillwald, Gilles Bretaudeau, Nicolas Dondaine, Alison Bouzenard, Megane Pizzimenti, Bruno Eymard, Ana Ferreiro, Jocelyn Laporte, Julien Faure, Johann Bohm
Summary: The recurrent RYR1 mutation previously classified as VUS was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, providing evidence of its pathogenicity. This mutation causes an atypical congenital myopathy with slowly improving motor function over the first decades of life, indicating a potential for directing molecular diagnosis for patients with similar clinical presentation.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Alexandre Prola, Jordan Blondelle, Aymeline Vandestienne, Jerome Piquereau, Raphael G. P. Denis, Stephane Guyot, Hadrien Chauvin, Arnaud Mourier, Marie Maurer, Celine Henry, Nahed Khadhraoui, Cindy Gallerne, Thibaut Molinie, Guillaume Courtin, Laurent Guillaud, Melanie Gressette, Audrey Solgadi, Florent Dumont, Julien Castel, Julien Ternacle, Jean Demarquoy, Alexandra Malgoyre, Nathalie Koulmann, Genevieve Derumeaux, Marie-France Giraud, Frederic Joubert, Vladimir Veksler, Serge Luquet, Frederic Relaix, Laurent Tiret, Fanny Pilot-Storck
Summary: Mice deficient for a muscle-specific enzyme of very-long-chain fatty acid synthesis displayed increased basal energy expenditure and protection against high-fat diet-induced obesity. Muscle-specific modulation of the very-long-chain fatty acid pathway was associated with a reduced content of inner mitochondrial membrane phospholipid cardiolipin and a blunted coupling efficiency between the respiratory chain and ATP synthase, which was restored by cardiolipin enrichment. Selective increase of lipid oxidative capacities in skeletal muscle, through the cardiolipin-dependent lowering of mitochondrial ATP production, provides an effective option against obesity at the whole-body level.
Review
Cardiac & Cardiovascular Systems
Hannah Campbell, Yuriana Aguilar-Sanchez, Ann P. Quick, Dobromir Dobrev, Xander H. T. Wehrens
Summary: Proper cardiac Ca2+ homeostasis is crucial for normal excitation-contraction coupling, and SPEG, as a key regulator in maintaining normal cardiac Ca2+ handling, plays a crucial role in both physiology and human disease processes, contributing to various genetic and acquired cardiovascular diseases.
CARDIOVASCULAR RESEARCH
(2021)
Review
Cardiac & Cardiovascular Systems
Hannah Campbell, Yuriana Aguilar-Sanchez, Ann P. Quick, Dobromir Dobrev, Xander H. T. Wehrens
Summary: Proper regulation of cardiac Ca2+ handling is crucial for normal excitation-contraction coupling, with SPEG playing a key role in maintaining this homeostasis and being implicated in various cardiovascular diseases.
CARDIOVASCULAR RESEARCH
(2021)
Article
Clinical Neurology
Bungo Hirose, Kazuna Ikeda, Daisuke Yamamoto, Emiko Tsuda, Rika Yamauchi, Takayoshi Hozuki, Yoshiki Masuda, Tomihiro Imai
Summary: The study aimed to develop a simple and reliable technique for early diagnosis of critical illness myopathy (CIM) by evaluating excitation-contraction (E-C) coupling. The measurement of E-C coupling time (ECCT) was found to be an effective method to detect reduced muscle membrane excitability in the early stage of CIM.
CLINICAL NEUROPHYSIOLOGY
(2022)
Article
Medicine, General & Internal
Narjara Castillo-Ferran, Juan Mario Junco-Rodriguez, Zurina Lestayo-O'Farrill, Maria de los Angeles Robinson-Agramonte, Zoilo Camejo-Leon, Hector Jesus Gomez-Suarez, Mercedes Salinas-Olivares, Evelyn Antiguas-Valdez, Elizabeth Falcon-Lamazares, Dario Siniscalco
Summary: Congenital myopathies (CMs) are a group of diseases characterized by muscle weakness and hypotonia. Centronuclear CM, characterized by centrally located nuclei in muscle fibers, was diagnosed in a 22-year-old male patient with muscle weakness since childhood. Neurogenic patterns were observed in electromyography and neuroconduction studies showed motor nerve involvement. The presence of fibers with central nuclei confirmed the diagnosis of CM. Understanding the pathological findings in CM is important for early treatment.
MEDICINA-LITHUANIA
(2023)
Article
Biochemistry & Molecular Biology
Roberto Silva-Rojas, Laura Perez-Guardia, Emma Lafabrie, David Moulaert, Jocelyn Laporte, Johann Bohm
Summary: This study evaluated the therapeutic potential of downregulating ORAI1 in Tubular Aggregate Myopathy (TAM) and Stormorken syndrome (STRMK), and found that ORAI1 silencing could partially prevent the development of the multi-systemic TAM/STRMK phenotype in mice.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Clinical Neurology
Charlotte Gineste, Alix Simon, Marie Braun, David Reiss, Jocelyn Laporte
Summary: The study shows that tamoxifen can improve muscle function and structure in mouse models of BIN1 and DNM2-related centronuclear myopathies, likely by reducing dynamin 2 levels. This suggests the potential repurposing of tamoxifen for the treatment of autosomal forms of centronuclear myopathies.
Article
Pharmacology & Pharmacy
Charlotte Gineste, Jocelyn Laporte
Summary: Congenital myopathies are rare and severe genetic diseases that affect the skeletal muscle function in children and adults. Various subgroups exist based on clinical and histopathological features. Currently, there are no approved treatments for any congenital myopathies. However, there are ongoing research efforts to explore pharmacological and genetic-based therapeutic approaches.
CURRENT OPINION IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Morie Ishida, Maria Gabriela Otero, Christina Freeman, Pedro A. Sanchez-Lara, Carlos M. Guardia, Tyler Mark Pierson, Juan S. Bonifacino
Summary: We report a pediatric patient with an ARF1-related disorder associated with a missense variant (c.296 G > A; p.R99H) in the ARF1 gene, causing developmental delay, hypotonia, intellectual disability, and motor stereotypies. Neuroimaging revealed brain abnormalities. The R99H-ARF1 variant protein showed alterations in Golgi apparatus, coat proteins recruitment, and endosomal morphology, similar to constitutively active ARF1 mutants. This study suggests the pathogenesis mechanism of the R99H variant involves constitutive activation and highlights the phenotypic variability of ARF1-related disorders.
HUMAN MOLECULAR GENETICS
(2023)
Article
Genetics & Heredity
Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Boennemann, Edmar Zanoteli
Summary: In this study, the clinical and genetic data of 33 patients with Nemaline myopathy caused by NEB variants were analyzed. The results showed that patients who used ventilatory support were more likely to have scoliosis and dysphagia, and older patients had a higher risk of respiratory dysfunction and skeletal deformities. Additionally, tongue atrophy in a triple furrow pattern was a novel and frequent finding associated with dysphagia.
NEUROLOGY-GENETICS
(2023)
Article
Biology
Jan Eckhardt, Alexis Ruiz, Stephane Koenig, Maud Frieden, Herve Meier, Alexander Schmidt, Susan Treves, Francesco Zorzato
Summary: Skeletal muscles are responsible for movement and metabolic regulation. Congenital myopathies, caused by mutations in genes such as RYR1, lead to weak muscles. This study found that RYR1 mutations decrease RyR1 protein content and alter the expression of proteins involved in calcium signaling, metabolism, and ER protein quality control. It also identified potential targets for treating RyR1-related congenital myopathies.
Article
Genetics & Heredity
Ivana Dabaj, Robert Y. Carlier, Klaus Dieterich, Isabelle Desguerre, Julien Faure, Norma B. Romero, Wenting Trang, Susana Quijano-Roy, Dominique P. Germain
Summary: Sheldon-Hall syndrome (SHS) is a rare congenital contracture syndrome caused by pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex. This study reports the association between a pathogenic variant in the TNNT3 gene and neurogenic features in a patient with SHS. Further research is needed to investigate the developmental abnormalities that may lead to pseudo-neurogenic EMG features.
FRONTIERS IN GENETICS
(2023)
Article
Cell Biology
Sergi Cesar, Oscar Campuzano, Jose Cruzalegui, Victori Fiol, Isaac Moll, Estefania Martinez-Barrios, Irene Zschaeck, Daniel Natera-de Benito, Carlos Ortez, Laura Carrera, Jessica Exposito, Ruben Berrueco, Carles Bautista-Rodriguez, Ivana Dabaj, Marta Gomez Garcia-de-la-Banda, Susana Quijano-Roy, Josep Brugada, Andres Nascimento, Georgia Sarquella-Brugada
Summary: LMNA-related muscular dystrophy is a rare condition that can lead to various laminopathies such as Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). It is associated with heart failure, malignant arrhythmias, and sudden death. This study aimed to comprehensively evaluate the cardiac status of pediatric patients with LMNA-related muscular dystrophy. The results showed that 20% of the patients had malignant arrhythmias, and early-onset EDMD was associated with worse cardiac prognosis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Clinical Neurology
Andreas C. Themistocleous, Georgios Baskozos, Iulia Blesneac, Maddalena Comini, Karyn Megy, Sam Chong, Sri V. V. Deevi, Lionel Ginsberg, David Gosal, Robert D. M. Hadden, Rita Horvath, Mohamed Mahdi-Rogers, Adnan Manzur, Rutendo Mapeta, Andrew Marshall, Emma Matthews, Mark McCarthy, Mary M. Reilly, Tara Renton, Andrew S. C. Rice, Tom A. Vale, Natalie van Zuydam, Suellen M. Walker, Christopher Geoffrey Woods, David L. H. Bennett
Summary: This study aimed to identify new variants in genes related to neuropathic pain, determine the prevalence of known pathogenic variants, and understand their relationship with clinical presentation. The results showed that clinically relevant variants were found in 12% of participants, mostly in ion channels. Combining genetic analysis with functional validation can provide a better understanding of how rare variants in ion channels lead to sensory neuron hyper-excitability and interaction with environmental triggers. This study highlights the role of ion channel variants in extreme neuropathic pain disorders.
BRAIN COMMUNICATIONS
(2023)
Article
Clinical Neurology
Quentin Giraud, Coralie Spiegelhalter, Nadia Messaddeq, Jocelyn Laporte
Summary: BIN1-related centronuclear myopathies can be prevented and partially reversed by overexpression of myotubularin in mice. This research provides a potential therapeutic strategy for BIN1- and DNM2-linked centronuclear myopathies.
Article
Biochemistry & Molecular Biology
Yukari Endo, Linda Groom, Sabrina M. Wang, Emanuela Pannia, Nigel W. Griffiths, Jenica L. M. Van Gennip, Brian Ciruna, Jocelyn Laporte, Robert T. Dirksen, James J. Dowling
Summary: CACNA1S-related myopathy is a congenital muscle disease with no effective therapies available. The lack of suitable animal models has hindered its study. Researchers have successfully generated zebrafish models that mimic key aspects of the severe and mild forms of the disease, providing a basis for future mechanistic studies and therapy development.
HUMAN MOLECULAR GENETICS
(2023)
Article
Clinical Neurology
Vinojini Vivekanandam, Karen Seutterlin, Emma Matthews, John Thornton, Dipa Jayaseelan, Sachit Shah, Jasper M. Morrow, Tarek Yousry, Michael G. Hanna
Summary: This study performed muscle MRI in patients with periodic paralyses and correlated it with clinical features. The results showed intramuscular fat accumulation in the muscles of patients with periodic paralysis, which may be helpful in detecting early muscle involvement. The study highlights the importance of muscle MRI as a potential biomarker in assessing disease progression and in clinical trials.
Article
Clinical Neurology
Anna Sarkozy, Mario Sa, Deborah Ridout, Miguel Angel Fernandez-Garcia, Maria Grazia Distefano, Marion Main, Jennie Sheehan, Adnan Y. Manzur, Pinki Munot, Stephanie Robb, Elizabeth Wraige, Rosaline Quinlivan, Mariacristina Scoto, Giovanni Baranello, Vasantha Gowda, Rachael Mein, Rahul Phadke, Heinz Jungbluth, Francesco Muntoni
Summary: This study provides long-term data on the natural history of RYR1-related myopathies, with a focus on dominant and recessive forms of the disease. The results suggest that recessive patients have more severe clinical presentations, respiratory outcomes, and feeding outcomes compared to dominant patients. However, the longitudinal analysis indicates a slower progression of motor and respiratory function in recessive patients.
Review
Clinical Neurology
Emma Matthews, Jacqueline Palace, Sithara Ramdas, Valeria Sansone, Martin Tristani-Firouzi, Savine Vicart, Tracey Willis
Summary: Significant progress has been made in the field of pediatric skeletal muscle channelopathies, leading to a broader understanding of clinical presentations and new phenotypes. However, there is a lack of data on epidemiology, natural history, and treatment efficacy, resulting in a lack of best practice care recommendations. Holistic management, including addressing work, education, activity, and additional symptoms, is important, and there is an urgent need for high-quality data on prevalence, burden, and optimal treatment.
PEDIATRIC NEUROLOGY
(2023)
Article
Clinical Neurology
Jordan Poulos, Martin Samuels, Jacqueline Palace, David Beeson, Stephanie Robb, Sithara Ramdas, Samantha Chan, Pinki Munot
Summary: This study presents a retrospective analysis of respiratory outcomes in a cohort of 40 genetically confirmed cases of congenital myasthenic syndromes. The findings provide key respiratory markers and insights for early diagnosis and respiratory management of this rare neuromuscular disorder.
BRAIN COMMUNICATIONS
(2023)