Article
Cell Biology
Ege Sarikaya, Nesrin Sabha, Jonathan Volpatti, Emanuela Pannia, Nika Maani, Hernan D. Gonorazky, Alper Celik, Yijng Liang, Paula Onofre-Oliveira, James J. Dowling
Summary: XLMTM is a severe monogenetic disorder of the skeletal muscle caused by mutations in the MTM1 gene. A study of Mtm1 KO mice revealed age-associated changes in gene expression, mitochondrial function, myofiber size, and key molecular markers, providing important insights into the disease pathomechanisms.
DISEASE MODELS & MECHANISMS
(2022)
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
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
Stacha F. Reumers, Frederik Braun, Jennifer E. Spillane, Johann Boehm, Maartje Pennings, Meyke Schouten, Anneke J. van der Kooi, A. Reghan Foley, Carsten G. Boennemann, Erik-jan Kamsteeg, Corrie E. Erasmus, Ulrike Schara-Schmidt, Heinz Jungbluth, Nicol C. Voermans
Summary: The study found a higher prevalence of manifesting XL-MTM carriers, mostly with a mild phenotype and a variety of symptoms, including fatigue and exercise intolerance. Manifesting carriers are particularly impacted by fatigue, pain, and reduced quality of life compared to nonmanifesting carriers.
Article
Biochemistry & Molecular Biology
Polina Chausova, Aysylu Murtazina, Anna Stepanova, Artem Borovicov, Valeriia Kovalskaia, Nina Ryadninskaya, Alena Chukhrova, Oxana Ryzhkova, Aleksander Poliakov
Summary: This study presents a case of X-linked centronuclear myopathy in a female carrier with a pathogenic c.1261-10A>G variant in the MTM1 gene.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Clinical Neurology
Danielle K. Franken, Karlijn Bouman, Stacha F. I. Reumers, Frederik Braun, Jennifer Spillane, Maartje Pennings, Saskia L. S. Houwen, Corrie E. Erasmus, Ulrike Schara-Schmidt, Erik-Jan Kamsteeg, Heinz Jungbluth, Nicol C. Voermans
Summary: This study investigated the clinical spectrum of neuromuscular features in X-linked myotubular myopathy (XL-MTM) carriers. The results showed that 52% of carriers exhibited muscle weakness, with some cases previously being misclassified. These findings are important for understanding the neuromuscular manifestations of XL-MTM carrier state and for future clinical trials.
Article
Multidisciplinary Sciences
Paula Samso, Philipp A. Koch, York Posor, Wen-Ting Lo, Hassane Belabed, Marc Nazare, Jocelyn Laporte, Volker Haucke
Summary: X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies. This study shows that defective focal adhesions and reduced active beta-integrin surface levels in XLCNM can be rescued by loss of PI3KC2 beta function. The researchers also demonstrate the unknown role of PI3KC2 beta in the endocytic trafficking of active beta 1-integrins, providing a potential treatment option for XLCNM patients.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Genetics & Heredity
Adele D'Amico, Antonella Longo, Fabiana Fattori, Michele Tosi, Luca Bosco, Maria Beatrice Chiarini Testa, Giovanna Paglietti, Claudio Cherchi, Adelina Carlesi, Irene Mizzoni, Enrico Bertini
Summary: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the MTM1 gene. Male patients typically present with severe symptoms at birth, requiring intensive care, and long-term survivors often depend on ventilators and feeding tubes, with possible additional organ involvement. Various therapeutic strategies are being investigated for XLMTM.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Rheumatology
Samuel Hawley, Nick J. Shaw, Antonella Delmestri, Daniel Prieto-Alhambra, Cyrus Cooper, Rafael Pinedo-Villanueva, M. Kassim Javaid
Summary: XLH patients have a higher risk of mental illness and are more likely to experience deprivation compared to matched controls. This may have implications for clinical practice guidelines and health care provision for XLH patients.
Article
Clinical Neurology
James J. Dowling, Wolfgang Mueller-Felber, Barbara K. Smith, Carsten G. Bonnemann, Nancy L. Kuntz, Francesco Muntoni, Laurent Servais, Lindsay N. Alfano, Alan H. Beggs, Deborah A. Bilder, Astrid Blaschek, Tina Duong, Robert J. Graham, Minal Jain, Michael W. Lawlor, Jun Lee, Julie Coats, Charlotte Lilien, Linda P. Lowes, Victoria MacBean, Sarah Neuhaus, Mojtaba Noursalehi, Teresa Pitts, Caroline Finlay, Sarah Christensen, Gerrard Rafferty, Andreea M. Seferian, Etsuko Tsuchiya, Emma S. James, Weston Miller, Bryan Sepulveda, Maria Candida Vila, Suyash Prasad, Salvador Rico, Perry B. Shieh
Summary: This study characterized the neuromuscular, respiratory, and extramuscular burden of X-linked myotubular myopathy (XLMTM) and found that it causes respiratory, motor, and feeding difficulties as well as early death. Additionally, hepatobiliary disease was identified as an under-recognized comorbidity.
JOURNAL OF NEUROMUSCULAR DISEASES
(2022)
Review
Biochemistry & Molecular Biology
Maria Derkaczew, Piotr Martyniuk, Robert Hofman, Krzysztof Rutkowski, Adam Osowski, Joanna Wojtkiewicz
Summary: Myo-inositol and its derivatives play important roles in intracellular processes and mutations can lead to various disorders. This review provides an in-depth analysis of the influence of phosphatidylinositols and their phosphates on diseases, emphasizing the need for further research on myo-inositol.
Article
Cell & Tissue Engineering
Liani G. Devito, Valentina M. Lionello, Francesco Muntoni, Francesco Saverio Tedesco, Lyn Healy
Summary: Centronuclear myopathies (CNMs) are rare inherited muscle disorders with abnormal position of the nucleus in muscle fibers. X-Linked Myotubular Myopathy (XLMTM) is a type of CNM caused by mutations in the MTM1 gene, leading to severe muscle hypotonia and weakness, as well as bulbar and respiratory involvement. In this study, an iPSC line derived from a severe XLMTM patient was generated, providing a valuable model for disease study and therapy development.
STEM CELL RESEARCH
(2023)
Article
Clinical Neurology
Jeremy M. Neese, Sabrina Yum, Susan Matesanz, Leslie J. Raffini, Hilary B. Whitworth, Kathleen M. Loomes, Oscar H. Mayer, Alicia M. Alcamo
Summary: X-linked myotubular myopathy is a rare congenital muscular disease characterized by severe muscle weakness and respiratory difficulties. Patients may also experience chronic respiratory insufficiency, reliance on feeding tubes, and in rare cases, vitamin K deficiency leading to bleeding and coagulation abnormalities.
NEUROMUSCULAR DISORDERS
(2021)
Article
Clinical Neurology
Andrea Gangfuss, Dirk Schmitt, Andreas Roos, Frederik Braun, Melanie Annoussamy, Laurent Servais, Ulrike Schara-Schmidt
Summary: X-linked myotubular myopathy (XLMTM) is a rare life-threatening neuromuscular disease caused by pathogenic variants in the MTM1 gene, with a wide phenotypic spectrum and no available curative therapy. German XLMTM patients appear to be more severely affected, with potential delays in diagnosis indicating a need for specialized treatment centers.
JOURNAL OF NEUROMUSCULAR DISEASES
(2021)
Article
Multidisciplinary Sciences
Ji Hyun Kim, Seon Hee Lim, Ji Yeon Song, Myung Hyun Cho, HyeSun Hyun, Eun Mi Yang, Jung Won Lee, Min Hyun Cho, Min Ji Park, Joo Hoon Lee, Jiwon Jung, Kee Hwan Yoo, Kyung Mi Jang, Ki Soo Pai, Jin-Soon Suh, Mee Kyung Namgoong, Woo Yeong Chung, Su Jin Kim, Eun Young Cho, Kyung Min Kim, Nam Hee Kim, Minsun Kim, Jin Ho Paik, Hee Gyung Kang, Yo Han Ahn, Hae Il Cheong
Summary: In this study, the genotype-phenotype correlation was analyzed in 216 Korean patients with X-linked Alport syndrome. It was found that male patients had a higher risk of kidney failure and sensorineural hearing loss compared to female patients. The study supports the presence of genotype-phenotype correlation in both male and female patients with XLAS.
SCIENTIFIC REPORTS
(2023)
Article
Anesthesiology
Thomas Poulard, Damien Bachasson, Quentin Fosse, Marie-Cecile Nierat, Jean-Yves Hogrel, Alexandre Demoule, Jean-Luc Gennisson, Martin Dres
Summary: This study investigated the relationship between diaphragm thickening fraction and transdiaphragmatic pressure. The results showed a weak correlation between the two variables, both globally and within individuals. Therefore, diaphragm thickening fraction should not be used to evaluate diaphragm function in healthy individuals or mechanically ventilated patients.
Article
Biotechnology & Applied Microbiology
Hugh J. McMillan, Crystal M. Proud, Michelle A. Farrar, Ian E. Alexander, Francesco Muntoni, Laurent Servais
Summary: Gene therapy for spinal muscular atrophy (SMA) is a significant advancement in the treatment of neurologic diseases. Onasemnogene abeparvovec, a one-time gene replacement therapy, has shown improved survival and motor milestones for SMA patients. However, gene therapy is still in its early stages and faces challenges in transgene delivery.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2022)
Article
Pharmacology & Pharmacy
Theodora Markati, Gemma Fisher, Sithara Ramdas, Laurent Servais
Summary: In this review, the authors critically evaluate the role of risdiplam in the treatment of spinal muscular atrophy (SMA). They provide an overview of the current market for SMA, discuss the mechanism of action and pharmacological properties of risdiplam, and present the results from phase 2/3 clinical trials. The authors conclude that risdiplam has shown efficacy and a satisfactory safety profile in pivotal trials for different types of SMA.
EXPERT OPINION ON INVESTIGATIONAL DRUGS
(2022)
Article
Clinical Neurology
Irina T. Zaharieva, Mariacristina Scoto, Karolina Aragon-Gawinska, Deborah Ridout, Bruno Doreste, Laurent Servais, Francesco Muntoni, Haiyan Zhou
Summary: Blood microRNAs could serve as biomarkers to indicate the response of SMA patients to nusinersen treatment and monitor the efficacy of the intervention.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2022)
Article
Clinical Neurology
Tamara Dangouloff, Mickael Hiligsmann, Nicolas Deconinck, Adele D'Amico, Andreea M. Seferian, Francois Boemer, Laurent Servais
Summary: This study aims to compare the societal financial costs and quality of life (QoL) between untreated patients with spinal muscular atrophy (SMA) and treated patients identified by symptoms or early testing. The results show that the total costs are lower for untreated patients, but lower for patients identified by early testing. Early patient identification and treatment can reduce the overall societal costs of SMA.
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Kevin A. Strauss, Michelle A. Farrar, Francesco Muntoni, Kayoko Saito, Jerry R. Mendell, Laurent Servais, Hugh J. McMillan, Richard S. Finkel, Kathryn J. Swoboda, Jennifer M. Kwon, Craig M. Zaidman, Claudia A. Chiriboga, Susan T. Iannaccone, Jena M. Krueger, Julie A. Parsons, Perry B. Shieh, Sarah Kavanagh, Melissa Wigderson, Sitra Tauscher-Wisniewski, Bryan E. McGill, Thomas A. Macek
Summary: Onasemnogene abeparvovec was effective and well tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.
Review
Clinical Neurology
Angus Livingstone, Laurent Servais, Dominic J. C. Wilkinson
Summary: In the past decade, crowdfunding has become a common way to raise funds for the treatment of rare disorders. However, it also raises ethical concerns. This review focuses on the ethical challenges crowdfunding poses in pediatric neurology, using gene therapy for spinal muscular atrophy as an example. The article discusses the responsibilities of physicians and suggests actions that can be taken to reduce harms.
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY
(2023)
Review
Biochemistry & Molecular Biology
Laurane Mackels, Xincheng Liu, Gisele Bonne, Laurent Servais
Summary: Human TOR1AIP1 encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various human diseases. Mutations in TOR1AIP1 is associated with diseases such as muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease. Understanding LAP1 and mutant TOR1AIP1-associated phenotypes is crucial for therapeutic development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Manon Hustinx, Ann-Marie Shorrocks, Laurent Servais
Summary: The management of inherited neuropathies mostly relies on symptomatic treatment, but in recent years, disease-modifying therapies have been developed due to a better understanding of the pathogenic mechanisms. This systematic review focuses on the therapies emerged in the field of inherited neuropathies in the past five years. The analysis identified diseases associated with neuropathy for which approved therapies exist, but further investigations are needed to assess treatment efficacy on neuropathies using objective and consistent methods.
Review
Health Care Sciences & Services
Seya Colloud, Thomas Metcalfe, Scott Askin, Shibeshih Belachew, Johannes Ammann, Ernst Bos, Timothy Kilchenmann, Paul Strijbos, Damien Eggenspieler, Laurent Servais, Chloe Garay, Athanasios Konstantakopoulos, Armin Ritzhaupt, Thorsten Vetter, Claudia Vincenzi, Francesca Cerreta
Summary: Digital health technology tools (DHTTs) offer opportunities for innovation, patient care improvement, shortened clinical trials, and reduced risk in medicines development. This review presents four case studies highlighting the regulatory requirements and the need for increased collaboration between stakeholders. The complexity of interactions, combined with unique challenges related to DHTTs, is addressed. These case studies provide insight into the regulatory approach and propose potential solutions for sponsors.
NPJ DIGITAL MEDICINE
(2023)
Letter
Biochemistry & Molecular Biology
Laurent Servais, Damien Eggenspieler, Margaux Poleur, Marc Grelet, Francesco Muntoni, Paul Strijbos, Melanie Annoussamy
Review
Genetics & Heredity
Karolina Aragon-Gawinska, Charlotte Mouraux, Tamara Dangouloff, Laurent Servais
Summary: Early treatment in spinal muscular atrophy has a significant impact on patient prognosis, and the results vary depending on the number of SMN2 copies and the initial neurological status of the patient.
Article
Pediatrics
Miranda Rogers, Stephane Motola, Yacine Bechichi, Celine Cluzeau, Tanguy Terray, Allyson Berent, Jennifer Panagoulias, Jessica Duis, Damien Eggenspieler, Laurent Servais, Mario Mastrangelo
Summary: This study explores the motor-related features, influencing factors, and impact on patients and caregivers in Angelman syndrome (AS) through interviews with 24 caregivers. The study found that gait, walking, and stair-climbing were the most severely impacted motor features, with half of the caregivers ranking motor symptoms as one of the most burdensome. Caregivers mentioned physical therapy, motivation, medical management, and age as factors influencing motor function in AS, and highlighted the effects of impaired motor function on both patients and caregivers.
Article
Clinical Neurology
Magali Ngawa, Fabian Dal Farra, Andrei-Dan Marinescu, Laurent Servais
Summary: Spinal muscular atrophy (SMA) is caused by a mutation in the SMN1 gene. Recent drug approvals have extended the life expectancy of SMA patients. This study aimed to assess the psychomotor development of treated SMA patients. The results showed that patients treated before symptom onset had better motor scores compared to those treated after symptom onset. The study highlights the importance of considering intellectual development as an outcome in treated SMA patients. Rating: 8/10.
THERAPEUTIC ADVANCES IN NEUROLOGICAL DISORDERS
(2023)
Review
Pharmacology & Pharmacy
Gemma Fisher, Laurane Mackels, Theodora Markati, Anna Sarkozy, Julien Ochala, Heinz Jungbluth, Sithara Ramdas, Laurent Servais
Summary: The article explores experimental treatments for nemaline myopathies, identifying at least eleven mainly pre-clinical approaches using murine and/or human muscle cells. These approaches target various aspects including the causative gene, pathophysiologically relevant mechanisms, myogenesis, and other therapies to improve muscle function. The wide range of experimental therapies shows promise for the treatment of nemaline myopathies, but challenges in clinical translation still exist.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2022)