Article
Cell Biology
Carissa M. Feliciano, Kenneth Wu, Hannah L. Watry, Chiara B. E. Marley, Gokul N. Ramadoss, Hana Y. Ghanim, Angela Z. Liu, Lyandysha Zholudeva, Todd C. McDevitt, Mario A. Saporta, Bruce R. Conklin, Luke M. Judge
Summary: Many neuromuscular disorders are caused by dominant missense mutations, for which effective treatments are lacking. Targeted inactivation of disease alleles through gene editing shows promise as a therapeutic approach for these dominant diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Marina Stavrou, Irene Sargiannidou, Elena Georgiou, Alexia Kagiava, Kleopas A. Kleopa
Summary: CMT disease is a genetically heterogeneous disorder affecting the peripheral nerves, with diverse molecular genetic mechanisms discovered over the past three decades. There are currently various treatment approaches in preclinical testing and clinical trials, including disease-specific targeted therapies and treatments targeting common pathways shared by different CMT types. As promising treatments advance to clinical translation, optimizing outcome measures, novel biomarkers, and appropriate trial designs are crucial to facilitate successful testing and validation of novel treatments for CMT patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Cara R. Schiavon, Gerald S. Shadel, Uri Manor
Summary: CMT disease is a progressive, inherited neurological disorder associated with mutations in at least 80 different genes. Clinical manifestations typically involve peripheral neurons, with some mutations potentially leading to mitochondrial mobility defects, suggesting a common underlying disease mechanism.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Clinical Neurology
Rafael Sivera, Vincenzo Lupo, Marina Frasquet, Herminia Argente-Escrig, Jorge Alonso-Perez, Jordi Diaz-Manera, Luis Querol, Maria del Mar Garcia-Romero, Samuel Ignacio Pascual, Tania Garcia-Sobrino, Carmen Paradas, Juan Francisco Vazquez-Costa, Nuria Muelas, Elvira Millet, Juan Jesus Vilchez, Carmen Espinos, Teresa Sevilla
Summary: This study identified 15 patients with CMT2Z caused by MORC2 mutations in Spain, with most exhibiting a scapuloperoneal phenotype and a few showing a neurodevelopmental phenotype. The findings suggest a diverse spectrum of disease characteristics and clinical presentations.
EUROPEAN JOURNAL OF NEUROLOGY
(2021)
Article
Neurosciences
Mariapaola Sidoli, Chelsey B. Reed, Cristina Scapin, Pablo Paez, Douglas R. Cavener, Randal J. Kaufman, Maurizio D'Antonio, M. Laura Feltri, Lawrence Wrabetz
Summary: Despite the interaction between Perk and calcineurin in P0S63del nerves, Perk deletion paradoxically improved S63del myelin defects. Additionally, genetic manipulation of calcineurin subunits showed context-dependent protective or toxic effects in S63del, suggesting high sensitivity of Schwann cells to alterations in calcineurin activity.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Clinical Neurology
Young Hee Kim, Byeol-A Yoon, Young Rae Jo, Soo Hyun Nam, Nam Hee Kim, Kyoung Hee Kim, Jong Kuk Kim, Byung-Ok Choi, Hwan Tae Park
Summary: The plasma concentration of NCAM1 is specifically increased in demyelinating subtypes of CMT, indicating that it may serve as a surrogate biomarker for pathological Schwann cell status and disease progression.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Review
Genetics & Heredity
Yuji Okamoto, Hiroshi Takashima
Summary: Charcot-Marie-Tooth disease (CMT) is the most common genetically transmitted neuromuscular condition without effective pharmacological treatments. The genetic heterogeneity of CMT poses a significant barrier to comprehensive therapies. This review discusses prospective therapeutic strategies for common CMT variants and evaluates the progress in gene therapy techniques, which have the potential to advance future research.
Review
Pharmacology & Pharmacy
Karen Libberecht, Tim Vangansewinkel, Ludo Van Den Bosch, Ivo Lambrichts, Esther Wolfs
Summary: This article reviews the role of protein quality control systems in CMT1 and introduces potential treatment strategies to restore proteostasis.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Clinical Neurology
Adriana P. Rebelo, Andrea Cortese, Amit Abraham, Yael Eshed-Eisenbach, Gal Shner, Anna Vainshtein, Elena Buglo, Vladimir Camarena, Gabriel Gaidosh, Ramin Shiekhattar, Lisa Abreu, Steve Courel, Dennis K. Burns, Yunhong Bai, Chelsea Bacon, Shawna M. E. Feely, Diana Castro, Elior Peles, Mary M. Reilly, Michael E. Shy, Stephan Zuchner
Summary: The CADM family of proteins mediate direct contact and interaction between axons and glia, with mutations in CADM3 potentially causing abnormal axon-glia interaction and disease manifestation in CMT patients.
Article
Clinical Neurology
Marta Bellofatto, Luca Gentile, Alessandro Bertini, Irene Tramacere, Fiore Manganelli, Gian Maria Fabrizi, Angelo Schenone, Lucio Santoro, Tiziana Cavallaro, Marina Grandis, Stefano Previtali, Marina Scarlato, Isabella Allegri, Luca Padua, Costanza Pazzaglia, Flavio Villani, Eleonora Cavalca, Paola Saveri, Aldo Quattrone, Paola Valentino, Stefano Tozza, Massimo Russo, Anna Mazzeo, Giuseppe Vita, Sylvie Piacentini, Giuseppe Didato, Chiara Pisciotta, Davide Pareyson, CMT Network
Summary: This study investigated the presence of sleep abnormalities in Charcot-Marie-Tooth disease (CMT) patients and their correlation with disease severity and characteristics. The results showed that CMT patients had poor sleep quality and daytime somnolence, which were associated with anxiety, depression, and fatigue.
JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
Elena Abati, Stefania Magri, Megi Meneri, Giulia Manenti, Daniele Velardo, Francesca Balistreri, Chiara Pisciotta, Paola Saveri, Nereo Bresolin, Giacomo Pietro Comi, Dario Ronchi, Davide Pareyson, Franco Taroni, Stefania Corti
Summary: This study identified two cases of biallelic HSPB1 p.S135F and p.R136L mutations in two families, confirming their association with severe CMT2F/dHMN and a strictly dominant inheritance pattern.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2021)
Article
Clinical Neurology
Marta Bellofatto, Alessandro Bertini, Irene Tramacere, Fiore Manganelli, Gian Maria Fabrizi, Angelo Schenone, Lucio Santoro, Tiziana Cavallaro, Marina Grandis, Stefano C. Previtali, Yuri Falzone, Isabella Allegri, Luca Padua, Costanza Pazzaglia, Daniela Calabrese, Paola Saveri, Aldo Quattrone, Paola Valentino, Stefano Tozza, Luca Gentile, Massimo Russo, Anna Mazzeo, Giuseppe Vita, Sylvie Piacentini, Chiara Pisciotta, Davide Pareyson
Summary: This study investigated fatigue in CMT patients and found that 36% of the patients experienced abnormal fatigue. Abnormal fatigue was correlated with disease severity, anxiety, depression, sleepiness, and obesity. Therefore, the management of CMT patients should involve treating fatigue and addressing other factors such as anxiety, depression, sleepiness, and obesity.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
Marta Bellofatto, Alessandro Bertini, Irene Tramacere, Fiore Manganelli, Gian Maria Fabrizi, Angelo Schenone, Lucio Santoro, Tiziana Cavallaro, Marina Grandis, Stefano C. Previtali, Yuri Falzone, Isabella Allegri, Luca Padua, Costanza Pazzaglia, Daniela Calabrese, Paola Saveri, Aldo Quattrone, Paola Valentino, Stefano Tozza, Luca Gentile, Massimo Russo, Anna Mazzeo, Giuseppe Vita, Sylvie Piacentini, Chiara Pisciotta, Davide Pareyson
Summary: This study investigated the presence of fatigue and its correlations in Charcot-Marie-Tooth disease (CMT). The results showed that 36% of the patients had abnormal fatigue, which was correlated with disease severity, anxiety, depression, sleepiness, and obesity. Therefore, the management of CMT patients should include treatment for fatigue and its different generators.
EUROPEAN JOURNAL OF NEUROLOGY
(2022)
Review
Clinical Neurology
Eppie M. Yiu, Paula Bray, Jonathan Baets, Steven K. Baker, Nina Barisic, Katy de Valle, Timothy Estilow, Michelle A. Farrar, Richard S. Finkel, Jana Haberlova, Rachel A. Kennedy, Isabella Moroni, Garth A. Nicholson, Sindhu Ramchandren, Mary M. Reilly, Kristy Rose, Michael E. Shy, Carly E. Siskind, Sabrina W. Yum, Manoj P. Menezes, Monique M. Ryan, Joshua Burns
Summary: This study aims to develop evidence and consensus-based clinical management guidelines for children with CMT, and provides practical and implementable guidance for improving access to multidisciplinary care.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Article
Clinical Neurology
Christopher P. Ptak, Tabitha A. Peterson, Jesse B. Hopkins, Christopher A. Ahern, Michael E. Shy, Robert C. Piper
Summary: Mutations in MPZ can cause various neurological disorders, and the study focuses on understanding how MPZ functions and forms oligomeric assemblies.
Article
Biochemistry & Molecular Biology
Phu Duong, Ki H. Ma, Raghu Ramesh, John J. Moran, Seongsik Won, John Svaren
Summary: The study indicates that H3K27 demethylation is not necessary for the induction of injury response genes in Schwann cells, suggesting other mechanisms may be involved in activating Polycomb-repressed injury genes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Genetics & Heredity
Bianca R. Grosz, John Svaren, Gonzalo Perez-Siles, Garth A. Nicholson, Marina L. Kennerson
Summary: This study assessed the IRES activity of the human GJB1 5' UTR and found no significant differences in expression levels between the wild-type UTR and the UTR with the c.-103C > T mutation, suggesting an alternate pathogenic mechanism for this non-coding mutation.
Article
Multidisciplinary Sciences
Hye-Jin Park, Eric Tsai, Dennis Huang, Michael Weaver, Luciana Frick, Ace Alcantara, John J. Moran, Julia Patzig, Carmen V. Melendez-Vasquez, Gerald R. Crabtree, M. L. Feltri, John Svaren, Patrizia Casaccia
Summary: In response to external signals, cells use the protein ACTL6A to integrate axonal caliber recognition with the process of myelination in peripheral nerves, ensuring proper nerve function.
Article
Biochemistry & Molecular Biology
Francesca A. Veneri, Valeria Prada, Rosa Mastrangelo, Cinzia Ferri, Lucilla Nobbio, Mario Passalacqua, Maria Milanesi, Francesca Bianchi, Ubaldo Del Carro, Jean-Michel Vallat, Phu Duong, John Svaren, Angelo Schenone, Marina Grandis, Maurizio D'Antonio
Summary: This study investigates the impact of misglycosylation on the functionality of P0, the major structural glycoprotein of peripheral nerve myelin. Through the use of CRISPR/Cas9, a mouse model carrying the MPZ(D61N) mutation was generated to mimic the severe early-onset form of CMT1B seen in humans. The findings suggest that hyperglycosylation interferes with myelin formation and leads to motor impairment and other pathological changes.
HUMAN MOLECULAR GENETICS
(2022)
Article
Immunology
Amanda Contreras, Darin L. Wiesner, Brock Kingstad-Bakke, Woojong Lee, John P. Svaren, Bruce S. Klein, M. Suresh
Summary: This study investigated the role of Bach2 in regulating Treg homeostasis and effector functions in peripheral Tregs. The results suggest that Bach2 plays vital roles in limiting the premature differentiation of Tregs into effector Tregs in lymphoid tissues and restraining Type 2 inflammation in the lungs. The findings of this study highlight the importance of dysregulated Tregs in the pathogenesis of airway hypersensitivities, asthma, and other allergic disorders.
JOURNAL OF IMMUNOLOGY RESEARCH
(2022)
Article
Clinical Neurology
Menelaos Pipis, Seongsik Won, Roy Poh, Stephanie Efthymiou, James M. Polke, Mariola Skorupinska, Julian Blake, Alexander M. Rossor, John J. Moran, Pinki Munot, Francesco Muntoni, Matilde Laura, John Svaren, Mary M. Reilly
Summary: CMT1A is the most common form of inherited neuropathy, characterized by early onset progressive weakness and sensory loss, caused by duplication of the PMP22 gene. The study indirectly demonstrates that microRNA miR-29a represses the expression of PMP22, and loss of this effect can lead to more severe disease.
Article
Neurosciences
Phu Duong, Raghu Ramesh, Andrew Schneider, Seongsik Won, Aaron J. J. Cooper, John Svaren
Summary: Schwann cell programming during myelination involves activation of gene expression and repression of neural crest/embryonic differentiation genes. The loss of EED subunit of PRC2 leads to inappropriate gene activation and premature activation of the nerve injury program. The H2AK119 deubiquitinase Bap1 is required for myelin homeostasis and restriction of polycomb-associated histone modifications in Schwann cells.
Meeting Abstract
Clinical Neurology
Silvia Cipriani, Emanuela Porrello, Roberta Di Guardo, Matteo Cerea, Amanda Heslegrave, Phu Duong, John Svaren, Stefano Previtali, Alessandra Bolino
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Meeting Abstract
Clinical Neurology
Mehdi Momen, Emily Binversie, Lauren Baker, Jordan Gruel, Margaret Patterson, Alexander Chu, Ryan Anderson, Nyah Kohler, Kearney Hannah, John Svaren, Peter Muir, Susannah Sample
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Meeting Abstract
Clinical Neurology
Mehdi Momen, Emily Binversie, Lauren Baker, Jordan Gruel, Margaret Patterson, Alexander Chu, Ryan Anderson, Nyah Kohler, Kearney Hannah, John Svaren, Peter Muir, Susannah Sample
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Meeting Abstract
Clinical Neurology
Emma Nicolaisen, Mary Reilly, John Svaren, Steven Scherer, Davide Pareyson, David Herrmann, Michael Shy
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Meeting Abstract
Clinical Neurology
Emma Nicolaisen, Xingyao Wu, Valeria Prada, Sydney Stork, Nidia Villalpando, Riccardo Zuccarino, Yunhong Bai, John Moran, Seongsik Won, Phu Duong, Alexander Rossor, Mary Reilly, Maurizio D'Antonio, Michael Shy, John Svaren
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Meeting Abstract
Clinical Neurology
Raghu Ramesh, Yanti Manurung, Todd Blakely, Ki Ma, Seongsik Won, Eugene Wyatt, Rajeshwar Awatramani, John Svaren
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Meeting Abstract
Clinical Neurology
Thierry Touvier, Francesca Veneri, Anke Claessens, Cinzia Ferri, Rosa Mastrangelo, Ubaldo Del Carro, Christina Barkauskas, Laurie Glimcher, Randal J. Kaufman, Phu Duong, John Svaren, Michael Shy, Lawrence Wrabetz, Maurizio D'Antonio
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2022)
Article
Chemistry, Medicinal
Natalia J. Martinez, John C. Braisted, Patricia K. Dranchak, John J. Moran, Hunter Larson, Bryan Queme, Evgenia Pak, Amalia Dutra, Ganesha Rai, Ken Chih-Chien Cheng, John Svaren, James Inglese
Summary: CMT1A is characterized by genetic duplication of the myelin gene PMP22, leading to abnormal Schwann cell differentiation and muscle wasting. A screening platform using genome editing and high-throughput screening identified compounds that reduce PMP22 transcript levels, potentially offering new therapeutic approaches for CMT1A.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2021)