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)
Review
Clinical Neurology
Miaomiao Ma, Yao Li, Shimiao Dai, Ming Chu, Litao Sun, Longjian Liu, Ji-Chang Zhou
Summary: Charcot-Marie-Tooth disease and related inherited peripheral neuropathies (CMT & RIPNs) cause significant suffering and burden to patients, but there is a lack of comprehensive understanding of their global prevalence rates. Further epidemiological studies with well-defined diagnostic criteria are needed to improve the assessment of prevalence and raise awareness for better healthcare support.
JOURNAL OF NEUROLOGY
(2023)
Article
Biology
Chiara Gemelli, Alessandro Geroldi, Sara Massucco, Lucia Trevisan, Ilaria Callegari, Lucio Marinelli, Giulia Ursino, Mehrnaz Hamedani, Giulia Mennella, Silvia Stara, Giovanni Maggi, Laura Mori, Cristina Schenone, Fabio Gotta, Serena Patrone, Alessia Mammi, Paola Origone, Valeria Prada, Lucilla Nobbio, Paola Mandich, Angelo Schenone, Emilia Bellone, Marina Grandis
Summary: This study presents the results of a CMT clinic in Italy, showing that CMT1A is the most common subtype and HSPB1 and MPZ genes are related to a distinct phenotype.
Review
Clinical Neurology
Brett A. McCray, Steven S. Scherer
Summary: Inherited peripheral neuropathies are a group of genetically and phenotypically diverse disorders that result in degeneration of peripheral neurons, leading to sensory and motor dysfunction. Recent research has identified common pathological mechanisms among these diseases, including defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation. These insights have informed emerging treatment strategies for inherited neuropathies, offering promising therapeutic opportunities.
Article
Clinical Neurology
Alessandro Bertini, Fiore Manganelli, Gian Maria Fabrizi, Angelo Schenone, Lucio Santoro, Tiziana Cavallaro, Matteo Tagliapietra, Marina Grandis, Stefano Carlo Previtali, Yuri Matteo Falzone, Isabella Allegri, Luca Padua, Costanza Pazzaglia, Irene Tramacere, Eleonora Cavalca, Paola Saveri, Andrea Quattrone, Paola Valentino, Stefano Tozza, Luca Gentile, Massimo Russo, Anna Mazzeo, Giuseppe Vita, Valeria Prada, Riccardo Zuccarino, Francesco Ferraro, Chiara Pisciotta, Davide Pareyson, Italian CMT Network
Summary: This study investigated the use, benefits, and tolerance of shoe inserts, orthopaedic shoes, and ankle-foot orthoses (AFOs) in Charcot-Marie-Tooth disease (CMT) patients. The results showed that although most patients were prescribed these devices, there was a low usage rate and high rates of complications and emotional distress, leading to reduced use of AFOs. Thus, a patient-oriented and multidisciplinary approach to orthoses prescription should be encouraged.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2023)
Article
Clinical Neurology
Silvia Cipriani, Marta Guerrero-Valero, Stefano Tozza, Edward Zhao, Veith Vollmer, Danique Beijer, Matt Danzi, Cristina Rivellini, Dejan Lazarevic, Giovanni Battista Pipitone, Bianca Rose Grosz, Costanza Lamperti, Stefania Bianchi Marzoli, Paola Carrera, Marcella Devoto, Chiara Pisciotta, Davide Pareyson, Marina Kennerson, Stefano C. Previtali, Stephan Zuchner, Steven S. Scherer, Fiore Manganelli, Martin Bahler, Alessandra Bolino
Summary: The study identified that novel or very rare variants in the MYO9B gene are associated with CMT2 and isolated OA. Functional studies showed that variants in MYO9B impair protein expression level and motor activity, indicating its essential role in peripheral and central nervous system axons.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
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
Clinical Neurology
Andrea Cortese, Riccardo Curro, Riccardo Ronco, Julian Blake, Alex M. Rossor, Enrico Bugiardini, Matilde Laura, Tom Warner, Tarek Yousry, Roy Poh, James Polke, Adriana Rebelo, Maike F. Dohrn, Mario Saporta, Henry Houlden, Stephan Zuchner, Mary M. Reilly
Summary: Mutations in the CRYAB gene have been associated with myofibrillar myopathy, dilated cardiomyopathy, and cataracts. This study reports peripheral neuropathy as a novel phenotype associated with CRYAB, particularly in cases with late onset CMT2 and congenital cataracts.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Health Care Sciences & Services
Jihyun Park, So Young Joo, Byung-Ok Choi, Dae-Hyun Kim, Jong Bum Park, Jong Weon Lee, Deog Young Kim
Summary: This study evaluated the characteristics of gait patterns in CMT1A patients and classified them according to disease severity. The results showed significant differences in gait parameters between CMT1A patients and healthy controls, as well as variations in gait patterns within different severity groups.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Article
Clinical Neurology
Luce Barbat du Closel, Nathalie Bonello-Palot, Yann Pereon, Andoni Echaniz-Laguna, Jean Philippe Camdessanche, Aleksandra Nadaj-Pakleza, Jean-Baptiste Chanson, Simon Frachet, Laurent Magy, Julien Cassereau, Pascal Cintas, Ariane Choumert, Perrine Devic, Sarah Leonard Louis, Robinson Gravier Dumonceau, Emilien Delmont, Emmanuelle Salort-Campana, Francoise Bouhour, Philippe Latour, Tanya Stojkovic, Shahram Attarian
Summary: This study investigated the clinical presentation of patients with CMTX1 and found that women usually have milder clinical symptoms compared to men. The study also identified two subgroups of women over the age of 48, with one group showing similar disease progression to men.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Biology
Hye Mi Kwon, Hyun Su Kim, Sang Beom Kim, Jae Hong Park, Da Eun Nam, Ah Jin Lee, Soo Hyun Nam, Soohyun Hwang, Ki Wha Chung, Byung-Ok Choi
Summary: Through studying Korean CMT families, it was found that mutations in the GNB4 gene can cause not only intermediate type CMT, but also demyelinating-type neuropathy. Patients with the p.Lys89Glu mutation exhibited distinct demyelinating pathologic features and abnormalities in muscle MRI. Therefore, these findings are helpful for the differential diagnosis of CMT patients with unknown GNB4 variants.
Article
Clinical Neurology
Menelaos Pipis, Andrea Cortese, James M. Polke, Roy Poh, Jana Vandrovcova, Matilde Laura, Mariola Skorupinska, Arnaud Jacquier, Raul Juntas-Morales, Philippe Latour, Philippe Petiot, Guilhem Sole, Yves Fromes, Sachit Shah, Julian Blake, Byung-Ok Choi, Ki Wha Chung, Tanya Stojkovic, Alexander M. Rossor, Mary M. Reilly
Summary: This study reveals the unique phenotype of CMT2CC, which is more similar to spinal muscular atrophy than classic CMT. The disease progresses rapidly, requiring wheelchair use at an early stage and exhibiting early ankle plantarflexion weakness in a significant portion of patients.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Review
Genetics & Heredity
Laura Morant, Maria-Luise Erfurth, Albena Jordanova
Summary: CMT is a common neuromuscular disorder, with aaRS mutations causing different subtypes and similar clinical manifestations. Drosophila models are valuable for studying the molecular pathways of CMT and testing candidate drugs.
Review
Genetics & Heredity
Paulius Palaima, Jose Berciano, Kristien Peeters, Albena Jordanova
Summary: Mutations in the LRSAM1 gene have been identified as the genetic cause of CMT2P, showing both dominant and recessive forms with slightly different characteristics. There is significant phenotypic variability in patients with CMT2P, necessitating serial clinical evaluation for correct diagnosis. LRSAM1 functions as a ubiquitin ligase in cells, playing a crucial role in the pathogenesis of CMT disease.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Cell Biology
Yingying Zhao, Liangguo Xie, Chao Shen, Qian Qi, Yicai Qin, Juan Xing, Dejian Zhou, Yun Qi, Zhiqiang Yan, Xinhua Lin, Rongyang Dai, Jinzhong Lin, Wei Yu
Summary: Mutations in GARS affect the deacetylation activity of SIRT2 on alpha-tubulin, leading to CMT neuropathies, while reducing SIRT2 can rescue the disease and extend lifespan.
Article
Genetics & Heredity
Allyn McConkie-Rosell, Kelly Schoch, Jennifer Sullivan, Rebecca C. Spillmann, Heidi Cope, Queenie K-G Tan, Christina G. S. Palmer, Stephen R. Hooper, Vandana Shashi
Summary: The Genome Empowerment Scale (GEmS) is a research tool to assess parents' perspectives on empowerment during exome or genome sequencing for children with undiagnosed disorders, with emotion-focused and action-oriented scales. The purpose of the study is to provide a strategy for interpreting GEmS results and present illustrative cases to guide genetic counseling for parents of children with undiagnosed conditions.
JOURNAL OF GENETIC COUNSELING
(2022)
Article
Genetics & Heredity
Jennefer N. Kohler, Emily G. Kelley, Brenna M. Boyd, Catherine H. Sillari, Shruti Marwaha, Matthew T. Wheeler
Summary: This study explores the roles of genetic counselors in the Undiagnosed Diseases Network research team and investigates their common tasks and professional fulfillment through surveys. The findings highlight that GCs primarily fulfill roles in clinical care, collaboration, and curation. Additionally, the study emphasizes the applicability of genetic counselors' unique skill set in a clinical translational research network.
JOURNAL OF GENETIC COUNSELING
(2022)
Article
Genetics & Heredity
Jennifer Schymick, Peter Leahy, Tina Cowan, Maura R. Z. Ruzhnikov, Ryan Gates, Liliana Fernandez, Gopal Pramanik, Vamsi Yarlagadda, Matthew Wheeler, Jonathan A. Bernstein, Gregory M. Enns, Chung Lee
Summary: Biallelic pathogenic variants in the TANGO2 gene can lead to a rare metabolic disorder with diverse clinical features and severity. Significant intrafamilial variability has been observed, highlighting the potential underrecognition of milder phenotypes.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Editorial Material
Neurosciences
Robert W. Burgess, Mario A. Saporta
Article
Genetics & Heredity
Suma P. Shankar, Kristin Grimsrud, Louise Lanoue, Alena Egense, Brandon Willis, Johanna Horberg, Lama AlAbdi, Klaus Mayer, Koray Utkur, Kristin G. Monaghan, Joel Krier, Joan Stoler, Maha Alnemer, Prabhu R. Shankar, Raffael Schaffrath, Fowzan S. Alkuraya, Ulrich Brinkmann, Leif A. Eriksson, Kent Lloyd, Katherine A. Rauen
Summary: This study identified DPH5 as a novel disease-causing gene associated with embryonic lethality and profound neurodevelopmental delays. The DPH5 variants were found to be related to craniofacial abnormalities, multisystem abnormalities, and miscarriages. Functional experiments demonstrated the impact of DPH5 mutations on protein structure and function.
GENETICS IN MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Scott Barish, Mumine Senturk, Kelly Schoch, Amanda L. Minogue, Diego Lopergolo, Chiara Fallerini, Jake Harland, Jacob H. Seemann, Nicholas Stong, Peter G. Kranz, Sujay Kansagra, Mohamad A. Mikati, Joan Jasien, Mays El-Dairi, Undiagnosed Diseases Network, Paolo Galluzzi, Francesca Ariani, Alessandra Renieri, Francesca Mari, Michael F. Wangler, Swathi Arur, Yong-Hui Jiang, Shinya Yamamoto, Vandana Shashi, Hugo J. Bellen
Summary: In this study, two individuals with intellectual disability, epilepsy, and dysmorphic features were found to carry damaging variants in the DROSHA gene. Functional studies in model organisms suggest that these variants have a severe impact on the nervous system.
HUMAN MOLECULAR GENETICS
(2022)
Article
Genetics & Heredity
Nicholas Borja, Stephanie Bivona, Le Shon Peart, Brittany Johnson, Joanna Gonzalez, Deborah Barbouth, Henry Moore, Shengru Guo, Guney Bademci, Mustafa Tekin
Summary: This article introduces the use of genome sequencing and RNA analysis to identify causative noncoding variants in patients with progressive neurologic diseases. By performing genome sequencing on two patients, researchers identified potential pathogenic variants and made definitive diagnoses based on clinical presentations.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2022)
Article
Neurosciences
Melanie J. Plastini, Haritha L. Desu, Maureen C. Ascona, Anna L. Lang, Mario A. Saporta, Roberta Brambilla
Summary: Multiple sclerosis (MS) is a common neurological disorder, and the underlying cause remains unknown. Dysfunction in oligodendrocytes (OLs) may contribute to the pathophysiology of the disease, especially in primary progressive MS (PPMS).
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Shashwat Deepali Nagar, Priscilla Pemu, Jun Qian, Eric Boerwinkle, Mine Cicek, Cheryl R. Clark, Elizabeth Cohn, Kelly Gebo, Roxana Loperena, Kelsey Mayo, Stephen Mockrin, Lucila Ohno-Machado, Andrea H. Ramirez, Sheri Schully, Ashley Able, Ashley Green, Stephan Zuchner, I. King Jordan, Robert Meller
Summary: The World Health Organization has defined hypertension and type 2 diabetes as modifiable comorbidities leading to dementia and Alzheimer's disease. In the United States, there are higher prevalence rates of hypertension and type 2 diabetes among Black and Hispanic minority groups, which may be associated with dementia disparities.
SCIENTIFIC REPORTS
(2022)
Review
Clinical Neurology
Mary M. Reilly, David N. Herrmann, Davide Pareyson, Steven S. Scherer, Richard S. Finkel, Stephan Zuechner, Joshua Burns, Michael E. Shy
Summary: Heritable neurological disorders provide insights into disease mechanisms, facilitating the development of novel therapeutic approaches. The challenges of measuring disease progression in rare and slowly progressive neurogenetic diseases are addressed through the development of clinical outcome assessments and disease biomarkers in inherited peripheral neuropathies. It is proposed that carefully developed biomarkers from imaging, plasma, or skin can predict meaningful progression in functional and patient-reported outcome assessments, enabling feasible clinical trials within a shorter duration for these rare and ultra-rare disorders.
ANNALS OF NEUROLOGY
(2023)
Article
Genetics & Heredity
Rebecca C. Spillmann, Queenie K. -G. Tan, Chloe Reuter, Kelly Schoch, Jennefer Kohler, Devon Bonner, Diane Zastrow, Anna Alkelai, Evan Baugh, Heidi Cope, Shruti Marwaha, Matthew T. Wheeler, Jonathan A. Bernstein, Vandana Shashi
Summary: Next-generation sequencing has transformed the diagnostic process for rare/ultrarare conditions. However, the diagnosis rates vary depending on the analytical pipelines. A dual analysis approach combining the expertise of core laboratories and clinical sites can improve both variant detection and prioritization.
GENETICS IN MEDICINE
(2023)
Article
Clinical Neurology
Tong Tong Wu, Richard S. S. Finkel, Carly E. E. Siskind, Shawna M. E. Feely, Joshua Burns, Mary M. M. Reilly, Francesco Muntoni, Timothy Estilow, Michael E. E. Shy, Sindhu Ramchandren
Summary: This study developed and validated the parent-proxy version of the pCMT-QOL outcome measure for children aged 8 to 18 with CMT, which is a reliable and valid measure of health-related QOL.
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2023)
Article
Clinical Neurology
Tong Tong Wu, Richard Finkel, Carly E. Siskind, Shawna M. E. Feely, Joshua Burns, Mary M. Reilly, Francesco Muntoni, Evelin Milev, Timothy Estilow, Michael E. Shy, Sindhu Ramchandren
Summary: The objective of this study was to evaluate the parent-proxy version of the pediatric Charcot Marie Tooth specific quality of life (pCMT-QOL) outcome instrument for children aged 7 or younger with CMT. The parent-proxy version of the pCMT-QOL outcome measure, known as the pCMT-QOL (0-7 years parent-proxy), was validated as a valid and sensitive proxy measure of health-related quality of life for children aged 0-7 years with CMT.
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2023)
Article
Medicine, Research & Experimental
Yi Zhu, Amanda G. Lobato, Adriana P. Rebelo, Tijana Canic, Natalie Ortiz-Vega, Xianzun Tao, Sheyum Syed, Christopher Yanick, Mario Saporta, Michael Shy, Riccardo Perfetti, Shoshana Shendelman, Stephan Zuechner, R. Grace Zhai
Summary: In this study, synaptic degeneration, neurotransmission defect, locomotor impairment, and structural abnormalities in neuromuscular junctions were observed in a Drosophila model of SORD deficiency. Mitochondrial dysfunction and ROS accumulation were also found. AT-007, a new drug, significantly reduced sorbitol levels and improved synaptic degeneration, locomotor activity, and mitochondrial function. These findings provide a potential treatment strategy for SORD deficiency.
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.
