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
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
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)
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
Neurosciences
Azahara Civera-Tregon, Laura Dominguez, Paula Martinez-Valero, Claudia Serrano, Alex Vallmitjana, Raul Benitez, Janet Hoenicka, Jorgina Satrustegui, Francesc Palau
Summary: The loss of GDAP1 leads to mitochondrial and calcium homeostasis disruption in axons, affecting bioenergetic status and axonal transport. This study provides insights into the cellular mechanisms associated with axonal degeneration in GDAP1-related neuropathies.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Neurosciences
Tara C. Tassin, Barbara Barylko, Per Niklas Hedde, Yan Chen, Derk D. Binns, Nicholas G. James, Joachim D. Mueller, David M. Jameson, Ronald Taussig, Joseph P. Albanesi
Summary: Mutations in the DNM2 gene are associated with motor disorders affecting nerve and muscle, such as CMT and CNM; CMT and CNM mutations have distinct effects on DNM2 function, suggesting different pathogenic mechanisms and genetic overlap should be re-examined.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
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)
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
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)
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
Neurosciences
Fan Chu, Jiaming Xu, Yong Wang, Yingjie Li, Yaling Wang, Zhijun Liu, Chuanzhou Li
Summary: X-linked Charcot-Marie-Tooth Disease type 1 (CMT1X) is a common form of inherited peripheral neuropathy caused by mutations in the GJB1 gene. This study investigated four CMT families in China and identified new and previously reported variants of GJB1. Cell biological analysis revealed that all mutants showed increased expression and aggregation compared to the wild-type. The study also found that mutated GJB1 induced intracellular stress granule formation and cytotoxicity.
FRONTIERS IN NEUROSCIENCE
(2022)
Article
Clinical Neurology
Menelaos Pipis, Shawna M. E. Feely, James M. Polke, Mariola Skorupinska, Laura Perez, Rosemary R. Shy, Matilde Laura, Jasper M. Morrow, Isabella Moroni, Chiara Pisciotta, Franco Taroni, Dragan Vujovic, Thomas E. Lloyd, Gyula Acsadi, Sabrina W. Yum, Richard A. Lewis, Richard S. Finkel, David N. Herrmann, John W. Day, Jun Li, Mario Saporta, Reza Sadjadi, David Walk, Joshua Burns, Francesco Muntoni, Sindhu Ramchandren, Rita Horvath, Nicholas E. Johnson, Stephan Zuchner, Davide Pareyson, Steven S. Scherer, Alexander M. Rossor, Michael E. Shy, Mary M. Reilly
Summary: The study of 196 CMT2A patients (including dominant and recessive) found that childhood onset of autosomal dominant CMT2A is associated with more severe disease severity compared to adult onset, with significantly higher rates of using orthoses, wheelchairs, dexterity difficulties, and higher CMT Examination Score and CMT Neuropathy Score at initial assessment. Longitudinal data analysis showed significant increases in CMTESv2 and CMTESv2-R over 1-2 years, providing guidance for prognosis and clinical trial design.
Article
Biochemistry & Molecular Biology
Burcak Ozes, Morgan Myers, Kyle Moss, Jennifer Mckinney, Alicia Ridgley, Lei Chen, Shasha Bai, Charles K. Abrams, Mona M. Freidin, Jerry R. Mendell, Zarife Sahenk
Summary: This study demonstrated that delivering scAAV1.tMCK.NT-3 to the muscle of Cx32 knockout mice can increase NT-3 levels and improve functional, electrophysiological, and histological parameters related to CMTX1.
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
Alexander G. Thompson, Kevin Talbot, Martin R. Turner
Summary: The study examined the relationship between metabolic parameters and the risk of ALS, revealing that HDL and apoA1 levels are associated with a reduced risk, while total cholesterol:HDL ratio is linked to an increased risk. Models incorporating multiple metabolic markers showed that high levels of LDL or apoB are associated with an increased risk, while higher levels of HDL or apoA are associated with a lower risk. Additionally, coronary artery disease, cerebrovascular disease, and increasing age were also found to be associated with an increased risk of ALS.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Review
Cell Biology
Timothy J. Hines, Cathleen Lutz, Stephen A. Murray, Robert W. Burgess
Summary: As sequencing technology improves, our understanding of the genetic basis of rare diseases is increasing. However, studying rare diseases in patient populations is challenging. By using genetically engineered model organisms and induced pluripotent stem cells, we can create accurate disease models and explore disease mechanisms and potential therapies.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Clinical Neurology
Johnathan Cooper-Knock, Thomas H. Julian, Emily Feneberg, J. Robin Highley, Maurice Sidra, Martin R. Turner, Kevin Talbot, Olaf Ansorge, Scott P. Allen, Tobias Moll, Tatyana Shelkovnikova, Lydia Castelli, Guillaume M. Hautbergue, Christopher Hewitt, Janine Kirby, Stephen B. Wharton, Richard J. Mead, Pamela J. Shaw
Summary: We describe a multi-generational pedigree of amyotrophic lateral sclerosis (ALS) with an autosomal dominant, fully penetrant mutation in the TDP-43 gene. The hallmark pathology of ALS is the mislocalization of TDP-43 and the formation of insoluble TDP-43-positive neuronal cytoplasmic inclusions. While the lower motor neurons showed typical TDP-43 pathology, the motor cortex did not show classical TDP-43-positive inclusions. Despite reduced overall TDP-43 protein expression, the mutated allele was transcribed and translated in patient fibroblasts and motor cortex tissue. Furthermore, the motor cortex tissue carrying the mutation showed atypical TDP-43 protein species but not typical C-terminal fragments. Our findings suggest that the p.Y374X mutation is responsible for a monogenic, fully penetrant form of ALS and expands the molecular phenotypes associated with TDP-43 mutations and ALS.
Article
Clinical Neurology
Carolyn A. Young, John Ealing, Christopher J. McDermott, Tim L. Williams, Ammar Al-Chalabi, Tahir Majeed, Kevin Talbot, Timothy Harrower, Christina Faull, Andrea Malaspina, Joe Annadale, Roger J. Mills, Alan Tennant
Summary: The aim of this study was to investigate whether the WHODAS 2.0 can provide interval level measurement of disability in ALS, allowing parametric analyses. The results showed that the WHODAS 2.0 can be used as a brief patient reported outcome measure to assess disability in ALS and can be used for surveillance of at risk populations.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Review
Biochemistry & Molecular Biology
Sachiko Kanaji, Wenqian Chen, Yosuke Morodomi, Ryan Shapiro, Taisuke Kanaji, Xiang-Lei Yang
Summary: Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by circulating autoantibodies against aminoacyl-tRNA synthetases (aaRSs). The roles of these autoantibodies in ASSD pathogenesis are still unclear. This article discusses the potential involvement of specific aaRSs, extracellular tRNAs or tRNA fragments, and Toll-like receptor signaling in ASSD pathogenesis.
TRENDS IN BIOCHEMICAL SCIENCES
(2023)
Article
Clinical Neurology
C. A. Young, J. Ealing, C. J. McDermott, T. L. Williams, A. Al-Chalabi, T. Majeed, K. Talbot, T. Harrower, C. Faull, A. Malaspina, J. Annadale, R. J. Mills, A. Tennant
Summary: This study reveals that the prevalence of depression in ALS patients is close to a quarter, with most patients belonging to a single trajectory group. Estimates based on screening for current depressive symptoms underestimate the actual prevalence of depression.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Article
Biochemistry & Molecular Biology
Paige B. Martin, Sarah E. Holbrook, Amy N. Hicks, Timothy J. Hines, Laurent P. Bogdanik, Robert W. Burgess, Gregory A. Cox
Summary: This paragraph discusses Charcot-Marie-Tooth disease, an inherited peripheral neuropathy that is clinically and genetically heterogeneous. Mutations in the IGHMBP2 gene have been found to cause this disease. Researchers created mouse models of CMT2S using CRISPR-cas9 mutagenesis, which will be crucial for understanding the pathogenic mechanisms of IGHMBP2.
HUMAN MOLECULAR GENETICS
(2023)
Article
Neurosciences
David M. Steffen, Camille M. Hanes, Kar Men Mah, Paula Valino Ramos, Peter J. Bosch, Dalton C. Hinz, Jason J. Radley, Robert W. Burgess, Andrew M. Garrett, Joshua A. Weiner
Summary: The establishment of a functional cerebral cortex relies on the proper execution of various developmental steps, which includes dendritic and axonal outgrowth, synaptic connection formation and maturation. Dysregulation of these processes can result in improper neuronal connectivity, including neurodevelopmental disorders. The y-Protocadherins (y-Pcdhs) are involved in multiple aspects of neurodevelopment, including neuronal survival, dendrite arborization, and synapse development. The specific role of each individual y-Pcdh family member remains unclear.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Clinical Neurology
Hugo M. De Oliveira, Arunachalam Soma, Mark R. Baker, Martin R. Turner, Kevin Talbot, Timothy L. Williams
Summary: There is considerable variation in the practice of genetic testing for patients with sporadic motor neurone disease/amyotrophic lateral sclerosis (MND/ALS) and asymptomatic at-risk relatives in specialized care centers in the UK. Many healthcare professionals feel uncomfortable discussing genetic testing with MND/ALS patients and believe that routine genetic testing is not necessary for all patients with apparently sporadic disease. There are concerns regarding testing asymptomatic at-risk individuals and the majority view is that clinical genetics services should play a role in supporting genetic testing in MND/ALS, especially in asymptomatic individuals at risk of carrying pathogenic variants.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Article
Multidisciplinary Sciences
Lu Han, Zhiteng Luo, Yingchen Ju, Bingyi Chen, Taotao Zou, Junjian Wang, Jun Xu, Qiong Gu, Xiang-Lei Yang, Paul Schimmel, Huihao Zhou
Summary: Aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are essential enzymes in protein translation, categorized into two classes with distinct active site architectures. The orphan GlyRS in bacteria has a unique X-shaped structure. A cocrystal structure elucidates how this orphan GlyRS specifically recognizes its substrate tRNA. The X shape of orphan GlyRS suggests potential nonactive site targets for aaRS-directed antibiotics.
Article
Medicine, Research & Experimental
Anna J. Kordala, Jessica Stoodley, Nina Ahlskog, Muhammad Hanifi, Antonio Garcia Guerra, Amarjit Bhomra, Wooi Fang Lim, Lyndsay M. Murray, Kevin Talbot, Suzan M. Hammond, Matthew J. A. Wood, Carlo Rinaldi
Summary: Spinal muscular atrophy (SMA) is an important genetic cause of infant mortality. The discovery of PRMT inhibitor MS023 shows promising potential for treating SMA and improving the disease phenotype, especially when combined with nusinersen. Further clinical investigation of PRMT inhibition as a standalone or add-on therapy for SMA is warranted.
EMBO MOLECULAR MEDICINE
(2023)
Article
Clinical Neurology
A. L. D. Tadenev, C. L. Hatton, B. Pattavina, T. Mullins, R. Schneider, L. P. Bogdanik, Robert W. Burgess
Summary: Two new mouse models of CMT1X have been generated in this study, which can accurately simulate the pathological mechanisms of human CMT1X-related mutations. Analysis of these mice shows the characteristics of peripheral neuropathy, with thinly myelinated and demyelinated axons, as well as degenerating and regenerating axons mainly in distal motor nerves. Assessment results indicate that these mouse models perform comparably to wild type mice in neuromuscular functional tests.
JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM
(2023)
Article
Clinical Neurology
Eleni Christoforidou, Fabio A. Simoes, David Gordon, Kevin Talbot, Majid Hafezparast
Summary: This study examined the intracellular motor neuron pathology of mice with a combination of defective dynein and a TDP-43 mutation. The results showed upregulation of p62 and aggregation of TDP-43, partially recapitulating the human disease. These findings provide new insights into the relationship between dynein and TDP-43 and could be useful for further research on the TDP-43 pathology in ALS.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Article
Clinical Neurology
Alexander G. Thompson, Rachael Marsden, Kevin Talbot, Martin R. Turner
Summary: Using routine health screening blood test data, this study found distinct pre-symptomatic biphasic blood cholesterol trajectories in individuals who later developed amyotrophic lateral sclerosis. The findings suggest that metabolic alterations may occur prior to the onset of motor symptoms in this disease. These findings provide further evidence for the importance of monitoring blood cholesterol levels for early detection and potential preventative therapy in amyotrophic lateral sclerosis.
BRAIN COMMUNICATIONS
(2023)
Article
Clinical Neurology
Jennifer C. Davies, Thanuja Dharmadasa, Alexander G. Thompson, Evan C. Edmond, Katie Yoganathan, Jiali Gao, Kevin Talbot, Martin R. Turner
Summary: A reliable biomarker for diagnosing amyotrophic lateral sclerosis (ALS) across different clinical conditions is necessary. Neurofilament light chain levels are correlated with the progression of disability in ALS patients. Previous studies have only compared neurofilament light chain levels in ALS patients with healthy individuals or controls with diagnoses distinct from ALS. In this study, neurofilament light chain levels were measured in ALS patients referred to a specialized clinic, and it was found that neurofilament light chain levels can confirm ALS diagnosis but have limited ability to exclude alternative diagnoses. The current importance of neurofilament light chain is its potential use in stratifying ALS patients by disease activity and as a biomarker in therapeutic trials.
BRAIN COMMUNICATIONS
(2023)