Materiały źródłowe

• #1 Charcot-Marie-Tooth Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562163/

  Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, characterized by progressive weakness of the extremities due to peripheral nerve damage. […] CMT is heterogeneous in its clinical, electrophysiological, genetic, and pathological features. Based on neurophysiological findings, CMT was previously classified into the demyelinating form, CMT type 1 (CMT1), and the axonal form, CMT type 2 (CMT2). However, the increasing use of next-generation gene sequencing (NGS) technologies has altered the classification and diagnosis of CMT. […] CMT and related disorders are genetically determined, involving more than 100 genes. About 80% to 90% of the genetic abnormalities are due to copy number variations (CNVs) in peripheral myelin protein 22 (PMP22) and mutations in GJB1, MPZ, and MFN2 genes.

• #2 Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success

  https://www.mdpi.com/2073-4425/5/1/13

  Charcot-Marie-Tooth (CMT) neuropathies comprise a group of monogenic disorders affecting the peripheral nervous system. CMT is characterized by a clinically and genetically heterogeneous group of neuropathies, involving all types of Mendelian inheritance patterns. Over 1,000 different mutations have been discovered in 80 disease-associated genes. […] CMT genetic study also unraveled common pathomechanisms for peripheral nerve degeneration, elucidated gene networks, and initiated the development of therapeutic approaches. […] The availability of the Human Genome also contributed to the identification of mutations in genes that were not the primary functional candidates for CMT neuropathies. […] The identification of the CMT1A duplication and reciprocal HNPP deletion on 17p12 has also shown that rare CNVs involving both coding and non-coding sequences can cause human disorders.

• #2 Charcot-Marie-Tooth Disease | National Institute of Neurological Disorders and Stroke

  https://www.ninds.nih.gov/health-information/disorders/charcot-marie-tooth-disease

  Charcot-Marie-Tooth disease (CMT) is a group of genetic conditions that affect the nerves connecting the brain and spinal cord to the rest of the body. […] Gene mutations are changes in a gene’s DNA that can affect how the gene works. These changes can cause the body to not function properly. More than 100 genes are linked to CMT. Depending on the gene problem, CMT can affect the axon, the myelin sheath, or both. Peripheral nerves send electrical signals over long distances down a long, thin part of the nerve cell called the axon. The axon is covered by myelin, which works like the insulation on an electrical wire to help signals travel quickly. The protective coating that wraps around the axon is called the myelin sheath. It helps the signals travel quickly and smoothly through the nerves. When the axon or myelin sheath is damaged, signals slow down, weaken, or fail to transmit properly. This makes it harder for nerves to control muscles or send sensory information from the skin, muscles, or other organs back to the spinal cord and the brain.

• #3 Genetic approaches and pathogenic pathways in the clinical management of Charcot-Marie-Tooth disease

  https://www.oaepublish.com/articles/jtgg.2022.04

  Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting at least 1 in 2500 individuals. […] Over the last decades, there have been important advances not only in the identification of causative genes but also in understanding the molecular basis for many forms of CMT. […] In fact, to date, around 100 genes have been related to CMT disease, thanks to next generation sequencing techniques, and they have been proven to affect either the myelin or axon of peripheral nerves. […] We also address the disrupted cellular processes and pathophysiological mechanisms involved in the disease. A better understanding of the pathogenic mechanisms responsible for each type of CMT would be essential to identifying molecular targets and therapeutic strategies. […] The molecular genetics of CMT began in 1991 with the discovery of the 1.4 Mb duplication in the short arm of chromosome 17, which contains the dose-sensitive peripheral myelin protein 22 (PMP22) gene, causing CMT1A and became the most common cause of genetic neuropathies.

• #4 Charcot-Marie-Tooth Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1232386-overview

  CMT disease is a heterogeneous group of genetically distinct disorders with similar clinical presentations. Its genetic spectrum spans more than 80 genes. Gene discovery has been revolutionized by new high-throughput molecular technologies. CMT disease is divided into several types, as follows. […] CMT type 1 is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP22) gene. Mutations in the gene encoding the major PNS myelin protein, myelin protein zero (MPZ), account for 5% of patients with CMT disease. The mutation results in abnormal myelin that is unstable and spontaneously breaks down. […] This process results in demyelination, leading to uniform slowing of conduction velocity. Slowing of conduction in motor and sensory nerves was believed to cause weakness and numbness. However, a study by Krajewski et al suggested that neurologic dysfunction and clinical disability in CMT 1A are caused by loss of or damage to large-diameter motor and sensory axons.

• #5 Charcot-Marie-Tooth Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562163/

  About 90% of mutations in individuals with CMT type 1 are caused by 3 genetic defects PMP22 duplication, GJB1 point mutations, and MPZ point mutations which cause damage to Schwann cells and the myelin sheath of the axon. […] This genomic duplication results from an unequal meiotic crossover facilitated in the male germline by flanking homologous repeat sequences. […] Frameshift mutations in MPZ lead to mutant proteins aggregating in the endoplasmic reticulum of the neuron and consequent apoptosis. Other variations of CMT are usually the result of loss-of-function mutations in different genes and are uncommonly due to a toxic gain of function. […] The normal structure and functions of peripheral nerves depend upon the close anatomical and physiological interaction between Schwann cells and axons. Axons regulate the survival, proliferation, and differentiation of Schwann cells, which in turn have a crucial role in regulating ion channels and their maintenance, supporting survival, and facilitating regeneration of axons. Abnormalities in genes involved in myelin assembly and axonal transport can lead to primary demyelination and axonopathy.

• #6 Charcot-Marie-Tooth Disease: Lessons in Genetic Mechanisms | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1007/BF03401724

  The molecular mechanism responsible for the majority of patients with the CMT phenotype linked to the proximal short arm of chromosome 17 (17p11.2p12) is a submicroscopic DNA duplication. This CMT1A duplication is 3 million base pairs (3 megabases or 3 Mb) in length! It consists of a duplicated 1.5 Mb monomeric unit, arranged in tandem, and flanked by a 24,000 base pair (24 kilobases or 24 Kb) direct repeat, named CMT1A-REP. The molecular mechanism responsible for the CMT1A duplication is an unequal crossing-over event mediated by the homologous CMT1A-REP repeats. […] Several mechanisms were proposed to explain how the CMT1A duplication might affect a CMT1 gene. These included gene interruption at the duplication junction, a position effect, and a gene dosage effect due to a dosage-sensitive gene located within the duplicated region.

• #7 Charcot–Marie–Tooth disease – Wikipedia

  https://en.wikipedia.org/wiki/Charcot%E2%80%93Marie%E2%80%93Tooth_disease

  The most common cause (70-80% of cases) of CMT is a duplication on the short arm of chromosome 17, involving the gene PMP22. This duplication leads to an excess of PMP22 protein, disrupting the normal structure and function of the myelin sheath. […] Mutations affecting the gene MFN2, located on chromosome 1, impair the function of mitochondrial proteins. Mutated MFN2 causes mitochondria to form clusters or aggregates, restricting their movement along axons toward synapses, and thus impairing synaptic function.

• #8 Charcot-Marie-Tooth Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1232386-overview

  In response to demyelination, Schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons. These changes cause what is referred to as an onion bulb appearance. […] CMT type 2 primarily is a neuronal (ie, axonal) disorder, not a demyelinating disorder. It results in peripheral neuropathy through direct axonal death and wallerian degeneration. It has been associated with mutations in the ATP1A1 gene. […] Characterized by infantile onset, CMT type 3 (also known as Dejerine-Sottas disease) results in severe demyelination with delayed motor skills; it is much more severe than CMT type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination. […] CMT X (X-linked CMT) and CMT 4 also are demyelinating neuropathies. CMT X has been associated with mutations in the PRPS1 gene.

• #9 Charcot-Marie-Tooth disease type 1A | MedLink Neurology

  https://www.medlink.com/articles/charcot-marie-tooth-disease-type-1a

  Although demyelination is the pathological and physiological hallmark of Charcot-Marie-Tooth type 1, the clinical signs and symptoms of this disease, weakness and sensory loss, are probably produced by axonal degeneration and not by demyelination. […] Together, these data suggest that distal axonal degeneration, not demyelination, is the major cause of clinical disability in Charcot-Marie-Tooth disease type 1A.

• #10 Charcot-Marie-Tooth disease | Revista Médica Clínica Las Condes

  https://www.elsevier.es/es-revista-revista-medica-clinica-las-condes-202-articulo-charcot-marie-tooth-disease-S0716864018301068

  The axonal forms of CMT are mainly represented by CMT2A2. The mutated gene in this presentation is MFN2, which encodes mitofusin-2. This protein is located in the outer layer of the mitochondria and interacts with the Miro-Milton complex, which functions in the anchorage of the mitochondria with the motor proteins of the kinesins family. […] Mutations in the GJB1 gene are responsible for CMTX1, which corresponds to the most prevalent form of X-linked CMT and it is also the second most common CMT in the general population. The product of this gene (the gap junction protein, beta-1, also known as connexin 32) has the function of connecting with the different folds in the cytoplasm of Schwann cells, allowing the transfer of nutrients, ions and molecules to the layers internal myelin.

• #11 Understanding Charcot-Marie-Tooth Pathogenesis Using in vivo and Gene Networking Studies – University of Miami

  https://scholarship.miami.edu/esploro/outputs/991031447935202976

  Charcot-Marie-Tooth disease (CMT) is a common, hereditary, length-dependent peripheral neuropathy roughly classified as either demyelinating (CMT1) or axonal (CMT2). […] Though the disease is highly heterogeneous, many of the most severe axonal cases are caused by dominant mutations in mitofusin 2 (MFN2). The mechanism by which MFN2 mutations cause CMT are unknown. […] Over 80 genes are known to cause CMT, with wide-ranging cellular functions and proposed mechanisms. MFN2 is involved in mitochondrial fusion, axonal transport, mitochondrial tethering to the ER, mitophagy, and mitochondrial metabolism, further confounding pathological understanding of the disease. […] In conclusion, we have described the first Mfn2 knock-in model of CMT, which displays homozygous lethality, mostly mild heterozygous phenotypes, and a unique vulnerability to optic nerve crush. Expression analysis revealed differential expression of known CMT genes and genes involved in Schwann cell functions, indicating cohesive forces among the broad genotypic and phenotypic variance of this disease. Future studies may reveal the nature of these interactions.

• #12 Charcot-Marie-Tooth Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562163/

  Some of the molecular and cellular mechanisms thought to be involved in inducing CMT are mentioned below. Myelin assembly: Genes such as MPZ (involved in myelin compaction), GJB1 (gap junction formation), and PMP22 (synthesis and maintenance of myelin) lead to impaired myelin sheath formation, the primary cause of demyelinating CMT. […] Due to the close functional interaction between Schwann cells and axons, demyelinating neuropathies in CMT often progress to functional axonopathies, leading to secondary axonal degeneration. […] Significant phenotypic heterogeneity exists with mutations that can cause both demyelinating and axonal forms of CMT. Similarly, mutations in MFN2, MPZ, GDAP1, and EGR2 may have CMTs with autosomal dominant or recessive inheritance patterns.

• #13 Genetic approaches and pathogenic pathways in the clinical management of Charcot-Marie-Tooth disease

  https://www.oaepublish.com/articles/jtgg.2022.04

  Currently, around 100 genes have been identified in Mendelian inheritance of genetic neuropathies. […] Although there are myriad gene associations and pathophysiologic mechanisms, it is clear that the mutations associated with the disease are closely related to the formation, compaction, and maintenance of myelin (PMP22, P0, Cx32, EGR2, NDGR1, PRX, etc.), the neuronal soma, axon and cytoskeleton conservation (NEFL, LMNA, MORC2, etc.), the axonal transport (RAB7), and the mitochondrial dynamics (MFN2, GDAP1, GARS, HSP22, HSP27, etc.). […] This means that, independently of the defect (metabolic, cytoplasmic, or structural) that primarily affects the myelin or axon, as well as the Schwann cell-axon structure, the axonal degenerative process is the final common pathway in neuropathies that primarily affect the largest and longest fibers.

• #14 Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2 | Scientific Reports

  https://www.nature.com/articles/s41598-017-06781-0

  Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies. Recently, three CMT1-associated point mutations (I43N, T51P, and I52T) were discovered in the abundant peripheral myelin protein P2. These mutations trigger abnormal myelin structure, leading to reduced nerve conduction velocity, muscle weakness, and distal limb atrophy. […] Our findings demonstrate that altered biophysical properties and functional dynamics of P2 may cause myelin defects in CMT1 patients. At the molecular level, a few malformed hydrogen bonds lead to structural instability and misregulation of conformational changes related to ligand exchange and membrane binding. […] The three P2 mutations (I43N, T51P, and I52T) studied here increase the tendency of P2 to form insoluble aggregates, when expressed in E. coli.

• #15 Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2 | Scientific Reports

  https://www.nature.com/articles/s41598-017-06781-0

  The thermal stability of all three CMT-linked P2 variants is dramatically reduced compared to P2wt. […] The altered stability, dynamics, and fatty acid/lipid membrane binding of the disease-associated P2 protein variants may be involved in CMT1 etiology and give rise to myelin defects, including abnormal myelin compaction and irregular myelin sheaths, in P2-linked CMT1 patients.

• #16

  https://link.springer.com/article/10.1007/s13311-021-01099-2

  Axonal transport is an energy-dependent and highly regulated process of directed movement of various organelles and essential cargo, including mRNA transcripts, translation machinery, and trophic factor signaling complexes, along axonal microtubules. […] Genes involved directly with microtubule transport include BICD2, RAB7, DCTN1, DYNC1H1, KIF1A, and KIF5A among others. […] Mutations in mitofusin-2 (MFN2), which cause CMT2A, likely impact mitochondrial trafficking within axons, among other aspects of mitochondrial biology, as discussed in more depth below. […] Proper mitochondrial function requires precise regulation of mitochondrial dynamics—the complex and dynamic processes of mitochondrial fission and fusion as well as trafficking along microtubules. […] The study of defects due to pathogenic MFN2 mutations provides a window into the myriad mechanisms by which mitochondrial dynamics can contribute to axonal pathology.

• #17 Investigating the Pathogenesis of Rare Congenital Nerve Disorder – News Center

  https://news.feinberg.northwestern.edu/2023/11/15/investigating-the-pathogenesis-of-rare-congenital-nerve-disorder/

  A new Northwestern Medicine study has uncovered previously unidentified intracellular mechanisms in the peripheral nervous system that cause Charcot-Marie-Tooth Type 2B disease, a rare congenital disorder that causes sensory deficits and muscle atrophy and weakness. […] These findings are important as they highlight an essential role for properly regulated mitochondria-lysosome contact site dynamics and function in the axons of sensory peripheral neurons, and demonstrate that this may be an important pathway in the pathogenesis of Charcot-Marie-Tooth Type 2B disease, said Yvette Wong, PhD, assistant professor of in the Department of Neurology’s Division of Movement Disorders and co-lead author of the study. […] Charcot-Marie-Tooth Type 2B disease is specifically caused by mutations in a GTPase protein called Rab7, which leads to the degeneration of axons of peripheral sensory neurons.

• #18 Investigating the Pathogenesis of Rare Congenital Nerve Disorder – News Center

  https://news.feinberg.northwestern.edu/2023/11/15/investigating-the-pathogenesis-of-rare-congenital-nerve-disorder/

  In the context of Charcot-Marie-Tooth Type 2B disease, Wong and colleagues also previously discovered that disease mutant Rab7 prevents the untethering of these contact sites, resulting in downstream defects in mitochondrial dynamics. […] The findings suggest that targeted therapies which help improve mitochondria-lysosome contact site tethering dynamics and function may improve mitochondrial health in these axons, according to the authors. […] Our study demonstrates a critical role for mitochondria-lysosome contact sites to maintain the health of peripheral nerves. Moreover, defects in this important pathway have been recently linked to the pathogenesis of multiple neurodegenerative diseases, including Parkinson’s disease and lysosomal storage disorders, said Menichella, who is also an associate professor of Pharmacology. […] Together, this work provides important insights into mitochondria-lysosome contact site regulation in peripheral neuropathy and has important consequences for advancing the fields of organelle contact site biology and neurodegeneration, Menichella said.

• #19 Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27 induced Charcot Marie Tooth Disease | Crick

  https://www.crick.ac.uk/research/publications/mitochondrial-deficits-and-abnormal-mitochondrial-retrograde-axonal-transport-play-a-role-in-the-pathogenesis-of-mutant-hsp27-induced-charcot-marie-tooth-disease

  Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27 induced Charcot Marie Tooth Disease. […] Mutations in the small heat shock protein Hsp27, encoded by the HSPB1 gene, have been shown to cause Charcot Marie Tooth Disease type 2 (CMT-2) or distal hereditary motor neuropathy (dHMN). […] Protein aggregation and axonal transport deficits have been implicated in the disease. […] We found significantly slower retrograde transport of mitochondria in Ser135Phe, Pro39Leu and Arg140Gly mutant Hsp27 expressing motor neurons than in wild type Hsp27 neurons, although anterograde movement velocities remained normal. […] Investigation of mitochondrial function revealed a decrease in mitochondrial membrane potential in mutant Hsp27 expressing motor axons, as well as a reduction in mitochondrial complex 1 activity, increased vulnerability of mitochondria to mitochondrial stressors, leading to elevated superoxide release and reduced mitochondrial glutathione (GSH) levels, although cytosolic GSH remained normal.

• #20

  https://link.springer.com/article/10.1007/s00018-025-05612-0

  Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production. […] Although multiple mutations associated with CMT were identified, the cellular and molecular mechanisms of this pathology are still unclear, although most of the subtype of this disease involve mitochondrial dysfunction and oxidative stress in the mechanism of pathology. […] Mitochondrial dysfunction is associated with most of the neurological conditions including CMT. […] Changes in the activity of mitochondrial electron transport chain complexes was also shown for CMT4B3. […] Reactive oxygen species overproduction and oxidative stress are shown to be one of the major triggers for development of neurological conditions. […] For some of the inherited forms of CMT an increased level of ROS production has also been shown that induces oxidative stress resulting in the decrease of major endogenous antioxidant glutathione.

• #21

  https://link.springer.com/article/10.1007/s00018-025-05612-0

  We have found that mitochondrial membrane potential in most of the CMT4B3 patients fibroblasts was lower than in control cells and pathology in mitochondrial electron transport chain was partially compensated by pumping protons by the F0-F1-ATPase. […] All cells with CMT4B3 pathology had a significantly lower level of GSH although the rate of reactive oxygen species production was similar and, in some cells, even lower that in control. […] Thus, CMT4B3 pathology leads to mitochondrial depolarisation and a change in the mechanism of maintenance of m. […] Importantly, the residual NADH autofluorescence after the application of FCCP can also be taken to assess NADPH levels. […] However, CMT4B3 pathology led to a decrease in the NADH redox index in all patients fibroblasts that may be an indicator of higher activity of mitochondrial respiration in these cells.

• #22

  https://www.jci.org/articles/view/161566

  Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. […] Sterile and Toll/IL-1 receptor motifcontaining 1 (SARM1), the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. […] We generated Sarm1-KO (Sarm1/) and Mfn2H361YSarm1 double-mutant rats and found that deletion of Sarm1 rescued axonal, synaptic, muscle, and functional phenotypes, demonstrating that SARM1 was responsible for much of the neuropathology in this model. […] This surprising finding indicates that dysfunctional mitochondria activated SARM1 and that activated SARM1 fed back on mitochondria to exacerbate the mitochondrial pathology.

• #23

  https://www.jci.org/articles/view/161566

  Hence, SARM1 inhibition is a compelling therapeutic candidate for the treatment of CMT2A and, potentially, the many other neurodegenerative diseases characterized by mitochondrial dysfunction. […] SARM1 is an essential driver of neuropathology in CMT2A. […] Our analysis of pathology in the recently described Mfn2H361Y-KI rat model of CMT2A demonstrated good concordance with the human disease, i.e., progressive distal-predominant axonopathy with muscle atrophy and NMJ defects. […] Hence, although compromised mitochondrial function initiates disease, SARM1 is the ultimate driver of neuropathology. […] A mitochondrial-SARM1 feedback loop exacerbates mitochondrial dysfunction in CMT2A. […] This idea of a mitochondria-SARM1 feedback loop is consistent with the demonstration that SARM1 is activated by mitochondrial dysfunction and that SARM1 activation causes mitochondrial dysfunction. […] Taken together, these findings suggest that, while mitochondrial morphology was surely impacted by the direct loss of MFN2 function, all other mitochondrial phenotypes resulted primarily from the actions of SARM1.

• #24 Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association

  https://www.mdpi.com/2076-3921/14/3/331

  Charcot–Marie–Tooth disease (CMT) is the most common hereditary peripheral neuropathy worldwide, presenting clinically as muscle weakness that progresses to impaired ambulation or quadriplegia with age. CMT1A, the most common subtype, is caused by a duplication in PMP22, encoding an essential membrane protein for Schwann cell myelin integrity. While the mechanisms of peripheral neurodegeneration in CMT1A are poorly understood, excessive oxidative stress, particularly lipid peroxidation, is a known pathological feature, and antioxidant therapy has reversed the CMT1A phenotype in a mouse model. For the first time, we define the pathogenic link between CMT1A and ferroptosis, a form of regulated cell death caused by excessive lipid peroxidation and hindered antioxidant defenses. Human-derived CMT1A fibroblasts showed greater susceptibility to RSL3, a pro-ferroptosis agent, compared with controls, alongside several ferroptosis markers, including elevated lipid peroxides and depleted GPX4, a critical anti-ferroptosis repressor. Similarly, transcriptomic analysis of human iPSC-derived Schwann cells revealed elevated ferroptosis activation and cellular stress markers in CMT1A. We propose that chronic, sublethal ferroptotic stress, mediated by lipid peroxide accumulation, depletes antioxidant defenses in CMT1A Schwann cells, leading to decompensation with age, manifesting as symptomatic disease. These results emphasize ferroptosis as a driver of CMT1A pathology, potentially revealing a new therapeutic path.

• #25 Charcot-Marie-Tooth Disease | National Institute of Neurological Disorders and Stroke

  https://www.ninds.nih.gov/health-information/disorders/charcot-marie-tooth-disease

  NIH and NINDS-supported researchers are studying genes to better understand what causes CMT and to learn how to treat it. This includes understanding the role of specific genes in CMT, how gene mutations affect nerve function and myelin production, using gene editing to target faulty genes linked to CMT, and potential treatments. […] Researchers also are learning how gene mutations in several subtypes of CMT cause problems in the protein synthesis of neurons. […] In other studies, researchers are testing nerve growth factors to prevent nerve damage.

• #26 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20191121/Charcot-Marie-Tooth-disease-study-unearths-a-new-mechanism-of-neurodegeneration.aspx

  Charcot-Marie-Tooth disease (CMT) is an inherited neurodegenerative condition that affects 1 in 2500 individuals. New research has demonstrated that a class of cytoplasmic enzymes called tRNA synthetases can cause CMT by interfering with the gene transcription in the nucleus. […] The researchers uncovered that an important group of molecules known as aminoacyl-tRNA synthetases – which help in translating RNA into proteins – can also interfere with the transcription of DNA into RNA. This interference was found to be at the core of CMT disease in both fly and cellular models. […] We demonstrate for the first time that their nuclear role has pathological implications and can cause a neurodegenerative disease. […] Pharmaceutical inhibition of the tRNA synthetase entry into the nucleus prevented the onset of disease symptoms in our CMT Drosophila model, which could have great implications for CMT patients. […] Only when these research questions have been addressed, we can start thinking about a therapeutic approach that cures the origin and not only the symptoms of the disease.

• #27

  https://link.springer.com/article/10.1007/s13311-021-01099-2

  The pathogenesis of ARS-related CMT2 remains unresolved, with multiple potential pathological mechanisms. […] With the finding that CMT2-causing mutations in various amino-acyl-tRNA synthetases lead to suppression of global translation that is particularly detrimental to neuronal homeostasis, a pattern emerges suggesting that many distinct forms of CMT may share the common pathological insult of impaired axonal protein translation. […] This confluence of neuropathy-related genes onto pathways involved in microtubule transport, mitochondrial energetics, organelle-organelle interactions, and local protein translation underscores the delicate nature of axonal physiology, particularly in the longest peripheral nerves, and suggests that multiple perturbations of metabolic processes can expose the unique vulnerability of this highly specialized portion of the nervous system.

• #28 Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A | Nature Medicine

  https://www.nature.com/articles/nm.3664

  Duplication of the gene encoding the peripheral myelin protein of 22 kDa (PMP22) underlies the most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without a known cure. […] Here, we show in Pmp22-transgenic rodent models of CMT1A that Schwann cells acquire a persistent differentiation defect during early postnatal development, caused by imbalanced activity of the PI3K-Akt and the Mek-Erk signaling pathways. […] We demonstrate that enhanced PI3K-Akt signaling by axonally overexpressed neuregulin-1 (NRG1) type I drives diseased Schwann cells toward differentiation and preserves peripheral nerve axons. […] Notably, in a preclinical experimental therapy using a CMT1A rat model, when treatment is restricted to early postnatal development, soluble NRG1 effectively overcomes impaired peripheral nerve development and restores axon survival into adulthood. […] Our findings suggest a model in which Schwann cell differentiation within a limited time window is crucial for the long-term maintenance of axonal support.

• #29 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200608/Researchers-discover-important-molecular-mechanism-of-Charcot-Marie-Tooth-disease.aspx

  Charcot-Marie-Tooth (CMT) disease is the most common form of inherited neuropathies. A genetic mutation causes the insulating myelin layer of peripheral nerves to become progressively damaged, resulting in severe disabilities in the case of CMT type 4B, for instance. […] Now researchers from the Leibniz-Forschungsinstitut fr Molekulare Pharmakologie (FMP) in Berlin, in collaboration with colleagues from Milan, Paris and Mexico, have been able to highlight a new molecular mechanism: According to their discovery, the protein Rab35 and the mTOR signaling pathway it regulates play a central role in the formation of myelin sheaths in the peripheral nervous system. […] „Our study revealed that the protein Rab35 regulates the longitudinal growth of the myelin sheath by binding and recruiting the two pseudophosphatases MTMR13 and MTMR5, and hence, also the active phosphatase MTMR2 bound to it in a complex,” reported Linda Sawade, lead author of the study.

• #30 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200608/Researchers-discover-important-molecular-mechanism-of-Charcot-Marie-Tooth-disease.aspx

  The new finding was that Rab35 binds this lipid phosphatase complex, and therefore plays a key role in regulating myelin sheath formation. […] Coincidentally, the researchers observed an abnormally elevated activity of the mTORC1 signaling pathway- one of the central signaling complexes for regulating myelin sheath formation in nerve tissue. […] The researchers were also able to draw an important conclusion from the absence of the Rab35 protein: mTORC1 is hyperactive because PI 3-phosphates are no longer regulated, causing the accumulation of PI(3)P and PI(3,5)P2 lipids. […] „We assume that this pathological process results from an impaired recruitment of MTMR complexes,” explained biochemist and cell biologist Linda Sawade. […] In a nutshell, the results have a great impact for basic research: Rab35 is a previously unidentified regulator of myelin sheath formation in the peripheral nervous system and a repressor of mTORC1.

• #31 Researchers Identify Mechanism Behind Inherited Neuropathy Charcot-Marie-Tooth Disease | Technology Networks

  https://www.technologynetworks.com/neuroscience/news/researchers-identify-mechanism-behind-inherited-neuropathy-charcot-marie-tooth-disease-335869

  The new finding was that Rab35 binds this lipid phosphatase complex, and therefore plays a key role in regulating myelin sheath formation. […] Coincidentally, the researchers observed an abnormally elevated activity of the mTORC1 signaling pathway one of the central signaling complexes for regulating myelin sheath formation in nerve tissue. […] The researchers were also able to draw an important conclusion from the absence of the Rab35 protein: mTORC1 is hyperactive because PI 3-phosphates are no longer regulated, causing the accumulation of PI(3)P and PI(3,5)P 2 lipids. […] Rab35 is a previously unidentified regulator of myelin sheath formation in the peripheral nervous system and a repressor of mTORC1. […] Therapeutic treatment using mTORC1-inhibiting drugs such as Rapamycin could improve disease progression.

• #32 Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002104

  CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositide phosphatase FIG4/SAC3. […] Analysis using the yeast two-hybrid system demonstrated that the I41T mutation impairs interaction of FIG4 with the scaffold protein VAC14. […] The critical role of this interaction was confirmed by the demonstration of loss of FIG4 protein in VAC14 null mice. […] The data demonstrate that FIG4-I41T is a hypomorphic allele encoding a protein that is unstable in vivo. […] Expression of FIG4-I41T protein at 10% of normal level is sufficient for long-term survival, suggesting that patients with CMT4J could be treated by increased production or stabilization of the mutant protein. […] We also demonstrate that the pathogenic mechanism of the I41T allele is based on defective interaction with the scaffold protein VAC14, resulting in destabilization of the FIG4 protein in vivo.

• #33 Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002104

  The low level of FIG4 protein in rescued mice and in patient fibroblasts appears to be a consequence of the direct effect of the I41T mutation on interaction with the scaffold protein VAC14. […] Because of its reduced affinity for VAC14, FIG4-I41T is a hypomorphic allele encoding an unstable protein, resulting in a very low steady-state level of protein in vivo. […] This model of pathogenesis is consistent with the structure of the FIG4 protein, which was predicted by superimposition with the crystal structure of Sac1p, a closely related lipid phosphatase. […] Based on our observations, increased expression or stabilization of the FIG4-I41T protein in patients with CMT4J should be therapeutic and could achieve complete rescue of this progressive neurodegenerative disorder.

• #34 NMD Pharma Reports Results from the ESTABLISH Study – an International Observational Study of Neuromuscular Function in Charcot-Marie-Tooth Type 1 and 2 — NMD Pharma

  https://www.nmdpharma.com/news/cmt-establish2

  Results from the study establish, for the first time, neuromuscular junction (NMJ) transmission deficit as a new disease characteristic in patients with Charcot-Marie-Tooth (CMT) type 1 and 2. […] The level of NMJ transmission deficit in patients with CMT was associated with disease severity assessed through a range of clinical measurements of muscle strength and motor function. […] Here we show that patients with CMT are characterized by deficits of the neuromuscular junction to effectively transmit signals from nerves to muscles and that the level of transmission failure correlates with the functional capabilities of the patients. […] This opens the door for pharmacologically targeting the transmission failure to improve symptoms in patients with CMT. […] uncovering NMJ transmission failure as a new disease mechanism in CMT represents a significant milestone for the development of new therapies including our novel ClC-1 inhibitor treatment approach.

• #35 Target for CMT treatment seen in impaired nerve-muscle signals | Charcot-Marie-Tooth NewsEnvelope icon

  https://charcot-marie-toothnews.com/news/target-cmt-treatment-seen-impaired-nerve-muscle-signals/

  The transmission of signals between the nerves and muscles is impaired in people with Charcot-Marie-Tooth (CMT) type 1 or 2, and the severity of this impairment appears to be related to the disease’s. […] With no currently approved treatments or therapies for this debilitating disease, uncovering NMJ transmission failure as a new disease mechanism in CMT represents a significant milestone for the development of new therapies including our novel ClC-1 inhibitor treatment approach. […] This means NMJ may fail to “effectively transmit signals from nerves to muscles and that the level of transmission failure correlates with the functional capabilities of the patients.” […] This opens the door for pharmacologically targeting the transmission failure to improve symptoms in patients with CMT.

• #36 Inherited Neuropathies: Giant Axonal Neuropathy, Charcot-Marie-Tooth Disease, and Hereditary Transthyretin Amyloidosis

  https://practicalneurology.com/articles/2023-aug/inherited-neuropathies-giant-axonal-neuropathy-charcot-marie-tooth-disease-and-hereditary-transthyretin-amyloidosis

  Different alterations in the same gene can lead to varying pathologic and clinical phenotypes; for example, different sequence variations in the MPZ gene can lead to either an axonal or demyelinating neuropathy. […] The nomenclature of CMT is evolving as genetic causes are replacing phenotypic descriptions. […] The hallmark of the disease is slowly progressive muscle weakness and atrophy initially affecting the distal extremities. […] Symptoms typically start in the feet and progress to involve the hands. […] Characteristic foot and ankle deformities, such as hammertoes, pes cavus, pes planus, and shin and hand atrophy, can provide clues about the chronicity of symptoms. […] Some forms of CMT may present with distinct symptoms that can be helpful in diagnosis. TRPV4 and SORD alterations are 2 important causes of CMT2.

• #37 Charcot-Marie-Tooth Disease Type 1A and Inflammatory-Demyelinating Lesions in the Central Nervous System

  https://clinmedjournals.org/articles/ijnn/international-journal-of-neurology-and-neurotherapy-ijnn-6-080.php?jid=ijnn

  Cases of CNS involvement have been reported in both subtypes of CMT and with different genetic mutations, e.g. in CMT1A (PMP22), CMT2A (mitofuscin2) and X-linked CMT (CMTX) due to mutations in GBJ1. CMT1A is caused by a duplication of the 17p11.2 region of the PMP22 gene, while deletion of this region gives rise to HNPP, and both polyneuropathies are associated with CNS abnormalities which can be asymptomatic in some cases and associated with neurological (e.g. pyramidal) symptoms in others. […] A possible physiopathogenic explanation that would interrelate concomitant inflammatory-demyelinating disease in the central and peripheral nervous systems in the case of different types of CMT may lie in the detection of the PMP22 protein, mitofuscin2 and GBJ1 in different structures of the CNS (optic nerves, brain and spinal cord), which could trigger an autoimmune response against these proteins.

• #38 Charcot-Marie-Tooth Disease: Updates in Diagnosis and Treatment Guidelines Pertaining to the Lower Extremity and Case Study

  https://clinmedjournals.org/articles/ijfa/international-journal-of-foot-and-ankle-ijfa-7-080.php?jid=ijfa

  In order to understand the pathogenesis of pes cavus, Sabir, et al. studied 22 persons from a single kinship with CMT. They noted that all patients presented with a pes cavus deformity. The researchers also noted that the cause was due to the atrophy of the intrinsic foot muscles which progressively lead to further soft tissue and bone deformities. […] Most recent studies on CMT suggested that pes cavus is an early and age-dependent manifestation of a CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, seems to be the initial mechanism causing cavus deformity, leading to reduced ankle flexibility via compensatory mechanisms. […] Mann described the pathogenesis of pes cavus in patients with CMT disease. He described an agonist and antagonist model for how the muscles determine the deformity. Often in CMT, the anterior tibialis muscle and the peroneus brevis muscle develop weaknesses. Antagonist muscles, such as tibialis posterior and peroneus longus, pull harder than the other muscles, causing a deformity. Specifically, the peroneus longus pulls harder than the weak anterior tibialis muscle, causing plantarflexion of the first ray and forefoot valgus. The tibialis posterior pulls harder than the weak peroneus brevis, causing forefoot adduction. Intrinsic muscles of the foot develop contractures while the long extensor to the toes is recruited to assist in ankle dorsiflexion, causing cock-up or claw toe deformity.

• #39 Charcot-Marie-Tooth Disease: Updates in Diagnosis and Treatment Guidelines Pertaining to the Lower Extremity and Case Study

  https://clinmedjournals.org/articles/ijfa/international-journal-of-foot-and-ankle-ijfa-7-080.php?jid=ijfa

  Claw toe deformity in CMT is an associated deformity involving intrinsic musculature and/or long flexors and extensor muscles. Balance in the toes results from the modifying force of the intrinsic musculature to flex the metatarsophalangeal joints and extend the interphalangeal joints. When function of the intrinsic muscles is lost, as characteristically occurs in CMT1A, the unopposed force of the extrinsic muscles dorsiflexes the metatarsophalangeal joints and flexes the interphalangeal joints, resulting in a clawfoot deformity.

• #40 Inherited Neuropathies: Giant Axonal Neuropathy, Charcot-Marie-Tooth Disease, and Hereditary Transthyretin Amyloidosis

  https://practicalneurology.com/articles/2023-aug/inherited-neuropathies-giant-axonal-neuropathy-charcot-marie-tooth-disease-and-hereditary-transthyretin-amyloidosis

  Genetic testing remains the standard for diagnosis. […] PMP22 duplication (CMT1A), GJB1 alterations (CMTX1), PMP22 deletion (hereditary neuropathy with liability to pressure palsies), MPZ alterations (CMT1B), and MFN2 alterations (CMT2A) are the most common variants, with CMT1A accounting for about 50% of all cases. […] Management of CMT typically has focused on supportive measures. […] Gene therapy is another promising avenue of active research. Both antisense oligonucleotides and small interfering RNAs were shown to decrease PMP22 levels and improve motor function in a rat model. […] Gene therapy trials targeting CMT-associated alterations with loss-of-function sequence variations using AAV vectors in both GJB1 and MPZ mutated rat models also are underway.

• #41 Discovery of important molecular mechanism of Charcot-Marie-Tooth disease

  https://medicalxpress.com/news/2020-06-discovery-important-molecular-mechanism-charcot-marie-tooth.html

  Loss of the Rab35 protein led to the abnormalities and, eventually, the degenerative destruction (demyelination) of myelin sheaths in the sciatic nerve. […] The researchers were also able to draw an important conclusion from the absence of the Rab35 protein: mTORC1 is hyperactive because PI 3-phosphates are no longer regulated, causing the accumulation of PI(3)P and PI(3,5)P2 lipids. […] In a nutshell, the results have a great impact for basic research: Rab35 is a previously unidentified regulator of myelin sheath formation in the peripheral nervous system and a repressor of mTORC1. […] The results also offer a glimmer of hope to CMT4B patients: Therapeutic treatment using mTORC1-inhibiting drugs such as Rapamycin could improve disease progression.

• #42 Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association

  https://www.mdpi.com/2076-3921/14/3/331

  To test this hypothesis, we exposed cultured primary fibroblasts from CMT1A and wild-type (WT) patients to RAS-selective lethal 3 (RSL3), a potent and specific inducer of ferroptosis that inhibits GPX4, and assessed the differences in cell death progression between the groups. […] Our findings demonstrate that cultured CMT1A fibroblasts exhibit compromised antioxidant defenses, while transcriptomic data from CMT1A Schwann cells suggest a compensatory response to chronic ferroptotic stress. These results identify ferroptosis as a novel pathogenic mechanism in CMT1A, which may serve as a potential target for anti-ferroptotic therapies for this disease and related peripheral neuropathies.

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