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International Journal of Molecular... Jul 2019Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are... (Review)
Review
Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are X-linked and autosomal recessive subtypes. In addition to a variety of inheritance patterns, there are a myriad of genes associated with CMT, reflecting the heterogeneity of this disorder. Next generation sequencing (NGS) has expanded and simplified the diagnostic yield of genes/molecules underlying and/or associated with CMT, which is of paramount importance in providing a substrate for current and future targeted disease-modifying treatment options. Considerable research attention for disease-modifying therapy has been geared towards the most commonly encountered genetic mutations (, , , and ). In this review, we highlight the clinical background, molecular understanding, and therapeutic investigations of these CMT subtypes, while also discussing therapeutic research pertinent to the remaining less common CMT subtypes.
Topics: Animals; Biomarkers; Charcot-Marie-Tooth Disease; Clinical Trials as Topic; Combined Modality Therapy; Genes, Recessive; Genes, X-Linked; Genetic Association Studies; Genetic Therapy; Humans; Mutation; Phenotype; Treatment Outcome
PubMed: 31336816
DOI: 10.3390/ijms20143419 -
Neurotherapeutics : the Journal of the... Oct 2021Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory... (Review)
Review
Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.
Topics: Axonal Transport; Axons; Charcot-Marie-Tooth Disease; Humans; Mutation
PubMed: 34606075
DOI: 10.1007/s13311-021-01099-2 -
Neuroepidemiology 2016Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: CMT type 1 (CMT1; demyelinating form) and CMT type 2... (Review)
Review
BACKGROUND
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: CMT type 1 (CMT1; demyelinating form) and CMT type 2 (CMT2; axonal form). The objectives of this study were to systematically review and assess the quality of studies reporting the incidence and/or prevalence of CMT worldwide.
SUMMARY
A total of 802 studies were initially identified, with only 12 meeting the inclusion criteria. CMT prevalence was reported in 10 studies and ranged from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. The frequency of the main subtypes varied from 37.6 to 84% for CMT1 and from 12 to 35.9% for CMT2; the country with the lowest prevalence of CMT1 was Norway, and the country with the highest prevalence of CMT1 was Iceland; on the other hand, CMT2 was least prevalent in the United Kingdom and most prevalent in Norway.
KEY MESSAGES
This review reveals the gaps that still exist in the epidemiological knowledge of CMT around the world. Published studies are of varying quality and utilise different methodologies, thus precluding a robust conclusion. Additional research focusing on epidemiological features of CMT in different nations and different ethnic groups is needed.
Topics: Charcot-Marie-Tooth Disease; Epidemiologic Studies; Humans; Population Surveillance
PubMed: 26849231
DOI: 10.1159/000443706 -
Genes Jul 2023Charcot-Marie-Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective... (Review)
Review
Charcot-Marie-Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and causes lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, are appraised. Each of these gene therapies has the potential for substantial advancements in future research.
Topics: Charcot-Marie-Tooth Disease; Humans; Mutation; Intracellular Space; Calcium; Gene Silencing; Genetic Therapy; Animals
PubMed: 37510296
DOI: 10.3390/genes14071391 -
Journal of Neurology Sep 2022In this update, we review the recent discovery of autosomal recessive variants in sorbitol dehydrogenase as one of the commonest and potentially treatable causes of... (Review)
Review
In this update, we review the recent discovery of autosomal recessive variants in sorbitol dehydrogenase as one of the commonest and potentially treatable causes of hereditary motor neuropathy and CMT2. We also report on recent therapeutic advances in hereditary neuropathy including the use of lipid nanoparticle sequestered antisense oligonucleotides in CMT1A and lipid nanoparticle delivered CRISPR-Cas9 gene editing in ATTR amyloidosis.
Topics: Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy; Humans; Liposomes; Nanoparticles
PubMed: 35596796
DOI: 10.1007/s00415-022-11164-1 -
[Charcot Marie Tooth disease: principles of rehabilitation, physiotherapy and occupational therapy].Medecine Sciences : M/S Nov 2017
Topics: Charcot-Marie-Tooth Disease; Disability Evaluation; France; Gait Analysis; Humans; Locomotion; Occupational Therapy; Physical Therapy Modalities; Postural Balance; Practice Guidelines as Topic; Proprioception; Range of Motion, Articular; Walk Test
PubMed: 29139387
DOI: 10.1051/medsci/201733s110 -
Acta Neurologica Scandinavica Oct 2022Traditionally, neurophysiology is the primary diagnostic and prognostic biomarker in peripheral neuropathy clinical practice; however, it may lack responsiveness in the... (Review)
Review
Traditionally, neurophysiology is the primary diagnostic and prognostic biomarker in peripheral neuropathy clinical practice; however, it may lack responsiveness in the context of slowly progressive neuropathies and where there is significant axonal damage. The development of ultrasensitive platforms for measuring serum proteins at the lower limit of detection of traditional ELISA techniques has transformed the field of blood biomarkers of peripheral neuropathy. A variety of blood biomarkers have been identified from inflammatory cytokines and apokines in diabetic neuropathy through to neuron-specific proteins such as neurofilament light chain, Schwann cell-specific proteins such as TMPRSS5 and microRNAs in other acquired and hereditary neuropathies. In this article, we review blood biomarkers of disease activity for the common subtypes of peripheral neuropathy including inflammatory demyelinating neuropathies, vasculitic neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy and Charcot-Marie-Tooth disease and related disorders including TTR amyloidosis.
Topics: Antineoplastic Agents; Biomarkers; Charcot-Marie-Tooth Disease; Cytokines; Humans; MicroRNAs
PubMed: 35611606
DOI: 10.1111/ane.13650 -
European Journal of Human Genetics :... Jun 2009Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the...
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity. Population based studies have determined the contributions of the various genes to disease burden enabling evidence-based approaches to genetic testing.
Topics: Charcot-Marie-Tooth Disease; Genotype; Humans; Mutation; Phenotype
PubMed: 19277060
DOI: 10.1038/ejhg.2009.31 -
Molecular Neurobiology Apr 2013Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since... (Review)
Review
Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50 % of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While overexpression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene.
Topics: Amino Acid Sequence; Animals; Charcot-Marie-Tooth Disease; Humans; Molecular Sequence Data; Mutation; Myelin Proteins; Peripheral Nervous System Diseases
PubMed: 23224996
DOI: 10.1007/s12035-012-8370-x -
Neuroscience Bulletin Dec 2014Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a... (Review)
Review
Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.
Topics: Charcot-Marie-Tooth Disease; Connexins; Electrodiagnosis; Humans; Mutation; Neural Conduction
PubMed: 25326399
DOI: 10.1007/s12264-014-1475-7