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Biomedicines 2022 Jun 15;10(6). Epub 2022 Jun 15.

Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.

Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the () gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms of the disease. Read More

Neurochem Res 2022 Apr 5. Epub 2022 Apr 5.

Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.

Hereditary peripheral neuropathies called Charcot-Marie-Tooth (CMT) disease affect the sensory nerves as well as motor neurons. CMT diseases are composed of a heterogeneous group of diseases. They are characterized by symptoms such as muscle weakness and wasting. Read More

Hum Mutat 2022 Jul 21;43(7):869-876. Epub 2022 Apr 21.

Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.

Heterozygosity for missense variants and small in-frame deletions in GARS1 has been reported in patients with a range of genetic neuropathies including Charcot-Marie-Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and infantile spinal muscular atrophy (iSMA). We identified two unrelated patients who are each heterozygous for a previously unreported missense variant modifying amino-acid position 336 in the catalytic domain of GARS1. One patient was a 20-year-old woman with iSMA, and the second was a 41-year-old man with CMT2D. Read More

Genes (Basel) 2022 03 5;13(3). Epub 2022 Mar 5.

Department of Biological Sciences, Kongju National University, 56 Gongjudaehak-ro, Gongju 32588, Korea.

Small heat shock proteins (sHSPs) are ATP-independent chaperones that help correct the folding of denatured proteins and protect cells from stress. Mutations in , , and are implicated in inherited peripheral neuropathies (IPNs), such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathies (dHMN). This study, using whole exome sequencing or targeted gene sequencing, identified 9 pathogenic or likely pathogenic variants in these three sHSP genes from 11 Korean IPN families. Read More

Biomolecules 2022 03 16;12(3). Epub 2022 Mar 16.

Laboratorio de Biología Celular del Sistema Nervioso Periférico, Departamento de Proteínas y Ácidos Nucleicos, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay.

Myelination of the peripheral nervous system requires Schwann cells (SC) differentiation into the myelinating phenotype. The peripheral myelin protein-22 (PMP22) is an integral membrane glycoprotein, expressed in SC. It was initially described as a growth arrest-specific () gene product, up-regulated by serum starvation. Read More

Eur J Neurol 2022 Jul 23;29(7):2056-2065. Epub 2022 Mar 23.

Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background And Purpose: Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot-Marie-Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms.

Methods: Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. Read More

EMBO J 2022 03 8;41(5):e108899. Epub 2022 Feb 8.

Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The mechanochemical coupling of ATPase hydrolysis and conformational dynamics in kinesin motors facilitates intramolecular interaction cycles between the kinesin motor and neck domains, which are essential for microtubule-based motility. Here, we characterized a charge-inverting KIF1A-E239K mutant that we identified in a family with axonal-type Charcot-Marie-Tooth disease and also in 24 cases in human neuropathies including spastic paraplegia and hereditary sensory and autonomic neuropathy. We show that Glu239 in the β7 strand is a key residue of the motor domain that regulates the motor-neck interaction. Read More

Mol Genet Genomic Med 2022 02 19;10(2):e1870. Epub 2022 Jan 19.

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy. Mutations in the neurofilament light polypeptide (NEFL) gene produce diverse clinical phenotypes, including demyelinating (CMT1F), axonal (CMT2E), and intermediate (CMTDIG) neuropathies. From 2005 to 2020, 1,143 Korean CMT families underwent gene sequencing, and we investigated the clinical, genetic, and neuroimaging spectra of NEFL-related CMT patients. Read More

J Anat 2021 Dec 7. Epub 2021 Dec 7.

The Jackson Laboratory, Bar Harbor, Maine, USA.

Animal models of neurodegenerative diseases such as inherited peripheral neuropathies sometimes accurately recreate the pathophysiology of the human disease, and sometimes accurately recreate the genetic perturbations found in patients. Ideally, models achieve both, but this is not always possible; nonetheless, such models are informative. Here we describe two animal models of inherited peripheral neuropathy: mice with a mutation in tyrosyl tRNA-synthetase, Yars , modeling dominant intermediate Charcot-Marie-Tooth disease type C (diCMTC), and mice with a mutation in serine palmitoyltransferase long chain 1, Sptlc1 , modeling hereditary sensory and autonomic neuropathy type 1 (HSAN1). Read More

Orphanet J Rare Dis 2021 10 16;16(1):433. Epub 2021 Oct 16.

Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, USA.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0. Read More

Bol Med Hosp Infant Mex 2021 ;78(5):474-478

Departamento de Genética, Facultad de Medicina, Benemérita Universidad Autónoma de Puebla. Puebla, Puebla, Mexico.

Background: Charcot-Marie-Tooth disease type 2Q (CMT2Q) is a rare disorder (< 1/1,000,000 individuals worldwide) linked to chromosome 10p14 in the DHTKD1 gene. This phenotype is characterized by an adolescent or adulthood-onset, slowly progressive distal muscle weakness and symmetrical atrophy associated with reduced or absent deep tendon reflexes. Currently, only two familiar cases from China have been reported: one familiar case of eight individuals affected by isolated DHTKD1 gene mutation and one familiar case of two individuals affected by DHTKD1 gene mutation and GJB1 gene mutation. Read More

Neurol Sci 2022 Jan 16;43(1):705-707. Epub 2021 Sep 16.

Service of Neuromuscular Disorders, Division of Neurology, Department of Internal Medicine, Hospital de Clínicas, Universidade Federal Do Paraná (UFPR), Curitiba, 80060-900, Brazil.

We reported one patient with Charcot-Marie-Tooth type 4C (CMT4C) who developed seropositive myasthenia gravis. Neuromuscular junction alterations in CMT4C patients have not yet been reported. However, few patients have been reported to simultaneously have MG and CMT, but none with CMT4C. Read More

Comput Struct Biotechnol J 2021 30;19:4265-4272. Epub 2021 Jul 30.

Univ. Limoges, MMNP, EA6309, F-87000 Limoges, France.

Next-generation sequencing (NGS) allows the detection of mutations in inherited genetic diseases, like the Charcot-Marie-Tooth disease (CMT) which is the most common hereditary peripheral neuropathy. The majority of mutations detected by NGS are single nucleotide variants (SNVs) or small indels, while structural variants (SVs) are often underdiagnosed. was the first gene described as being involved in CMT via a SV of duplication type. Read More

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 Jun 23.

Centre de recherche en CardioVasculaire et Nutrition, Aix-Marseille Université, INRA 1260-INSERM 1263, 13005 Marseille, France.

Charcot-Marie-Tooth disease (CMT) is the most frequent hereditary peripheral neuropathies. It is subdivided in two main groups, demyelinating (CMT1) and axonal (CMT2). CMT1 forms are the most frequent. Read More

Aging Cell 2021 06 30;20(6):e13391. Epub 2021 May 30.

State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.

Charcot-Marie-Tooth disease is the most common inherited peripheral neuropathy. Dominant mutations in the glycyl-tRNA synthetase (GARS) gene cause peripheral nerve degeneration and lead to CMT disease type 2D. The underlying mechanisms of mutations in GARS (GARS ) in disease pathogenesis are not fully understood. Read More

Surg Neurol Int 2021 24;12:114. Epub 2021 Mar 24.

Department of Neurosurgery, Salford Royal NHS Foundation Trust, Greater Manchester, United Kingdom.

Background: Spinal cord compression secondary to nerve root hypertrophy is often attributed to hereditary neuropathies. However, to avoid misdiagnosis, rare immune-mediated neuropathy such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) should not be overlooked. This report presents a case of multilevel nerve root hypertrophy leading to significant cord compression from CIDP. Read More

Medicine (Baltimore) 2021 Mar;100(11):e25163

Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, China.

Rationale: Charcot-Marie-Tooth disease (CMT) is a group of hereditary neuropathies with clinical features of muscle atrophy, sensory loss, and foot deformities. CMT is related to a number of genes, such as peripheral myelin protein 22 gene (PMP22). Missense mutations, small deletion mutations, and duplications of PMP22 are common in CMT patients, but few insertion mutation cases of PMP22 have been reported. Read More

J Pak Med Assoc 2020 Dec;70(12(B)):2342-2345

Department of Zoology, The Women University Multan, Pakistan.

Objective: To find the effect of pathogenic Mitofusin 2 mutations, responsible for Charcot-Marie-Tooth hereditary neuropathy type 2A, on protein structure.

Methods: The study was conducted at department of biosciences COMSATS University Islamabad, Sahiwal campus from September 2016 to July 2017, and comprised patients with Charcot Marie-Tooth hereditary neuropathy type 2A who were divided into early-onset severe group A and late-onset mild group B. Bioinformatics and molecular analysis was done to find the changes in the protein structure caused by the mutation. Read More

Neurosci Lett 2021 01 24;744:135595. Epub 2020 Dec 24.

Department of Neurology, Neuromuscular Division, Johns Hopkins School of Medicine, Baltimore, MD, United States. Electronic address:

Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. Read More

Brain Behav 2021 01 13;11(1):e01948. Epub 2020 Nov 13.

National Neuromuscular Centre Norway and Department of Neurology, University Hospital of North Norway, Tromsø, Norway.

Aim: To investigate the point prevalence of hereditary neuromuscular disorders on January 1, 2020 in Northern Norway.

Methods: From January 1, 1999, until January 1, 2020, we screened medical and genetic hospital records in Northern Norway for hereditary neuromuscular disorders.

Results: We identified 542 patients with a hereditary neuromuscular disorder living in Northern Norway, giving a point prevalence of 111. Read More

Brain Sci 2020 Jun 27;10(7). Epub 2020 Jun 27.

CHU de Limoges, Service de Biochimie et Génétique Moléculaire, F-87000 Limoges, France.

Modelling rare neurogenetic diseases to develop new therapeutic strategies is highly challenging. The use of human-induced pluripotent stem cells (hiPSCs) is a powerful approach to obtain specialized cells from patients. For hereditary peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) Type II, spinal motor neurons (MNs) are impaired but are very difficult to study. Read More

Neurol Sci 2020 Dec 10;41(12):3719-3727. Epub 2020 Jun 10.

Statistics Unit, Department of Economics, University "G. d'Annunzio", Chieti-Pescara, Italy.

Objective: The interpretation of electrophysiological findings may lead to misdiagnosis in polyneuropathies. We investigated the electrodiagnostic accuracy of three supervised learning algorithms (SLAs): shrinkage discriminant analysis, multinomial logistic regression, and support vector machine (SVM), and three expert and three trainee neurophysiologists.

Methods: We enrolled 434 subjects with the following diagnoses: chronic inflammatory demyelinating polyneuropathy (99), Charcot-Marie-Tooth disease type 1A (124), hereditary neuropathy with liability to pressure palsy (46), diabetic polyneuropathy (67), and controls (98). Read More

Glia 2020 11 8;68(11):2300-2315. Epub 2020 Jun 8.

Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.

Abnormalities of the peripheral myelin protein 22 (PMP22) gene, including duplication, deletion and point mutations are a major culprit in Type 1 Charcot-Marie-Tooth (CMT) diseases. The complete absence of PMP22 alters cholesterol metabolism in Schwann cells, which likely contributes to myelination deficits. Here, we examined the subcellular trafficking of cholesterol in distinct models of PMP22-linked neuropathies. Read More

Clin Genet 2020 08 29;98(2):185-190. Epub 2020 Jun 29.

Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Diagnostic yield of genetic studies for Charcot-Marie-Tooth disease (CMT) is little known, with a lack of epidemiological data to build better diagnostic strategies outside the United States and Europe. We aimed to evaluate the performance of two molecular diagnostic strategies for patients with CMT, and to characterize epidemiological findings of these conditions in southern Brazil. We performed a single-center cross-sectional study, in which 94 patients (55 families) with CMT suspicion were evaluated. Read More

Neurogenetics 2020 10 3;21(4):301-304. Epub 2020 Jun 3.

The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

Mutations in myotubularin-related protein 2 (MTMR2) were shown to underlie Charcot-Marie-Tooth type 4B1 (CMT4B1) disease, a rare autosomal recessive demyelinating neuropathy, characterized by severe early-onset motor and sensory neuropathy. We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c. Read More

Eur J Neurol 2020 10;27(10):2109-2110

Institute for Biomedical Research and Innovation, National Research Council (CNR), Mangone (CS), Italy.

Background: Charcot-Marie-Tooth disease (CMT) constitutes a group of heterogeneous hereditary motor and sensor neuropathies. Mutations in the periaxin (PRX) gene cause CMT4F with an autosomal recessive early-onset demyelinating neuropathy and are extremely rare in a non-Romani white population.

Methods: We report on a 66-year-old Italian man presenting with slowly progressive and late-onset demyelinating CMT. Read More

J Peripher Nerv Syst 2020 06 12;25(2):132-137. Epub 2020 May 12.

Department of Neurosciences and Behavior Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common type of hereditary neuropathy worldwide and diabetes mellitus (DM) is the most frequent cause of peripheral neuropathy in the Western world. CMT1A typically manifest as a predominant motor neuropathy, while, DM-related neuropathy often manifests as a predominant sensory disorder. There are some evidences that CMT1A patients that also had DM had a more severe neuropathy. Read More

J Neurol Sci 2020 06 27;413:116809. Epub 2020 Mar 27.

Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; University of Queensland, Centre for Clinical Research, Brisbane, Queensland, Australia.

Background: Heat shock protein beta-1 (HSPB1) is a ubiquitously expressed molecular chaperone that is important in protecting cells against cellular injury. Mutations in this protein are known to cause autosomal dominant hereditary distal axonal neuropathies, including Charcot Marie Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). However, patients with HSPB1 mutations have also been described with upper motor neuron signs. Read More

Cell Stress Chaperones 2020 07 16;25(4):655-665. Epub 2020 Apr 16.

Department of Biochemistry, School of Biology, Moscow State University, Moscow, Russian Federation, 119991.

Charcot-Marie-Tooth (CMT) disease is major hereditary neuropathy. CMT has been linked to mutations in a range of proteins, including the small heat shock protein HspB1. Here we review the properties of several HspB1 mutants associated with CMT. Read More