Search Our Scientific Publications & Authors

Nat Commun 2018 08 2;9(1):3025. Epub 2018 Aug 2.

Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Göttingen, 37075, Germany.

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Read More

Front Mol Neurosci 2018 10;11:227. Epub 2018 Jul 10.

Department of Physics and Astronomy G. Galilei, University of Padua, Padua, Italy.

Connexin 32 (Cx32) is a fundamental protein in the peripheral nervous system (PNS) as its mutations cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), the second most common form of hereditary motor and sensory neuropathy and a demyelinating disease for which there is no effective therapy. Since mutations of the gene encoding Cx32 were first reported in 1993, over 450 different mutations associated with CMT1X including missense, frameshift, deletion and non-sense ones have been identified. Despite the availability of a sizable number of studies focusing on normal and mutated Cx32 channel properties, the crucial role played by Cx32 in the PNS has not yet been elucidated, as well as the molecular pathogenesis of CMT1X. Read More

Adv Exp Med Biol 2018;1076:97-117

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Charcot-Marie-Tooth disease (CMT) was initially described in 1886. It is characterized by defects in the peripheral nervous system, including sensory and motor neurons. Although more than 80 CMT-causing genes have been identified to date, an effective therapy has not yet been developed for this disease. Read More

BMC Struct Biol 2018 06 25;18(1). Epub 2018 Jun 25.

Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.

Background: Myelin is a multilayered proteolipid sheath wrapped around selected axons in the nervous system. Its constituent proteins play major roles in forming of the highly regular membrane structure. P2 is a myelin-specific protein of the fatty acid binding protein (FABP) superfamily, which is able to stack lipid bilayers together, and it is a target for mutations in the human inherited neuropathy Charcot-Marie-Tooth disease. Read More

Case Rep Med 2018 26;2018:1760978. Epub 2018 Mar 26.

Department of Otorhinolaryngology, Mayo Clinic, Rochester, MN, USA.

Introduction: Charcot-Marie-Tooth (CMT) disease is a peripheral hereditary neuropathy associated with motor and sensory impairment and can result in profound sensorineural hearing loss (SNHL). Currently, the role of cochlear implantation in the setting of CMT and other progressive peripheral neurodegenerative disorders is not well established.

Methods: Case report and review of the English literature. Read More

Arq Neuropsiquiatr 2018 Apr;76(4):273-276

Setor de doenças Neuromusculares, Departamento de Neurologia / Neurociências, Universidade Federal Fluminense, Niterói, RJ, Brasil.

Charcot-Marie-Tooth (CMT) disease, the most common inherited peripheral neuropathy, has pain as one of its clinical features, yet it remains underdiagnosed and undertreated. This literature review assessed data related to pain from CMT to determine its prevalence, type and importance as a symptom, which, unlike other symptoms, is likely to be treated. The research encompassed 2007 to 2017 and included five articles that addressed pain from CMT. Read More

J Hum Genet 2018 Jul 24;63(7):795-801. Epub 2018 Apr 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Multiple genomic disorders result from recurrent deletions or duplications between low copy repeat (LCR) clusters, mediated by nonallelic homologous recombination. These copy number variants (CNVs) often exhibit variable expressivity and/or incomplete penetrance. However, the population prevalence of many genomic disorders has not been estimated accurately. Read More

Science 2018 04;360(6386):336-341

Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Mitofusins (MFNs) promote fusion-mediated mitochondrial content exchange and subcellular trafficking. Mutations in cause neurodegenerative Charcot-Marie-Tooth disease type 2A (CMT2A). We showed that MFN2 activity can be determined by Met and His interactions with Asp and Leu and controlled by PINK1 kinase-mediated phosphorylation of adjacent MFN2 Ser Small-molecule mimics of the peptide-peptide interface of MFN2 disrupted this interaction, allosterically activating MFN2 and promoting mitochondrial fusion. Read More

J Peripher Nerv Syst 2018 Jun 9;23(2):138-142. Epub 2018 May 9.

The Human Genetics institute, Carmel Medical Center, Haifa, Israel.

Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis. Read More

Dtsch Arztebl Int 2018 02;115(6):91-97

Institute of Human Genetics, Uniklinik RWTH Aachen; Department of Neurology, Uniklinik RWTH Aachen; Department of Pediatrics, Division of Neuropediatrics and Social Pediatrics, Uniklinik RWTH Aachen; Department of Neuropediatrics, Developmental Medicine and Epileptology, Children's Medical Center; Giessen, University of Giessen; Institute of Neuropathology, Uniklinik RWTH Aachen.

Background: Hereditary peripheral neuropathies constitute a large group of genetic diseases, with an overall prevalence of 1:2500. In recent years, the use of so-called next-generation sequencing (NGS) has led to the identification of many previously unknown involved genes and genetic defects that cause neuropathy. In this article, we review the procedures and utility of genetic evaluation for hereditary neurop - athies, while also considering the implications of the fact that causally directed treatment of these disorders is generally unavailable. Read More

Hum Mol Genet 2018 04;27(8):1460-1473

Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, 1683 Nicosia, Cyprus.

Gap junction beta-1 (GJB1) gene mutations affecting the gap junction protein connexin32 (Cx32) cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a common inherited neuropathy. Targeted expression of virally delivered Cx32 in Schwann cells following intrathecal injection of lentiviral vectors in the Cx32 knockout (KO) mouse model of the disease has led to morphological and functional improvement. To examine whether this approach could be effective in CMT1X patients expressing different Cx32 mutants, we treated transgenic Cx32 KO mice expressing the T55I, R75W or N175D CMT1X mutations. Read More

Nat Commun 2018 02 13;9(1):651. Epub 2018 Feb 13.

Department of Medicine, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0QH, UK.

Missense mutations in MORC2 cause neuropathies including spinal muscular atrophy and Charcot-Marie-Tooth disease. We recently identified MORC2 as an effector of epigenetic silencing by the human silencing hub (HUSH). Here we report the biochemical and cellular activities of MORC2 variants, alongside crystal structures of wild-type and neuropathic forms of a human MORC2 fragment comprising the GHKL-type ATPase module and CW-type zinc finger. Read More

FEBS Lett 2018 03 1;592(5):703-717. Epub 2018 Feb 1.

Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA-encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl-tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Read More

Neuromuscul Disord 2018 Feb 24;28(2):169-172. Epub 2017 Nov 24.

Division of Neuromuscular Diseases, Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.

Axonal Charcot-Marie-Tooth disease (CMT) represents an expanding group of inherited motor and sensory neuropathies in clinical practice. SACS-gene related disorders have been associated with complex neurological phenotypes of early-onset cerebellar ataxia, spastic-ataxia, spastic paraplegia, demyelinating neuropathy and variable ophthalmological, cognitive and psychiatric disturbances, but never related to pure axonal neuropathy phenotypes. Two unrelated Brazilian men with early-onset axonal CMT-like presentations associated with SACS gene mutations are presented. Read More

Clin Neurophysiol 2018 01 20;129(1):21-32. Epub 2017 Oct 20.

Neurology Division, Pederzoli Hospital, Peschiera del Garda, Verona, Italy.

Objective: Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology.

Methods: We recruited 36 patients (12 MPZ mutations), and correlated nerve US to clinical, electrodiagnostic measures, and sural nerve biopsy. Read More

Hum Mutat 2018 02 27;39(2):193-196. Epub 2017 Nov 27.

Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.

Single-nucleotide variants that abolish the stop codon ("nonstop" alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C-terminally extended protein depends on the absence or presence of a downstream in-frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized. Read More

Neurologist 2017 Nov;22(6):234-236

2nd Neurology Department, AHEPA University Hospital, Thessaloniki, Greece.

X-linked Charcot-Marie-Tooth disease (CMT 1X) is the second most common form of inherited demyelinating neuropathy. It is established that patients suffering from CMT 1X can have episodes of hemiparesis, paraparesis, quadriparesis, ataxia, aphasia, and dysarthria, which can be fully reversible, and 'trigger' factors for these episodes are usually febrile illness, high altitudes, hyperventilation, and physical activity. We describe a 22-year-old patient with a history of viral infection and sleep deprivation who presented to our department because of acute difficulty in walking and neurophysiological findings suggesting Guillain-Barre syndrome. Read More

J Neurol 2017 12 23;264(12):2431-2435. Epub 2017 Oct 23.

Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.

Varying degrees of optic neuropathy can be seen in patients with Charcot-Marie-Tooth (CMT) disease. To define and characterize the extent of optic neuropathy in patients with CMT2A and CMT1A, two patients from both sub-classifications were evaluated. All patients underwent complete neuro-ophthalmic examinations, and optical coherence (OCT) measurements of the retinal nerve fiber layer (RNFL) and ganglion cell layer complex (GCC) were obtained, along with pattern visual evoked potential (VEP) and pattern electroretinogram (ERG) recordings. Read More

Continuum (Minneap Minn) 2017 10;23(5, Peripheral Nerve and Motor Neuron Disorders):1360-1377

Purpose Of Review: Genetic polyneuropathies are rare and clinically heterogeneous. This article provides an overview of the clinical features, neurologic and electrodiagnostic findings, and management strategies for Charcot-Marie-Tooth disease and other genetic polyneuropathies as well as an algorithm for genetic testing.

Recent Findings: In the past 10 years, many of the mutations causing genetic polyneuropathies have been identified. Read More

Eur J Neurol 2017 12 7;24(12):1499-1506. Epub 2017 Oct 7.

Department of Neurology, Center for Human Genetic Research and Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN.

Background And Purpose: Apoptosis-inducing factor mitochondrion-associated-1 (AIFM1) in mitochondria has captured a great deal of attention due to its well-described function in apoptosis. Mutations in AIFM1 have resulted in multiple clinical phenotypes, including X-linked Charcot-Marie-Tooth disease type 4. These syndromes usually involve multiple locations within the nervous system and/or multiple organs. Read More

Muscle Nerve 2018 Jan 24;57(1):E18-E23. Epub 2017 Aug 24.

Department of Neurosciences, University of Padova, Padova, Italy.

Introduction: Nerve ultrasound in Charcot-Marie-Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves.

Methods: Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Read More

Neurology 2017 Aug 2;89(9):927-935. Epub 2017 Aug 2.

From the Department of Neurology (F.B.P., D.N.H.), University of Rochester Medical Center, NY; MRC Centre for Neuromuscular Diseases (M.L., A.M.R., M.M.R.), UCL Institute of Neurology, UK; Department of Neurology (C.P., D.P.), Carlo Besta Neurological Institute, Milan, Italy; Department of Neurosciences (G.P.), Institute of Telese Terme (BN), Italy; Children's Hospital at Westmead (J.B.), University of Sydney, Australia; Department of Neurology (J.L.), Vanderbilt University, Nashville, TN; Neuromuscular Program (S.W.Y.), Children's Hospital of Philadelphia, PA; Department of Neurology (R.A.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (J.D.), Stanford University, CA; Institute of Genetic Medicine (R.H.), Newcastle University, UK; Department of Neurology (M.E.S.), University of Iowa Hospitals and Clinics; and Department of Neurology (S.S.S.), University of Pennsylvania, Philadelphia.

Objective: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships.

Methods: Mutations in cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. Read More

Clin Genet 2018 Feb 12;93(2):301-309. Epub 2017 Dec 12.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Read More

Curr Opin Neurol 2017 10;30(5):471-480

Unit of Rare Neurological Diseases of Adulthood, Department of Clinical Neurosciences, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy.

Purpose Of Review: Charcot-Marie-Tooth disease (CMT) and related neuropathies represent a heterogeneous group of hereditary disorders. The present review will discuss the most recent advances in the field.

Recent Findings: Knowledge of CMT epidemiology and frequency of the main associated genes is increasing, with an overall prevalence estimated at 10-28/100 000. Read More

Hum Mutat 2017 10 14;38(10):1412-1420. Epub 2017 Jul 14.

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in myriad dominant and recessive disease phenotypes. Glycyl-tRNA synthetase (GARS) is a bifunctional ARS that charges tRNA in the cytoplasm and mitochondria. Read More

PLoS One 2017 27;12(6):e0180038. Epub 2017 Jun 27.

Department of Pathology and Cell Biology and Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians & Surgeons, New York, New York, United States of America.

Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy is the most prevalent inherited peripheral neuropathy and is associated with over 90 causative genes. Mutations in neurofilament light polypeptide gene, NEFL cause CMT2E, an axonal form of CMT that results in abnormal structures and/or functions of peripheral axons in spinal cord motor neurons and dorsal root ganglion neurons. We have previously generated and characterized a knock-in mouse model of CMT2E with the N98S mutation in Nefl that presented with multiple inclusions in spinal cord neurons. Read More

Hum Mol Genet 2017 09;26(17):3313-3326

Sobell Department of Motor Neuroscience and Movement Disorders.

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. In this study, we conducted analysis of bidirectional movements of mitochondria in primary motor neuron axons expressing wild type and mutant Hsp27. Read More

J Neurol Neurosurg Psychiatry 2017 07 13;88(7):575-585. Epub 2017 May 13.

MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK.

Objectives: To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene ().

Methods: Combined analysis of newly identified patients with -related CMT and all previously reported cases from the literature.

Results: Five new unrelated patients with CMT carrying the mutations P8R and N98S and the novel variant L311P were identified. Read More

Hum Mol Genet 2017 06;26(11):2034-2041

Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

Charcot-Marie-Tooth (CMT) disease type 2 is a genetically heterogeneous group of inherited neuropathies characterized by motor and sensory deficits as a result of peripheral axonal degeneration. We recently reported a frameshift (FS) mutation in the Really Interesting New Gene finger (RING) domain of LRSAM1 (c.2121_2122dup, p. Read More

Eur J Neurol 2017 03;24(3):530-538

Centre de Référence des Maladies Neuromusculaires Paris Est, Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris, France.

Background And Purpose: Charcot-Marie-Tooth (CMT) 1C due to mutations in LITAF/SIMPLE is a rare subtype amongst the autosomal dominant demyelinating forms of CMT. Our objective was to report the clinical and electrophysiological characteristics of 18 CMT1C patients and compare them to 20 patients with PMP22 mutations: 10 CMT1A patients and 10 patients with hereditary neuropathy with liability to pressure palsies (HNPP).

Methods: Charcot-Marie-Tooth 1C patients were followed-up in referral centres for neuromuscular diseases or were identified by familial survey. Read More

J Hum Genet 2017 Jun 9;62(6):599-604. Epub 2017 Mar 9.

Department of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Japan.

Immunoglobulin helicase μ-binding protein 2 (IGHMBP2) gene is responsible for Charcot-Marie-Tooth disease (CMT) type 2S and spinal muscular atrophy with respiratory distress type 1 (SMARD1). From June 2014 to December 2015, we collected 408 cases, who referred to our genetic laboratory for genetic analysis, suspected with CMT disease or other inherited peripheral neuropathies (IPNs) on the basis of clinical manifestations and electrophysiological studies. Mutation screening was performed using Ion AmpliSeq Custom Panels, which comprise 72 disease-causing or candidate genes of IPNs. Read More

Microsurgery 2017 Sep 7;37(6):558-563. Epub 2017 Feb 7.

Division of Plastic and Reconstructive Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Introduction: Today, reconstructive surgeons offer an array of options to reconstruct the lip defects. Herein we present our experience of using free double-paddle peroneal flaps for extensive lip defect reconstruction.

Patients And Methods: From 1996 to 2014, 16 patients with extensive lip defects after tumor ablation were included. Read More

Acta Neuropathol Commun 2017 01 11;5(1). Epub 2017 Jan 11.

Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, Institute Born Bunge and University of Antwerp, Antwerpen, Belgium.

The small heat shock protein HSPB1 (Hsp27) is an ubiquitously expressed molecular chaperone able to regulate various cellular functions like actin dynamics, oxidative stress regulation and anti-apoptosis. So far disease causing mutations in HSPB1 have been associated with neurodegenerative diseases such as distal hereditary motor neuropathy, Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis. Most mutations in HSPB1 target its highly conserved α-crystallin domain, while other mutations affect the C- or N-terminal regions or its promotor. Read More

PLoS One 2017 11;12(1):e0169999. Epub 2017 Jan 11.

Molecular Biology Unit, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.

Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant axonal peripheral neuropathy caused by mutations in the mitofusin 2 gene (MFN2). Mitofusin 2 is a GTPase protein present in the outer mitochondrial membrane and responsible for regulation of mitochondrial network architecture via the fusion of mitochondria. As that fusion process is known to be strongly dependent on the GTPase activity of mitofusin 2, it is postulated that the MFN2 mutation within the GTPase domain may lead to impaired GTPase activity, and in turn to mitochondrial dysfunction. Read More

Sci Rep 2017 01 10;7:40166. Epub 2017 Jan 10.

Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, Chicago IL, USA.

CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. Read More

Biochim Biophys Acta Mol Cell Res 2017 Feb 30;1864(2):440-448. Epub 2016 Nov 30.

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address:

We previously showed that MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also CHCHD2) functions in two subcellular compartments, displaying a different function in each. In the mitochondria it is a stress regulator of respiration that binds to cytochrome c oxidase (COX) whereas in the nucleus it is a transactivator of COX4I2 and other hypoxia-stimulated genes. We now show that binding of MNRR1 to COX is promoted by phosphorylation at tyrosine-99 and that this interaction stimulates respiration. Read More

Acta Neuropathol 2017 04 28;133(4):493-515. Epub 2016 Nov 28.

Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Ziemssenstr. 1a, 80336, Munich, Germany.

A growing number of hereditary neuropathies have been assigned to causative gene defects in recent years. The study of human nerve biopsy samples has contributed substantially to the discovery of many of these neuropathy genes. Genotype-phenotype correlations based on peripheral nerve pathology have provided a comprehensive picture of the consequences of these mutations. Read More

J Clin Neurosci 2017 Mar 22;37:59-62. Epub 2016 Nov 22.

Department of Radiology and Biomedical Imaging, Yale School of Medicine, Box 208042, Tompkins East 2, 333 Cedar St, New Haven, CT 06520-8042, USA. Electronic address:

Background: Charcot-Marie-Tooth Disease (CMT) is a rare disorder with less than 200,000 cases reported in the US every year, making diagnosis challenging. MR and CT imaging has become more common in the evaluation of CMT to identify areas of disease involvement.

Case Report: A 27-year-old female from Guatemala with a past history of polio initially presented to the emergency room for necrotizing pneumonia. Read More

Clin Pharmacol Ther 2017 Jun 11;101(6):754-762. Epub 2017 Jan 11.

Center for iPS Cells for Research and Application (CiRA), Kyoto University, Kyoto, Japan.

Drugs under development can cause unpredicted toxicity in humans due to differential drug responsiveness between humans and other disease models, resulting in clinical trial failures. Human induced pluripotent stem cells (iPSCs) are expected to represent a useful tool for toxicity testing. However, among many assays, appropriate cellular assays for predicting neurotoxicity in an iPSC-based model are still uncertain. Read More

J Peripher Nerv Syst 2016 12;21(4):365-369

PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.

Charcot-Marie-Tooth type 2A disease (CMT2A) is an inherited peripheral neuropathy mainly caused by mutations in the MFN2 gene coding for the mitochondrial fusion protein mitofusin 2. Although the disease is mainly inherited in a dominant fashion, few cases of early-onset autosomal recessive CMT2A (AR-CMT2A) have been reported in recent years. In this study, we characterized the structure of the mitochondrial network in cultured primary fibroblasts obtained from AR-CMT2A family members. Read More

Cerebellum 2017 04;16(2):599-601

Division of General Neurology and Ataxia Unit, Department of Neurology, Universidade Federal de São Paulo, São Paulo, Brazil.

Herein, we report a patient that presented with late-onset progressive steppage gait, neuropathy and pes cavus, suggesting Charcot-Marie-Tooth (CMT) disease. Subsequent genetic investigation confirmed Friedreich's ataxia (FRDA). We demonstrate that late-onset Friedreich's ataxia (LOFA) may be a CMT mimicker. Read More

Muscle Nerve 2017 May 13;55(5):752-755. Epub 2017 Feb 13.

Department of Neurology, University Hospital Würzburg, Josef-Schneider-Strasse 11, 97080 Würzburg, Germany.

Introduction: Charcot-Marie-Tooth neuropathy (CMT) 2E/1F is caused by mutations in the neurofilament light-chain polypeptide (NEFL) gene. Giant axons are a histological hallmark frequently seen in nerves of patients with CMT2E.

Methods: We describe the case of a 43-year-old patient with a painful, predominantly sensory neuropathy. Read More

Acta Neuropathol Commun 2016 09 1;4(1):95. Epub 2016 Sep 1.

Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus.

X-linked Charcot-Marie-Tooth disease (CMT1X) is a common form of inherited neuropathy resulting from different mutations affecting the gap junction (GJ) protein connexin32 (Cx32). A subset of CMT1X patients may additionally present with acute fulminant CNS dysfunction, typically triggered by conditions of systemic inflammation and metabolic stress. To clarify the underlying mechanisms of CNS phenotypes in CMT1X we studied a mouse model of systemic inflammation induced by lipopolysaccharide (LPS) injection to compare wild type (WT), connexin32 (Cx32) knockout (KO), and KO T55I mice expressing the T55I Cx32 mutation associated with CNS phenotypes. Read More

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2016 Oct;33(5):649-52

Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China; Key Laboratory of Birth Defects and related Obstetric, Gynecologic and Pediatric Diseases of Ministry of Education, Chengdu, Sichuan 610041, China. Email:

Objective: To analyze mutation of the PMP22 gene in a pedigree affected with Charcot-Marie-Tooth disease.

Methods: Genomic DNA was extracted from peripheral blood samples of the proband and members from his family, and fetal DNA was extracted from amniotic fluid sample. Multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (array-CGH) analyses were carried out to determine the copy number of the PMP22 gene. Read More

Neuromuscul Disord 2016 08 24;26(8):516-20. Epub 2016 May 24.

Human Genetics Laboratory, Department of Health Sciences, Amedeo Avogadro University, Via Solaroli 17, 28100 Novara, Italy; Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Amedeo Avogadro University, Novara, Italy.

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with a heterogeneous genetic background. Here, we describe two CMT1B families with a mild sensory-motor neuropathy and a novel synonymous variant (c.309G > T, p. Read More

Hum Mol Genet 2016 07 10;25(14):3055-3069. Epub 2016 Jun 10.

Waisman Center, Madison, WI, USA

Schwann cells are myelinating glia in the peripheral nervous system that form the myelin sheath. A major cause of peripheral neuropathy is a copy number variant involving the Peripheral Myelin Protein 22 (PMP22) gene, which is located within a 1.4-Mb duplication on chromosome 17 associated with the most common form of Charcot-Marie-Tooth Disease (CMT1A). Read More

Eur J Neurol 2016 08 10;23(8):1343-50. Epub 2016 May 10.

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Background And Purpose: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy, but therapeutic options have been limited to symptom management. Past pharmacological trials have failed, possibly due to insensitive outcome measures (OMs). The aim of the current study was to evaluate the validity and reliability of the 6-min walk test (6MWT) and StepWatch(™) Activity Monitoring (SAM) with other previously validated OMs in CMT disease. Read More

ASN Neuro 2016 Mar-Apr;8(2). Epub 2016 Apr 19.

Hunter James Kelly Research Institute, University at Buffalo, NY, USA Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, NY, USA

In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot-Marie-Tooth disease type 1B (CMT1B)-S63del mice. Read More

Neuromuscul Disord 2016 Apr-May;26(4-5):316-21. Epub 2016 Apr 5.

Department of Neurology, National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France. Electronic address:

Congenital hypomyelinating neuropathy appears early in life, resulting in a delay of motor and sensory development. Mutations involve genes such as myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), and early growth response 2 (EGR2). We present a patient with two compound mutations in PMP22: a point mutation causing a premature STOP codon in exon 3 was inherited from the mother on the first allele, and the "typical" PMP22 deletion in the 17p11. Read More

JAMA Neurol 2016 Jun;73(6):645-51

University of Sydney & Children's Hospital at Westmead, Sydney Australia.

Importance: Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date.

Objective: To assess the variability of disease severity in a large cohort of children and adolescents with CMT.

Design, Setting, And Participants: A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Read More