DOCSLIB.ORG

Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis Presented for the Degree of Doctor of Medicine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis Presented for the Degree of Doctor of Medicine The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgementTown of the source. The thesis is to be used for private study or non- commercial research purposes only. Cape Published by the University ofof Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine PERIPHERAL NEUROPATHIES OF CHILDHOOD: Jo M Wilmshurst MB BS (London), MRCP (London), FCP (SA) Thesis presented for the Degree of DOCTOR OF MEDICINE Town Department of Paediatric Neurology School of Child and AdolescentCape Health Faculty of Healthof Sciences UNIVERSITY OF CAPE TOWN University 1 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine CONTENTS PAGE Title 1 Contents 2-7 Acknowledgements 8 Funding 9 Previous publications 9 Permissions / ethics 9 Declaration 10 Synopsis 11-13 Chapter 1: 14-39 Introduction, literature review and diagnostic tables Table 1.1: Summary of previous large studies of peripheralTown neuropathies in childhood 18 Table 1.2: Hereditary peripheral neuropathies 19-29 Figure 1.1: Transverse sectionCape of HNPP 30 Figure 1.2 Transverse sectionof of CMT3 30 Figure 1.3 Electron micrograph of CMTX 31 Table 1.3: Neurodegenerative disorders with peripheral neuropathy 32-33 Table 1.4: Specific protein deficiency or mutation 34-39 Chapter 2: 40-67 The role of nerveUniversity biopsy a. Introduction 41-42 b. Principles and technique 42-54 Figure 2.1: Transverse section of a patient with CMTIA 45 Figure 2.2: Transverse section of a patient with CMT 45 Figure 2.3: Teased fibre appearance of demyelination 46 Figure 2.4: Teased fibre appearance of axonal degeneration 47 Figure 2.5: Electron micrograph of neuroaxonal dystrophy. 48 Figure 2.6: Electron micrograph of a patient with Po mutation 49 2 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Figure 2.7: Electron micrograph active axonal degeneration. 50 Figure 2.8: Normal MF diameter changes with age.4 54 c. Biopsy findings in relevant diseases 54-64 Table 2.1: Inflammatory and infectious disorders 56 Table 2.2: Neurodegenerative and Metabolic disorders 57-59 Figure 2.9: Transverse section from a patient with Friedreich’s ataxia 59 Figure 2.10: Electron micrograph from a patient with giant axonal neuropathy. 60 Figure 2.11: Electron micrograph of a patient with metachromatic leukodystrophy 61 Figure 2.12: Transverse section from a patient with Cockayne syndrome Town 61 Table 2.3: Toxic, nutritional deficiencies and miscellaneous 62-63 Figure 2.13: Transverse section from a patient with neurofibromatosis. Cape 64 d. Conclusion of 64 e. Case examples 65-67 Chapter 3: 68-125 Chronic Peripheral Neuropathies Presenting In Childhood – 37 Years of Data from an Australian Population a. SummaryUniversity 68-69 b. Introduction 70 c. Methodology 70-71 d. Results 72-115 Figure 3.1: Summary of total group with peripheral neuropathies 73 Table 3.1: Summary of the motor sensory neuropathies with genetic correlation 73-74 Figure 3.2: Flow chart of patient breakdown leading to definitive genetic confirmation in the CMT group 75 3 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine 1. Hereditary neuropathies 76-108 Figure 3.3: Charcot Marie Tooth diseases broad categories 76 i. Demyelinating forms of CMT 77-85 Figure 3.4: Demyelinating group n=73 77 Figure 3.4a: Teased fibre analysis of patient with CMT1A. 78 Figure 3.4b: Light microscopy study of a patient with CMT3 due to PMP22 mutation. 81 Figure 3.4c: Teased fibre analysis of a patient with CMT3 due to myelin protein zero mutation 81 Figure 3.4d: Transverse section of a CMT4B patient 84 Figure 3.4e: Transverse section of a patient with CMT4B due to fabrin mutation. Town 85 ii. Axonal forms of CMT 86-96 Figure 3.5: Axonal neuropathies n=81 86 Figure 3.5a: TransverseCape section of a patient with EOHMSN due to ofmitofusin mutation. 90 Figure 3.5b: EM section of a patient with MFN2 mutation with reduced myelinated fibre density and an onion bulb formation 91 Figures 3.5c i and ii EM from a patient with Universityconfirmed MFN2 mutation 91-92 Figure 3.6: Hereditary sensory and autonomic neuropathies n=6 96 iii. Mixed forms of CMT 97-98 Figure 3.7: Mixed axonal / demyelinating neuropathies n=7 97 iv. Summary of genetic data from patients with CMT spectrum 99-101 4 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Figure 3.8: Summary of patients who underwent genetic screens 99 Figure 3.9: Summary of the genetic mutations 101 Peripheral neuropathies associated with inherited disorders 102-108 v. Neurodegenerative and metabolic disorders 102-107 Figure 3.10: Neurodegenerative progressive and metabolic disorders with peripheral neuropathy 102 vi. Inherited structural disorders 107-108 2. Acquired neuropathies 109-115 Figure 3.11: Acquired disorders and pathology types n=48 109 Figure 3.11a: Teased fibre analysis of a patient with CIDP 111 Figure 3.11b: Transverse section of a patientTown with a vasculitic neuropathy. 113 Figure 3.11c: Transverse section 3 month old infant, vasculitis demonstrating recanalised vessel.Cape 114 Figure 3.11d: Transverseof section perineuroma 114 d. Discussion 116-125 Chapter 4: 126-141 Peripheral Neuropathies presenting in Infancy from an Australian Population a. Summary 126 b. IntroductionUniversity 127 c. Method 127 d. Results 128-136 Table 4.1: Summary of the diagnostic categories of infantile-onset peripheral neuropathy 128 Figure 4.1: Sural nerve section electron micrography plate from a patient with myelin protein zero mutation CMT3. 130 Figure 4.2: Transverse section from the sural nerve of a patient with CMT with myelin-outfolding 131 5 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine e. Discussion 137-140 Algorithm 4.1: An approach through nerve conduction studies to Hereditary Motor and Sensory Neuropathies 141 Chapter 5: 142-183 Children presenting with Chronic Peripheral neuropathy in a South African population a. Summary 142 b. Introduction 143-145 c. Methods 145-146 d. Results 146-178 Figure 5.1: Summary of hereditary peripheral neuropathies 146 Figure 5.2: Patient with confirmed CMT1A. 148 Figure 5.3: Nerve biopsy of a patient with CMT1ATown 149 Figure 5.4: Affected CMT3 patient 150 Figure 5.5. Nerve biopsy of a patient with clinical phenotype of CMT3 Cape 151 Figure 5.6. Electron microscopyof onion bulb formation 151 Figure 5.7: Hands from father and son with CMT2. 153 Figure 5.8: Electron microscopy of patient with axonal neurophysiology but genetic diagnosis of CMT1A. 154 Figure 5.9: Clinical phenotype of patient with EOHMSN 155 UniversityFigure 5.10: (a & b). Clinical phenotype of patient with EOHMSN with extreme distal wasting. 156 Figures 5.11 Light microscopy from patient in Figure 5.9. 156 Figure 5.12 (a & b): Light microscopy patient with EOHMSN (Figure 5.10) 157 Figure 5.13: EM from the patient in Figure 5.10 158 Figure 5.14 (a & b). Girl with miscellaneous axonal disease 160 Figure 5.15: Patient with SIANR 162 Figure 5.16: Patient with the juvenile form of SIANR 162 6 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Figure 5.17: Chest X-ray patient with juvenile SIANR 163 Figure 5.18. Muscle biopsy patient with Vitamin E deficiency 167. Figure 5.19: Summary of acquired conditions 170 Figure 5.20a. Image of the hands from the eleven year old girl with HIV-1 infection 172 Figure 5.20b. The lower limbs of the patient in Figure 5.20a. 173 Table 5.1: Summary of the patients who underwent peripheral nerve biopsy 174-178 e. Discussion 179-183 Chapter 6: 184-193 Conclusion and recommendations - guideline approach to investigations and diagnosis of Peripheral Neuropathies in childhood in resource-limited setting Table 6.1: Summary of conditions commonlyTown associated with specific clinical features. 192 Figure 6.1: Approach to the child with suspected peripheral neuropathy in a resourceCape-limited setting 193 Figure 6.2: Approach toof the HIV infected child with distal weakness / sensory disturbances. 194 References 195-220 University 7 Peripheral Neuropathies of Childhood Jo M Wilmshurst Thesis presented for the Degree of Doctor of Medicine Acknowledgements My husband Mark, and daughters Tabitha and Jasmine for their understanding and support. My parents and friends for their support both with child care and patient interest in a topic they had never heard of. My father especially, for proof reading the text. The neurology team at Red Cross Children’s Hospital who covered my clinical duties for 3 months. Dr Komala Pillay and her team for their assistance with the South African histopathology analysis and providing images of the biopsy samples. My Supervisors, Professor Robert Ouvrier, Head of the Institute for Neuromuscular Research at The Children’s Hospital at Westmead in Sydney, Australia, for his great support and patience during the creation of this magnum opus. Prof Colin Sinclair-Smith, Head of Histopathology, at Red Cross Children’sTown Hospital, University of Cape Town, who sadly died in October 2008, for his enthusiasm and interest in such a specialized area. Professor Heather Zar, who stepped in at short noticeCape to cover Colin’s place. Dr Min Wang from the Institute of Nerve Research,of University of Sydney for assisting me with access to the pathology and images from many of the patients.
Load more

Recommended publications
  • NBD-17-173R1 Title
    Elsevier Editorial System(tm) for Neurobiology of Disease Manuscript Draft Manuscript Number: NBD-17-173R1 Title: KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects Article Type: Research paper Keywords: Motoneuron; Andermann syndrome; chloride homeostasis; electrical activity; neuromuscular junction; Na+/K+ ATPase Corresponding Author: Dr frederique scamps, Corresponding Author's Institution: Inserm First Author: Mélissa Bowerman Order of Authors: Mélissa Bowerman; Céline Salsac; Véronique Bernard; Claire Soulard; Annie Dionne; Emmanuelle Coque; Salim Benlefki; Pascale Hince; Patrick Dion; Gillian Butler-Browne; William Camu; Jean-Pierre Bouchard; Eric Delpire; Guy Rouleau; Cédric Raoul; frederique scamps Abstract: Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre- synaptic neurotransmission defects observed in patients. KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na+/K+-ATPase α1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na+/K+-ATPase α1 localization and reduces NMJ denervation in Slc12a6-/- mice. We here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome. Cover Letter Dear Editor Thank you for your interest in this study. We have answered to all the points addressed by the Referees. We now provide discussion and references concerning the pertinence of using motoneuron primary culture relative to recordings from post-natal or adult spinal cord slices.
    [Show full text]
  • Peripheral Neuropathy in Complex Inherited Diseases: an Approach To
    PERIPHERAL NEUROPATHY IN COMPLEX INHERITED DISEASES: AN APPROACH TO DIAGNOSIS Rossor AM1*, Carr AS1*, Devine H1, Chandrashekar H2, Pelayo-Negro AL1, Pareyson D3, Shy ME4, Scherer SS5, Reilly MM1. 1. MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK. 2. Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK. 3. Unit of Neurological Rare Diseases of Adulthood, Carlo Besta Neurological Institute IRCCS Foundation, Milan, Italy. 4. Department of Neurology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA 5. Department of Neurology, University of Pennsylvania, Philadelphia, PA 19014, USA. * These authors contributed equally to this work Corresponding author: Mary M Reilly Address: MRC Centre for Neuromuscular Diseases, 8-11 Queen Square, London, WC1N 3BG, UK. Email: [email protected] Telephone: 0044 (0) 203 456 7890 Word count: 4825 ABSTRACT Peripheral neuropathy is a common finding in patients with complex inherited neurological diseases and may be subclinical or a major component of the phenotype. This review aims to provide a clinical approach to the diagnosis of this complex group of patients by addressing key questions including the predominant neurological syndrome associated with the neuropathy e.g. spasticity, the type of neuropathy, and the other neurological and non- neurological features of the syndrome. Priority is given to the diagnosis of treatable conditions. Using this approach, we associated neuropathy with one of three major syndromic categories - 1) ataxia, 2) spasticity, and 3) global neurodevelopmental impairment. Syndromes that do not fall easily into one of these three categories can be grouped according to the predominant system involved in addition to the neuropathy e.g.
    [Show full text]
  • 2017PNS Final Programme W
    2017 PNS Annual Meeting 8-12 July | Sitges, Spain Programme and Abstracts Programme Programme and Abstracts 2017 PNS Annual Meeting 8 – 12 July Sitges, Spain Welcome On behalf of the Peripheral Nerve Society, we are delighted to welcome you to the 2017 Annual Meeting at the Meliá in Sitges, Spain. The PNS Annual Meeting continues to be the premier meeting for cutting-edge innovation and advances in peripheral neuropathy. The 2017 Meeting will provide a mixture of excellent plenary lectures, oral platforms, oral posters, poster sessions, an education course and dedicated symposia organised by special interest groups for Charcot Marie Tooth and related neuropathies (CMTR), the Inflammatory Neuropathy Consortium (INC) and diabetes. There will also be clinical trials update sessions and a hot topic symposium. We look forward to you being part of it. Join us for the Opening Ceremony on Saturday, 8 July, from 18.00 to 20.00, in the Auditorium Hall. The reception will feature complimentary drinks and hors d’oeuvres. Coffee breaks and lunch for registrants will only be provided daily for registrants. Please see the programme for details. Complimentary internet will be provided. Instructions for access can be found on page 11 of the programme. Be sure to attend the Business Meeting on Monday at 13.00 in the Main Auditorium. We will be reviewing Society business, and your input is needed. Monday night, the PNS will be honoring Junior and new Members of the Society with a cocktail reception from 19.00 to 20.00. For those who have registered for this event during the online registration, please join us for the PNS Closing Dinner on Tuesday, 11 July, from 19.00 to 22.00 in the Tramuntana room.
    [Show full text]
  • Andermann Syndrome
    Andermann syndrome Description Andermann syndrome is a disorder that damages the nerves used for muscle movement and sensation (motor and sensory neuropathy). Absence (agenesis) or malformation of the tissue connecting the left and right halves of the brain (corpus callosum) also occurs in most people with this disorder. People affected by Andermann syndrome have abnormal or absent reflexes (areflexia) and weak muscle tone (hypotonia). They experience muscle wasting (amyotrophy), severe progressive weakness and loss of sensation in the limbs, and rhythmic shaking ( tremors). They typically begin walking between ages 3 and 4 and lose this ability by their teenage years. As they get older, people with this disorder frequently develop joint deformities called contractures, which restrict the movement of certain joints. Most affected individuals also develop abnormal curvature of the spine (scoliosis), which may require surgery. Andermann syndrome also results in abnormal function of certain cranial nerves, which emerge directly from the brain and extend to various areas of the head and neck. Cranial nerve problems may result in facial muscle weakness, drooping eyelids (ptosis), and difficulty following movements with the eyes (gaze palsy). Individuals with Andermann syndrome usually have intellectual disability, which may be mild to severe, and some experience seizures. They may also develop psychiatric symptoms such as depression, anxiety, agitation, paranoia, and hallucinations, which usually appear in adolescence. Some people with Andermann syndrome have atypical physical features such as widely spaced eyes (ocular hypertelorism); a wide, short skull (brachycephaly); a high arch of the hard palate at the roof of the mouth; a big toe that crosses over the other toes; and partial fusion (syndactyly) of the second and third toes.
    [Show full text]
  • Abadie Sign, 400 Abducens Nerve Palsy. See Sixth Nerve Palsy
    Cambridge University Press 978-1-107-01455-8 - Neurologic Differential Diagnosis: A Case-Based Approach Edited by Alan B. Ettinger and Deborah M.Weisbrot Index More information Index Abadie sign, 400 auditory agnosias, 20–1 hallucinations, 189 abducens nerve palsy. See sixth nerve case vignette, 18–19 memory impairment, 233 palsy classification of types, 19 myoclonus related to, 277 abetalipoproteinemia, 301 definition, 18, 39, 408 psychosis related to, 352 abulia, 5 differential diagnosis, 19 amaurosis fugax, 494 acalculia, 39, 433 distinction from aphasia, 39 amnesia, 5 achalasia, 153 for scenes, 19 approach to diagnosis, 223 achromatopsia, 5 for words, 19 case vignette (scopolamine-related acquired hepatocerebral degeneration, tactile agnosia, 21 amnesia), 234 229 visual agnosias, 18–20 case vignettes (transient global acquired neuromyotonia, 282 agnostic alexia, 20 amnesia), 223–34 acrophobia, 349 agoraphobia, 22 definition, 223 acute cardiogenic shock, 378 agraphesthesia, 5 differential diagnosis, 224–33 acute disseminated encephalomyelitis, agraphia, 433 dissociative amnesia, 135–6 226, 532 definition, 39 distinction from delirium, 223 acute inflammatory demyelinating distinction from aphasia, 39 distinction from dementia, 223 polyneuropathy (AIDP), 9, 523, Aicardi syndrome, 353 etiologies, 224–33 551, 565, 569 AIDS, 83, 400 for non-verbal material, 5 acute intermittent porphyria, 229 cognitive impairment, 109 for verbal material, 5 acute pulmonary edema, 378 AIDS myelopathy, 531 transient global amnesia, 225 acute stress disorder,
    [Show full text]
  • A Role for KCC3 in Maintaining Cell Volume of Peripheral Nerve Fibers
    Neurochemistry International 123 (2019) 114e124 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci A role for KCC3 in maintaining cell volume of peripheral nerve fibers * Bianca Flores, Cara C. Schornak, Eric Delpire Neuroscience Graduate Program and Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States article info abstract Article history: The potassium chloride cotransporter, KCC3, is an electroneutral cotransporter expressed in the pe- þ À Received 18 December 2017 ripheral and central nervous system. KCC3 is responsible for the efflux of K and Cl in neurons to help Received in revised form maintain cell volume and intracellular chloride levels. A loss-of-function (LOF) of KCC3 causes Hereditary 17 January 2018 Motor Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC) in a population of in- Accepted 17 January 2018 dividuals in the Charlevoix/Lac-Saint-Jean region of Quebec, Canada. A variety of mouse models have Available online 31 January 2018 been created to understand the physiological and deleterious effects of a KCC3 LOF. Though this KCC3 LOF in mouse models has recapitulated the peripheral neuropathy phenotype of HMSN/ACC, we still know Keywords: KCC3 little about the development of the disease pathophysiology. Interestingly, the most recent KCC3 mouse HMSN/ACC model that we created recapitulated a peripheral neuropathy-like phenotype originating from a KCC3 ACCPN gain-of-function (GOF). Despite the past two decades of research in attempting to understand the role of Andermann syndrome KCC3 in disease, we still do not understand how dysfunction of this cotransporter can lead to the T991A pathophysiology of peripheral neuropathy.
    [Show full text]
  • The Andermann Syndrome: Agenesis of the Corpus Callosum Associated with Mental Retardation and Progressive Sensorimotor Neuronop
    LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES The Andermann Syndrome: Agenesis of the Corpus Callosum Associated with Mental Retardation and Progressive Sensorimotor Neuronopathy Albert Larbrisseau, Michel Vanasse, Pierre Brochu and Gaetan Jasmin ABSTRACT: Andermann et al. described in 1972 an autosomal recessive inherited syndrome which associates agenesis of the corpus callosum, mental deficiency, and a peripheral motor deficit. We had the opportunity to study in detail 15 patients affected by this syndrome. As in the cases previously reported, the families of these children all originated from Charlevoix County and the Saguenay-Lac St-Jean area in the Province of Quebec. Clinically, these patients have a characteristic facies and moderate mental retardation associated with a progressive motor neuropathy leading to loss of ambulation by adolescence and progressive scoliosis. In 13 of these 15 patients, neuroradiological investigation has shown either total or partial agenesis of the corpus callosum. In every patient in whom these tests were done, sensory nerve action potentials were absent and motor nerve conduction velocities reduced. We also found neurogenic abnormalities both on EMG and neuromuscular biopsies. These abnormalities are similar to those described in Friedreich's ataxia and in hereditary motor and sensory neuropathy type II, although in our patients the motor deficit is much more severe than in these diseases. The pathogenesis of the peripheral nervous system involvement is still unknown since there have so far been no autopsy studies of this syndrome. RESUME: Andermann et coll. ont identifie en 1972 un syndrome hereditaire a transmission autosomale recessive associant une ag£n6sie du corps calleux a une deficience intellectuelle et a une atteinte motrice peripherique.
    [Show full text]
  • WO 2017/037079 Al 9 March 2017 (09.03.2017) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/037079 Al 9 March 2017 (09.03.2017) P O P C T (51) International Patent Classification: (74) Agent: COLLIN, Matthieu; 7 rue Watt, 75013 Paris (FR). A61K 31/55 (2006.01) A61P 25/02 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/EP20 16/070449 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) Date: International Filing DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 3 1 August 2016 (3 1.08.2016) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 15306342.5 1 September 2015 (01.09.2015) EP TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicants: INSERM (INSTITUT NATIONAL DE LA (84) Designated States (unless otherwise indicated, for every SANTE ET DE LA RECHERCHE MEDICALE) kind of regional protection available): ARIPO (BW, GH, [FR/FR]; 101, rue de Tolbiac, 75013 Paris (FR).
    [Show full text]
  • BRAIN-2019-01762.R2 Proof Hi.Pdf
    This is a repository copy of SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/160142/ Version: Accepted Version Article: McNeill, A., Iovino, E., Mansard, L. et al. (17 more authors) (2020) SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. Brain. awaa176. ISSN 0006-8950 https://doi.org/10.1093/brain/awaa176 This is a pre-copyedited, author-produced version of an article accepted for publication in Brain following peer review. The version of record Alisdair McNeill, Emanuela Iovino, Luke Mansard, Christel Vache, David Baux, Emma Bedoukian, Helen Cox, John Dean, David Goudie, Ajith Kumar, Ruth Newbury-Ecob, Chiara Fallerini, Alessandra Renieri, Diego Lopergolo, Francesca Mari, Catherine Blanchet, Marjolaine Willems, Anne-Francoise Roux, Tommaso Pippucci, Eric Delpire, SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect, Brain, awaa176 is available online at: https://doi.org/10.1093/brain/awaa176 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request.
    [Show full text]
  • Clinical, Laboratory, and Genetic Studies of Families with Charcot- Marie-Tooth Type 2C Disease
    Clinical, laboratory, and genetic studies of families with Charcot- Marie-Tooth type 2C disease Guida Landouré A thesis submitted to the University College London for the degree of Doctor of Philosophy August 2011 Department of Medicine University College London 1 „I, Guida Landouré, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.‟ 2 Dedication and acknowledgements I dedicate this work to: GOD the Almighty, the clement and merciful who gave me the chance and courage to accomplish this work, and to his Prophet Muhammad, Peace upon Him. My parents: thanks for your unshakable love and support throughout my life. All my relatives and friends: thanks for being there whenever I needed you. My wife and son for their love and support. My friend Addis Taye and our patient Kelly Clever (in memoriam). First, my thanks to my supervisor Professor Robert Kleta. You have given me the chance to accomplish a dream that would be unlikely in other situations. It has sometimes been hard, but you have been patient and understanding to make this happen. Your sense of good and high standard work is remarkable. I am thankful to my supervisor Professor John Hardy. Your guidance and encouragement throughout this work were most helpful. To my scientific Godfather Dr. Kenneth Fischbeck: I met you when I did not know that a gene was made of exons and introns, but you have trusted me from the beginning and gave me an opportunity that not many would give to unskilled people like me.
    [Show full text]
  • Diseases of the Nervous System: Clinical Neuroscience and Therapeutic Principles, Third Edition Edited by Arthur K
    Cambridge University Press 0521793513 - Diseases of the Nervous System: Clinical Neuroscience and Therapeutic Principles, Third Edition Edited by Arthur K. Asbury, Guy M. McKhann, W. Ian McDonald, Peter J. Goadsby and Justin C. McArthur Index More information Index Note: this is a complete two-volume index Note: page numbers in italics refer to figures and tables; ‘Fig.’ refers to illustrations in the plates section Abbreviations of conditions used in subheadings (without explanation): AD Alzheimer’s disease AIDS Acquired immune deficiency syndrome ALS Amyotrophic lateral sclerosis CJD Creutzfeldt–Jakob disease FTD Frontotemporal dementia HIV Human immunodeficiency virus HD Huntington’s disease PD Parkinson’s disease SIADH syndrome of inappropriate secretion of antidiuretic hormone A-fibres 873–4 abdominoperineal resection of carcinoma acetaminophen activation 875 846 migraine 1940 brain-derived nerve growth factor 884, abducens motoneurons 636 shingle pain 1678 885 abducens nerve acetazolamide sprouted 885, Fig. 58.12 fascicle lesions 650 acidification 1235 A2M genetic locus 5 middle ear disease 670 idiopathic intracranial hypertension A␣ fibres 874 palsy 649–51 2027 A␤ antibody passive transfer 1853–4 petrous bone infection 651 periodic paralysis 1201–2 A␤ fibres 874 abducens nucleus acetyl CoA 1210 AD 1844 abducens nerve palsy 649 acetylcholine formation in familial AD 1845 horizontal conjugate eye movements AD 256 see also amyloid 635, 636, 637 brain aging 198 A␤ immunization 1853–4 lesions 635 Lewy body dementia 273, 274 A␤ peptide 12, 215
    [Show full text]
  • ACTA MYOLOGICA (Myopathies, Cardiomyopathies and Neuromyopathies)
    ISSN 2532-1900 ACTA MYOLOGICA (Myopathies, Cardiomyopathies and Neuromyopathies) Vol. XXXVII - June 2018 Official Journal of Mediterranean Society of Myology and Associazione Italiana di Miologia Founders: Giovanni Nigro and Lucia Ines Comi Three-monthly EDITOR-IN-CHIEF Luisa Politano ASSISTANT EDITOR Vincenzo Nigro CO-EDITORS Valerie Askanas Giuseppe Novelli Lefkos Middleton Reinhardt Rüdel Official Journal of Mediterranean Society of Myology and Associazione Italiana di Miologia Founders: Giovanni Nigro and Lucia Ines Comi Three-monthly EDITORIAL BOARD Corrado Angelini, Padova Francesco Muntoni, London Enrico Bertini, Roma Carmen Navarro, Vigo Serge Braun, Paris Gerardo Nigro, Napoli Kate Bushby, Newcastle upon Tyne Anders Oldfors, Göteborg Kevin P. Campbell, Iowa City Elena Pegoraro, Padova Marinos Dalakas, Athens Heinz Reichmann, Dresden Feza Deymeer, Instanbul Filippo Maria Santorelli, Pisa Salvatore Di Mauro, New York Serenella Servidei, Roma Denis Duboc, Paris Piraye Serdaroglu, Instanbul Victor Dubowitz, London Yeuda Shapira, Jerusalem Massimiliano Filosto, Brescia Osman I. Sinanovic, Tuzla Fayçal Hentati, Tunis Michael Sinnreich, Montreal Michelangelo Mancuso, Pisa Andoni J. Urtizberea, Hendaye Giovanni Meola, Milano Gert-Jan van Ommen, Leiden Eugenio Mercuri, Roma Steve Wilton, Perth Carlo Minetti, Genova Massimo Zeviani, London Clemens Müller, Würzburg Janez Zidar, Ljubliana EDITOR-IN-CHIEF CO-EDITORS Luisa Politano, Napoli Lefkos Middleton, Nicosia Giuseppe Novelli, Roma ASSISTANT EDITOR Reinhardt Rüdel, Ulm Vincenzo Nigro, Napoli Gabriele Siciliano, Pisa Haluk Topaloglu, Ankara Antonio Toscano, Messina EDITORIAL STAFF TBA BOARD OF THE MEDITERRANEAN SOCIETY OF MYOLOGY H. Topaloglu, President L.T. Middleton, G. Siciliano, Vice-presidents K. Christodoulou, Secretary L. Politano, Treasurer E. Abdel-Salam, M. Dalakas, F. Deymeer, F. Hentati, G. Meola, Y. Shapira, E.
    [Show full text]