Molecular Neurology This page intentionally left blank Molecular Neurology Edited by Stephen G Waxman AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Elsevier Academic Press 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, California 92101-4495, USA 84 Theobald’s Road, London WC1X 8RR, UK This book is printed on acid-free paper Copyright © 2007, Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone: (+44) 1865 843830, fax: (+44) 1865 853333, E-mail: permissions@elsevier.co.uk You may also complete your request on-line via the Elsevier homepage (http://elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions.” Library of Congress Cataloging-in-Publication Data Application submitted British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-369509-3 For all information on all Elsevier Academic Press publications visit our Web site at www.books.elsevier.com Printed in China 07 08 09 10 Contents Contributor's List Preface xi vii 10 Metabolic Diseases of the Nervous System Juan M Pascual 11 Section I Principles of Molecular Neurology Genetics as a Tool in Neurology Dennis R Johnson and Fuki M Hisama Neurology and Genomic Medicine Jeffery M Vance Section III Stroke and Trauma 19 Mitochondrial Function and Dysfunction in the Nervous System 29 Neggy Rismanchi and Craig Blackstone Neuronal Channels and Receptors Alan L Goldin 12 Molecular Mechanisms of Ischemic Brain Disease 177 Thomas M Hemmen and Justin A Zivin 13 Hemorrhagic Brain Disease 187 Michael L DiLuna, Kaya Bilguvar, Gamze Tanriover, and Murat Gunel 43 Metabolic Biopsy of the Brain Ognen A C Petroff Gene Therapy Approaches in Neurology Edward A Burton, Joseph C Glorioso, and David J Fink 14 The Dawn of Molecular and Cellular Therapies for Traumatic Spinal Cord Injury 207 Noam Y Harel, Yvonne S Yang, Stephen M Strittmatter, Jeffery D Kocsis, and Stephen G Waxman 77 101 Section IV Degenerative Diseases Programmed Cell Death and Its Role in Neurological Disease 125 D E Bredesen, R V Rao, and P Mehlen 15 Parkinson Disease: Molecular Insights Joseph M Savitt, Valina L Dawson, and Ted M Dawson 16 The Molecular Basis of Alzheimer’s Disease 241 Martin Ingelsson and Bradley T Hyman 17 Polyglutamine Disorders Including Huntington’s Disease 257 Sokol V Todi, Aislinn J Williams, and Henry L Paulson Section II Disorders of Development Genetic Disorders of Neuromuscular Development 163 Juan M Pascual Protein Misfolding, Chaperone Networks, and the Heat Shock Response in the Nervous System 59 Cindy Voisine, Kai Orton, and Richard I Morimoto 149 Developmental Neurology: A Molecular Perspective 145 Juan M Pascual v 221 vi Contents 18 Friedreich’s Ataxia and Related DNA Loss-of-Function Disorders 277 Massimo Pandolfo and Chantal Depondt 19 DYT1, An Inherited Dystonia 295 Susan B Bressman and Laurie Ozelius 28 Section VIII Peripheral Nerve Disease 20 Motor Neuron Disease: Amyotrophic Lateral Sclerosis 307 Nicholas J Maragakis and Jeffrey D Rothstein 21 Genetic Disorders of the Autonomic Nervous System 321 Stephen J Peroutka 22 Multiple Sclerosis as a Neurodegenerative Disease 333 Stephen G Waxman 29 Myelin Protein Zero and CMT1B: A Tale of Two Phenotypes 463 John A Kamholz, Michelle Brucal, Jun Li, and Michael Shy Section IX Neuro-Immunology 30 Demyelinating Diseases: Immunological Mechanisms in the Pathogenesis of Multiple Sclerosis 475 Hartmut Wekerle and Alexander Flügel 31 Autoimmune and Genetic Disorders of the Neuromuscular Junction and Motor Nerve Terminal 499 Angela Vincent 32 Paraneoplastic Neurologic Syndromes Josep Dalmau Section V Disorders of Excitation and Transmission 23 Acquired Epilepsy: Cellular and Molecular Mechanisms 347 Christopher B Ransom and Hal Blumenfeld 24 Genetic Epilepsies 371 Ingo Helbig, Ingrid E Scheffer, and Samuel F Berkovic 25 Tourette’s Syndrome 385 James F Leckman and Michael H Bloch 33 Disorders of Sleep and Circadian Rhythms Sebastiaan Overeem, Gert Jan Lammers, and Mehdi Tafti Mitochondrial Disorders 535 Salvatore DiMauro and Eric A Schon 409 Section XI Infectious Disorders 34 Section VII Pain 27 Chronic Pain as a Molecular Disorder John N Wood and Stephen G Waxman 517 Section X Mitochondrial Disorders Section VI Disorders of Sleep and Circadian Rhythms 26 Migraine as a Cerebral Ionopathy with Impaired Central Sensory Processing 439 Michel D Ferrari, Arn M.J.M van den Maagdenberg, Rune R Frants, and Peter J Goadsby Molecular Neurology of HIV-1 Infection and AIDS 553 Marcus Kaul, and Stuart A Lipton 427 Index 573 Contributor's List Samuel F Berkovic Epilepsy Research Centre and Department of Medicine (Neurology), University of Melbourne, Austin Health, Heidelberg, Victoria, Australia Kaya Bilguvar Program of Neurogenetics, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Health Sciences Institute, Department of Medical Biology and Genetics, Marmara University, Turkey Craig Blackstone Cellular Neurology Unit, NINDS, National Institutes of Health, Bethesda, MD, USA Michael H Bloch Child Study Center and the Departments of Pediatrics and Psychology, Yale University School of Medicine, New Haven, CT, USA Hal Blumenfeld Departments of Neurology, Neurobiology, and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA D E Bredesen Buck Institute for Age Research, Novato, CA, USA; Department of Neurology, University of California at San Francisco, CA, USA Susan B Bressman Department of Neurology, Beth Israel Medical Center, New York, NY, USA Michelle Brucal Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, MI, USA Edward A Burton Departments of Neurology, and Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Josep Dalmau Department of Neurology, Division of Neurooncology, University of Pennsylvania, Philadelphia, PA, USA Ted M Dawson Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Valina L Dawson Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Chantal Depondt Erasme Hospital, Brussels, Belgium Michael L DiLuna Resident, Department of Neurosurgery, Yale University Center of Medicine, New Haven, CT, USA Salvatore DiMauro Department of Neurology, Columbia University Medical Center, New York, NY, USA Michel D Ferrari Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands David J Fink Department of Neurology, University of Michigan; VA Ann Arbor Healthcare System, Ann Arbor, MI, USA Alexander Flügel Max-Planck Institute for Neurobiology, Department of Neuroimmunology, Martinsried, Germany Rune R Frants Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Joseph C Glorioso Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA vii viii Peter J Goadsby Queen Square, Institute of Neurology, London, United Kingdom; Department of Neurology, University of California, San Francisco, CA, USA Alan L Goldin Departments of Microbiology and Molecular Genetics, and Anatomy and Neurobiology, University of California, Irvine, CA, USA Murat Gunel Program of Neurogenetics, Section of Neurovascular Surgery; Neuroscience Intensive Care Unit, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA Noam Y Harel Department of Neurology, Yale University School of Medicine, New Haven, CT, USA Ingo Helbig Epilepsy Research Centre and Department of Medicine (Neurology), University of Melbourne, Austin Health, Heidelberg, Victoria, Australia Thomas M Hemmen Department of Neuroscience, University of California, La Jolla, CA, USA Fuki M Hisama Division of Genetics, Childrens Hospital Boston, Harvard Medical School, Boston, MA, USA Bradley T Hyman Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA Martin Ingelsson Uppsala University, Department of Public Health, Molecular Geriatrics, Uppsala, Sweden Dennis R Johnson Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA John Kamholz Wayne State University School of Medicine, Center for Molecular Medicine and Genetics; Department of Neurology, Detroit, MI, USA Marcus Kaul Center for Neuroscience and Aging Research, Burnham Institute for Medical Research; Department of Psychiatry, University of California at San Diego, La Jolla, CA, USA Jeffery D Kocsis Department of Neurology, Yale University School of Medicine, New Haven, CT, USA Gert Jan Lammers Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands James F Leckman Child Study Center and the Departments of Pediatrics and Psychology, Yale University School of Medicine, New Haven, CT, USA Contributors Jun Li Wayne State University School of Medicine, Department of Neurology, Detroit, MI, USA Stuart A Lipton Center for Neuroscience, Stem Cells, and Aging Research, Burnham Institute for Medical Research; Department of Neurosciences, and Department of Psychiatry, University of California at San Diego; Molecular Neurobiology Laboratory, The Salk Institute for Biological/Studies, Department of Molecular and Integrative Neurosciences and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA Nicholas J Maragakis Department of Neurology, Johns Hopkins University, Baltimore, MD, USA P Mehlen Apoptosis, Cancer, and Development Laboratory, Université de Lyon, Centre Léon Bérard, Lyon, France; Buck Institute for Age Research, University of California, Novato, CA, USA Richard I Morimoto Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA Kai Orton Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL, USA Sebastiaan Overeem Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegan, the Netherlands; Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands Laurie Ozelius Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA Massimo Pandolfo Department of Neurology, Brussels Free University; Erasme Hospital, Brussels, Belgium Juan M Pascual Departments of Neurology, Physiology, and Pediatrics, University of Texas Southwestern Medical Center; Children’s Medical Center; UT Southwestern Hospitals and Clinics, Dallas, TX, USA Henry L Paulson Department of Neurology, University of Iowa College of Medicine, Iowa City, IA, USA Stephen J Peroutka Franchise Development Leader, Pain, Johnson & Johnson, Titusville, NJ, USA Ognen A C Petroff Department of Neurology, Yale University, School of Medicine, New Haven, CT, USA Contributors Christopher B Ransom Department of Neurology, Yale University School of Medicine, New Haven, CT, USA R V Rao Buck Institute for Age Research, Novato, CA, USA Neggy Rismanchi Cellular Neurology Unit, NINDS, National Institutes of Health, Bethesda, MD, USA Jeffrey D Rothstein Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA Joseph M Savitt Institute for Cell Engineering and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Ingrid E Scheffer Department of Medicine and Paediatrics and Royal Children’s Hospital, University of Melbourne, Austin Health Hospital, Melbourne, Australia Eric A Schon Departments of Neurology and Genetics and Development, Columbia University Medical Center, New York, NY, USA Michael Shy Wayne State University School of Medicine, Center for Molecular Medicine and Genetics; Department of Neurology, Detroit, MI, USA Stephen M Strittmatter Department of Neurology, Yale University School of Medicine, New Haven, CT, USA Mehdi Tafti Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Gamze Tanriover Program of Neurogenetics, Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.; Department of Histology, School of Medicine, Akdeniz University, Turkey ix Sokol V Todi Department of Neurology, University of Iowa College of Medicine, Iowa City, IA, USA Arn M.J.M van den Maagdenberg Departments of Neurology and Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Jeffery M Vance Duke University Medical Center, Center for Human Genetics, Durham, NC, USA Angela Vincent Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom Cindy Voisine Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA Stephen G Waxman Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine; Rehabilitation Research Center, Veterans Affairs Medical Center, New Haven, CT, USA Hartmut Wekerle Max-Planck Institute for Neurobiology, Department of Neuroimmunology, Martinsried, Germany Aislinn J Williams Department of Neurology, University of Iowa, Iowa City, IA, USA John N Wood Molecular Nociception Group, Biology Department, University College, London, United Kingdom Yvonne S Yang Department of Neurology, Yale 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CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia J Neuroimmunol 98, 185–200 Zou, Y R., Kottmann, A H., Kuroda, M., Taniuchi, I., and Littman, D R (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development Nature 393, 595–599 This page intentionally left blank Index A Acetylcholine receptor, see Nicotinic acetylcholine receptors Acetylcholinesterase deficiency, 172 neuromuscular junction, 165–166, 499–501 Acid sensing ion channels, mechanosensation, 430 AD, see Alzheimer’s disease Adeno-associated virus, gene therapy vectors, 107 Adenovirus, gene therapy vectors, 106 ADHD, see Attention deficit hyperactivity disorder ADNFLE, see Autosomal dominant nocturnal frontal lobe epilepsy ADPEAF, see Autosomal dominant partial epilepsy with auditory features α2B-Adrenergic receptor, polymorphisms and increased sympathetic nervous system activity, 327 β2-Adrenergic receptor, polymorphisms and agonist responsiveness, 327–328 Advanced-sleep-phase syndrome clinical features, 422 familial forms, 422 molecular biology, 422–424 AERSACS, see Autosomal recessive ataxia of Charlevoix and Saguenay AIDS, see Human immunodeficiency virus-associated dementia ALK1, angiogenic switch and intracranial hemorrhage, 198–200 Allele, definition, 4, 20 ALS, see Amyotrophic lateral sclerosis Alzheimer’s disease amyloid biology, 243–245 animal models amyloid precursor protein models, 248 Tau models, 248–249 clinical features, 241–242 diagnosis, 250–251 genetics early-onset disease, 243–245 late-onset disease, 27 neuron death mechanisms, 249–250 neuropathology, 242–243 progression, 245–246 protein conformation changes, 250 Tau biology, 246–247 treatment prospects, 250–252 Ammonia, magnetic resonance spectroscopy, 88–89 Amyloid precursor protein Alzheimer’s disease animal models, 248 diagnostic value of Aβ42, 250–251 mutations, 243–244 pathology, 244–245 573 Amyotrophic lateral sclerosis animal models ALS2 knockout mouse, 310 dynein/dynactin mutant mice, 309–310 predictive value, 316 progressive motor neuronopathy mouse, 308–309 superoxide dismutase mutant transgenic mouse, 308 wobbler mouse, 309 apoptosis, 311 axonal pathology, 311–313 cell autonomy, 313–314 clinical manifestations, 308 epidemiology, 307 excitotoxicity, 310–311 mitochondrial dysfunction, 311 neuroinflammation, 313 oxidative stress, 310 regional differences in pathophysiology, 314 therapeutic targeting antioxidants, 315 glutaminergic pathways, 314–315 growth factors, 315 neuroinflammation modulators, 315–316 RNA interference and antisense, 316 vascular endothelial growth factor dysregulation, 312–313 Andersen syndrome, features, 173 Angiogenesis 574 Angiogenesis (Continued) activation stages, 188–190 brain blood supply development, 188 definition, 188 regulators, 188, 190–191, 198–199 Angiopoietin, angiogenesis regulation, 190 ANS, see Autonomic nervous system AOA, see Ataxia with oculomotor apraxia Apaf-1, apoptosis modulation, 129 APDK, see Autosomal polycystic kidney disease Apomorphine, Parkinson disease management, 233 Apoptosis amyotrophic lateral sclerosis, 311 cerebral ischemia, 183 history of study, 126 misfolded protein induction, 136–137 mitochondrial function in neurons, 38 neurodegeneration role, 137–138 pathways and components, 126–130 therapeutic targeting, 138 trophic factors and cellular dependence, 134–135 APP, see Amyloid precursor protein Aprataxin, ataxia with oculomotor apraxia mutations, 288–289 ARTN, autonomic nervous system development role, 325 ASICs, see Acid sensing ion channels ASPS, see Advanced-sleep-phase syndrome Association analysis disease gene identification, 11, 21 migraine, 454 Ataxia, channel defects, 54–55 Ataxia with oculomotor apraxia epidemiology, 277 type disease features, 288–289 type disease features, 289–290 Ataxia with vitamin E deficiency animal model, 288 clinical and pathological features, 286 epidemiology, 277 pathogenesis, 288 TTPA gene mutations and detection, 288 Index structure and expression, 286, 288 ATP magnetic resonance spectroscopy, see Magnetic resonance spectroscopy mitochondrial synthesis, see Mitochondria ATP1A2 cell mutation studies, 452 familial hemiplegic migraine mutations, 449–450 transgenic mouse mutants, 452 ATP7A, see Menkes disease Attention deficit hyperactivity disorder, Tourette’s syndrome comorbidity, 387–388 Autonomic nervous system developmental disorders efferent portion diseases, 324–325 overview, 321–323 sensory portion diseases, 325–327 functional abnormalities and gene defects, 327–329 subdivisions, 321 Autosomal dominant, definition, Autosomal dominant nocturnal frontal lobe epilepsy, features, 379 Autosomal dominant partial epilepsy with auditory features, features, 379 Autosomal polycystic kidney disease, aneurysms, 193–194 Autosomal recessive ataxia of Charlevoix and Saguenay animal model, 291 clinical and pathological features, 290 epidemiology, 277–278 pathogenesis, 291 sacsin gene structure and function, 290 mutations and detection, 290–291 Autosomal recessive, definition, AVED, see Ataxia with vitamin E deficiency B Bcl-2, apoptosis modulation, 128 BDNF, see Brain-derived neurotrophic factor Behr syndrome, features, 291 Benign familial infantile seizures, features, 374 Benign familial neonatal-infantile seizures, features, 374 Benign familial neonatal seizures, features, 373–374 Benign rolandic epilepsy, genetics, 381 BFIS, see Benign familial infantile seizures BFNIS, see Benign familial neonatalinfantile seizures BFNS, see Benign familial neonatal seizures Bioinformatics, overview, 26 Brain-derived neurotrophic factor, temporal lobe epilepsy expression, 350 Brain metabolism, see Magnetic resonance spectroscopy BRE, see Benign rolandic epilepsy C CACNA1A cell mutation studies, 451 familial hemiplegic migraine mutations, 448–449 mouse mutant studies natural mutants, 451–452 transgenic mouse, 452 CADASIL, see Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CAE, see Childhood absence epilepsy CAG repeats, see, see PolyQ diseases Calcitonin gene-related peptide, migraine role, 442–443 Calcium channels Lambert-Eaton myasthenic syndrome pathophysiology, 507–508 migraine, see CACNA1A pain transduction, 434 physiological roles, 52–53 structure and function, 48 temporal lobe epilepsy expression, 358 types and nomenclature, 44–45 cAMP, see Cyclic AMP Candidate gene, disease gene identification, 10 Caspases apoptosis modulation, 127, 129–130 Index Caspases (Continued) therapeutic targeting in stroke, 183 CCM, see Cerebral cavernous malformation Celecoxib, amyotrophic lateral sclerosis trials, 315 Central hypoventilation syndrome, gene mutations, 323 Cerebellar degeneration, paraneoplastic syndrome, 525 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, features, 453 Cerebral cavernous malformation familial disease and genetics, 196–197 hemorrhage, 194–195 magnetic resonance imaging, 195 Cerebral ischemia apoptosis, 183 excitotoxicity, 178–179 focal ischemia, 178 free radicals, 179–180 gene expression response, 182–183 growth factors in regeneration, 181–182 inflammation, 180–181 irreversible damage threshold, 177–178 morphological changes, 178 Cerebral venous thrombosis, clotting disorders, 202 CGH, see Comparative genomic hybridization CGRP, see Calcitonin gene-related peptide Charcot-Marie-Tooth disease axonal energy metabolism, 467 classification, 463–464 Schwann cell biology, 464–467 type 1B clinical phenotypes, 468 myelin protein zero mutations H10P, 471–472 neuropathy mechanisms, 470–471 R69C, 471 prospects for study, 472–473 Chemokine receptors, human immunodeficiency virus entry into brain, 555, 557–558 Childhood absence epilepsy, features, 377 Chloride channels 575 myotonia congenita mutations, 174–175 physiological roles, 53 structure and function, 50 types and nomenclature, 46 Choline acetyltransferase, deficiency, 171 Chondroitin sulfate, therapeutic targeting in spinal cord injury, 212 Chromosome, structure, Chronic pain, see Pain Circadian rhythm advanced-sleep-phase syndrome clinical features, 422 familial forms, 422 molecular biology, 422–424 clock genes, 414 pacemakers, 413–414 sleep/wake cycle, 410–411 Clock, circadian rhythm, 414 Clotting disorders, hemorrhagic brain disease, 201–202 CMS, see Congenital myasthenic syndromes CMT, see Charcot-Marie-Tooth disease Comparative genomic hybridization, principles, 26 Congenital myasthenic syndromes, pathophysiology, 509–510 Cortical spreading depression migraine aura, 441 migraine headache triggering, 445–446 Cryptochrome, circadian rhythm, 414 CSD see Cortical spreading depression CVT, see Cerebral venous thrombosis Cyclic AMP, therapeutic targeting in spinal cord injury, 212–213 Cyclic nucleotide-gated channels physiological roles, 53 structure and function, 50 types and nomenclature, 45–46 D Deep brain stimulation, Parkinson disease management, 234 Deep venous thrombosis, clotting disorders, 202 Dentatorubral-pallidoluysian atrophy, clinical and genetic features, 259 Developmental neurology molecular perspective, 145–147 neuromuscular diseases, see specific diseases Dihydroergotamine, central sensitization blockade, 442 DJ-1, Parkinson disease mutations, 227 DNA, structure and replication, DNA microarray, principles, 24–25 Dopamine β-hydroxylase, deficiency, 328 Dopamine D4 receptor, defects and autonomic hyperactivity, 328–329 Dravet syndrome, features, 375 DRPLA, see Dentatorubralpallidoluysian atrophy DVT, see Deep venous thrombosis Dystonia, see also DYT1 dystonia causes, 296 classification, 296 definition, 295 primary dystonia features, 295–296 treatment, 297 Dystrophin binding partners, 176 mutations, 175–176 DYT1 dystonia DYT1 discovery, 297–298 focal dystonia role, 301–302 gene and protein properties, 298–299 models cells, 299–300 invertebrates, 300 mouse, 300–301 neuropathology, 299 phenotype and endophenotype, 302 prospects for study, 302–303 E ECE1, see Endothelin-converting enzyme-1 Endogenous opioid peptides, Tourette’s syndrome findings, 394 Endoglin, angiogenic switch and intracranial hemorrhage, 198–200 Endothelin-3, mutation in autonomic nervous system disorders, 323 Endothelin-converting enzyme-1, mutation in autonomic nervous system disorders, 323 576 Endothelin receptor type B, mutation in autonomic nervous system disorders, 323 Enzyme replacement therapy, indications, 14–15 Epilepsy acquired epilepsy animal models, 348 etiology, 348 glia and brain microenvironment, 363–364 mass lesion-induced epilepsy, 363 post-infectious epilepsy, 362–363 post-stroke epilepsy, 360–361 post-traumatic epilepsy, 360–361 prospects for study, 364–365 Rasmussen’s syndrome, 361–362 temporal lobe epilepsy cellular morphology, synaptogenesis, and neurogenesis, 351–353 clinical features, 348–349 febrile seizures, 359–360 GABAergic neurotransmission, 355–358 gene expression changes, 349–351 glutamate neurotransmission, 353–355 voltage-gated ion channels, 358 channel defects, 53–54 classification, 372 familial idiopathic epilepsy syndromes benign rolandic epilepsy, 381 channelopathy concept, 379–380 febrile seizures, 374–375, 377 focal epilepsies, 379 genetic architecture, 380–381 idiopathic generalized epilepsies, 377–379 infancy, 372–374 genes, 371–372 glutamate magnetic resonance spectroscopy studies, 92–94 heterogeneity, 372 magnetization transfer measurements of ATP and phosphocreatine synthesis, 82–83 phenotypyng, 372 prevalence, 347 Index Erythropoietin, human immunodeficiency virus-associated dementia management, 563 Excitation-contraction coupling, muscle, 168–169 Excitotoxicity amyotrophic lateral sclerosis, 310–311 cerebral ischemia, 178–179 mitochondria and calcium overload, 38 polyQ diseases, 266–267 Experimental autoimmune encephalitis, see Multiple sclerosis genotype-phenotype correlation, 282–283 mutations detection, 282 intronic GAA triplet repeat, 281–282 point mutations, 282 history of study, 277 pathogenesis, 285 pathology, 278 prognosis, 280 rating scales, 279–280 treatment, 286 F GABAA epilepsy familial idiopathic epilepsy defects, 379–380 temporal lobe epilepsy expression, 351, 356–358 physiological roles, 53 structure and function, 51 types and nomenclature, 47 Galactosemia diagnosis, 158 pathophysiology, 157–158 treatment, 158 Gene environment interactions, 23–24 expression and transcription, 2, 24–26 mutations deletion/amplification, 13–14 microsatellite expansion, 13 nucleotide substitutions, 12–13 single gene disorders versus complex diseases, 20 Generalized epilepsy with febrile seizures plus, features, 375 Gene therapy central nervous system degenerative brain diseases, 110 malignant glioma, 114 neuro-inflammatory diseases and meningeal transduction, 113 ribozyme, 112 RNA interference, 111–112 single gene disorders, 111 sporadic neurodegenerative diseases, 112–113 vector delivery, 110 G Familial hemiplegic migraine, see Migraine Family history, disease risk analysis, 22–23 Febrile seizures Dravet syndrome, 375 gene expression, 359–360 gene mutations, 375 generalized epilepsy with febrile seizures plus, 375 pathogenesis, 377 phenotypic heterogeneity in sodium channelopathies, 375 Fibroblast growth factor-2, neuroregeneration in stroke, 181 Fragile X syndrome, gene mutations, 13 Frataxin, see Friedreich’s ataxia Free radicals cerebral ischemia, 179–180 mitochondrial production and neuronal damage, 37 Friedreich’s ataxia ancillary tests and differential diagnosis, 280 animal models, 283, 285 clinical features diabetes, 279 heart disease, 279 neurological examination, 279 neurological symptoms, 278–279 variant phenotypes, 279 epidemiology, 277 frataxin function, 283 gene structure and expression, 280–281 Index Gene therapy (Continued) muscle muscular dystrophy, 117 myotonic dystrophy, 117–118 vector delivery, 117 peripheral nervous system pain, 114–116 polyneuropathy, 116–117 vector delivery, 114 prospects, 15, 118 strategic approaches, 101–102 vectors adeno-associated viruses, 107 adenoviruses, 106 gene expression regulation, 110 herpes simplex virus, 108–109 retroviruses, 104–105 targeting, 109–110 viral versus nonviral, 103–104 Genetic counseling, neurogenetic evaluation, 9–10 Genome Human Genome Project, 3, 22 mitochondria, see Mitochondria overview, Glioma, gene therapy approaches, 114 GLUT1 deficiency diagnosis, 152 SLC2A1 mutations and structure, 151–152 treatment, 153 Glutamate, magnetic resonance spectroscopy antiepileptic drug effects, 89 epilepsy, 92–94 glia, 90 glucose metabolism coupling to neurotransmission, 91 glutamate-glutamine cycle, 90 physiological stimulation, 89–92 synthesis, 87–88 visual cortex studies, 92 Glutamate receptors autoantibodies, 509 human immunodeficiency-induced neuronal injury and death role, 559–562 physiological roles, 53 structure and function, 52 temporal lobe epilepsy expression, 353–355 types and nomenclature, 47–48 Glycine receptors physiological roles, 53 577 structure and function, 52 types and nomenclature, 47–48 Glycolysis, magnetic resonance spectroscopy, 86 Glycosylation, congenital disorders, 156 Glycosyl-phosphatidylinositol-anchored coreceptors, autonomic nervous system development role, 323–324 GM-1, spinal cord injury management, 209 H Haplotype Mapping Project, overview, 22 HCHWA, see Hereditary cerebral hemorrhage with cortical amyloid angiopathy HD, see Huntington’s disease Heat shock proteins cerebral ischemia response, 182 cochaperones, 65 Heat shock proteins (Cont'd) expression regulation heat shock elements, 65 HSF transcription factors HSF1 activation cycle regulation, 67 nervous system, 67–68 types, 66–67 Hsp40, 63–64 Hsp60, 64 Hsp70, 61–63 Hsp90, 64 Hsp100, 64 neurodegenerative diseases chaperone hypothesis, 70–72 Parkinson disease models, 70 polyQ disease models, 69–70, 264 protein folding quality control, 60–61 small heat shock proteins, 64–65 therapeutic targeting, 72 transgenic mice, 264 Hemorrhagic brain disease, see Intracranial hemorrhage Hereditary cerebral hemorrhage with cortical amyloid angiopathy, features, 200–201 Hereditary hemorrhagic telangiectasia clinical features, 197–198 linkage studies, 198 Hereditary sensory and autonomic neuropathy type I, 325–326 type II, 326 type III, 326 type IV, 326 type V, 326–327 Herpes simplex virus, gene therapy vectors, 108–109 HGP, see Human Genome Project HHT, see Hereditary hemorrhagic telangiectasia Hippocalcin, temporal lobe epilepsy expression, 351 Hirschsprung disease, gene mutations, 323–324 HIV-associated dementia, see Human immunodeficiency virus-associated dementia HLA, see Human leukocyte antigen HSAN, see Hereditary sensory and autonomic neuropathy HSN2, mutation in autonomic nervous system disorders, 326 Hsps, see Heat shock proteins HSV, see Herpes simplex virus Human Genome Project, overview, 3, 22 Human immunodeficiency virusassociated dementia brain entry by virus, 555–558 epidemiology, 553 highly-active antiretroviral therapy impact, 554 macrophages and microglia, 558–559 molecular mechanisms of neuronal injury and death glutamate receptors, 559–562 signaling pathways, 560–561 neural stem and progenitor cells, 558 neuropathology and pathogenesis, 554–555 treatment and prevention prospects, 562–565 Human leukocyte antigen, multiple sclerosis genetic susceptibility, 479 Huntington’s disease axonal transport defects, 268 excitotoxicity and calcium homeostasis, 266–267 huntingtin mutation and function, 258–259 578 Index Huntington’s disease (Continued) neuronal dysfunction before degeneration, 269 nuclear localization of protein, 263 protein fragments, 263 Hyperekplexia, channel defects, 56 Hypocretin, narcolepsy defects, 419–420 I ICH, see Intracranial hemorrhage IKBKAP, mutation in autonomic nervous system disorders, 326 Immune privilege, central nervous system, 476–477 Immunological honunculus, concept of beneficial immunity, 490–491 Imprinting, diseases, Infantile-onset spinocerebellar ataxia, features, 291 Inflammation amyotrophic lateral sclerosis neuroinflammation, 313 central nervous system immune reactivity, 477–479 cerebral ischemia, 180–181 Intracranial aneurysm pathogenesis, 192 pedigree analysis, 192–193 prevalence, 191 Intracranial hemorrhage diagnosis, 187 epidemiology, 187 Mendelian forms, 191–192 primary diseases autosomal polycystic kidney disease aneurysms, 193–194 cerebral cavernous malformation, 194–197 hereditary hemorrhagic telangiectasia, 197–198 intracranial aneurysm, 191–193 moyamoya, 194 prospects for study, 202 secondary diseases cerebral amyloid angiopathies, 200–201 clotting disorders, 201–202 IOSCA, see Infantile-onset spinocerebellar ataxia Ischemia, see Cerebral ischemia J M JME, see Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy, features, 377–378 Macrophage human immunodeficiency virusassociated dementia, 558–559 sodium channels in multiple sclerosis, 341 Magnetic resonance imaging Alzheimer’s disease, 250 cerebral cavernous malformation, 195 Friedreich’s ataxia, 280 pain studies, 436 Tourette’s syndrome functional imaging, 391–392 structural imaging, 391 trigeminal pain studies, 445 Magnetic resonance spectroscopy ammonia studies, 88–89 carbon spectroscopy, 84–85 clinical prospects, 94 glutamate studies antiepileptic drug effects, 89 epilepsy, 92–94 glia, 90 glucose metabolism coupling to neurotransmission, 91 glutamate-glutamine cycle, 90 physiological stimulation, 89–92 synthesis, 87–88 visual cortex studies, 92 lactate analysis astrocyte-neuron lactate shuttle hypothesis, 86–88 glycolysis, 86 inflammation, 85 seizure, 85–86 magnetization transfer measurements of ATP and phosphocreatine synthesis animal models, 82 creatine deficiency syndromes, 82 epilepsy, 82–83 mitochondrial cytopathies, 81 overview, 80–81 Parkinson disease, 82 phosphocreatine shuttle hypothesis, 79–80 phosphorous spectroscopy evoked metabolism effects on high-energy phosphates, 79 K Kearns-Sayre syndrome, features, 539, 543 Kinins, nociception, 430 KRIT1, cerebral cavernous malformation defects, 196–197 L Lactate, magnetic resonance spectroscopy astrocyte-neuron lactate shuttle hypothesis, 86–88 glycolysis, 86 inflammation, 85 seizure, 85–86 Lambert-Eaton myasthenic syndrome clinical features, 506–507 etiology, 507 paraneoplastic syndrome, 528–529 pathophysiology, 507–508 LEMS, see Lambert-Eaton myasthenic syndrome Lenalidomide, amyotrophic lateral sclerosis trials, 316 Lesch-Nyhan disease, features and treatment, 159–160 Leucine-rich repeat kinase-2, Parkinson disease mutations, 229 Levodopa, Parkinson disease management, 233–234 Ligand-gated ion channels channelopathies, 53–56 physiological roles, 53 structure and function, 50–52 types and nomenclature, 47–48 Limbic encephalitis, paraneoplastic syndrome, 525–527 Linkage analysis linkage disequilibrium, 21–22 migraine, 453–454 susceptibility gene identification, 21–22 LRRK2, see Leucine-rich repeat kinase-2 Index Magnetic resonance spectroscopy (Continued) high-energy phosphate metabolism, 78 intracellular magnesium measurement, 79 intracellular pH measurement, 78 proton spectroscopy, 83–84 Magnetoencephalography, trigeminal pain studies, 445 Malcavernin, cerebral cavernous malformation defects, 197 MAPK, see Mitogen-activated protein kinase Maternally inherited Leigh syndrome, features, 540 Meiosis, overview, 2–3 MELAS, see Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes Memantine, human immunodeficiency virus-associated dementia management, 563–565 Menkes disease ATP7A mutation, 153–154 clinical features, 154 Messenger RNA splicing, see Splice variants Metabolic diseases, see also specific diseases diagnosis, 149, 151 membrane disorders, 150 molecular therapy, 151 types, 150 Metabolism, see Magnetic resonance spectroscopy N-Methyl-D-aspartate receptors, see Glutamate receptors Methylprednisolone, spinal cord injury management, 209 MG, see Myasthenia gravis Microglia chronic pain role, 434–436 human immunodeficiency virusassociated dementia, 558–559 sodium channels in multiple sclerosis, 341 MicroRNA gene expression control, 26 therapeutic application, 15 Migraine channel defects, 55 classification, 439 clinical phases and pathophysiology 579 cortical spreading depression and migraine aura, 441 headache phase central modulation of trigeminal pain, 444–445 cortical spreading depression triggering, 445–446 neurogenic plasma protein extravasation, 442 neuropeptides, 442–443 symptomatology, 446 trigeminal innervation of painproducing intracranial structures, 441–442 trigeminocervical complex, 443–444 overview, 440 premonitory phase and hypothalamus, 440–441 comorbidity, 440 epidemiology, 439–440 genetics association studies, 454 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, 453 epidemiology, 447 familial hemiplegic migraine, 448–453 gene highway, 447–448 linkage studies, 453–454 mouse mutants, 451–452 sporadic hemiplegic migraine, 450 vascular retinopathy, 453 prospects for study, 454–455 prospects for study, 454–455 triggers, 446–447 Mitochondria amyotrophic lateral sclerosis dysfunction, 311 bioenergetics and calcium signaling, 31–33 disease classification, 536, 539, 545 DNA depletion, 547 encoded proteins, 535–536 genome features, 27, 535 heredity, 7–8 multiple deletions, 546 mutation map and diseases, 538–543 translation defects, 547 fission and fusion, 34–35 function, 30–31, 536–537 genetics, 31 magnetization transfer measurements of ATP and phosphocreatine synthesis in cytopathies, 81 neurodegenerative disease dysfunction, 39–40 neuronal cell death mechanisms abnormal distribution, 37 apoptosis, 38 ATP production decrease, 36 calcium overload and excitotoxicity, 38 free radical damage, 37 overview, 35–36 protein import impairment, 38 neuronal function specialization, 35 nuclear DNA mutations and disease intergenomic signaling defects, 545–547 lipid metabolism, 547–548 mitochondrial motility, fusion, and fission defects, 548–549 protein import machinery, 548 respiratory chain mutations, 543–545 Parkinson disease dysfunction, 230 polyQ disease dysfunction, 266 protein import, 33–34 structure, 29–30 Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, features, 540, 543 Mitogen-activated protein kinase human immunodeficiency-induced neuronal injury and death role, 560 Parkinson disease pathogenesis, 232 Tau as substrate, 246 Modifier gene, definition, 24 Motor neuron, structure and function, 164 Motor unit development, 163–164 diseases, see specific diseases excitation-contraction coupling, 168–169 580 Motor unit (Continued) structure and function motor neuron, 164 muscle, 166–168 neuromuscular junction, 164–166 Moyamoya, features, 194 MPZ, see Myelin protein zero MRI, see Magnetic resonance imaging MRS, see Magnetic resonance spectroscopy MS, see Multiple sclerosis Multiple sclerosis autoimmunity versus self-tolerance, 475–476 axonal degeneration, 334 B cell autoimmunity, 487–488 central nervous system immune reactivity immune privilege, 476–477 inflammation, 477–479 demyelination, 334, 488–490 experimental autoimmune encephalitis autoimmune lymphocytes, 486–487 clinical course, 486 clinical relevance, 480, 485 genetics, 486 induction and autoantigens, 480, 484 lesion pathology and distribution, 484–486 rodent and primate models, 481–483 genetic susceptibility, 479 immunological honunculus concept of beneficial immunity, 490–491 immunomodulatory therapies, 480 myelin-specific antibodies and R cells, 479–480 sodium channels axonal injury, 335–337 distribution in myelinated axons, 334 experimental autoimmune encephalitis studies demyelinated axons, 338 injured axons, 338–339 functional roles in demyelinated axons Nav1.2, 339–340 Nav1.6, 340–341 Index macrophage channels, 341 microglia channels, 341 neuroprotection targeting, 342–345 recovery of conduction in demyelinated axons, 337 types in axons, 337–338 Muscle diseases, see specific diseases gene therapy, 117–118 structure and function, 166–168 Muscular dystrophy dystrophin mutations, 175–176 gene therapy, 117 MuSK, myasthenia gravis autoantibodies, 505–506 Myasthenia gravis acetylcholine receptor antibodies, 502–505 antibody-negative disease, 505 arthrogryposis multiplex congenita, 503 clinical features, 501–502 epidemiology, 502 etiology, 503–504 genetic versus autoimmune diseases, 510–511 history of study, 501–502 MuSK autoantibodies, 505–506 neonatal myasthenia gravis, 503 pathophysiology, 504–505 thymus role, 505 Myelin protein zero Charcot-Marie-Tooth disease type 1B mutations H10P, 471–472 neuropathy mechanisms, 470–471 R69C, 471 function, 468 protein-protein interactions, 470 structure, 468–470 Myotonia, channel defects, 56 Myotonia congenita, chloride channel mutations, 174–175 Myotonic dystrophy gene mutations, 13 gene therapy, 117–118 splice variants, 173–174 N Narcolepsy clinical features, 418 genetics, 419 hypocretin defects, 419–420 symptomatology, 420–422 NCY-059, neuroprotection trials, 180 Necrosis, overview, 126 Nerve growth factor mutation in autonomic nervous system disorders, 326–327 temporal lobe epilepsy expression, 349 Neural stem cell neurodegeneration response, 138–139 Parkinson’s disease replacement therapy, 234 Neurogenetic evaluation clinical evaluation, 8–9 genetic counseling, 9–10 genetic testing clinical diagnostic, research, Neuromuscular junction diseases, see specific diseases structure and function, 164–166, 499–501 Neuromyotonia central nervous system disease, 509 clinical features, 508 etiology, 508 pathophysiology, 508 Neurotrophic tyrosine kinase receptor, mutation in autonomic nervous system disorders, 326 NgR1, see Nogo-66 receptor-1 Nicotinic acetylcholine receptors congenital myasthenic syndromes, 509–510 deficiency, 171 myasthenia gravis antibodies, 502–505 antibody-negative disease, 505 neuromuscular junction, 165–166, 499–501 physiological roles, 53 structure and function, 50 types and nomenclature, 47 Nitroglycerin, human immunodeficiency virus-associated dementia management, 564–565 NMT, see Neuromyotonia Nociception, see Pain Nogo-66 receptor-1, therapeutic targeting in spinal cord injury, 209–211 Index 581 O Obsessive-compulsive disorder, Tourette’s syndrome comorbidity, 387–388 OCD, see Obsessive-compulsive disorder OEC, see Olfactory ensheathing cell Olfactory ensheathing cell, transplantation for spinal cord injury animal studies, 214–215 clinical studies, 215–216 rationale, 213–214 Opsoclonus-myoclonus, paraneoplastic syndrome, 528 Organic acidurias clinical features, 157 types, 156–157 P Pain channel defects, 55–56 damage sensing, 428–429 functional imaging, 436 gene therapy, 114–116 incidence of chronic pain, 427–428 mechanosensation, 430–431 microglial interactions and chronic pain, 434–436 nociception chemical mediators, 429–430 thermoreception, 431–432 voltage-gated ion channels calcium channels, 434 potassium channels, 433–434 sodium channels, 432–433 Pantothenate kinase, deficiency, 160 Paraneoplastic neurologic syndromes clinical manifestations cerebellar degeneration, 525 Lambert-Eaton myasthenic syndrome, 528–529 limbic encephalitis, 525–527 opsoclonus-myoclonus, 528 sensory neuronopathy, 527–528 definition, 517 diagnosis criteria, 524–525 immune response analysis, 523–524 frequency, 517 immune response effects on tumor, 529 pathogenesis antibodies, 518–519 antigens, 520–521 neoplastic cell immune components, 522–523 steps, 520–521 T cells, 518–520 treatment, 529–530 types, 519 Parkin Parkinson disease mutations, 226 structure and function, 226–227 Parkinson disease chaperone studies in models, 70 diagnosis, 222–223 epidemiology, 221 etiology, 223–224 gene mutations candidate gene search, 229–230 DJ-1, 227 LRRK2, 229 parkin, 226–227 PINK-1, 227 α-synuclein, 224–226 history of study, 221–222 magnetization transfer measurements of ATP and phosphocreatine synthesis, 82 pathogenesis mitochondrial dysfunction, 230 phosphoregulation, 232–233 ubiquitin-proteasome system dysfunction, 230–232 pathology, 223 treatment neuroprotection, 234 replacement therapy, 234 symptomatic treatment, 233–234 PCR, see Polymerase chain reaction PD, see Parkinson disease PDCD10, cerebral cavernous malformation defects, 197 Pearson syndrome, features, 539 Pedigree, Mendelian patterns of inheritance, 4, Periaqueductal grey, migraine activation, 444 Period, circadian rhythm, 414 Periodic paralysis, channel defects, 56 PET, see Positron emission tomography Pharmacogenomics, overview, 23 Phenotype, overview, Phenylketonuria clinical features, 158–159 gene mutations, 158 Phosphocreatine magnetization transfer measurements of ATP and phosphocreatine synthesis animal models, 82 creatine deficiency syndromes, 82 epilepsy, 82–83 mitochondrial cytopathies, 81 overview, 80–81 Parkinson disease, 82 shuttle hypothesis, 79–80 PHOX2B, mutation in autonomic nervous system disorders, 323 PINK-1, see PTEN-induced putative kinase PKU, see Phenylketonuria Plasma protein extravasation, migraine role, 442 PNS, see Paraneoplastic neurologic syndromes Polycystins, mechanosensation, 431 Polyglutamate diseases, see PolyQ diseases Polymerase chain reaction, molecular diagnostics, 12 Polyneuropathy, gene therapy, 116–117 PolyQ diseases, see also specific diseases axonal transport defects, 267–268 cell autonomous versus non-cell autonomous effects, 269 clinical and genetic features, 258–260 common features, 257–258 excitotoxicity and calcium homeostasis, 266–267 mitochondria dysfunction, 266 neuronal dysfunction versus death, 268–269 protein misfolding and quality control failure aggregation, 262 heat shock protein response, 69–70, 264 nuclear localization of disease protein, 262–263 overview, 260–261 582 PolyQ diseases, see also specific diseases (Continued) post-translational modifications and protein context, 263 toxic protein fragments, 263 transcriptional dysregulation, 264–266 Positional cloning, disease gene identification, 10–11 Positron emission tomography Alzheimer’s disease, 250 pain studies, 436 Tourette’s syndrome findings, 392 trigeminal pain studies, 444 Potassium channels Andersen syndrome mutations, 173 idiopathic infantile seizure syndrome mutations, 374 neuromyotonia autoantibodies, 580–509 pain transduction, 433–434 paraneoplastic limbic encephalitis antibodies, 527 physiological roles, 53 structure and function, 49–50 types and nomenclature, 45–46 Pramipexole, Parkinson disease management, 233 Presenilins, Alzheimer’s disease mutations, 244–245 Programmed cell death, see also Apoptosis autophagic programmed cell death, 132–133 history of study, 126 neurodegeneration role, 137–138 therapeutic targeting, 138 trophic factors and cellular dependence, 134–135 types, 130–134 Progressive external ophthalmoplegia, features, 539 Proteasome, see Ubiquitinproteasome system Protein folding apoptosis induction by misfolded proteins, 136–137 chaperones, see Heat shock proteins mutations and disease, 59–60 polyQ diseases and quality control failure aggregation, 262 heat shock protein response, 69–70, 264 Index nuclear localization of disease protein, 262–263 overview, 260–261 post-translational modifications and protein context, 263 toxic protein fragments, 263 Proteomics, overview, 26PTEN-induced putative kinase 1, Parkinson disease mutations, 227 Purinergic receptors mechanosensation, 431 nociception, 429 Pyruvate carboxylase deficiency, features, 156 Pyruvate dehydrogenase, mutations and disease, 154–156 R Rapsyn, deficiency, 172 Rasagiline, Parkinson disease management, 234 Rasmussen’s syndrome, epilepsy pathogenesis, 361–362 Rendu-Osler-Weber syndrome, see Hereditary hemorrhagic telangiectasia Repulsive guidance molecule, therapeutic targeting in spinal cord injury, 211–212 RET, mutation in autonomic nervous system disorders, 324 Retrovirus, gene therapy vectors, 104–105 RGM, see Repulsive guidance molecule RhoA, therapeutic targeting in spinal cord injury, 23 Ribozyme, gene therapy, 112 Riluzole, amyotrophic lateral sclerosis trials, 314 RNA interference amyotrophic lateral sclerosis studies, 316 gene therapy, 111–112 therapeutic application, 15 Ropinerole, Parkinson disease management, 233 S SAGE, see Serial analysis of gene expression SBMA, see Spinobulbar muscular atrophy SCA, see Spinocerebellar ataxia SCAN1, see Spinocerebellar ataxia with axonal neuropathy Schwann cell, biology, 464–467 SCI, see Spinal cord injury SCN, see Suprachiasmatic nucleus SCNA1, familial hemiplegic migraine mutations, 450, 452 Segawa disease, features, 154 Seizure, see Epilepsy Selegiline, Parkinson disease management, 234 Senataxin, ataxia with oculomotor apraxia mutations, 289–290 Sensory neuronopathy, paraneoplastic syndrome, 527–528 Serial analysis of gene expression, principles, 25 Serine palmitoyltransferase, mutation in autonomic nervous system disorders, 325–326 Serotonin receptors physiological roles, 53 structure and function, 50–51 types and nomenclature, 47 Sex-linked, definition, 6–7 Single nucleotide polymorphism definition, 20 Haplotype Mapping Project, 22 SL6A2, mutation and orthostatic intolerance, 329 SLC2A1, see GLUT1 deficiency Sleep disorders advanced-sleep-phase syndrome clinical features, 422 familial forms, 422 molecular biology, 422–424 genetics, 413 narcolepsy clinical features, 418 genetics, 419 hypocretin defects, 419–420 symptomatology, 420–422 prospects for study, 424 sleep animals, 410 functions, 410 neural correlates higher order regulation, 418 non-rapid eye movement sleep, 417 Index Sleep disorders (Continued) overview, 414–415 rapid eye movement sleep, 417 wakefulness, 415–417 stages, 410–412 sleep/wake cycle, 410–411 symptoms, 412–413 SMA, see Spinal muscular atrophy Smith-Leml-Opitz syndrome, features, 160 SNP, see Single nucleotide polymorphism Sodium channels migraine, see SCNA1 multiple sclerosis axonal injury, 335–337 channel distribution in myelinated axons, 334 experimental autoimmune encephalitis studies demyelinated axons, 338 injured axons, 338–339 functional roles in demyelinated axons Nav1.2, 339–340 Nav1.6, 340–341 macrophage channels, 341 microglia channels, 341 neuroprotection targeting, 342–345 recovery of conduction in demyelinated axons, 337 types in axons, 337–338 muscle channels and hereditary disorders of excitability, 172–173 mutation in autonomic nervous system disorders, 327 pain transduction, 432–433 physiological roles, 52 spinal cord injury response, 217 structure and function, 48 types and nomenclature, 44 SOX10, mutation in autonomic nervous system disorders, 323 Spinal cord injury axon regeneration barriers cyclic AMP response, 212–213 glial scar and chondroitin sulfate proteoglycans, 212 myelin-associated inhibitors, 209–212 583 RhoA, 213 epidemiology, 207–208 molecular adaptations, 216–217 olfactory ensheathing cell therapy, 213–216 prognosis, 208 secondary injury pathology acute phase, 208 early phase, 208 late phase, 208–20 treatment, 209 Spinal muscular atrophy, phenotypes, 169–170 Spinobulbar muscular atrophy clinical and genetic features, 258 heat shock protein transgenic mouse model, 264 neuronal dysfunction before degeneration, 270 Spinocerebellar ataxia clinical and genetic features SCA1, 259 SCA2, 259 SCA3, 259–260 SCA6, 260 SCA7, 260 SCA8, 260 SCA17, 260 excitotoxicity and calcium homeostasis, 267 mitochondrial dysfunction, 266 neuronal dysfunction before degeneration, 29–270 protein aggregation, 262 transcriptional dysregulation, 265–266 Spinocerebellar ataxia with axonal neuropathy, features, 291 Splice variants diseases, 26 myotonic dystrophy, 173–174 Stroke, see Cerebral ischemia; Intracranial hemorrhage Substantia nigra, cell therapy in Parkinson disease management Superoxide dismutase, see Amyotrophic lateral sclerosis Suprachiasmatic nucleus, circadian rhythm, 413–414 Susceptibility gene linkage analysis, 21–22 overview, 23 α-Synuclein Parkinson disease mutations, 224 pathology, 224–226 T Tau, Alzheimer’s disease animal models, 248–249 biology, 246–247 diagnostic value, 250–251 Temporal lobe epilepsy, see Epilepsy TGF-β, see Transforming growth factor-β Thalidomide, amyotrophic lateral sclerosis trials, 316 Tic disorder, see Tourette’s syndrome Tie, angiogenesis regulation, 190 Tourette’s syndrome clinical features and natural history, 385–387 comorbid conditions, 387–388 endocrine factors, 395 genetic factors, 389–390 history of study, 385 integrative hypotheses basal ganglia control loss, 398–399 frontal lobe compensation, 400–401 neural oscillations, 397–398 testing, 401–402 thalamocortical dysrhythmia, 399–400 neural circuits imaging functional, 391–392 structural, 391 neuroanatomy, 390 neuropathology, 390–391 neurophysiology, 392–393 neuropsychological findings, 388–389 neurotransmitters and neuromodulators, 393–395 perinatal risk factors, 395–396 post-infectious autoimmune mechanisms, 396–397 prevalence, 388 prospects for study, 402 psychological factors, 397 Transforming growth factor-β angiogenesis regulation, 190, 198–199 receptors, 190 584 Index Translocases, mitochondria, 33–34 Transthyretin, mutations and amyloid polyneuropathy, 329 Trigeminal nerve, migraine central modulation of trigeminal pain, 444–445 innervation of pain-producing intracranial structures, 441–442 trigeminocervical complex, 443–444 TRVP channels mechanosensation, 431 thermoreception, 431–432 TS, see Tourette’s syndrome TTPA, see Ataxia with vitamin E deficiency TTR, see Transthyretin U Ubiquitin-proteasome system, Parkinson disease dysfunction, 230–232 Urea cycle, disorders, 157 V Vascular endothelial growth factor amyotrophic lateral sclerosisdys regulation, 312–313 therapy, 315 angiogenesis regulation, 188, 190 neuroregeneration in stroke, 181–182 receptors, 190 Vascular retinopathy, migraine, 453 Vasculogenesis definition, 188 regulators, 188 Vasoactive intestinal polypeptide, migraine role, 443 VEGF, see Vascular endothelial growth factor Ventroposteromedial thalamus, migraine role, 443–444 VIP, see Vasoactive intestinal polypeptide Vitamin D, amyotrophic lateral sclerosis trials, 315 Voltage-gated ion channels channelopathies, 53–56 physiological roles, 52–53 structure and function, 48–50 types and nomenclature, 44–47 W Waardenburg-Shah syndrome, gene mutations, 323 X X-linked, definition, ... medical tests such as blood pressure, cholesterol, and glucose, as well as causes the development of diseases such as neurofibromatosis, familial Alzheimer s disease, certain forms of epilepsy, among... simplest human genetic diseases are those in which the genotype at a single locus is necessary and sufficient to result in the disease This category of diseases is known as Mendelian diseases,... Neurology traditionally has rested upon a systematic and meticulous system of diagnosis and classification of disorders of the nervous system, based first on localization within the nervous system,