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Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
Dewan, Ramita; Chia, Ruth; Ding, Jinhui; Hickman, Richard A; Stein, Thor D; Abramzon, Yevgeniya; Ahmed, Sarah; Sabir, Marya S; Portley, Makayla K; Tucci, Arianna; Ibáñez, Kristina; Shankaracharya, F N U; Keagle, Pamela; Rossi, Giacomina; Caroppo, Paola; Tagliavini, Fabrizio; Waldo, Maria L; Johansson, Per M; Nilsson, Christer F; Rowe, James B; Benussi, Luisa; Binetti, Giuliano; Ghidoni, Roberta; Jabbari, Edwin; Viollet, Coralie; Glass, Jonathan D; Singleton, Andrew B; Silani, Vincenzo; Ross, Owen A; Ryten, Mina; Torkamani, Ali; Tanaka, Toshiko; Ferrucci, Luigi; Resnick, Susan M; Pickering-Brown, Stuart; Brady, Christopher B; Kowal, Neil; Hardy, John A; Van Deerlin, Vivianna; Vonsattel, Jean Paul; Harms, Matthew B; Morris, Huw R; Ferrari, Raffaele; Landers, John E; Chiò, Adriano; Gibbs, J Raphael; Dalgard, Clifton L; Scholz, Sonja W; Traynor, Bryan J.
Afiliación
  • Dewan R; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
  • Chia R; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
  • Ding J; Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
  • Hickman RA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • Stein TD; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA 02118, USA; Research and Development Service, Veterans Affairs Boston Healthcare System, Boston
  • Abramzon Y; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK.
  • Ahmed S; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
  • Sabir MS; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
  • Portley MK; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
  • Tucci A; Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
  • Ibáñez K; Clinical Pharmacology, William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
  • Shankaracharya FNU; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Keagle P; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Rossi G; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
  • Caroppo P; Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
  • Tagliavini F; Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.
  • Waldo ML; Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund, Lund University, Lund 221 84, Sweden.
  • Johansson PM; Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund, Lund University, Lund 221 84, Sweden; Department of Internal Medicine, Sahlgrenska Academy, University of Gottenburg, Gottenburg 413 45, Sweden.
  • Nilsson CF; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden.
  • Rowe JB; Cambridge University Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge Biomedical Campus, Cambridge CB2 02Z, UK.
  • Benussi L; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.
  • Binetti G; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy; MAC Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.
  • Ghidoni R; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.
  • Jabbari E; Department of Neurology, Royal Free Hospital, London NW3 2PF, UK; Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
  • Viollet C; Department of Anatomy, Physiology and Genetics, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
  • Glass JD; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • Singleton AB; Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
  • Silani V; Department of Neurology - Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan 20149, Italy; Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan 20122, Italy.
  • Ross OA; Department of Neuroscience & Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Ryten M; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, UK; NIHR Great Ormond Street Hospital Biomedical Research Cen
  • Torkamani A; The Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • Tanaka T; Longitudinal Studies Section, National Institute on Aging, Baltimore, MD 21224, USA.
  • Ferrucci L; Longitudinal Studies Section, National Institute on Aging, Baltimore, MD 21224, USA.
  • Resnick SM; Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD 21224, USA.
  • Pickering-Brown S; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK.
  • Brady CB; Department of Neurology & Program in Behavioral Neuroscience, Boston University School of Medicine, Boston, MA 02118, USA; Research and Development Service, Veterans Affairs Boston Healthcare System, Boston, MA 02130, USA.
  • Kowal N; Department of Neurology, Veterans Affairs Boston Healthcare System, Boston, MA 02130, USA; Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA 02118, USA.
  • Hardy JA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; UK Dementia Research Institute at UCL and Department
  • Van Deerlin V; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Vonsattel JP; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • Harms MB; Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • Morris HR; Department of Neurology, Royal Free Hospital, London NW3 2PF, UK; Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
  • Ferrari R; Department of Neurology, Royal Free Hospital, London NW3 2PF, UK.
  • Landers JE; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Chiò A; Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin 10126, Italy; Institute of Cognitive Sciences and Technologies, C.N.R., Rome 00185, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin 10126, Italy.
  • Gibbs JR; Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
  • Dalgard CL; Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
  • Scholz SW; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA.
  • Traynor BJ; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London WC1N 1PJ, UK; Department of Neurology, Johns Hopkins University Medical C
Neuron ; 109(3): 448-460.e4, 2021 02 03.
Article en En | MEDLINE | ID: mdl-33242422
ABSTRACT
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Expansión de las Repeticiones de ADN / Demencia Frontotemporal / Proteína Huntingtina / Esclerosis Amiotrófica Lateral Límite: Humans Idioma: En Revista: Neuron Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Expansión de las Repeticiones de ADN / Demencia Frontotemporal / Proteína Huntingtina / Esclerosis Amiotrófica Lateral Límite: Humans Idioma: En Revista: Neuron Asunto de la revista: NEUROLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos