Article Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Por:
Dewan, R, Chia, R, Ding, JH, Hickman, RA, Stein, TD, Abramzon, Y, Ahmed, S, Sabir, MS, Portley, MK, Tucci, A, Ibanez, K, Shankaracharya, FNU, Keagle, P, Rossi, G, Caroppo, P, Tagliavini, F, Waldo, ML, Johansson, PM, Nilsson, CF, Rowe, JB, Benussi, L, Binetti, G, Ghidoni, R, Jabbari, E, Viollet, C, Glass, JD, Singleton, AB, Silani, V, Ross, OA, Ryten, M, Torkamani, A, Tanaka, T, Ferrucci, L, Resnick, SM, Pickering-Brown, S, Brady, CB, Kowal, N, Hardy, JA, Van Deerlin, V, Vonsattel, JP, Harms, MB, Morris, HR, Ferrari, R, Landers, JE, Chio, A, Gibbs, JR, Dalgard, CL, Scholz, SW, Traynor, BJ, Clarimón J., Dols-Icardo O., Illan-Gala, I, Lleó A., Vaughan, Jenny R.
Publicada:
3 feb 2021
Ahead of Print:
1 feb 2021
Resumen:
The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32
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.
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.
Filiaciones:
Dewan, R:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD 20892 USA
Chia, R:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD 20892 USA
Ding, JH:
NIA, Computat Biol Grp, Lab Neurogenet, Bethesda, MD 20892 USA
Hickman, RA:
Columbia Univ, Dept Pathol & Cell Biol, Irving Med Ctr, New York, NY 10032 USA
Stein, TD:
Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA
Boston Univ, Alzheimers Dis Ctr, Sch Med, Boston, MA 02118 USA
Vet Affairs Boston Healthcare Syst, Res & Dev Serv, Boston, MA 02130 USA
Dept Vet Affairs Med Ctr, Bedford, MA 01730 USA
Abramzon, Y:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD 20892 USA
UCL, UCL Queen Sq Inst Neurol, Reta Lila Weston Inst, London WC1N 1PJ, England
Ahmed, S:
NINDS, Neurodegenerat Dis Res Unit, Lab Neurogenet, Bethesda, MD 20892 USA
Sabir, MS:
NINDS, Neurodegenerat Dis Res Unit, Lab Neurogenet, Bethesda, MD 20892 USA
Portley, MK:
NINDS, Neurodegenerat Dis Res Unit, Lab Neurogenet, Bethesda, MD 20892 USA
Tucci, A:
Queen Mary Univ London, Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London EC1M 6BQ, England
Ibanez, K:
Queen Mary Univ London, Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London EC1M 6BQ, England
Shankaracharya, FNU:
Univ Massachusetts, Dept Neurol, Med Sch, Worcester, MA 01605 USA
Keagle, P:
Univ Massachusetts, Dept Neurol, Med Sch, Worcester, MA 01605 USA
Rossi, G:
Fdn IRCCS Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, I-20133 Milan, Italy
Caroppo, P:
Fdn IRCCS Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, I-20133 Milan, Italy
Tagliavini, F:
Fdn IRCCS Ist Neurol Carlo Besta, Sci Directorate, I-20133 Milan, Italy
Waldo, ML:
Lund Univ, Dept Clin Sci Lund, Div Clin Sci Helsingborg, S-22184 Lund, Sweden
Johansson, PM:
Lund Univ, Dept Clin Sci Lund, Div Clin Sci Helsingborg, S-22184 Lund, Sweden
Univ Gottenburg, Sahlgrenska Acad, Dept Internal Med, S-41345 Gottenburg, Sweden
Nilsson, CF:
Lund Univ, Skane Univ Hosp, Dept Clin Sci Malmo, Clin Memory Res Unit, S-20502 Malmo, Sweden
Rowe, JB:
Univ Cambridge, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge CB2 02Z, England
Cambridge Univ Hosp NHS Trust, Cambridge Biomed Campus, Cambridge CB2 02Z, England
Benussi, L:
IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Mol Markers Lab, I-25125 Brescia, Italy
Binetti, G:
IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Mol Markers Lab, I-25125 Brescia, Italy
IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, MAC Memory Clin, I-25125 Brescia, Italy
Ghidoni, R:
IRCCS Ist Ctr San Giovanni di Dio Fatebenefratell, Mol Markers Lab, I-25125 Brescia, Italy
Jabbari, E:
Royal Free Hosp, Dept Neurol, London NW3 2PF, England
UCL, Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London WC1N 3BG, England
Viollet, C:
Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet Physiol & Genet, Bethesda, MD 20814 USA
Glass, JD:
Emory Univ, Dept Neurol, Sch Med, Atlanta, GA 30322 USA
Singleton, AB:
NIA, Mol Genet Sect, Lab Neurogenet, Bethesda, MD 20892 USA
Silani, V:
IRCCS Ist Auxol Italiano, Stroke Unit, Dept Neurol, I-20149 Milan, Italy
IRCCS Ist Auxol Italiano, Lab Neurosci, I-20149 Milan, Italy
Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy
Ross, OA:
Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
Mayo Clin, Dept Clin Genom, Jacksonville, FL 32224 USA
Ryten, M:
UCL, UCL Queen Sq Inst Neurol, Reta Lila Weston Inst, London WC1N 1PJ, England
UCL, Great Ormond St Inst Child Hlth, Genet & Genom Med, London WC1E 6BT, England
UCL, NIHR Great Ormond St Hosp, Biomed Res Ctr, London WC1E 6BT, England
Torkamani, A:
Scripps Res Inst, Scripps Translat Sci Inst, La Jolla, CA 92037 USA
Tanaka, T:
NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA
Ferrucci, L:
NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA
Resnick, SM:
NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA
Pickering-Brown, S:
Univ Manchester, Fac Biol Med & Hlth, Div Neurosci & Expt Psychol, Manchester M13 9PT, Lancs, England
Brady, CB:
Vet Affairs Boston Healthcare Syst, Res & Dev Serv, Boston, MA 02130 USA
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Boston Univ, Sch Med, Program Behav Neurosci, Boston, MA 02118 USA
Kowal, N:
Boston Univ, Alzheimers Dis Ctr, Sch Med, Boston, MA 02118 USA
Vet Affairs Boston Healthcare Syst, Dept Neurol, Boston, MA 02130 USA
Hardy, JA:
UCL, UCL Queen Sq Inst Neurol, Reta Lila Weston Inst, London WC1N 1PJ, England
UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London WC1N 3BG, England
UCL, UK Dementia Res Inst, UCL Queen Sq Inst Neurol, London WC1N 3BG, England
UCL, NINR Univ Coll London Hosp, Biomed Res Ctr, London W1T 7DN, England
Hong Kong Univ Sci & Technol, Inst Adv Study, Hong Kong, Peoples R China
Van Deerlin, V:
Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
Vonsattel, JP:
Columbia Univ, Dept Pathol & Cell Biol, Irving Med Ctr, New York, NY 10032 USA
Harms, MB:
Columbia Univ, Dept Neurol, Irving Med Ctr, New York, NY 10032 USA
Morris, HR:
Royal Free Hosp, Dept Neurol, London NW3 2PF, England
UCL, Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London WC1N 3BG, England
Ferrari, R:
Royal Free Hosp, Dept Neurol, London NW3 2PF, England
Landers, JE:
Univ Massachusetts, Dept Neurol, Med Sch, Worcester, MA 01605 USA
Chio, A:
Univ Turin, Rita Levi Montalcini Dept Neurosci, I-10126 Turin, Italy
CNR, Inst Cognit Sci & Technol, I-00185 Rome, Italy
Azienda Osped Univ Citta Salute & Sci, I-10126 Turin, Italy
Gibbs, JR:
NIA, Computat Biol Grp, Lab Neurogenet, Bethesda, MD 20892 USA
Dalgard, CL:
Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA
Uniformed Serv Univ Hlth Sci, Collaborat Hlth Initiat Res Program, Amer Genome Ctr, Bethesda, MD 20814 USA
Scholz, SW:
NINDS, Neurodegenerat Dis Res Unit, Lab Neurogenet, Bethesda, MD 20892 USA
Johns Hopkins Univ, Dept Neurol, Med Ctr, Baltimore, MD 21287 USA
Traynor, BJ:
NIA, Neuromuscular Dis Res Sect, Lab Neurogenet, Bethesda, MD 20892 USA
UCL, UCL Queen Sq Inst Neurol, Reta Lila Weston Inst, London WC1N 1PJ, England
Johns Hopkins Univ, Dept Neurol, Med Ctr, Baltimore, MD 21287 USA
Clarimón J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Dols-Icardo O.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Illan-Gala, I:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Lleó A.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Vaughan, Jenny R.:
Charing Cross Hospital, London, United Kingdom
Green Accepted, Green Submitted, All Open Access, Bronze, Green
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