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Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis
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 HD_neuron_main_revision2_v1_RDK.docx | Accepted version | 78.86 kB | Microsoft Word | View/Open |
| Title: | Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis |
| Authors: | Dewan, R Chia, R Ding, J Hickman, RA Stein, TD Abramzon, Y Ahmed, S Sabir, MS Portley, MK Tucci, A Ibáñez, 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 Chiò, A Gibbs, JR Dalgard, CL Scholz, SW Traynor, BJ Adeleye, A Alba, C Bacikova, D Hupalo, DN Martinez, EM Pollard, HB Sukumar, G Soltis, AR Tuck, M Zhang, X Wilkerson, MD Smith, BN Ticozzi, N Fallini, C Gkazi, AS Topp, SD Kost, J Scotter, EL Kenna, KP Miller, JW Tiloca, C Vance, C Danielson, EW Troakes, C Colombrita, C Al-Sarraj, S Lewis, EA King, A Calini, D Pensato, V Castellotti, B De Belleroche, J Baas, F Ten Asbroek, ALMA Sapp, PC McKenna-Yasek, D McLaughlin, RL Polak, M Asress, S Esteban-Pérez, J Muñoz-Blanco, JL Stevic, Z D’Alfonso, S Mazzini, L Comi, GP Del Bo, R Ceroni, M Gagliardi, S Querin, G Bertolin, C Van Rheenen, W Diekstra, FP Rademakers, R Van Blitterswijk, M Boylan, KB Lauria, G Duga, S Corti, S Cereda, C Corrado, L Sorarù, G Williams, KL Nicholson, GA Blair, IP Leblond-Manry, C Rouleau, GA Hardiman, O Morrison, KE Veldink, JH Van den Berg, LH Al-Chalabi, A Pall, H Shaw, PJ Turner, MR Talbot, K Taroni, F García-Redondo, A Wu, Z Gellera, C Ratti, A Brown, RH Shaw, CE Ambrose, JC Arumugam, P Baple, EL Bleda, M Boardman-Pretty, F Boissiere, JM Boustred, CR Brittain, H Caulfield, MJ Chan, GC Craig, CEH Daugherty, LC De Burca, A Devereau, A Elgar, G Foulger, RE Fowler, T Furió-Tarí, P Hackett, JM Halai, D Hamblin, A Henderson, S Holman, JE Hubbard, TJP Jackson, R Jones, LJ Kasperaviciute, D Kayikci, M Lahnstein, L Lawson, K Leigh, SEA Leong, IUS Lopez, JF Maleady-Crowe, F Mason, J McDonagh, EM Moutsianas, L Mueller, M Murugaesu, N Need, AC Odhams, CA Patch, C Perez-Gil, D Polychronopoulos, D Pullinger, J Rahim, T Rendon, A Riesgo-Ferreiro, P Rogers, T Savage, K Sawant, K Scott, RH Siddiq, A Sieghart, A Smedley, D Smith, KR Sosinsky, A Spooner, W Stevens, HE Stuckey, A Sultana, R Thomas, ERA Thompson, SR Tregidgo, C Walsh, E Watters, SA Welland, MJ Williams, E Witkowska, K Wood, SM Zarowiecki, M Arepalli, S Auluck, P Baloh, RH Bowser, R Brice, A Broach, J Camu, W Chiò, A Cooper-Knock, J Corcia, P Drepper, C Drory, VE Dunckley, TL Faghri, F Farren, J Feldman, E Floeter, MK Fratta, P Gerhard, G Gibson, SB Goutman, SA Heiman-Patterson, TD Hernandez, DG Hoover, B Jansson, L Kamel, F Kirby, J Kowall, NW Laaksovirta, H Landi, F Le Ber, I Lumbroso, S MacGowan, DJL Maragakis, NJ Mora, G Mouzat, K Myllykangas, L Nalls, MA Orrell, RW Ostrow, LW Pamphlett, R Pioro, E Pulst, SM Ravits, JM Renton, AE Robberecht, W Robey, I Rogaeva, E Rothstein, JD Sendtner, M Shaw, PJ Sidle, KC Simmons, Z Stone, DJ Tienari, PJ Trojanowski, JQ Troncoso, JC Valori, M Van Damme, P Van Den Bosch, L Zinman, L Albani, D Borroni, B Padovani, A Bruni, A Clarimon, J Dols-Icardo, O Illán-Gala, I Lleó, A Danek, A Galimberti, D Scarpini, E Serpente, M Graff, C Chiang, H-H Khoshnood, B Öijerstedt, L Morris, CM Nacmias, B Sorbi, S Nielsen, JE Hjermind, LE Novelli, V Puca, AA Pastor, P Alvarez, I Diez-Fairen, M Aguilar, M Perneczky, R Diehl-Schimd, J Rogaeva, E Rossi, M Ruiz, A Boada, M Hernández, I Moreno-Grau, S Schlachetzki, JC Aarsland, D Alba, C Albert, MS Al-Sarraj, S Attems, J Bacikova, D Barrett, MJ Beach, TG Bekris, LM Bennett, DA Besser, LM Bigio, EH Black, SE Boeve, BF Bohannan, RC Brett, F Brice, A Brunetti, M Caraway, CA Palma, J-A Calvo, A Canosa, A Clarimon, J Dickson, D Diez-Fairen, M Duyckaerts, C Faber, K Ferman, T Flanagan, ME Floris, G Foroud, TM Fortea, J Gan-Or, Z Gentleman, S Ghetti, B Gibbs, JR Goate, A Goldstein, D González-Aramburu, I Graff-Radford, NR Hodges, AK Hu, H-C Hupalo, D Infante, J Iranzo, A Kaiser, SM Kaufmann, H Keith, J Kim, RC Klein, G Krüger, R Kukull, W Kuzma, A Lage, C Lesage, S Lleó, A Leverenz, JB Logroscino, G Lopez, G Love, S Mao, Q Marti, MJ Martinez-McGrath, E Masellis, M Masliah, E May, P McKeith, I Mesulam, M-M Monuki, ES Morris, CM Newell, KL Norcliffe-Kaufmann, L Palmer, L Pastor, P Perkins, M Pletnikova, O Molina-Porcel, L Renton, AE Reynolds, RH Rodríguez-Rodríguez, E Rogaeva, E Rohrer, JD Sanchez-Juan, P Scherzer, CR Serrano, GE Shakkottai, V Sidransky, E Tayebi, N Thomas, AJ Tilley, BS Troakes, C Troncoso, JC Walton, RL Woltjer, R Wszolek, ZK Xiromerisiou, G Zecca, C Phatnani, H Kwan, J Sareen, D Broach, JR Simmons, Z Arcila-Londono, X Lee, EB Shneider, NA Fraenkel, E Ostrow, LW Baas, F Zaitlen, N Berry, JD Malaspina, A Fratta, P Cox, GA Thompson, LM Finkbeiner, S Dardiotis, E Miller, TM Chandran, S Pal, S Hornstein, E MacGowan, DJ Heiman-Patterson, T Hammell, MG Patsopoulos, NA Butovsky, O Dubnau, J Nath, A Bowser, R Harms, M Aronica, E Poss, M Phillips-Cremins, J Crary, J Atassi, N Lange, DJ Adams, DJ Stefanis, L Gotkine, M Baloh, RH Babu, S Raj, T Paganoni, S Shalem, O Smith, C Zhang, B Harris, B Broce, I Drory, V Ravits, J McMillan, C Menon, V Wu, L Altschuler, S Amar, K Archibald, N Bandmann, O Capps, E Church, A Coebergh, J Costantini, A Critchley, P Ghosh, BCP Hu, MTM Kobylecki, C Leigh, PN Mann, C Massey, LA Morris, HR Nath, U Pavese, N Paviour, D Sharma, J Vaughan, J |
| Item Type: | Journal Article |
| 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. |
| Issue Date: | Feb-2021 |
| Date of Acceptance: | 4-Nov-2020 |
| URI: | http://hdl.handle.net/10044/1/86996 |
| DOI: | 10.1016/j.neuron.2020.11.005 |
| ISSN: | 0896-6273 |
| Publisher: | Elsevier BV |
| Start Page: | 448 |
| End Page: | 460.e4 |
| Journal / Book Title: | Neuron |
| Volume: | 109 |
| Issue: | 3 |
| Copyright Statement: | © 2020 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Sponsor/Funder: | Parkinson's UK |
| Funder's Grant Number: | J - 1901 |
| Keywords: | Neurology & Neurosurgery 1109 Neurosciences 1701 Psychology 1702 Cognitive Sciences |
| Publication Status: | Published |
| Online Publication Date: | 2020-11-26 |
| Appears in Collections: | Department of Brain Sciences |
This item is licensed under a Creative Commons License
