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Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

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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



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