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; Adeleye, Adelani; Alba, Camille; Bacikova, Dagmar; Hupalo, Daniel N; Martinez, Elisa McGrath; Pollard, Harvey B; Sukumar, Gauthaman; Soltis, Anthony R; Tuck, Meila; Zhang, Xijun; Wilkerson, Matthew D; Smith, Bradley N; Ticozzi, Nicola; Fallini, Claudia; Gkazi, Athina Soragia; Topp, Simon D; Kost, Jason; Scotter, Emma L; Kenna, Kevin P; Miller, Jack W; Tiloca, Cinzia; Vance, Caroline; Danielson, Eric W; Troakes, Claire; Colombrita, Claudia; Al-Sarraj, Safa; Lewis, Elizabeth A; King, Andrew; Calini, Daniela; Pensato, Viviana; Castellotti, Barbara; de Belleroche, Jacqueline; Baas, Frank; Ten Asbroek, Anneloor L M A; Sapp, Peter C; McKenna-Yasek, Diane; McLaughlin, Russell L; Polak, Meraida; Asress, Seneshaw; Esteban-Pérez, Jesús; Muñoz-Blanco, José Luis; Stevic, Zorica; D'Alfonso, Sandra; Mazzini, Letizia; Comi, Giacomo P; Del Bo, Roberto; Ceroni, Mauro; Gagliardi, Stella; Querin, Giorgia; Bertolin, Cinzia; van Rheenen, Wouter; Diekstra, Frank P; Rademakers, Rosa; van Blitterswijk, Marka; Boylan, Kevin B; Lauria, Giuseppe; Duga, Stefano; Corti, Stefania; Cereda, Cristina; Corrado, Lucia; Sorarù, Gianni; Williams, Kelly L; Nicholson, Garth A; Blair, Ian P; Leblond-Manry, Claire; Rouleau, Guy A; Hardiman, Orla; Morrison, Karen E; Veldink, Jan H; van den Berg, Leonard H; Al-Chalabi, Ammar; Pall, Hardev; Shaw, Pamela J; Turner, Martin R; Talbot, Kevin; Taroni, Franco; GarcÃa-Redondo, Alberto; Wu, Zheyang; Gellera, Cinzia; Ratti, Antonia; Brown, Robert H Jr; Shaw, Christopher E; Ambrose, John C; Arumugam, Prabhu; Baple, Emma L; Bleda, Marta; Boardman-Pretty, Freya; Boissiere, Jeanne M; Boustred, Christopher R; Brittain, H; Caulfield, Mark J; Chan, Georgia C; Craig, Clare E H; Daugherty, Louise C; de Burca, Anna; Devereau, Andrew; Elgar, Greg; Foulger, Rebecca E; Fowler, Tom; Furió-TarÃ, Pedro; Hackett, Joanne M; Halai, Dina; Hamblin, Angela; Henderson, Shirley; Holman, James E; Hubbard, Tim J P; Jackson, Rob; Jones, Louise J; Kasperaviciute, Dalia; Kayikci, Melis; Lahnstein, Lea; Lawson, Kay; Leigh, Sarah E A; Leong, Ivonne U S; Lopez, Javier F; Maleady-Crowe, Fiona; Mason, Joanne; McDonagh, Ellen M; Moutsianas, Loukas; Mueller, Michael; Murugaesu, Nirupa; Need, Anna C; Odhams, Chris A; Patch, Christine; Perez-Gil, Daniel; Polychronopoulos, Dimitris; Pullinger, John; Rahim, Tahrima; Rendon, Augusto; Riesgo-Ferreiro, Pablo; Rogers, Tim; Savage, Kevin; Sawant, Kushmita; Scott, Richard H; Siddiq, Afshan; Sieghart, Alexander; Smedley, Damian; Smith, Katherine R; Sosinsky, Alona; Spooner, William; Stevens, Helen E; Stuckey, Alexander; Sultana, Razvan; Thomas, Ellen R A; Thompson, Simon R; Tregidgo, Carolyn; Walsh, Emma; Watters, Sarah A; Welland, Matthew J; Williams, Eleanor; Witkowska, Katarzyna; Wood, Suzanne M; Zarowiecki, Magdalena; Arepalli, Sampath; Auluck, Pavan; Baloh, Robert H; Bowser, Robert; Brice, Alexis; Broach, James; Camu, William; Chiò, Adriano; Cooper-Knock, John; Corcia, Philippe; Drepper, Carsten; Drory, Vivian E; Dunckley, Travis L; Faghri, Faraz; Farren, Jennifer; Feldman, Eva; Floeter, Mary Kay; Fratta, Pietro; Gerhard, Glenn; Gibson, Summer B; Goutman, Stephen A; Heiman-Patterson, Terry D; Hernandez, Dena G; Hoover, Ben; Jansson, Lilja; Kamel, Freya; Kirby, Janine; Kowall, Neil W; Laaksovirta, Hannu; Landi, Francesco; Le Ber, Isabelle; Lumbroso, Serge; MacGowan, Daniel Jl; Maragakis, Nicholas J; Mora, Gabriele; Mouzat, Kevin; Myllykangas, Liisa; Nalls, Mike A; Orrell, Richard W; Ostrow, Lyle W; Pamphlett, Roger; Pioro, Erik; Pulst, Stefan M; Ravits, John M; Renton, Alan E; Robberecht, Wim; Robey, Ian; Rogaeva, Ekaterina; Rothstein, Jeffrey D; Sendtner, Michael; Shaw, Pamela J; Sidle, Katie C; Simmons, Zachary; Stone, David J; Tienari, Pentti J; Trojanowski, John Q; Troncoso, Juan C; Valori, Miko; Van Damme, Philip; Van Den Bosch, Ludo; Zinman, Lorne; Albani, Diego; Borroni, Barbara; Padovani, Alessandro; Bruni, Amalia; Clarimon, Jordi; Dols-Icardo, Oriol; Illán-Gala, Ignacio; Lleó, Alberto; Danek, Adrian; Galimberti, Daniela; Scarpini, Elio; Serpente, Maria; Graff, Caroline; Chiang, Huei-Hsin; Khoshnood, Behzad; Öijerstedt, Linn; Morris, Christopher M; Nacmias, Benedetta; Sorbi, Sandro; Nielsen, Jorgen E; Hjermind, Lynne E; Novelli, Valeria; Puca, Annibale A; Pastor, Pau; Alvarez, Ignacio; Diez-Fairen, Monica; Aguilar, Miquel; Perneczky, Robert; Diehl-Schimd, Janine; Rogaeva, Ekaterina; Rossi, Mina; Ruiz, Agustin; Boada, Mercè; Hernández, Isabel; Moreno-Grau, Sonia; Schlachetzki, Johannes C; Aarsland, Dag; Alba, Camille; Albert, Marilyn S; Al-Sarraj, Safa; Attems, Johannes; Bacikova, Dagmar; Barrett, Matthew J; Beach, Thomas G; Bekris, Lynn M; Bennett, David A; Besser, Lilah M; Bigio, Eileen H; Black, Sandra E; Boeve, Bradley F; Bohannan, Ryan C; Brett, Francesca; Brice, Alexis; Brunetti, Maura; Caraway, Chad A; Palma, Jose-Alberto; Calvo, Andrea; Canosa, Antonio; Clarimon, Jordi; Dickson, Dennis; Diez-Fairen, Monica; Duyckaerts, Charles; Faber, Kelley; Ferman, Tanis; Flanagan, Margaret E; Floris, Gianluca; Foroud, Tatiana M; Fortea, Juan; Gan-Or, Ziv; Gentleman, Steve; Ghetti, Bernardino; Gibbs, Jesse Raphael; Goate, Alison; Goldstein, David; González-Aramburu, Isabel; Graff-Radford, Neill R; Hodges, Angela K; Hu, Heng-Chen; Hupalo, Daniel; Infante, Jon; Iranzo, Alex; Kaiser, Scott M; Kaufmann, Horacio; Keith, Julia; Kim, Ronald C; Klein, Gregory; Krüger, Rejko; Kukull, Walter; Kuzma, Amanda; Lage, Carmen; Lesage, Suzanne; Lleó, Alberto; Leverenz, James B; Logroscino, Giancarlo; Lopez, Grisel; Love, Seth; Mao, Qinwen; Marti, Maria Jose; Martinez-McGrath, Elisa; Masellis, Mario; Masliah, Eliezer; May, Patrick; McKeith, Ian; Mesulam, Marek-Marsel; Monuki, Edwin S; Morris, Christopher M; Newell, Kathy L; Norcliffe-Kaufmann, Lucy; Palmer, Laura; Pastor, Pau; Perkins, Matthew; Pletnikova, Olga; Molina-Porcel, Laura; Renton, Alan E; Reynolds, Regina H; RodrÃguez-RodrÃguez, Eloy; Rogaeva, Ekaterina; Rohrer, Jonathan D; Sanchez-Juan, Pascual; Scherzer, Clemens R; Serrano, Geidy E; Shakkottai, Vikram; Sidransky, Ellen; Tayebi, Nahid; Thomas, Alan J; Tilley, Bension S; Troakes, Claire; Troncoso, Juan C; Walton, Ronald L; Woltjer, Randy; Wszolek, Zbigniew K; Xiromerisiou, Georgia; Zecca, Chiara; Phatnani, Hemali; Kwan, Justin; Sareen, Dhruv; Broach, James R; Simmons, Zachary; Arcila-Londono, Ximena; Lee, Edward B; Shneider, Neil A; Fraenkel, Ernest; Ostrow, Lyle W; Baas, Frank; Zaitlen, Noah; Berry, James D; Malaspina, Andrea; Fratta, Pietro; Cox, Gregory A; Thompson, Leslie M; Finkbeiner, Steve; Dardiotis, Efthimios; Miller, Timothy M; Chandran, Siddharthan; Pal, Suvankar; Hornstein, Eran; MacGowan, Daniel J; Heiman-Patterson, Terry; Hammell, Molly G; Patsopoulos, Nikolaos A; Butovsky, Oleg; Dubnau, Joshua; Nath, Avindra; Bowser, Robert; Harms, Matt; Aronica, Eleonora; Poss, Mary; Phillips-Cremins, Jennifer; Crary, John; Atassi, Nazem; Lange, Dale J; Adams, Darius J; Stefanis, Leonidas; Gotkine, Marc; Baloh, Robert H; Babu, Suma; Raj, Towfique; Paganoni, Sabrina; Shalem, Ophir; Smith, Colin; Zhang, Bin; Harris, Brent; Broce, Iris; Drory, Vivian; Ravits, John; McMillan, Corey; Menon, Vilas; Wu, Lani; Altschuler, Steven; Amar, Khaled; Archibald, Neil; Bandmann, Oliver; Capps, Erica; Church, Alistair; Coebergh, Jan; Costantini, Alyssa; Critchley, Peter; Ghosh, Boyd Cp; Hu, Michele T M; Kobylecki, Christopher; Leigh, P Nigel; Mann, Carl; Massey, Luke A; Morris, Huw R; Nath, Uma; Pavese, Nicola; Paviour, Dominic; Sharma, Jagdish; Vaughan, Jenny
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.
PMID: 33242422
ISSN: 1097-4199
CID: 5429222