Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

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, Adeleye, A, Alba, C, Bacikova, D, Hupalo, DN, Martinez, EMG, 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 (February 2021) Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Neuron, 109 (3). 448-460.e4. ISSN 0896-6273

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.

Item Type:	Paper
Subjects:	diseases & disorders > neurodegenerative diseases > ALS diseases & disorders > nervous system diseases and disorders > amyotrophic lateral sclerosis diseases & disorders > nervous system diseases and disorders > frontotemporal dementia organism description > animal > mammal > primates > hominids > human Investigative techniques and equipment > assays > whole genome sequencing
CSHL Authors:	Hammell, Molly
Communities:	CSHL labs > Hammell M. lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 February 2021
Date Deposited:	30 Apr 2021 18:59
Last Modified:	30 Apr 2021 18:59
PMCID:	PMC7864894
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39963

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