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Dewan, R.; Chia, R.; Ding, J.H.; Hickman, R.A.; Stein, T.D.; Abramzon, Y.; ... ; PROSPECT Consortium (2021)

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

Article / Letter to editor
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...Show more

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.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; huntingtin; repeat expansions; whole-genome sequencing.

Published by Elsevier Inc.

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Dewan, R.; Chia, R.; Ding, J.H.; Hickman, R.A.; Stein, T.D.; Abramzon, Y.; Ahmed, S.; Sabir, M.S.; Portley, M.K.; Tucci, A.; Ibanez, K.; Shankaracharya, F.N.U.; Keagle, P.; Rossi, G.; Caroppo, P.; Tagliavini, F.; Waldo, M.L.; Johansson, P.M.; Nilsson, C.F.; Rowe, J.B.; Benussi, L.; Binetti, G.; Ghidoni, R.; Jabbari, E.; Viollet, C.; Glass, J.D.; Singleton, A.B.; Silani, V.; Ross, O.A.; Ryten, M.; Torkamani, A.; Tanaka, T.; Ferrucci, L.; Resnick, S.M.; Pickering-Brown, S.; Brady, C.B.; Kowal, N.; Hardy, J.A.; Deerlin, V. van; Vonsattel, J.P.; Harms, M.B.; Morris, H.R.; Ferrari, R.; Landers, J.E.; Chio, A.; Gibbs, J.R.; Dalgard, C.L.; Scholz, S.W.; Traynor, B.J.; Amer Genome Ctr TAGC; FALS Sequencing Consortium; Genomics England Res Consortium; Int ALS FTD Genomics Consortium iA; Int FTD Genetics Consortium IFGC; Int LBD Genomics Consortium iLBDGC; NYGC ALS Consortium; PROSPECT Consortium
Date
2021-02-03
Journal
Neuron
Volume
109
Issue
3
Pages
448 - 460.e4
DOI
doi:10.1016/j.neuron.2020.11.005
Link
https://www.sciencedirect.com/science/article/pii/S0896627320308837?via%...