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

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A Hickman, Thor D Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S Sabir, Makayla K Portley, Arianna Tucci, Kristina Ibáñez, F N U Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L Waldo, Per M Johansson, Christer F Nilsson, James B RoweLuisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D Glass, Andrew B Singleton, Vincenzo Silani, Owen A Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M Resnick, Stuart Pickering-Brown, Christopher B Brady, Neil Kowal, John A Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B Harms, Huw R Morris, Raffaele Ferrari, John E Landers, Adriano Chiò, J Raphael Gibbs, Clifton L Dalgard, Sonja W Scholz, Bryan J Traynor, Karen E. Morrison

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)448-460.E4
JournalNeuron
Volume109
Issue number3
Early online date25 Nov 2020
DOIs
Publication statusPublished - 03 Feb 2021

Bibliographical note

Published by Elsevier Inc.

Keywords

  • Amyotrophic Lateral Sclerosis/genetics
  • DNA Repeat Expansion
  • Frontotemporal Dementia/genetics
  • Humans
  • Huntingtin Protein/genetics
  • Mutation
  • Whole Genome Sequencing

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