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

International FTD-Genomics Consortium (IFGC) (BENUSSI L, BINETTI G, GHIDONI R sono autori IRCCS)

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. © 2020 Using large-scale whole-genome sequencing, Dewan et al. identify pathogenic HTT repeat expansions in patients diagnosed with FTD/ALS neurodegenerative disorders. Autopsies confirm the TDP-43 pathology expected in FTD/ALS and show polyglutamine inclusions within the frontal cortices but no striatal degeneration. These data broaden the phenotype resulting from HTT repeat expansions. © 2020
Original languageEnglish
JournalNeuron
DOIs
Publication statusE-pub ahead of print - Nov 26 2020

Keywords

  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • huntingtin
  • repeat expansions
  • whole-genome sequencing

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