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

The American Genome Center (TAGC), The FALS Sequencing Consortium, The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank, The PROSPECT Consortium

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 (US)
Pages (from-to)448-460.e4
JournalNeuron
Volume109
Issue number3
DOIs
StatePublished - Feb 3 2021

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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