Neuron
Volume 109, Issue 3, 3 February 2021, Pages 448-460.e4
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Article
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

https://doi.org/10.1016/j.neuron.2020.11.005Get rights and content
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Highlights

  • Pathogenic expansions in the HTT gene are a rare cause of FTD/ALS spectrum diseases

  • Autopsies showed both the expected TDP-43 pathology of FTD/ALS and polyQ inclusions

  • HTT repeat expansions were not seen in healthy subjects or Lewy body dementia cases

  • Clinicians should screen FTD/ALS patients for HTT repeat expansions

Summary

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
whole-genome sequencing
huntingtin
repeat expansions

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