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

Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A, Stein, Thor D, Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S, Portley, Makayla K, Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, F N U, Keagle, Pamela, Leigh, P Nigel, Paviour, Dominic and others, (2020) Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron. ISSN 0896-6273

[img] PDF - Accepted Version
Available under License Creative Commons Attribution-NonCommercial No Derivatives.

Download (17MB)

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 to 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.

Item Type: Article
Keywords: amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body dementia, Huntington’s disease, whole-genome sequencing, huntingtin, repeat expansions.
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 19 Nov 2020 08:01
Last Modified: 26 Nov 2021 02:00
URI: http://sro.sussex.ac.uk/id/eprint/95168

View download statistics for this item

📧 Request an update