NEURON-D-20-01249_R3_final.pdf (16.85 MB)
Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis
journal contribution
posted on 2023-06-09, 22:13 authored by 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, Nigel LeighNigel Leigh, Dominic Paviour, othersWe 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.
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Publication status
- Published
File Version
- Accepted version
Journal
NeuronISSN
0896-6273Publisher
ElsevierExternal DOI
Department affiliated with
- BSMS Neuroscience Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2020-11-19First Open Access (FOA) Date
2021-11-26First Compliant Deposit (FCD) Date
2020-11-18Usage metrics
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