| Literature DB >> 33242422 |
Ramita Dewan1, Ruth Chia1, Jinhui Ding2, Richard A Hickman3, Thor D Stein4, Yevgeniya Abramzon5, Sarah Ahmed6, Marya S Sabir6, Makayla K Portley6, Arianna Tucci7, Kristina Ibáñez7, F N U Shankaracharya8, Pamela Keagle8, Giacomina Rossi9, Paola Caroppo9, Fabrizio Tagliavini10, Maria L Waldo11, Per M Johansson12, Christer F Nilsson13, James B Rowe14, Luisa Benussi15, Giuliano Binetti16, Roberta Ghidoni15, Edwin Jabbari17, Coralie Viollet18, Jonathan D Glass19, Andrew B Singleton20, Vincenzo Silani21, Owen A Ross22, Mina Ryten23, Ali Torkamani24, Toshiko Tanaka25, Luigi Ferrucci25, Susan M Resnick26, Stuart Pickering-Brown27, Christopher B Brady28, Neil Kowal29, John A Hardy30, Vivianna Van Deerlin31, Jean Paul Vonsattel3, Matthew B Harms32, Huw R Morris17, Raffaele Ferrari33, John E Landers8, Adriano Chiò34, J Raphael Gibbs2, Clifton L Dalgard35, Sonja W Scholz36, Bryan J Traynor37.
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. Published by Elsevier Inc.Entities:
Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; huntingtin; repeat expansions; whole-genome sequencing
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Year: 2020 PMID： 33242422 PMCID： PMC7864894 DOI： 10.1016/j.neuron.2020.11.005
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 18.688