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

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

Neuron (2020-11-27)
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, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L Waldo, Per M Johansson, Christer F Nilsson, James B Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D Glass, Andrew B Singleton, Vincenzo Silani, Owen A Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M Resnick, Stuart Pickering-Brown, Christopher B Brady, Neil Kowal, John A Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B Harms, Huw R Morris, Raffaele Ferrari, John E Landers, Adriano Chiò, J Raphael Gibbs, Clifton L Dalgard, Sonja W Scholz, Bryan J Traynor
PMID33242422
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.

MATERIALS
Product Number
Brand
Product Description
MAB5492
Sigma-Aldrich
Anti-Huntingtin Antibody, a.a. 1-82, ascites fluid, clone 2B4, Chemicon®
MAB1574
Sigma-Aldrich
Anti-Polyglutamine-Expansion Diseases Marker Antibody, clone 5TF1-1C2, ascites fluid, clone 5TF1-1C2, Chemicon®