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

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; Genomics England Research Consortium; Lilah M. Besser

doi:10.1016/j.neuron.2020.11.005

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

Journal article

Peer reviewed

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

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A Hickman, Thor D Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S Sabir, Makayla K Portley, Arianna Tucci, …

Neuron (Cambridge, Mass.), Vol.109(3), pp.448-460.e4

2021-02-03

DOI: https://doi.org/10.1016/j.neuron.2020.11.005

PMID: 33242422

Abstract

Amyotrophic Lateral Sclerosis - genetics

Amyotrophic Lateral Sclerosis - pathology

DNA Repeat Expansion

Frontotemporal Dementia - genetics

Frontotemporal Dementia - pathology

Humans

Huntingtin Protein - genetics

Mutation

Whole Genome Sequencing

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.951 Huntington's Disease
Web Of Science research areas: Neurosciences
ESI research areas: Neuroscience & Behavior

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Details

Title: Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Creators: Ramita Dewan - National Institute on Aging
Ruth Chia - National Institute on Aging
Jinhui Ding - National Institute on Aging
Richard A Hickman - Columbia University
Thor D Stein
Yevgeniya Abramzon
Sarah Ahmed - National Institute of Neurological Disorders and Stroke
Marya S Sabir - National Institute of Neurological Disorders and Stroke
Makayla K Portley - National Institute of Neurological Disorders and Stroke
Arianna Tucci - Queen Mary University of London
Kristina Ibáñez - Queen Mary University of London
F N U Shankaracharya - University of Massachusetts Chan Medical School
Pamela Keagle - University of Massachusetts Chan Medical School
Giacomina Rossi - Fondazione IRCCS Istituto Neurologico Carlo Besta
Paola Caroppo - Fondazione IRCCS Istituto Neurologico Carlo Besta
Fabrizio Tagliavini - Fondazione IRCCS Istituto Neurologico Carlo Besta
Maria L Waldo - Lund University
Per M Johansson
Christer F Nilsson - Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden
James B Rowe - University of Cambridge
Luisa Benussi - Centro San Giovanni di Dio Fatebenefratelli
Giuliano Binetti
Roberta Ghidoni - Centro San Giovanni di Dio Fatebenefratelli
Edwin Jabbari
Coralie Viollet - Uniformed Services University of the Health Sciences
Jonathan D Glass - Emory University School of Medicine
Andrew B Singleton - National Institute on Aging
Vincenzo Silani
Owen A Ross - Department of Neuroscience & Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA
Mina Ryten
Ali Torkamani - Scripps Research Institute
Toshiko Tanaka - National Institute on Aging
Luigi Ferrucci - National Institute on Aging
Susan M Resnick - National Institute on Aging
Stuart Pickering-Brown - University of Manchester
Christopher B Brady
Neil Kowal
John A Hardy
Vivianna Van Deerlin - University of Pennsylvania
Jean Paul Vonsattel - Columbia University
Matthew B Harms - Columbia University
Huw R Morris
Raffaele Ferrari - Royal Free Hospital
John E Landers - University of Massachusetts Chan Medical School
Adriano Chiò
J Raphael Gibbs - National Institute on Aging
Clifton L Dalgard
Sonja W Scholz
Bryan J Traynor
Genomics England Research Consortium
Lilah M. Besser - UMMG Department of Neurology
Publication Details: Neuron (Cambridge, Mass.), Vol.109(3), pp.448-460.e4
Grant note: Department of Health Wellcome Trust ZIA NS003154 / Intramural NIH HHS MC_U105597119 / Medical Research Council ZIA NS003034 / Intramural NIH HHS MR/S000992/1 / Medical Research Council R01 NS073873 / NINDS NIH HHS MR/L501529/1 / Medical Research Council MR/R024804/1 / Medical Research Council K-1501 / Parkinson's UK MCLAUGHLIN/OCT15/957-799 / Motor Neurone Disease Association P30 AG066462 / NIA NIH HHS MR/N008324/1 / Medical Research Council G0600974 / Medical Research Council ZIA AG000934 / Intramural NIH HHS P30 AG066507 / NIA NIH HHS MR/R011354/1 / Medical Research Council P01 AG066597 / NIA NIH HHS MR/L016397/1 / Medical Research Council 103838 / Wellcome Trust J-0901 / Parkinson's UK MR/T018569/1 / Medical Research Council AL-CHALABI/APR15/844-791 / Motor Neurone Disease Association MR/S006753/1 / Medical Research Council R01 NS115144 / NINDS NIH HHS P30 AG066514 / NIA NIH HHS MC_EX_MR/N50192X/1 / Medical Research Council MR/M024962/1 / Medical Research Council ZIA AG000935 / Intramural NIH HHS P30 AG013854 / NIA NIH HHS MC_UU_00005/12 / Medical Research Council K08 AG065463 / NIA NIH HHS I01 BX002466 / BLRD VA ZIA AG000933 / Intramural NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Neurology
Language: English
Resource Type: Journal article
PMID: 33242422
Record Identifier: 991031725367702976