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

84 Pages Posted: 11 Aug 2020 Publication Status: Published

See all articles by Ramita Dewan

Ramita Dewan

National Institute on Aging - Neuromuscular Diseases Research Section

Ruth Chia

National Institutes of Health - Neuromuscular Diseases Research Section

Jinhui Ding

National Institutes of Health - Computational Biology Core

Richard Hickman

Columbia University - Department of Pathology and Cell Biology

Thor Stein

Boston University - Chronic Traumatic Encephalopathy Center; Department of Veterans Affairs (VA); Boston University - Alzheimer's Disease Center; Boston University - Department of Pathology and Laboratory Medicine

Yevgeniya Abramzon

National Institutes of Health - Neuromuscular Diseases Research Section

Sarah Ahmed

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit

Marya S. Sabir

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit

Makayla K. Portley

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit

Arianna Tucci

Queen Mary University of London - Clinical Pharmacology

Kristina Ibáñez

Queen Mary University of London - Clinical Pharmacology

Shankaracharya

University of Massachusetts Worcester - Department of Neurology

Pamela Keagle

University of Massachusetts Worcester - Department of Neurology

Giacomina Rossi

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Division of Neurology V and Neuropathology

Paola Caroppo

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Division of Neurology V and Neuropathology

Fabrizio Tagliavini

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Scientific Directorate

Maria L. Waldo

Lund University - Division of Clinical Sciences Helsingborg

Per M. Johansson

Lund University - Division of Clinical Sciences Helsingborg

Christer F. Nilsson

Lund University - Clinical Memory Research Unit

The American Genome Center (TAGC)

Independent

The FALS Sequencing Consortium

Independent

The Genomics England Research Consortium

Independent

The International ALS/FTD Genomics Consortium (iAFGC)

Independent

The International FTD Genetics Consortium (IFGC)

Independent

The International LBD Genomics Consortium (iLBDGC)

Independent

The NYGC ALS Consortium

Independent

The PROSPECT Consortium

Independent

James Rowe

University of Cambridge - MRC Cognition and Brain Sciences Unit

Luisa Benussi

IRCCS Centro San Giovanni di Dio Fatebenefratelli - Molecular Markers Laboratory

Giuliano Binetti

IRCCS Centro San Giovanni di Dio Fatebenefratelli - Molecular Markers Laboratory

Roberta Ghidoni

IRCCS Centro San Giovanni di Dio Fatebenefratelli - Molecular Markers Laboratory

Edwin Jabbari

University College London - Department of Molecular Neuroscience

Coralie Viollet

Uniformed Services University of the Health Sciences - Department of Anatomy, Physiology and Genetics

Jonathan D. Glass

Emory University - Department of Neurology

Andrew B. Singleton

Government of the United States of America - Center for Alzheimer's and Related Dementias (CARD); National Institute on Aging (NIA) - Molecular Genetics Section

Vincenzo Silani

University of Massachusetts Worcester - Department of Neurology

Owen A. Ross

Mayo Clinic - Department of Neuroscience

Mina Ryten

University College London - Department of Molecular Neuroscience

Ali Torkamani

Scripps Translational Science Institute

Toshiko Tanaka

National Institute on Aging - Translational Gerontology Branch

Luigi Ferrucci

Government of the United States of America - Translational Gerontology Branch; National Institute on Aging - Longitudinal Study Section

Susan M. Resnick

National Institute on Aging (NIA) - Laboratory of Behavioral Neuroscience

Stuart Pickering-Brown

The University of Manchester - Faculty of Human and Medical Sciences

Christopher B. Brady

Boston University - Department of Neurology

Neil Kowal

VA Boston Healthcare System - Department of Neurology

John A. Hardy

University College London - Department of Neurodegenerative Disease

Vivianna Van Deerlin

University of Pennsylvania - Department of Pathology and Laboratory Medicine

Jean Paul Vonsattel

Columbia University - Department of Pathology and Cell Biology

Matthew B. Harms

Columbia University - Department of Neurology

Huw R. Morris

University College London - Department of Clinical and Movement Neurosciences

Raffaele Ferrari

University College London - Department of Molecular Neuroscience

John E. Landers

University of Massachusetts Worcester - Department of Neurology

Adriano Chiò

University of Massachusetts Worcester - Department of Neurology

J. Raphael Gibbs

National Institute on Aging (NIA) - Computational Biology Group

Clifton L. Dalgard

Uniformed Services University of the Health Sciences - Department of Anatomy, Physiology and Genetics

Sonja Scholz

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit

Bryan J. Traynor

University of Massachusetts Worcester - Department of Neurology

More...

Abstract

To examine the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), we performed repeat sizing of ten genetic loci previously implicated in neurodegenerative diseases. We examined 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 cohort, and identified five (0.14%) out of 3,674 FTD/ALS patients harboring pathogenic HTT CAG expansions. Postmortem evaluations of two patients revealed huntingtin-positive, as well as TDP43- and ubiquitin-positive aggregates, predominantly in the frontal cortex, without neostriatal atrophy. 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.

Keywords: amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body dementia, Huntington’s disease, whole-genome sequencing, huntingtin, repeat expansions

Suggested Citation

Dewan, Ramita and Chia, Ruth and Ding, Jinhui and Hickman, Richard and Stein, Thor and Abramzon, Yevgeniya and Ahmed, Sarah and Sabir, Marya S. and Portley, Makayla K. and Tucci, Arianna and Ibáñez, Kristina and , Shankaracharya and Keagle, Pamela and Rossi, Giacomina and Caroppo, Paola and Tagliavini, Fabrizio and Waldo, Maria L. and Johansson, Per M. and Nilsson, Christer F. and Center (TAGC), The American Genome and Consortium, The FALS Sequencing and Consortium, The Genomics England Research and Consortium (iAFGC), The International ALS/FTD Genomics and Consortium (IFGC), The International FTD Genetics and Consortium (iLBDGC), The International LBD Genomics and Consortium, The NYGC ALS and Consortium, The PROSPECT and Rowe, James and Benussi, Luisa and Binetti, Giuliano and Ghidoni, Roberta and Jabbari, Edwin and Viollet, Coralie and Glass, Jonathan D. and Singleton, Andrew B. and Silani, Vincenzo and Ross, Owen A. and Ryten, Mina and Torkamani, Ali and Tanaka, Toshiko and Ferrucci, Luigi and Resnick, Susan M. and Pickering-Brown, Stuart and Brady, Christopher B. and Kowal, Neil and Hardy, John A. and Deerlin, Vivianna Van and Vonsattel, Jean Paul and Harms, Matthew B. and Morris, Huw R. and Ferrari, Raffaele and Landers, John E. and Chiò, Adriano and Gibbs, J. Raphael and Dalgard, Clifton L. and Scholz, Sonja and Traynor, Bryan J., Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Available at SSRN: https://ssrn.com/abstract=3652331 or http://dx.doi.org/10.2139/ssrn.3652331
This version of the paper has not been formally peer reviewed.

Ramita Dewan

National Institute on Aging - Neuromuscular Diseases Research Section ( email )

Bethesda, MD 20892
United States

Ruth Chia

National Institutes of Health - Neuromuscular Diseases Research Section

Bethesda, MD 20892
United States

Jinhui Ding

National Institutes of Health - Computational Biology Core

Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892
United States

Richard Hickman

Columbia University - Department of Pathology and Cell Biology ( email )

New York, NY 10032
United States

Thor Stein

Boston University - Chronic Traumatic Encephalopathy Center

Boston, MA 02118
United States

Department of Veterans Affairs (VA)

810 Vermont Avenue NW
Washington, DC 20420
United States

Boston University - Alzheimer's Disease Center

72 East Concord Street, B-7800
Boston, MA 02118
United States

Boston University - Department of Pathology and Laboratory Medicine

Boston, MA 02118
United States

Yevgeniya Abramzon

National Institutes of Health - Neuromuscular Diseases Research Section

Bethesda, MD 20892
United States

Sarah Ahmed

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit ( email )

Bethesda, MD
United States

Marya S. Sabir

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit ( email )

Bethesda, MD
United States

Makayla K. Portley

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit ( email )

Bethesda, MD
United States

Arianna Tucci

Queen Mary University of London - Clinical Pharmacology ( email )

Mile End Road
London, London E1 4NS
United Kingdom

Kristina Ibáñez

Queen Mary University of London - Clinical Pharmacology ( email )

Mile End Road
London, London E1 4NS
United Kingdom

Shankaracharya

University of Massachusetts Worcester - Department of Neurology ( email )

Worcester, MA
United States

Pamela Keagle

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Giacomina Rossi

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Division of Neurology V and Neuropathology ( email )

Via Celoria 11
Milan, 20133
Italy

Paola Caroppo

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Division of Neurology V and Neuropathology ( email )

Via Celoria 11
Milan, 20133
Italy

Fabrizio Tagliavini

Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’ - Scientific Directorate ( email )

Via Celoria 11
Milan, 20133
Italy

Maria L. Waldo

Lund University - Division of Clinical Sciences Helsingborg ( email )

Box 117
Lund, SC Skane S221 00
Sweden

Per M. Johansson

Lund University - Division of Clinical Sciences Helsingborg ( email )

Box 117
Lund, SC Skane S221 00
Sweden

Christer F. Nilsson

Lund University - Clinical Memory Research Unit ( email )

Box 117
Lund, SC Skane S221 00
Sweden

James Rowe

University of Cambridge - MRC Cognition and Brain Sciences Unit ( email )

15 Chaucer Road
Cambridge, CB2 7EF
United Kingdom

Luisa Benussi

IRCCS Centro San Giovanni di Dio Fatebenefratelli - Molecular Markers Laboratory ( email )

Brescia
Italy

Giuliano Binetti

IRCCS Centro San Giovanni di Dio Fatebenefratelli - Molecular Markers Laboratory ( email )

Brescia
Italy

Roberta Ghidoni

IRCCS Centro San Giovanni di Dio Fatebenefratelli - Molecular Markers Laboratory ( email )

Brescia
Italy

Edwin Jabbari

University College London - Department of Molecular Neuroscience ( email )

Gower Street
London, WC1E 6BT
United Kingdom

Coralie Viollet

Uniformed Services University of the Health Sciences - Department of Anatomy, Physiology and Genetics ( email )

4301 Jones Bridge Road
Bethesda, MD 20814
United States

Jonathan D. Glass

Emory University - Department of Neurology ( email )

201 Dowman Drive
Atlanta, GA 30322
United States

Andrew B. Singleton

Government of the United States of America - Center for Alzheimer's and Related Dementias (CARD) ( email )

National Institute on Aging (NIA) - Molecular Genetics Section ( email )

Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892
United States

Vincenzo Silani

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

Owen A. Ross

Mayo Clinic - Department of Neuroscience ( email )

200 First Street SW
Rochester, MN (507) 284-2511 55905
United States

Mina Ryten

University College London - Department of Molecular Neuroscience ( email )

Gower Street
London, WC1E 6BT
United Kingdom

Ali Torkamani

Scripps Translational Science Institute ( email )

3344 North Torrey Pines Court
Suite 300
La Jolla, CA 92037
United States

Toshiko Tanaka

National Institute on Aging - Translational Gerontology Branch ( email )

United States

Luigi Ferrucci

Government of the United States of America - Translational Gerontology Branch ( email )

National Institute on Aging - Longitudinal Study Section ( email )

Bethesda, MD 20892
United States

Susan M. Resnick

National Institute on Aging (NIA) - Laboratory of Behavioral Neuroscience ( email )

Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892
United States

Stuart Pickering-Brown

The University of Manchester - Faculty of Human and Medical Sciences

United Kingdom

Christopher B. Brady

Boston University - Department of Neurology ( email )

595 Commonwealth Avenue
Boston, MA 02215
United States

Neil Kowal

VA Boston Healthcare System - Department of Neurology ( email )

150 S Huntington Ave.
Boston, MA 02130
United States

John A. Hardy

University College London - Department of Neurodegenerative Disease ( email )

Gower Street
London, WC1E 6BT
United Kingdom

Vivianna Van Deerlin

University of Pennsylvania - Department of Pathology and Laboratory Medicine ( email )

Philadelphia, PA 19104
United States

Jean Paul Vonsattel

Columbia University - Department of Pathology and Cell Biology ( email )

New York, NY 10032
United States

Matthew B. Harms

Columbia University - Department of Neurology ( email )

New York, NY
United States

Huw R. Morris

University College London - Department of Clinical and Movement Neurosciences ( email )

London
United Kingdom

Raffaele Ferrari

University College London - Department of Molecular Neuroscience ( email )

Gower Street
London, WC1E 6BT
United Kingdom

John E. Landers

University of Massachusetts Worcester - Department of Neurology ( email )

Worcester, MA
United States

Adriano Chiò

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

J. Raphael Gibbs

National Institute on Aging (NIA) - Computational Biology Group ( email )

Building 31, Room 5C27
31 Center Drive, MSC 2292
Bethesda, MD 20892
United States

Clifton L. Dalgard

Uniformed Services University of the Health Sciences - Department of Anatomy, Physiology and Genetics ( email )

Sonja Scholz

National Institute of Neurological Disorders and Stroke - Neurodegenerative Diseases Research Unit ( email )

Bethesda, MD
United States

Bryan J. Traynor (Contact Author)

University of Massachusetts Worcester - Department of Neurology

Worcester, MA
United States

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