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.

Original languageEnglish
Pages (from-to)448-460.e4
Issue number3
StatePublished - 3 Feb 2021


FundersFunder number
American Journal of Neurodegenerative Diseases, and Frontiers in Neurology
Cerevel Therapeutics
National Institutes of Health
National Institute on AgingZIAAG000957
National Institute on Aging
National Heart, Lung, and Blood InstituteIAA-A-HL-007.001
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Institute of Neurological Disorders and Stroke1ZIAAG000935, 1ZIANS0030033, R01NS073873, 1ZIANS003034, 1ZIANS003154
National Institute of Neurological Disorders and Stroke
Huntington's Disease Society of America
ALS Association19-SI-459
ALS Association
Hereditary Disease Foundation
Wellcome Trust103838
Wellcome Trust
Tow Foundation
National Institute for Health Research
Ministero della SaluteP30 AG066462-01
Ministero della Salute
scientific advisory council of the Lewy Body Dementia Association


    • amyotrophic lateral sclerosis
    • frontotemporal dementia
    • huntingtin
    • repeat expansions
    • whole-genome sequencing


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