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

• Published in: Neuron (Cambridge, Mass.) Vol. 109; no. 3; pp. 448 - 460.e4
• Main Authors: Dewan, Ramita, Keagle, Pamela, Bacikova, Dagmar, Soltis, Anthony R., Kost, Jason, Colombrita, Claudia, Lewis, Elizabeth A., Pensato, Viviana, Castellotti, Barbara, McLaughlin, Russell L., Comi, Giacomo P., Ceroni, Mauro, Gagliardi, Stella, van Blitterswijk, Marka, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L., Morrison, Karen E., Veldink, Jan H., Brown, Robert H., Ambrose, John C., Brittain, H., Elgar, Greg, Halai, Dina, Holman, James E., Jackson, Rob, Leong, Ivonne U.S., Maleady-Crowe, Fiona, Mason, Joanne, Riesgo-Ferreiro, Pablo, Rogers, Tim, Watters, Sarah A., Arepalli, Sampath, Chiò, Adriano, Dunckley, Travis L., Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Gerhard, Glenn, Jansson, Lilja, Kirby, Janine, Mora, Gabriele, Nalls, Mike A., Pulst, Stefan M., Ravits, John M., Renton, Alan E., Robberecht, Wim, Robey, Ian, Dols-Icardo, Oriol, Illán-Gala, Ignacio, Lleó, Alberto, Khoshnood, Behzad, Sorbi, Sandro, Pastor, Pau, Bigio, Eileen H., Black, Sandra E., Brunetti, Maura, Canosa, Antonio, Gan-Or, Ziv, Goate, Alison, Hupalo, Daniel, Infante, Jon, Kaufmann, Horacio, Kim, Ronald C., Krüger, Rejko, Logroscino, Giancarlo, Love, Seth, Mao, Qinwen, Masliah, Eliezer, Pletnikova, Olga, Reynolds, Regina H., Scherzer, Clemens R., Serrano, Geidy E., Xiromerisiou, Georgia, Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Malaspina, Andrea, Thompson, Leslie M., Dardiotis, Efthimios, Chandran, Siddharthan, Butovsky, Oleg, Dubnau, Joshua, Harms, Matt, Poss, Mary, Phillips-Cremins, Jennifer, Altschuler, Steven, Hu, Michele T.M., Leigh, P. Nigel, Massey, Luke A., Pavese, Nicola, Vaughan, Jenny, Rowe, James B., Ghidoni, Roberta, Ryten, Mina, Tanaka, Toshiko, Ferrucci, Luigi, Vonsattel, Jean Paul, Landers, John E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2021; Elsevier Limited
• Subjects: Algorithms; Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Atrophy; Autopsy; Clinical Medicine; Cortex (frontal); Dementia; Dementia disorders; DNA Repeat Expansion; Family medical history; Frontotemporal Dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Genes; Genetic counseling; Genetic screening; genetics; Genomes; Haplotypes; Humans; Huntingtin; Huntingtin Protein; Huntingtin Protein - genetics; Huntingtons disease; Klinisk medicin; Lewy bodies; Medical and Health Sciences; Medical Genetics and Genomics; Medicin och hälsovetenskap; Medicinsk genetik och genomik; Mutation; Neostriatum; Neurodegeneration; Neurologi; Neurology; Nucleotide sequence; pathology; Polyglutamine; repeat expansions; Spinal cord; Trinucleotide repeats; Ubiquitin; Whole Genome Sequencing; frontotemporal dementia; repeat expansions; amyotrophic lateral sclerosis; whole-genome sequencing; huntingtin
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2020.11.005

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. [Display omitted] •Pathogenic expansions in the HTT gene are a rare cause of FTD/ALS spectrum diseases•Autopsies showed both the expected TDP-43 pathology of FTD/ALS and polyQ inclusions•HTT repeat expansions were not seen in healthy subjects or Lewy body dementia cases•Clinicians should screen FTD/ALS patients for HTT repeat expansions Using large-scale whole-genome sequencing, Dewan et al. identify pathogenic HTT repeat expansions in patients diagnosed with FTD/ALS neurodegenerative disorders. Autopsies confirm the TDP-43 pathology expected in FTD/ALS and show polyglutamine inclusions within the frontal cortices but no striatal degeneration. These data broaden the phenotype resulting from HTT repeat expansions.