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; American Genome Center (TAGC); International FTD-Genomics Consortium; Jørgen Erik Nielsen; Lynne Elisabeth Hjermind

doi:10.1016/j.neuron.2020.11.005

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 RoweLuisa 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, American Genome Center (TAGC), International FTD-Genomics Consortium, Jørgen Erik Nielsen (Member of study group), Lynne Elisabeth Hjermind (Member of study group)

Department of Neurology

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.

Original language	English
Journal	Neuron
Volume	109
Issue number	3
Pages (from-to)	448-460.e4
Number of pages	13
ISSN	0896-6273
DOIs	https://doi.org/10.1016/j.neuron.2020.11.005
Publication status	Published - 3 Feb 2021

Keywords

Amyotrophic Lateral Sclerosis/genetics
DNA Repeat Expansion
Frontotemporal Dementia/genetics
Humans
Huntingtin Protein/genetics
Mutation
Whole Genome Sequencing

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Dewan, R., Chia, R., Ding, J., Hickman, R. A., Stein, T. D., Abramzon, Y., Ahmed, S., Sabir, M. S., Portley, M. K., Tucci, A., Ibáñez, K., Shankaracharya, F. N. U., Keagle, P., Rossi, G., Caroppo, P., Tagliavini, F., Waldo, M. L., Johansson, P. M., Nilsson, C. F., ... Hjermind, L. E. (2021). Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Neuron, 109(3), 448-460.e4. https://doi.org/10.1016/j.neuron.2020.11.005

Dewan, R, Chia, R, Ding, J, Hickman, RA, Stein, TD, Abramzon, Y, Ahmed, S, Sabir, MS, Portley, MK, Tucci, A, Ibáñez, K, Shankaracharya, FNU, Keagle, P, Rossi, G, Caroppo, P, Tagliavini, F, Waldo, ML, Johansson, PM, Nilsson, CF, Rowe, JB, Benussi, L, Binetti, G, Ghidoni, R, Jabbari, E, Viollet, C, Glass, JD, Singleton, AB, Silani, V, Ross, OA, Ryten, M, Torkamani, A, Tanaka, T, Ferrucci, L, Resnick, SM, Pickering-Brown, S, Brady, CB, Kowal, N, Hardy, JA, Van Deerlin, V, Vonsattel, JP, Harms, MB, Morris, HR, Ferrari, R, Landers, JE, Chiò, A, Gibbs, JR, Dalgard, CL, Scholz, SW, Traynor, BJ, American Genome Center (TAGC), International FTD-Genomics Consortium, Nielsen, JE & Hjermind, LE 2021, 'Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis', Neuron, vol. 109, no. 3, pp. 448-460.e4. https://doi.org/10.1016/j.neuron.2020.11.005

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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.",

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AU - Dewan, Ramita

AU - Chia, Ruth

AU - Ding, Jinhui

AU - Hickman, Richard A

AU - Stein, Thor D

AU - Abramzon, Yevgeniya

AU - Ahmed, Sarah

AU - Sabir, Marya S

AU - Portley, Makayla K

AU - Tucci, Arianna

AU - Ibáñez, Kristina

AU - Shankaracharya, F N U

AU - Keagle, Pamela

AU - Rossi, Giacomina

AU - Caroppo, Paola

AU - Tagliavini, Fabrizio

AU - Waldo, Maria L

AU - Johansson, Per M

AU - Nilsson, Christer F

AU - Rowe, James B

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Jabbari, Edwin

AU - Viollet, Coralie

AU - Glass, Jonathan D

AU - Singleton, Andrew B

AU - Silani, Vincenzo

AU - Ross, Owen A

AU - Ryten, Mina

AU - Torkamani, Ali

AU - Tanaka, Toshiko

AU - Ferrucci, Luigi

AU - Resnick, Susan M

AU - Pickering-Brown, Stuart

AU - Brady, Christopher B

AU - Kowal, Neil

AU - Hardy, John A

AU - Van Deerlin, Vivianna

AU - Vonsattel, Jean Paul

AU - Harms, Matthew B

AU - Morris, Huw R

AU - Ferrari, Raffaele

AU - Landers, John E

AU - Chiò, Adriano

AU - Gibbs, J Raphael

AU - Dalgard, Clifton L

AU - Scholz, Sonja W

AU - Traynor, Bryan J

AU - American Genome Center (TAGC)

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N2 - 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.

AB - 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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KW - DNA Repeat Expansion

KW - Frontotemporal Dementia/genetics

KW - Humans

KW - Huntingtin Protein/genetics

KW - Mutation

KW - Whole Genome Sequencing

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ER -

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

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Keywords

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