Clinical and neuropathological features of ALS/FTD with TIA1 mutations

Veronica Hirsch-Reinshagen, Cyril Pottier, Alexandra M. Nicholson, Matt Baker, Ging Yuek R. Hsiung, Charles Krieger, Pheth Sengdy, Kevin B. Boylan, Dennis W. Dickson, Marsel Mesulam, Sandra Weintraub, Eileen Bigio, Lorne Zinman, Julia Keith, Ekaterina Rogaeva, Sasha A. Zivkovic, David Lacomis, J. Paul Taylor, Rosa Rademakers, Ian R.A. Mackenzie

Research output: Contribution to journalArticle

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Abstract

Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.

Original languageEnglish (US)
Number of pages1
JournalActa Neuropathologica Communications
Volume5
Issue number1
DOIs
StatePublished - Dec 7 2017

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Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
T-Lymphocytes
Antigens
Mutation
Lewy Bodies
Motor Neurons
Age of Onset
TDP-43 Proteinopathies
Immunohistochemistry
Frontotemporal Lobar Degeneration
Pathology
Inclusion Bodies
Parkinsonian Disorders
Sclerosis
Heat-Shock Proteins
Psychotic Disorders
Atrophy
Fluorescent Antibody Technique
Psychiatry

Keywords

  • Amyotrophic lateral sclerosis
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • T-cell restricted intracellular antigen-1
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Hirsch-Reinshagen, V., Pottier, C., Nicholson, A. M., Baker, M., Hsiung, G. Y. R., Krieger, C., ... Mackenzie, I. R. A. (2017). Clinical and neuropathological features of ALS/FTD with TIA1 mutations. Acta Neuropathologica Communications, 5(1). https://doi.org/10.1186/s40478-017-0493-x
Hirsch-Reinshagen, Veronica ; Pottier, Cyril ; Nicholson, Alexandra M. ; Baker, Matt ; Hsiung, Ging Yuek R. ; Krieger, Charles ; Sengdy, Pheth ; Boylan, Kevin B. ; Dickson, Dennis W. ; Mesulam, Marsel ; Weintraub, Sandra ; Bigio, Eileen ; Zinman, Lorne ; Keith, Julia ; Rogaeva, Ekaterina ; Zivkovic, Sasha A. ; Lacomis, David ; Taylor, J. Paul ; Rademakers, Rosa ; Mackenzie, Ian R.A. / Clinical and neuropathological features of ALS/FTD with TIA1 mutations. In: Acta Neuropathologica Communications. 2017 ; Vol. 5, No. 1.
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abstract = "Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.",
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Hirsch-Reinshagen, V, Pottier, C, Nicholson, AM, Baker, M, Hsiung, GYR, Krieger, C, Sengdy, P, Boylan, KB, Dickson, DW, Mesulam, M, Weintraub, S, Bigio, E, Zinman, L, Keith, J, Rogaeva, E, Zivkovic, SA, Lacomis, D, Taylor, JP, Rademakers, R & Mackenzie, IRA 2017, 'Clinical and neuropathological features of ALS/FTD with TIA1 mutations', Acta Neuropathologica Communications, vol. 5, no. 1. https://doi.org/10.1186/s40478-017-0493-x

Clinical and neuropathological features of ALS/FTD with TIA1 mutations. / Hirsch-Reinshagen, Veronica; Pottier, Cyril; Nicholson, Alexandra M.; Baker, Matt; Hsiung, Ging Yuek R.; Krieger, Charles; Sengdy, Pheth; Boylan, Kevin B.; Dickson, Dennis W.; Mesulam, Marsel; Weintraub, Sandra; Bigio, Eileen; Zinman, Lorne; Keith, Julia; Rogaeva, Ekaterina; Zivkovic, Sasha A.; Lacomis, David; Taylor, J. Paul; Rademakers, Rosa; Mackenzie, Ian R.A.

In: Acta Neuropathologica Communications, Vol. 5, No. 1, 07.12.2017.

Research output: Contribution to journalArticle

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T1 - Clinical and neuropathological features of ALS/FTD with TIA1 mutations

AU - Hirsch-Reinshagen, Veronica

AU - Pottier, Cyril

AU - Nicholson, Alexandra M.

AU - Baker, Matt

AU - Hsiung, Ging Yuek R.

AU - Krieger, Charles

AU - Sengdy, Pheth

AU - Boylan, Kevin B.

AU - Dickson, Dennis W.

AU - Mesulam, Marsel

AU - Weintraub, Sandra

AU - Bigio, Eileen

AU - Zinman, Lorne

AU - Keith, Julia

AU - Rogaeva, Ekaterina

AU - Zivkovic, Sasha A.

AU - Lacomis, David

AU - Taylor, J. Paul

AU - Rademakers, Rosa

AU - Mackenzie, Ian R.A.

PY - 2017/12/7

Y1 - 2017/12/7

N2 - Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.

AB - Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.

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Hirsch-Reinshagen V, Pottier C, Nicholson AM, Baker M, Hsiung GYR, Krieger C et al. Clinical and neuropathological features of ALS/FTD with TIA1 mutations. Acta Neuropathologica Communications. 2017 Dec 7;5(1). https://doi.org/10.1186/s40478-017-0493-x