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 journalArticlepeer-review

34 Scopus citations

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)
Pages (from-to)96
Number of pages1
JournalActa Neuropathologica Communications
Volume5
Issue number1
DOIs
StatePublished - Dec 7 2017

Funding

We would like to thank Margaret Luk and Simon Cheung for their excellent technical assistance. This work was supported by the Canadian Institutes of Health Research (74580), the Canadian Consortium on Neurodegeneration in Aging (137794) and the ALS Canada-Brain Canada Hudson Grant (IM, RH); NIH/NINDS grants R35 NS097261 and P01 NS084974 (RR); and EHB, MMM, and SW are supported by NIA P30 AG13854 (EB, MM, SW).

Keywords

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

ASJC Scopus subject areas

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

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