Clinical and neuropathological features of ALS/FTD with TIA1 mutations
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 T...
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-017-0493-x |
| _version_ | 1818525798761496576 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Veronica Hirsch-Reinshagen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T06:14:06Z |
| format | Article |
| id | doaj.art-e0d91199d2474d74ba7a17e9667fb08b |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-11T06:14:06Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-e0d91199d2474d74ba7a17e9667fb08b2022-12-22T01:18:02ZengBMCActa Neuropathologica Communications2051-59602017-12-015111310.1186/s40478-017-0493-xClinical and neuropathological features of ALS/FTD with TIA1 mutationsVeronica Hirsch-Reinshagen0Cyril Pottier1Alexandra M. Nicholson2Matt Baker3Ging-Yuek R. Hsiung4Charles Krieger5Pheth Sengdy6Kevin B. Boylan7Dennis W. Dickson8Marsel Mesulam9Sandra Weintraub10Eileen Bigio11Lorne Zinman12Julia Keith13Ekaterina Rogaeva14Sasha A. Zivkovic15David Lacomis16J. Paul Taylor17Rosa Rademakers18Ian R. A. Mackenzie19Department of Pathology and Laboratory Medicine, University of British ColombiaDepartment of Neuroscience, Mayo Clinic JacksonvilleDepartment of Neuroscience, Mayo Clinic JacksonvilleDepartment of Neuroscience, Mayo Clinic JacksonvilleDivision of Neurology, University of British ColumbiaDepartment of Biomedical Physiology & Kinesiology, Simon Fraser UniversityDivision of Neurology, University of British ColumbiaDepartment of Neuroscience, Mayo Clinic JacksonvilleDepartment of Neuroscience, Mayo Clinic JacksonvilleDepartment of Neurology, Northwestern University Feinberg School of MedicineDepartment of Neurology, Northwestern University Feinberg School of MedicineDepartment of Pathology, Northwestern University Feinberg School of MedicineDivision of Neurology, Sunnybrook Health Sciences CentreDepartment of Anatomic Pathology, Sunnybrook Health Sciences CentreTanz Centre for Research in Neurodegenerative Diseases, University of TorontoDepartment of Neurology, University of Pittsburgh School of MedicineDepartment of Neurology, University of Pittsburgh School of MedicineDepartment of Cell and Molecular Biology, St. Jude Children’s Research HospitalDepartment of Neuroscience, Mayo Clinic JacksonvilleDepartment of Pathology and Laboratory Medicine, University of British ColombiaAbstract 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.http://link.springer.com/article/10.1186/s40478-017-0493-xAmyotrophic lateral sclerosisFrontotemporal dementiaFrontotemporal lobar degenerationT-cell restricted intracellular antigen-1TDP-43 |
| spellingShingle | 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 Clinical and neuropathological features of ALS/FTD with TIA1 mutations Acta Neuropathologica Communications Amyotrophic lateral sclerosis Frontotemporal dementia Frontotemporal lobar degeneration T-cell restricted intracellular antigen-1 TDP-43 |
| title | Clinical and neuropathological features of ALS/FTD with TIA1 mutations |
| title_full | Clinical and neuropathological features of ALS/FTD with TIA1 mutations |
| title_fullStr | Clinical and neuropathological features of ALS/FTD with TIA1 mutations |
| title_full_unstemmed | Clinical and neuropathological features of ALS/FTD with TIA1 mutations |
| title_short | Clinical and neuropathological features of ALS/FTD with TIA1 mutations |
| title_sort | clinical and neuropathological features of als ftd with tia1 mutations |
| topic | Amyotrophic lateral sclerosis Frontotemporal dementia Frontotemporal lobar degeneration T-cell restricted intracellular antigen-1 TDP-43 |
| url | http://link.springer.com/article/10.1186/s40478-017-0493-x |
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