期刊
NEUROBIOLOGY OF AGING
卷 99, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2020.08.014
关键词
TBK1; Frontotemporal dementia; Primary progressive aphasia
资金
- Alzheimer's Research UK
- Brain Research Trust
- Wolfson Foundation
- NIHR Queen Square Dementia Biomedical Research Unit
- NIHR UCL/H Biomedical Research Center
- Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility
- Alzheimer's Society grant [AS-PG-16-007]
- MRC UK GENFI grant [MR/M023664/1]
- MRC Clinician Scientist Fellowship [MR/M008525/1]
- NIHR Rare Disease Translational Research Collaboration [BRC149/NS/MH]
- UK Dementia Research Institute - DRI Ltd
- UK Medical Research Council
- Alzheimer's Society
- Alzheimer's Society, UK [AS-JF-19a-004-517]
- MRC Clinical Research Training Fellowship [MR/M018288/1]
- Alzheimer's Research UKClinical Research Training Fellowship [ARUK-CRF2017B-2]
- Medical Research Council UK GENFI grant [MR/M023664/1]
- MRC [MR/T046015/1, MR/M008525/1, MR/M018288/1, MR/M023664/1] Funding Source: UKRI
TBK1 mutations have been associated with clinical syndromes across the whole FTD-ALS-atypical parkinsonism spectrum, including ALS syndrome, FTD-ALS overlap, cognitive presentations, and atypical parkinsonism. TBK1 may be pathogenic by causing truncated proteins.
TANK-binding kinase 1 (TBK1) mutations are a recently discovered cause of disorders in the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. We describe a novel L683* mutation, predicted to cause a truncated protein and therefore be pathogenic, in a patient presenting with nonfluent variant primary progressive aphasia at the age of 65 years. Her disease progressed over the following years, leading to her being mute and wheelchair bound seven years into her illness. Brain imaging showed asymmetrical left-sided predominant atrophy affecting the frontal, insular, and temporal cortices as well as the striatum in particular. Review of the literature found 60 different nonsense, frameshift, deletion, or splice site mutations, including the newly described mutation, with data on clinical diagnosis available in 110 people: 58% of the cases presented with an ALS syndrome, 16% with an FTD-ALS overlap, 19% with a cognitive presentation (including behavioral variant FTD and primary progressive aphasia) and 4% with atypical parkinsonism. Age at onset (AAO) data were available in 75 people: mean (standard deviation) AAO was 57.5 (10.3) in those with ALS, which was significantly younger than those with a cognitive presentation (AAO = 65.1 (10.5), p = 0.008), or atypical parkinsonism (AAO = 68.3 (8.7), p = 0.021), with a trend compared with the FTD-ALS group (AAO = 61.9 (7.0), p=0.065); there was no significant difference in AAO between the other groups. In conclusion, clinical syndromes across the whole FTD-ALS-atypical parkinsonism spectrum have been reported in conjunction with mutations in TBK1. It is therefore important to include TBK1 on future gene panels for each of these disorders and to suspect such mutations particularly when there are multiple different phenotypes in the same family. (C) 2020 The Authors. Published by Elsevier Inc.
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