Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/127116
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Type: Journal article
Title: A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders
Author: Lamb, R.
Rohrer, J.D.
Real, R.
Lubbe, S.J.
Waite, A.J.
Blake, D.J.
Jon Walters, R.
Lashley, T.
Revesz, T.
Holton, J.L.
Morris, H.R.
Citation: Cold Spring Harbor molecular case studies, 2019; 5(3):a003913-1-a003913-10
Publisher: Cold Spring Harbor Laboratory Press
Issue Date: 2019
ISSN: 2373-2873
2373-2873
Statement of
Responsibility: 
Ruth Lamb, Jonathan D. Rohrer, Raquel Real, Steven J. Lubbe, Adrian J. Waite ... Tamas Revesz ... et al.
Abstract: Mutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioral variant FTD, primary progressive aphasia, and pure ALS. We describe the clinical, anatomical, and pathological features of a patient who developed corticobasal syndrome (CBS)/progressive nonfluent aphasia (PNFA) overlap. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic–rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with four out of seven siblings developing either dementia or ALS in their 50s and 60s. The patient died at the age of 71 and the brain was donated for postmortem analysis. Histopathological examination showed frontotemporal lobar degeneration TDP-43 type A pathology. Genetic screening did not reveal a mutation in the GRN, MAPT, or C9orf72 genes, but exome sequencing revealed a novel p.E703X mutation in the TBK1 gene. Although segregation data were not available, this loss-of-function mutation is highly likely to be pathogenic because it is predicted to disrupt TBK1/optineurin interaction and impair cellular autophagy. In conclusion, we show that TBK1 mutations can be a cause of an atypical parkinsonian syndrome and screening should be considered in CBS patients with a family history of dementia or ALS.
Keywords: Progressive extrapyramidal movement disorder
Rights: © 2019 Lamb et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted reuse and redistribution provided that the original author and source are credited.
DOI: 10.1101/mcs.a003913
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