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A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders

Lamb, R; Rohrer, JD; Real, R; Lubbe, SJ; Waite, AJ; Blake, DJ; Walters, RJ; ... Morris, HR; + view all (2019) A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders. Cold Spring Harbor Molecular Case Studies , 5 (3) , Article a003913. 10.1101/mcs.a003913. Green open access

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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.

Type: Article
Title: A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1101/mcs.a003913
Publisher version: https://doi.org/10.1101/mcs.a003913
Language: English
Additional information: © 2019 Lamb et al.; Published by Cold Spring Harbor Laboratory Press. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/).
Keywords: progressive extrapyramidal movement disorder, Ontology Terms
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10075806
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