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.
Original language | English (US) |
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Article number | a003913 |
Journal | Cold Spring Harbor Molecular Case Studies |
Volume | 5 |
Issue number | 3 |
DOIs | |
State | Published - 2019 |
Funding
We thank Dr. Viorica Chelban for her assistance with the Sanger sequencing. This research was partly supported by the National Institute for Health Research (NIHR) Queen Square Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL). The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), the National Institute for Health Research (NIHR), or the Department of Health. R.L. is funded by CBD Solutions. The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre, and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility. J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). A.J.W. is supported by BRACE. T.L. is supported by an Alzheimer's Research UK senior fellowship. T.R. is supported by a research grant from Karin & Sten Mortstedt CBD Solutions. J.L.H. is supported by the Multiple System Atrophy Trust, the Multiple System Atrophy Coalition, Fund Sophia, managed by the King Baudouin Foundation, Alzheimer's Research UK, and CBD Solutions. R.R. is a Walker-Peltz Clinical Research Fellow. S.J.L. was funded by the Medical Research Council UK (G0700943). Queen Square Brain Bank is supported by the Reta Lila Weston Institute of Neurological Studies and the Medical Research Council UK. R.L. is funded by CBD Solutions. The Dementia Research Centre is supported by Alzheimer’s Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre, and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility. J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). A.J.W. is supported by BRACE. T.L. is supported by an Alzheimer’s Research UK senior fellowship. T.R. is supported by a research grant from Karin & Sten Mortstedt CBD Solutions. J.L.H. is supported by the Multiple System Atrophy Trust, the Multiple System Atrophy Coalition, Fund Sophia, managed by the King Baudouin Foundation, Alzheimer’s Research UK, and CBD Solutions. R.R. is a Walker-Peltz Clinical Research Fellow. S.J.L. was funded by the Medical Research Council UK (G0700943). Queen Square Brain Bank is supported by the Reta Lila Weston Institute of Neurological Studies and the Medical Research Council UK.
ASJC Scopus subject areas
- General Medicine