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.
Highlights
Mutations in the tumor necrosis factor receptor-associated factor NF-κB activator (TANK)binding kinase 1 (TBK1) gene, located on Chromosome 12, have recently been described as a cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Cirulli et al 2015; Freischmidt et al 2015; Pottier et al 2015)
Heterozygous loss of function variants have been shown to be enriched in familial FTD–ALS pedigrees and are likely to be pathogenic through nonsense-mediated mRNA decay (NMD) and global reduction of protein levels (Cirulli et al 2015; Freischmidt et al 2015; Pottier et al 2015)
Loss of the crucial highly conserved coiled-coil domain 2 (CC2) protein domain is likely to result in the abrogation of the interaction and complex formation with TANK-binding kinase 1 (TBK1)-associated adaptors that are essential in regulating TBK1 activation and its subcellular localization (Gonçalves et al 2011)
Summary
Mutations in the tumor necrosis factor receptor-associated factor NF-κB activator (TANK)binding kinase 1 (TBK1) gene, located on Chromosome 12, have recently been described as a cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (Cirulli et al 2015; Freischmidt et al 2015; Pottier et al 2015). TBK1 is a 729-amino acid protein kinase that acts as a mediator of inflammation and autophagy (Marion 2014; Ahmad et al 2016). It is a ubiquitously expressed serine–threonine kinase belonging to the “noncanonical IκB kinases” (IKKs) (Marion 2014; Ahmad et al 2016).
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