The clinical, neuroanatomical, and neuropathologic phenotype of TBK1‐associated frontotemporal dementia: A longitudinal case report

Abstract

IntroductionMutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype of TBK1-associated FTD is currently unclear.MethodsWe performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the TBK1 gene. He was assessed annually over a 7-year period with a series of clinical, cognitive, and magnetic resonance imaging assessments. His brain underwent pathological examination at postmortem.ResultsThe patient presented at the age of 64 years with an 18-month history of personality change including increased rigidity and obsessiveness, apathy, loss of empathy, and development of a sweet tooth. His mother had developed progressive behavioral and cognitive impairment from the age of 57 years. Neuropsychometry revealed intact cognition at first assessment. Magnetic resonance imaging showed focal right temporal lobe atrophy. Over the next few years his behavioral problems progressed and he developed cognitive impairment, initially with anomia and prosopagnosia. Neurological examination remained normal throughout without any features of motor neurone disease. He died at the age of 72 years and postmortem showed TDP-43 type A pathology but with an unusual novel feature of numerous TAR DNA-binding protein 43 (TDP-43)–positive neuritic structures at the cerebral cortex/subcortical white matter junction. There was also associated argyrophilic grain disease not previously reported in other TBK1 mutation cases.DiscussionTBK1-associated FTD can be associated with right temporal variant FTD with progressive behavioral change and relatively intact cognition initially. The case further highlights the benefits of next-generation sequencing technologies in the diagnosis of neurodegenerative disorders and the importance of detailed neuropathologic analysis.

Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

“…715/2984 samples that were analysed with the NGS gene-panel were also exome sequenced (see Methods), which allowed discovery of only two additional mutations classified as DVs, in TBK1 ( 25 ) , and DNMT1 (26), and no DVs in other neurology-relevant genes not included in the panel.…”

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

“…Mutations in many other genes, often initially discovered as uncommon causes of ALS, have subsequently been identified in patients with FTD ± ALS. Although reports on the associated neuropathology are still rare, TDP‐43 pathology has been described in cases with mutations in genes encoding TANK‐binding kinase 1 ( TBK1 ) , sequestosome 1 , ubiquilin 2 , optineurin and dynactin . Current information is insufficient to know if any of these mutations is associated with a unique pathological signature; however, in the case of TBK1 mutations, the associated pattern of TDP‐43 pathology is reported to be inconsistent (FTLD‐TDP type A or B) with unusual presence of numerous TDP‐43‐positive neuritic structures at the cerebral cortex/subcortical white matter junction reported in one case .…”

TBK1 interacts with tau and enhances neurodegeneration in tauopathy

“…Genetic studies of TBK1 have identified nonsense, frameshift, missense and deletion mutations in both sporadic and familial ALS, FTD and ALS/FTD, which predominately results in the loss-of-function phenotypes that reduce levels or activity of the kinase and pathological TDP-43 inclusions (45,66). Loss of TBK1 function in these diseases impacts multiple protein-protein interactions and cellular pathways including autophagy and inflammation (29,40).…”