Variable clinical phenotype in TBK1 mutations: case report of a novel mutation causing primary progressive aphasia and review of the literature

Abstract TBK1 mutations are a recently discovered cause of disorders in the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. We describe a novel L683* mutation, predicted to cause a truncated protein and therefore be pathogenic, in a patient presenting with nonfluent variant primary progressive aphasia (PPA) at the age of 65. Her disease progressed over the following years, leading to her being mute and wheelchair bound seven years into her illness. Brain imaging showed asymmetrical left-sided predominant atrophy affecting the frontal, insular and temporal cortices as well as the striatum in particular. Review of the literature found 60 different nonsense, frameshift, deletion or splice site mutations, including the newly described mutation, with data on clinical diagnosis available in 110 people: 58% of the cases presented with an ALS syndrome, 16% with an FTD-ALS overlap, 19% with a cognitive presentation (including behavioural variant FTD (bvFTD) and PPA) and 4% with atypical parkinsonism. Age at onset (AAO) data was available in 75 people: mean (standard deviation) AAO was 57.5 (10.3) in those with ALS, which was significantly younger than those with a cognitive presentation (AAO = 65.1 (10.5), p = 0.008), or atypical parkinsonism (AAO = 68.3 (8.7), p = 0.021), with a trend compared with the FTD-ALS group (AAO = 61.9 (7.0), p=0.065); there was no significant difference in AAO between the other groups. In conclusion, clinical syndromes across the whole FTD-ALS-atypical parkinsonism spectrum have been reported in conjunction with mutations in TBK1. It is therefore important to include TBK1 on future gene panels for each of these disorders, and to suspect such mutations particularly when there are multiple different phenotypes in the same family.