Abstract

Mutations in the TANK-binding kinase (TBK1) gene have been shown to cause frontotemporal dementia (FTLD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioural variant FTD, primary progressive aphasia and pure amyotrophic lateral sclerosis. We describe the clinical, anatomical and pathological features of a patient with onset of a corticobasal syndrome (CBS)/primary progressive aphasia overlap aged 59. 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 4/7 siblings developing either dementia or ALS in their 50’s-60’s. Following death at age 71, post mortem examination revealed FTLD TDP-43 type A pathology. Genetic screening did not reveal a mutation in the progranulin, microtubule-associated protein tau or C9orf72 genes. However exome sequencing revealed a novel E703X mutation in the TBK1 gene. Although segregation data was not available, this loss of function mutation is highly likely to be pathogenic. In conclusion, we show that TBK1 can be a cause of an atypical parkinsonian syndrome and screening for TBK1 should be considered in CBS patients with a family history of dementia, ALS or CBS.