In-depth phenotypic description of pathogenic TBK1 mutations: A frequent cause of FTD and ALS in the Flanders-Belgian population

Background
Pathogenic LOF and missense mutations in the TBK1 gene are associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We report the prevalence and phenotype of TBK1 mutation carriers in the Flanders-Belgian population.
Method
Screening Flanders-Belgian FTD (n = 678), ALS (n = 220) and FTD-ALS (n = 46) patient cohorts for mutations in TBK1 revealed 19 carriers of pathogenic mutations. We sampled and screened family members, totaling a carrier cohort of 47 individuals. We collected clinical and neuropathological data.
Result
Overall, frequency of TBK1 mutations was 2.0%, with 1.3% in FTD, 3.6% in ALS and 4.3% in FTD-ALS. Among 47 carriers, 30 were affected: FTD (n = 11, 36.7%), ALS (n = 10, 33.3%), unspecified dementia (n = 5, 16.7%), FTD-ALS (n = 2, 6.7%), mild cognitive impairment (n = 1, 3.3%) and Alzheimer’s disease (n = 1, 3.3%). In the FTD group, behavioral variant FTD (bvFTD) was the most common phenotype (81.8%) but primary progressive aphasia also occurred (18.2%). Mean onset age and disease duration were 63.0 and 6.4 years (ranges 41-86 and 0-24 years). ALS patients had a significantly shorter disease duration averaging 2.6 years (range 0-6). Neuropathology confirmed FTLD-TDP type B.
Conclusion
Pathogenic mutations in TBK1 are a frequent cause of FTD, ALS and particularly of FTD plus ALS in the Flanders-Belgian population. The most common phenotypes were FTD (81.8% bvFTD, 18.2% PPA), ALS and unspecified dementia. Disease duration significantly correlated with clinical phenotype. Neuropathology showed FTLD-TDP type B.