Abstract Details

Pathogenic TBK1 mutations are associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).

We report mutation frequency of pathogenic TBK1 mutations in FTD, ALS and FTD-ALS patients. We detail phenotypic and genetic characteristics of Belgian mutation carriers. We also present a pedigree segregating a new, previously unknown LOF mutation with autosomal dominant inheritance. Lastly, we describe phenotypes of genetic TBK1 variants with uncertain significance.

We screened TBK1 in Belgian FTD (n = 678), ALS (n = 220) and FTD-ALS (n = 46) cohorts. We identified 18 carriers of pathogenic mutations and 1 carrier of a novel LOF mutation. We sampled and screened family members, totalling a carrier cohort of 40. Another 6 patients carried missense mutations of uncertain significance. We collected data on clinical characteristics, biomarkers and neuropathology.

TBK1 LOF mutation frequency was 1.3% in FTD, 3.6% in ALS and 4.3% in FTD-ALS. Among 40 carriers, 23 were affected: FTD (n = 8; 7 bvFTD, 1 PPA), ALS (n = 7), unspecified dementia (n = 5), FTD-ALS (n = 2), Alzheimer’s disease (n = 1). Mean onset age and disease duration were 62.8 and 6.5 years (ranges 41-86 and 0-24 years). ALS patients had significantly shorter disease duration averaging 2.6 year. Neuropathology confirmed FTLD-TDP B. TBK1 missense mutations of uncertain significance were present in 3 ALS and 3 FTD patients (1 svPPA, 2 bvFTD).