Moderator of 1 Session
Presenter of 1 Presentation
GENOTYPE-PHENOTYPE CORRELATIONS IN BELGIAN CARRIERS OF PATHOGENIC TBK1 MUTATIONS
Abstract
Aims
Pathogenic TBK1 mutations are associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We report prevalence and phenotype of Belgian carriers of TBK1 mutations. We present a pedigree segregating a previously unknown LOF mutation with autosomal dominant inheritance, and carriers of genetic variants of uncertain significance.
Methods
Genetic screening of TBK1 in Belgian FTD (n = 678), ALS (n = 220) and FTD-ALS (n = 46) patient cohorts. We identified 18 carriers of pathogenic mutations and 1 carrier of a novel LOF mutation. Family members were sampled and screened. In total, we identified 40 carriers. Missense mutations of uncertain significance were observed in 6 patients. We collected data on clinical characteristics, biomarkers, and neuropathology.
Results
TBK1 LOF mutation frequency are 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).
Conclusions
Pathogenic TBK1 mutations are a frequent cause of FTD, ALS and particularly FTD plus ALS. The common phenotypes were FTD, ALS, unspecified dementia. Disease duration correlated with clinical phenotype. Brain autopsy revealed FTLD-TDP B.