Clinical Features of TBK1 Carriers and Comparison with C9orf72, GRN and Nonmutation Carriers in a Belgian Patient Cohort (S21.007)

Objective: We aim to describe the phenotypical characteristics of Belgian TBK1 mutation carriers and identify differences with C9orf72, GRN and nonmutation carriers. Background: In cohorts of FTD (n=481) and ALS (n=147) patients, we identified 10 patients carrying a TBK1 loss-of-function mutation. Additionally, 6 affected relatives were identified as TBK1 carriers.(Gijselinck I. et al., Neurology 2015) Methods: A descriptive study was performed of 6 FTD, 7 ALS, 1 FTD-ALS and 2 unspecified dementia patients carrying a TBK1 mutation. Further, we compared the phenotypic characteristics of FTD patients with a TBK1 mutation (n=7), with those of FTD patients with a C9orf72 repeat expansion (n=65), a GRN mutation (n=52) or without mutations in currently known causal genes (n=259). Results: The mean onset age of all 16 TBK1 carriers was 62.1 years (SD 8.9, range 41-73) with a mean disease duration of 4.7 years (SD 4.5, range 1-13). Among the TBK1 carriers, most FTD patients had the behavioral variant with disinhibition as predominant feature. Memory loss was an important associated symptom. Three ALS patients exhibited pronounced upper motor neuron symptoms. Overall, structural neuroimaging displayed widespread atrophy, and functional neuroimaging showed asymmetric, predominantly frontotemporal involvement. Neuropathology in two patients demonstrated TDP-43 type B pathology. TBK1 carriers had a later onset age (63.3 years) than C9orf72 carriers (54.3 years) (p = 0.019) and exhibited in case of the behavioral variant more frequent than GRN carriers with apathy as predominant characteristic (p = 0.004). Also, TBK1 carriers exhibited more often extrapyramidal symptoms than C9orf72 carriers (p = 0.038). Conclusions: The results of this study allow to suggest that after a negative result for C9orf72, FTD-ALS patients should be tested first for mutations in TBK1. Specifically in FTD patients with early memory difficulties, a relatively late onset age or extrapyramidal symptoms, screening for TBK1 mutations should be considered. Disclosure: Dr. Van Mossevelde has nothing to disclose. Dr. Van Der Zee has nothing to disclose. Dr. Gijselinck has nothing to disclose. Dr. Engelborghs has nothing to disclose. Dr. Sieben has nothing to disclose. Dr. Van Langenhove has nothing to disclose. Dr. De Bleecker has nothing to disclose. Dr. Baets has nothing to disclose. Dr. Vandenbulcke has nothing to disclose. Dr. Van Laere has received research support from Merck & Co., Inc. and GE Healthcare. Dr. Ceyssens has nothing to disclose. Dr. Van Den Broeck has nothing to disclose. Dr. Peeters has nothing to disclose. Dr. Mattheijssens has nothing to disclose. Dr. Cras has nothing to disclose. Dr. Vandenberghe has received research support from GE Healthcare, Wyeth, Eli Lilly & Company, Medivation, and Pfizer, Inc. Dr. De Jonghe has nothing to disclose. Dr. Martin has nothing to disclose. Dr. De Deyn has nothing to disclose. Dr. Cruts has nothing to disclose. Dr. Van Broeckhoven has nothing to disclose.