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Abstract Details

Prevalence and Phenotype of TBK1 Mutations: an In-Depth Description
Aging, Dementia, Cognitive, and Behavioral Neurology
P11 - Poster Session 11 (11:45 AM-12:45 PM)
3-001

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).

Pathogenic TBK1 mutations are prevalent in FTD, ALS and particularly FTD plus ALS in Belgium. We report a pedigree carrying a novel pathogenic TBK1 LOF mutation, and describe the phenotype of known LOF mutation carriers. The most common phenotypes in all carriers were FTD, ALS and unspecified dementia. Disease duration correlated with clinical phenotype. Brain autopsy revealed FTLD-TDP B.  Lastly, we detailed clinical data of carriers of mutations of uncertain significance.

Authors/Disclosures
Helena Gossye (VIB CMN)
PRESENTER
Mrs. Gossye has nothing to disclose.
Sara Van Mossevelde (University of Antwerp - CDE) The institution of Ms. Van Mossevelde has received research support from King Baudouin Foundation - Fund Mr and Ms Deelen-Hollanders.
Jan L. De Bleecker, MD, PhD, FAAN (Neurology/University Hospital) Dr. De Bleecker has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ArgNX. Dr. De Bleecker has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. Dr. De Bleecker has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. De Bleecker has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. De Bleecker has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. De Bleecker has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for CSL Behring. Dr. De Bleecker has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. De Bleecker has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. De Bleecker has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen pharmaceuticals.
Patrick Cras, MD, PhD (University of Antwerp) The institution of Dr. Cras has received research support from Belgian Fund for Scientific Research. Dr. Cras has received personal compensation in the range of $0-$499 for serving as a member with National Bioethics Committee.
Sebastiaan Engelborghs, MD, PhD (University of Antwerp, Biomedical Sciences) No disclosure on file
Peter P. De Deyn, MD, PhD Dr. De Deyn has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for elsevier.
Tim Van Langenhove, MD, PhD (UZ Gent) Dr. Van Langenhove has nothing to disclose.
Christine Van Broeckhoven, PhD (University of Antwerp - CDE) Dr. Van Broeckhoven has nothing to disclose.