title: Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort.
abstract: We identified in a cohort of patients with frontotemporal dementia (n = 481) or amyotrophic lateral sclerosis (n = 147), 10 index patients carrying a TBK1 loss of function mutation reducing TBK1 expression by 50%. Here, we describe the clinical and pathological characteristics of the 10 index patients and six of their affected relatives carrying a TBK1 mutation. Six TBK1 carriers were diagnosed with frontotemporal dementia, seven with amyotrophic lateral sclerosis, one with both clinical phenotypes and two with dementia unspecified. The mean age at onset of all 16 TBK1 carriers was 62.1 ± 8.9 years (range 41-73) with a mean disease duration of 4.7 ± 4.5 years (range 1-13). TBK1 carriers with amyotrophic lateral sclerosis had shorter disease duration than carriers with frontotemporal dementia. Six of seven TBK1 carriers were diagnosed with the behavioural variant of frontotemporal dementia, presenting predominantly as disinhibition. Memory loss was an important associated symptom in the initial phase of the disease in all but one of the carriers with frontotemporal dementia. Three of the patients with amyotrophic lateral sclerosis exhibited pronounced upper motor neuron symptoms. Overall, neuroimaging displayed widespread atrophy, both symmetric and asymmetric. Brain perfusion single-photon emission computed tomography or fluorodeoxyglucose-positron emission tomography showed asymmetric and predominantly frontotemporal involvement. Neuropathology in two patients demonstrated TDP-43 type B pathology. Further, we compared genotype-phenotype data of TBK1 carriers with frontotemporal dementia (n = 7), with those of frontotemporal dementia patients with a C9orf72 repeat expansion (n = 65) or a GRN mutation (n = 52) and with frontotemporal dementia patients (n = 259) negative for mutations in currently known causal genes. TBK1 carriers with frontotemporal dementia had a later age at onset (63.3 years) than C9orf72 carriers (54.3 years) (P = 0.019). In clear contrast with TBK1 carriers, GRN carriers were more often diagnosed with the language variant than the behavioural variant, and presented in case of the diagnosis of behavioural variant, more often than TBK1 carriers with apathy as the predominant characteristic (P = 0.004). Also, TBK1 carriers exhibited more often extrapyramidal symptoms than C9orf72 carriers (P = 0.038). In conclusion, our study identified clinical differences between the TBK1, C9orf72 and GRN carriers, which allows us to formulate guidelines for genetic diagnosis. After a negative result for C9orf72, patients with both frontotemporal dementia and amyotrophic lateral sclerosis should be tested first for mutations in TBK1. Specifically in frontotemporal dementia patients with early memory difficulties, a relatively late age at onset or extrapyramidal symptoms, screening for TBK1 mutations should be considered.
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium 4 Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Mossevelde
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.affiliation: 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 5 Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Sieben
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 4 Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van Langenhove
authors.affiliation: 5 Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Bleecker
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 4 Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: 6 Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium 7 Department of Old Age Psychiatry and Memory Clinic, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vandenbulcke
authors.affiliation: 8 Department of Nuclear Medicine and Molecular Imaging, KU Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Van Laere
authors.affiliation: 9 Molecular Imaging Centre Antwerp, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium 10 Department of Nuclear Medicine, Antwerp University Hospital Edegem, Edegem, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ceyssens
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.affiliation: 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 4 Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.affiliation: 6 Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium 11 Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 4 Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 3 Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: 1 Department of Molecular Genetics, VIB, Antwerp, Belgium 2 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D001530:Belgium / Q000453:epidemiology; D000073885:C9orf72 Protein; D015331:Cohort Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D000077153:Progranulins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011506:Proteins; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
keywords: C9orf72; TBK1; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; genotype–phenotype correlations