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Comparative Study
. 2016 Feb;139(Pt 2):452-67.
doi: 10.1093/brain/awv358. Epub 2015 Dec 15.

Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort

Sara Van Mossevelde  1 , Julie van der Zee  2 , Ilse Gijselinck  2 , Sebastiaan Engelborghs  3 , Anne Sieben  4 , Tim Van Langenhove  5 , Jan De Bleecker  6 , Jonathan Baets  5 , Mathieu Vandenbulcke  7 , Koen Van Laere  8 , Sarah Ceyssens  9 , Marleen Van den Broeck  2 , Karin Peeters  2 , Maria Mattheijssens  2 , Patrick Cras  10 , Rik Vandenberghe  11 , Peter De Jonghe  5 , Jean-Jacques Martin  12 , Peter P De Deyn  3 , Marc Cruts  2 , Christine Van Broeckhoven; Belgian Neurology consortium
Collaborators, Affiliations
Comparative Study

Clinical features of TBK1 carriers compared with C9orf72, GRN and non-mutation carriers in a Belgian cohort

Sara Van Mossevelde et al. Brain. 2016 Feb.

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.

Keywords: C9orf72; TBK1; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; genotype–phenotype correlations.

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Figures

None
Loss-of-function mutations in TBK1 have been identified in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Van Mossevelde et al. compare TBK1-mutation carriers with FTD, ALS or FTD-ALS to patients carrying GRN or C9orf72 mutations. Differences are seen in age of onset, extrapyramidal symptoms, and in memory, language and behaviour.
Figure 1
Figure 1
Families segregating the TBK1 mutation p.Glu643del. (A) DR158 pedigree; (B) DR663 pedigree. To protect the privacy of the family members, the gender of each person was masked, the order of sibs was scrambled and the number (n) of tested at-risk individuals shown in white diamonds was not specified. Filled symbols are clinically affected patients with their age at onset (AAO) in years (y) below the symbol. Age at death (AAD) is shown for individuals who died at old age without symptoms. Age at last evaluation (AALE) is shown for currently unaffected mutation carriers that are still alive. An asterisk identifies the family members of whom genomic DNA was available and a ‘c’ identifies the TBK1 p.Glu643del mutation carriers. A ‘+’ sign indicates which DR663 members are carriers of the C9orf72 repeat expansion. The arrow identifies the proband of the family. Only the clinically affected patients known to carry the mutation and of whom clinical records were available, were described in this paper. Other family members pictured as clinically affected were not described because the clinically affected state was only based on oral information obtained from relatives or because their mutation status was not known. (C) Liability risk curve for TBK1 loss of function (LOF) mutation carriers. This curve shows the proportion (%) of TBK1 loss of function mutation carriers (y-axis) that is affected at a certain age (years) (x-axis). The crosses stand for censoring of the patients that are clinically still unaffected at the last time of clinical evaluation or at death. The crosses are placed on the curve at the age of last evaluation or at the age of death.
Figure 2
Figure 2
Neuroimaging using FDG-PET. These images are z-map renderings of the FDG-PET in Patients DR1121 and DR1122. The z-maps are calculated by comparing the individual glucose metabolic pattern to the normal age-matched control. Both imaging series show a similar pattern of remarkable asymmetry with a severely decreased metabolism in the left frontal, and anterior and medial temporal lobe. These results are much more asymmetric than age could explain, do not follow typical age-related patterns, and are much more intense.
Figure 3
Figure 3
Neuropathology. (A) Macroscopy Patient DR189. Macroscopic picture of the right cerebral and cerebellar hemisphere of Patient DR189, from a lateral view (i) and a medial view (ii). (B) TDP-43 and p62 immunohistochemistry. Staining for TDP-43 and p62 of the frontal cortex (i and iv) and the hippocampus (ii and v) of FTLD Patient DR189 and for the spinal cord of ALS Patient DR1124 (iii and vi). TDP-43 and p62 positive neuronal cytoplasmic inclusions are indicated with an arrow. (C) AT8 staining of the hippocampus and parahippocampal gyrus DR1124. AT8 staining showed many neuronal cytoplasmic inclusions in the dentate gyrus of the hippocampus (i). In the parahippocampal cortex, neuronal neurofibrillary tangles or neuronal cytoplasmic inclusions were found (arrow, ii), whereas in the white matter, glial astrocytic cytoplasmic inclusions (arrowhead, iii and iv) and tufted astrocytes (double arrow, iv) were present.
Figure 4
Figure 4
Genotype–phenotype correlations in FTD patients. In these graphs, FTD patients are divided in groups based on their causal gene mutation, i.e. TBK1, C9orf72 and GRN carriers and non-mutation carriers. The latter group is further divided by familial history in familial and sporadic, and patients with unknown familial history. (A) Ages at onset. The boxplots illustrate the distribution of ages at onset in each FTD patient group. For each genetic subtype a boxplot is created in which the middle horizontal line represents the median age at onset. The upper and lower border of the box represent the value of the first quartile (25%) and the third quartile (75%) of the data. The whiskers represent the minimal and maximal age at onset with exception of the outliers. The outliers are presented as circles and refer to ages at onset that are greater than 1.5 interquartile ranges away from the 25th or the 75th percentile. (B) Subtype of behavioural FTD. This bar graph illustrates which proportion of the behavioural variant FTD patients of each patient group has frontal disinhibition or apathy as predominant feature, respectively. (C) Presence of extrapyramidal symptoms. In this bar graph, the proportion of patients who exhibit extrapyramidal symptoms are pictured for each patient group. (D) Psychiatric symptoms. This bar graph shows the proportion of FTD patients with psychiatric symptoms for each patient group. The bars are subdivided for the proportion of the major psychiatric characteristic.
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