The clinical, neuroanatomical, and neuropathologic phenotype of TBK1-associated frontotemporal dementia: A longitudinal case report

Carolin A.M Koriath,Martina Bocchetta,Emilie Brotherhood,Ione O.C Woollacott,Penny Norsworthy,Javier Simón-Sánchez,Cornelis Blauwendraat,Katrina M Dick,Elizabeth Gordon,Sophie R Harding,Nick C Fox,Sebastian Crutch,Jason D Warren,Tamas Revesz,Tammaryn Lashley,Simon Mead,Jonathan D Rohrer

doi:10.1016/j.dadm.2016.10.003

Abstract

IntroductionMutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype of TBK1-associated FTD is currently unclear.MethodsWe performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the TBK1 gene. He was assessed annually over a 7-year period with a series of clinical, cognitive, and magnetic resonance imaging assessments. His brain underwent pathological examination at postmortem.ResultsThe patient presented at the age of 64 years with an 18-month history of personality change including increased rigidity and obsessiveness, apathy, loss of empathy, and development of a sweet tooth. His mother had developed progressive behavioral and cognitive impairment from the age of 57 years. Neuropsychometry revealed intact cognition at first assessment. Magnetic resonance imaging showed focal right temporal lobe atrophy. Over the next few years his behavioral problems progressed and he developed cognitive impairment, initially with anomia and prosopagnosia. Neurological examination remained normal throughout without any features of motor neurone disease. He died at the age of 72 years and postmortem showed TDP-43 type A pathology but with an unusual novel feature of numerous TAR DNA-binding protein 43 (TDP-43)–positive neuritic structures at the cerebral cortex/subcortical white matter junction. There was also associated argyrophilic grain disease not previously reported in other TBK1 mutation cases.DiscussionTBK1-associated FTD can be associated with right temporal variant FTD with progressive behavioral change and relatively intact cognition initially. The case further highlights the benefits of next-generation sequencing technologies in the diagnosis of neurodegenerative disorders and the importance of detailed neuropathologic analysis.

Highlights

Frontotemporal dementia (FTD) is a frequent cause of young-onset dementia with around one-third of cases being familial
Patients with TANK-binding kinase 1 (TBK1) mutations have been described with the clinical syndrome of FTD, motor neurone disease (MND), or the combination of both [6], but few details are currently known about the clinical phenotype, atrophy pattern, and time-course of the disease
Cognitive, and neuroanatomical progression over 9 years of a patient with FTD due to a novel TBK1 mutation who was found to have frontotemporal lobar degeneration (FTLD)-TDP type A pathology

Summary

Introduction

Frontotemporal dementia (FTD) is a frequent cause of young-onset dementia with around one-third of cases being familial. Recent studies have identified mutations in the TANK-binding kinase 1 (TBK1) as a novel cause of both FTD and MND [1,2,3,4,5]. Patients with TBK1 mutations have been described with the clinical syndrome of FTD (usually the behavioral variant), MND (usually amyotrophic lateral sclerosis), or the combination of both [6], but few details are currently known about the clinical phenotype, atrophy pattern, and time-course of the disease. We present a longitudinal case report of a patient with a novel TBK1 mutation assessed over several years

Methods

Results

Conclusion