Beyond ALS and FTD: the phenotypic spectrum of TBK1 mutations includes PSP-like and cerebellar phenotypes

Neurobiol Aging. 2018 Feb;62:244.e9-244.e13. doi: 10.1016/j.neurobiolaging.2017.10.010. Epub 2017 Oct 24.


Mutations in the TANK-binding kinase 1 gene (TBK1) are a rare, but recurrent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the complete phenotypic spectrum of syndromes associated with TBK1 mutations remains to be elucidated. Using next-generation panel-sequencing of neurodegenerative disease genes, we identified a TBK1 index patient presenting with a progressive supranuclear palsy-like syndrome. Consecutively, we screened the whole-exome sequencing data of 439 index subjects presenting with various neurodegenerative syndromes outside the ALS-FTD spectrum for TBK1 mutations. Based on this genetic screen, we identified another TBK1 index patient presenting with progressive cerebellar ataxia. Both index patients carried the established p.Glu643del TBK1 mutation (c.1928_1930delAAG). In the index patients' families, we identified mesencephalic and cerebellar atrophy as recurrent imaging findings of TBK1-associated neurodegeneration, with cerebellar atrophy occurring even in presymptomatic mutation carriers. Our findings demonstrate that the phenotypic spectrum of TBK1 mutations extends beyond ALS and FTD to include also progressive supranuclear palsy-like and cerebellar syndromes, with mesencephalon and cerebellum representing recurrent sites of TBK1-associated neurodegeneration.

Keywords: Ataxia; FTD; Genetic screening; PSP; TBK1; Whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / genetics*
  • Atrophy
  • Cerebellar Ataxia / diagnostic imaging
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology
  • Cerebellum / diagnostic imaging
  • Cerebellum / pathology
  • Female
  • Frontotemporal Dementia / genetics*
  • Genetic Association Studies*
  • Genetic Testing
  • Heterozygote
  • Humans
  • Male
  • Mesencephalon / diagnostic imaging
  • Mesencephalon / pathology
  • Middle Aged
  • Mutation / genetics*
  • Neuroimaging
  • Phenotype*
  • Protein Serine-Threonine Kinases / genetics*
  • Supranuclear Palsy, Progressive / diagnostic imaging
  • Supranuclear Palsy, Progressive / genetics*
  • Supranuclear Palsy, Progressive / pathology
  • Whole Exome Sequencing


  • Protein Serine-Threonine Kinases
  • TBK1 protein, human