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

Authors

Wilke C1, Baets J2, De Bleecker JL3, Deconinck T4, Biskup S5, Hayer SN1, Züchner S6, Schüle R1, De Jonghe P2, Synofzik M7.
  1. Department of Neurodegenerative Diseases, hertie- institute for Clinical Brain Research and Center of Neurology, university of Tübingen, Tübingen, Germany; Germany Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
  2. Neurogenetics Group, Center for Moleculr Neurology, VIB, Antwerp, Belgium; Laboratories of Neurogenetics and Ultrastructural Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  3. Department of neurology, University Hospital Ghent, Ghent, Belgium.
  4. Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratories of Neurogenetics and Ultrastructural Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  5. CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany.
  6. Dr. John T. Macdonald Foundation, Department of Human Genetics, Miami, USA; John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, USA.
  7. Department of Neurodegenerative Dieseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Dieseases (DZNE), University of Tübingen, Tübingen, Germany. Electronic address: matthis.synofzik@uni-tuebingen.de.

Abstract

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.