期刊
NEUROBIOLOGY OF AGING
卷 62, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2017.10.010
关键词
TBK1; PSP; Ataxia; Whole-exome sequencing; Genetic screening; FTD
资金
- European Union's Horizon research and innovation program under the ERA-NET Cofund action [643578]
- BMBF [01GM1607]
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 neuro-degenerative 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 palsyelike and cerebellar syndromes, with mesencephalon and cerebellum representing recurrent sites of TBK1-associated neurodegeneration. (C) 2017 Elsevier Inc. All rights reserved.
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