What question did this study set out to answer?

To explore the relationship between TBK1 mutations and the development of primary lateral sclerosis and frontotemporal dementia.

February 8, 2026Open Access

TBK 1 ‐Associated Primary Lateral Sclerosis Followed by Right Temporal Variant Frontotemporal Dementia

Key Points

To explore the relationship between TBK1 mutations and the development of primary lateral sclerosis and frontotemporal dementia.
Detailed clinical assessment of a 58-year-old woman with TBK1 mutation.
Neuroimaging was conducted to assess brain atrophy.
Molecular analysis was performed to evaluate TBK1 transcript levels.
The patient exhibited progressive symptoms, starting with prosopagnosia.
Neuroimaging revealed atrophy in the right anterior temporal lobe prior to cognitive decline.
Molecular analysis indicated reduced levels of properly spliced TBK1 transcripts.

Abstract

ABSTRACT We report a 58‐year‐old woman with a novel splice‐site variant in the TANK‐binding kinase 1 ( TBK1 :c.993–2A>C p.Ala332TyrfsTer39) who sequentially developed primary lateral sclerosis (PLS) followed by right temporal variant frontotemporal dementia (rtvFTD). Neuroimaging demonstrated right anterior temporal atrophy before cognitive symptoms, and prosopagnosia represented the earliest manifestation of rtvFTD. Molecular analysis revealed reduced levels of correctly spliced TBK1 transcripts, consistent with haploinsufficiency. Given the shared involvement of TDP‐43 pathology in both PLS and rtvFTD, this case indicates TBK1 dysfunction as a fundamental genetic factor underlying the coexistence of these phenotypes, underscoring the clinical value of early neuroimaging and genetic evaluation.

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