Objective: Tumour necrosis factor NF-ƘB activator (TANK) binding kinase 1 (TBK1) is necessary for immune and inflammatory responses. Reports of TBK1 with neurodegeneration are noted in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Parkinsonism is rare, and we present an unusual MSA-like phenotypic presentation of TBK1, extending the clinical spectrum.

Background: TBK1 interacts with OPTN (optineurin), an autophagy receptor, and C9orf72 complexes, which help regulate autophagy. Mutations of TBK1 can impair autophagy contributing to neurodegeneration.

Method: A 64-year-old businessman insidious onset parkinsonism with postural instability since 2018, gradually worsening and interfering with his daily activities. He had urinary urgency with urge incontinence and REM sleep behaviour disorder. born to second-degree consanguineous parents. Clinically he had symmetrical parkinsonism with dysarthria and abnormal finger-nose test. He had broad-based gait with impaired tandem walk.

Results: With clinically probable multiple system atrophy-cerebellar (MSA-C) type (according to The Movement Disorder Society Criteria for the Diagnosis of MSA), brain magnetic resonance imaging (MRI) showed frontoparietal and mild cerebellar atrophy. Autonomic function test were normal. [18F] Fluorodeoxyglucose positron emission tomography (FDG-PET) brain revealed hypometabolism in bilateral basal ganglia, anterior cingulate gyri and bilateral temporal lobes. He complained then noticed fatiguability, proximal lower limbs weakness, dysphagia to liquids with additional clinical evidence of non-fluent speech with word-finding difficulty. Electrophysiological studies showed neurogenic potentials in C8-T1. Whole exome sequencing showed a disease-associated heterozygous 1 base pair deletion in exon 2 of the TBK1.

Conclusion: TBK1 mutations can present as atypical parkinsonism phenotype. Testing for the TBK1 variant must be considered in atypical parkinsonism, even with a negative family history. Medication response of Parkinsonism with TBK1 mutations is variable and can be unsatisfactory.

References: Wilke C, Baets J, Bleecker JL De, Deconinck T, Biskup S, Hayer SN, et al. Neurobiology of Aging Beyond ALS and FTD : the phenotypic spectrum of TBK1 mutations includes PSP-like and cerebellar phenotypes. Neurobiol Aging. 2017;1:1–5. https://doi.org/10.1016/j.neurobiolaging.2017.10.010

Swift IJ, Bocchetta M, Benotmane H, Oc I, Shafei R, Rohrer JD. Neurobiology of Aging Variable clinical phenotype in TBK1 mutations : case report of a novel mutation causing primary progressive aphasia and review of the literature. Neurobiol Aging [Internet]. 2021;99:100.e9-100.e15. https://doi.org/10.1016/j.neurobiolaging.2020.08.014

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unveiling-a-rare-case-novel-tbk1-variant-presenting-as-multiple-system-atrophy-like-phenotype/