Objective: To report a novel case of an MSA-like phenotype in a patient with a pathogenic mutation in the TBK1 gene.

Background: TANK-binding kinase 1 (TBK1), a serine/threonine kinase encoded by TBK1, functions in innate immunity, inflammation, and autophagy. Mutations in TBK1 have been associated with diverse clinical phenotypes, including familial frontotemporal lobar dementia (FTLD), familial ALS (fALS), progressive supranuclear palsy (PSP)-like syndrome, corticobasal syndrome (CBS), and progressive cerebellar ataxia (1,2,3). Here, we report the first instance of a patient with a multiple system atrophy (MSA)-like phenotype in TBK1 mutation.

Method: Case report.

Results: A 49-year-old male presented for evaluation of parkinsonism. Symptoms began at age 43 with asymmetric tremor and intermittent episodes of weakness and paralysis, lasting minutes to hours. Four years after onset of symptoms, he was hospitalized for one such episode and found to have rest tremor, rigidity, diffuse hyperreflexia and rhabdomyolysis. EMG/NCS was concerning for a central process. Subsequently he developed dysarthria, progressive asymmetric parkinsonism, diffuse hyperreflexia, limb dystonia, gait impairment with freezing and marked postural instability with frequent falls, neurogenic orthostatic hypotension (nOH), urinary incontinence, and REM-behavior disorder (confirmed on polysomnography). MRI of the brain and spine were unremarkable. DATscan was abnormal. Trials of carbidopa/levodopa, ropinirole, pramipexole, and amantadine had minimal clinical benefit. While he met diagnostic criteria for MSA, his young onset and history of episodic paralysis prompted referral for genetic testing.

Conclusion: Exome sequencing revealed a heterozygous nonsense mutation (c.1335 G>A; p.W445*) in exon 11 of TBK1, predicted to cause protein truncation or nonsense-mediated decay. This specific mutation has been reported in patients with FTD and one case of FTD-CBS (4,5). Soon after, patient developed severe stridor with vocal cord paralysis and worsening orthostatic hypotension requiring hospitalization and ultimately declined life-sustaining interventions. He was discharged home and later found deceased. This case represents the first report of a patient with an MSA-like phenotype associated with a known pathogenic TBK1 mutation and expands the phenotypic spectrum of TBK1-associated neurodegeneration.

References: 1. Y. Gurfinkel, N. Polain, K. Sonar, P. Nice, R. L. Mancera, S. L. Rea, Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurobiol. Dis. 174, 105859 (2022).
2. C. Wilke, J. Baets, J. L. De Bleecker, T. Deconinck, S. Biskup, S. N. Hayer, S. Züchner, R. Schüle, P. De Jonghe, M. Synofzik, Beyond ALS and FTD: the phenotypic spectrum of TBK1 mutations includes PSP-like and cerebellar phenotypes. Neurobiol. Aging 62, 244.e9-244.e13 (2018).
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MDS Abstracts - https://www.mdsabstracts.org/abstract/pathogenic-tbk1-mutation-associated-with-multiple-system-atrophy-like-phenotype/