Objective: To describe a case of novel genetic variant of TTBK2 gene in a woman with late-onset cerebellar ataxia and her symptomatic mother.

Background: Pathogenic variants in the tau-tubulin kinase 2 encoding gene (TTBK2) have been implicated as the cause of spinocerebellar ataxia type 11 (SCA11), a rare, dominantly inherited, relatively pure, slowly progressive cerebellar ataxia with abnormal eye signs. Other uncommon clinical features include pyramidal signs, dysarthria, swallowing difficulties, peripheral neuropathy and dystonia. Affected individuals have a variable age of onset but with a normal life expectancy. Historically, only frame-shift variants of TTBK2 were implicated in SCA11; however, more recent studies have identified additional pathogenic missense variants of TTBK2.

Method: Case report.

Results: A 74-year-old north American woman presented to the clinic with a long-standing history of nystagmus of unknown onset, slowly progressive balance and gait problems beginning at 60 years of age, and new-onset head tremor at 71 years of age. Variable manifestations of imbalance, tremor and nystagmus were reported in all three siblings, mother, maternal grandfather, one niece, two maternal uncles and two maternal aunts. Her physical exam was notable for mild dysarthria, horizontal gaze evoked nystagmus, left torticollis, retrocollis, head and neck tremor, dysmetria, wide based gait and inability to tandem walk. Her brain MRI showed mild generalized cerebral and cerebellar atrophy. Ataxia/Spastic paraplegia comprehensive panel identified a heterozygous missense variant of uncertain significance in the TTBK2 gene (c.3334G>T; p.(Ala1112Ser)). Whole genome sequencing for the patient, her mother and her sister demonstrated the same variant in her mother but not her sister. Amantadine and propranolol did not provide any benefit over physical therapy.

Conclusion: We report a novel missense mutation in the TTBK2 gene as a potential cause of SCA11.

References: – Houlden, H., Johnson, J., Gardner-Thorpe, C. et al. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39, 1434–1436 (2007). https://doi.org/10.1038/ng.2007.43
– Deng, Y., Fu, J., Zhong, Y. et al. First finding of familial spinal cerebellar Ataxia11 in China: clinical, imaging and genetic features. Neurol Sci 41, 155–160 (2020). https://doi.org/10.1007/s10072-019-04052-6
– Edener, Ulf et al. “Missense exchanges in the TTBK2 gene mutated in SCA11.” Journal of neurology vol. 256,11 (2009): 1856-9. doi:10.1007/s00415-009-5209-0
– Lindquist, Suzanne Granhøj et al. “A Novel TTBK2 De Novo Mutation in a Danish Family with Early-Onset Spinocerebellar Ataxia.” Cerebellum (London, England) vol. 16,1 (2017): 268-271. doi:10.1007/s12311-016-0786-9
– Bauer, Peter et al. “Spinocerebellar ataxia type 11 (SCA11) is an uncommon cause of dominant ataxia among French and German kindreds.” Journal of neurology, neurosurgery, and psychiatry vol. 81,11 (2010): 1229-32. doi:10.1136/jnnp.2009.202150
– Giunti P, Houlden H, Gardner-Thorpe C, et al. Spinocerebellar ataxia type 11. Handb Clin Neurol. 2012;103:521-534. doi:10.1016/B978-0-444-51892-7.00033-4

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-missense-variant-in-the-ttbk2-gene-in-a-north-american-family-with-late-onset-cerebellar-ataxia/