Objective: We describe four patients within a family who presented to our movement disorders centers for evaluation of various symptoms including unsteady gait, tremor, and cognitive impairment found to have the same pathogenic variant in TMEM240. We describe their clinical courses, response to tremor treatments to include  posterior subthalamic area deep brain stimulation (PSA DBS). Video segments of the patients are included.

Background: ataxia 21 (SCA21) is a rare cause of autosomal dominant ataxia with few patients (~50) published. It is an early-onset, slowly progressive cerebellar ataxia. Other movement disorders have also been described to include tremor and parkinsonism. Also associated with SCA21 are oculomotor abnormalities, cognitive impairment, and psychiatric conditions. Given its rarity, the neurodevelopmental phenotype has not been well defined and phenotypic variability within the same variant has not yet described.

Method: index case, 12 year-old girl, presented with mild intellectual disability, severe action tremor of the hands since infancy, oculomotor abnormalities (saccadic intrusions and nystagmus), anxiety, and depression. The full brother of the index was noted to have mild action tremor since early childhood, speech delay and growth delay. The index patient’s paternal half-brother presented with progressively worsening action tremor since early childhood which became impairing in adolescence as well as similar oculomotor abnormalities, learning disabilities, ADHD, and OCD. The father of the patients had onset of mild non-progressive action tremor of the hands since age 8, progressive ataxia, parkinsonism, mild intellectual disability and new onset progressive memory impairment. All patients were found to have the same pathogenic variant in TMEM240 (c.196G>A p.G66R)).

Results: The index patient tried numerous oral medications as well as botulinum neurotoxin (BoNT) injections without improvement. She underwent unilateral PSA DBS with marked improvement in tremor and plans of implantation of the contralateral side. Tremor in the paternal half-brother responded well to BoNT injections. The father underwent treatment for parkinsonism with carbidopa-levodopa and was started on rivastigmine without clear clinical improvement.

Conclusion: SCA21 is a slowly progressive autosomal dominant spinocerebellar ataxia with variable neurodevelopmental phenotypes including multiple movement disorders within the same variant.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spinocerebellar-ataxia-21-and-phenotypic-variability-within-a-family/