Objective: To identify the genetic cause of disease in a French family with multiple members affected by dystonic tremor with autosomal dominant inheritance.

Background: Spinocerebellar ataxia 21 (SCA21) is a slowly progressive early-onset autosomal dominant cerebellar ataxia variably combined with cognitive impairment, parkinsonism, dystonia, and myoclonus. Pathogenic variants in the TMEM240 gene are the cause of SCA21. Around 60 cases of TMEM240-related disease were reported to date, with the P170L variant recurring in several families with independent origin and different clinical phenotype: the most common manifestations are ataxia and cognitive impairment though in some cases dystonia has been reported as presenting feature. ^1–10

Method: Seven subjects were clinically evaluated by neurologists with additional training in movement disorders and a whole-exome sequencing (WES) was performed. The candidate variants were confirmed through Sanger sequencing.

Results: Six subjects, four female and two male, belonging to three consecutive generations, presented an autosomal dominant tremulous dystonia with disease onset at 4-6 years. They displayed dystonic tremor of upper and lower limbs, neck, and head, as well as writer’s cramp and foot dystonia. Additional neurological signs interested some subjects including minimal dysmetria at finger-nose test, action tremor, bradykinesia, saccade impairment, dysphagia, autism spectrum disorder, and learning disability. All of them presented the recurrent P170L TMEM240 variant at WES and at Sanger sequencing confirmation. All instrumental examinations including brain MRI, DaTscan, and EMG resulted normal. One additional subject complained hand tremor by the age of 12 years without dystonia nor ataxia. The TMEM240 pathogenic variant was not present in this subject, thus she likely represents a phenocopy.

Conclusion: This work expands the clinical spectrum of TMEM240-related disease, including dystonic tremor as a main clinical presentation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dystonic-tremor-as-main-manifestation-of-a-large-sca21-family/