Dystonic Tremor as Main Clinical Manifestation of SCA21.

Background: Spinocerebellar ataxia type 21 (SCA21) is a rare inherited neurological disorder characterized by motor, cognitive, and behavioral disturbances, caused by autosomal dominant TMEM240 variants.

Objectives: To identify the genetic cause of a dystonic tremor with autosomal dominant inheritance.

Methods: Six subjects of a multi-generational French family affected by tremor and dystonia were studied. Each patient underwent a comprehensive clinical assessment and a whole-exome sequencing analysis.

Results: All six subjects presented with early-onset prominent hand dystonic tremor and multifocal/generalized dystonia, secondarily developing mild cerebellar ataxia. The younger generation showed more pronounced cognitive and behavioral impairment. The known pathogenic TMEM240 c.509C>T (p.P170L) variant was found in heterozygosis in all subjects.

Conclusions: Dystonic tremor can represent the core clinical feature of SCA21, even in absence of overt cerebellar ataxia. Therefore, TMEM240 pathogenic variants should be considered disease-causing in subjects displaying dystonic tremor, variably associated with ataxia, parkinsonism, neurodevelopmental disorders, and cognitive impairment.