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.