Atypical gradual progression in rapid-onset dystonia-parkinsonism with a rare ATP1A3 variant and the long-term effectiveness of botulinum toxin therapy

Abstract

Background

Rapid-onset dystonia-parkinsonism (RDP) is a rare autosomal-dominant disorder caused by ATP1A3 variants. It is characterized by abrupt-onset asymmetrical dystonia, parkinsonism, and bulbar symptoms. Most cases present with sudden onset; however, atypical presentations with gradual onset have been rarely documented. In this report, we discuss the pathogenesis in a 28-year-old male patient with a rare ATP1A3 variant and atypical RDP manifestation.

Case report

A right-handed male patient developed handwriting difficulty and right-sided facial myoclonus at age 13, progressing to gradual dystonia predominantly affecting the right extremities. Neurological examinations at age 14 revealed right-sided dystonia, facial myoclonus, and bulbar symptoms without tremors or diurnal fluctuations. Brain MRI was normal, whereas single photon emission computed tomography (SPECT) showed hypoperfusion in the left basal ganglia associated with right-sided dystonia. Transcranial magnetic stimulation (TMS) clarified that the silent period, mediated by the gamma-aminobutyric acid (GABA)-B system, was normal. Genetic analysis identified a rare ATP1A3 variant (NM_152296.5):c.2438C>T,p.(Ala813Val) and confirmed it as de novo. Although oral medications, including levodopa, were ineffective, botulinum toxin (BT) therapy stabilized his dystonic symptoms for 13 years.

Discussion

This case highlights an atypical RDP presentation with gradual onset and minimal parkinsonism. Considering the results of SPECT and TMS, and the ineffectiveness of levodopa, one of the responsible lesions in this patient may be in the striatal output pathway rather than the dopaminergic system. The long-term effectiveness of BT therapy underscores its potential in managing dystonia in RDP.