Novel ATP1A3 mutation in a sporadic RDP patient with partial benefit from deep brain stimulation

Rapid Onset Dystonia-Parkinsonism (RDP) is a very rare, autosomal dominantly inherited movement disorder, characterized by abrupt or subacute onset of both dystonic symptoms and parkinsonism with prominent bulbar involvement. Recently, six missense mutations in highly conserved regions of the ATP1A3 gene have been identified in four families and three sporadic patients. This gene encodes a Na⁺/K⁺-Pase responsible for maintaining the electrochemical gradient across cell membranes.

We here report a novel de novo ATP1A3 mutation, a heterozygous in-frame deletion of three basepairs (CTG) at position 976–978 or 979–981, removing one of a pair of leucine residues (dL326/327), in a sporadic patient with typical RDP with predominant generalized limb dystonia. This mutation was found in a phylogenetically highly conserved region of the protein and is the first in-frame deletion reported. Further, this patient underwent bilateral DBS of the GPi and is, to our knowledge, the first patient reported to experience modest clinical benefit, reflected in a 30% reduction in the sum of the movement subscore of the Burke-Fahn-Marsden (BFM) dystonia scale three months postoperatively, as compared to the preoperative state.

Our results suggest that DBS of the GPi may provide some clinical benefit in carefully selected RDP patients, especially in those with predominant limb dystonia.