Alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism: Phenotypic spectrum of ATP1A3-associated disorders

Aim of study: Recently, heterozygous de novo mutations of ATP1A3 were described as the cause of alternating hemiplegia of childhood (AHC). Already in 2004, heterozygous mutations in this gene were discovered as the cause of rapid-onset dystonia-parkinsonism (RDP, DYT12). This study aimed at comparing the clinical phenotypes of AHC and RDP and clarifying whether these conditions are allelic disorders (phenotypic distinguishable disorders caused by mutations in the same gene) or whether they constitute a continuous phenotypic spectrum with some clinical variability.

Methods: Molecular, genetic, and clinical findings of 24 patients with AHC (ages ranging from 8 to 35 years) were compared with features of 2 own patients with RDP (aged 16 and 17 years, respectively) as well as with the genetic and clinical data of RDP patients reported in the literature (18 families or sporadic cases).

Results: Clinical phenotypes of AHC and RDP share several features in common: (1) abrupt onset of symptoms; (2) onset may be triggered by certain events including physical or emotional stress and hypo- or hyperthermia; (3) predominant dyskinetic movement disorder with bradykinesia, unsteady gait; (4) prominent bulbar symptoms comprising dysarthria, drooling, hypomimia, and episodic abnormal eye movements; (5) rostrocaudal gradient of dystonic involvement (head > arms > legs), which is uncommon in genetic dystonias; and (6) seizures in a subset of patients. However, both conditions show a clearly different course: polyphasic course with frequently recurrent paroxysms of hemi- and quadriplegia or hemidystonia in AHC versus monophasic or at most biphasic course in RDP. Cognitive impairment is much more frequent in AHC than in RDP, but various psychopathological symptoms are being recognized in RDP as well. Case reports of single patients carrying ATP1A3 mutations who were diagnosed as having RDP but with paroxysmal features matching AHC concern intermediate phenotypes.

Conclusion: AHC and RDP constitute a continuous phenotypic spectrum of ATP1A3-related disorders.