ATP1A3 – Rapid-onset dystonia-parkinsonism (Dystonia 12)

Rapid-onset dystonia-parkinsonism (RDP; Dystonia 12) is a rare autosomal dominant movement disorder characterised by abrupt-onset dystonia with parkinsonian features and a rostrocaudal gradient, often triggered by physical or emotional stress. ATP1A3 (HGNC:801), encoding the neuron-specific Na+/K+-ATPase α3-subunit, was first implicated in RDP through the identification of missense variants segregating in multiple families (PMID:15260953). This gene is essential for maintaining electrochemical gradients across neuronal membranes, underpinning both excitability and ion homeostasis.

Genetic evidence for ATP1A3-related RDP is robust. Initial linkage and sequencing in seven unrelated families revealed six distinct missense variants in 36 affected individuals (PMID:15260953), while subsequent studies encompassing 15 families (59 patients) and 36 sporadic cases further consolidated the genotype–phenotype correlation (PMID:35978945). Segregation analysis in a multigenerational Italian pedigree demonstrated co-segregation of the c.1838C>T (p.Thr613Met) variant with disease in three additional affected relatives (PMID:22534615). The inheritance is consistently autosomal dominant with reduced penetrance in some carriers.

The ATP1A3 variant spectrum in RDP is dominated by missense changes clustering in exons 8, 14, 17, and 18, with recurrent hotspots such as p.Thr613Met and p.Glu277Lys (PMID:15260953). Over 28 unique missense variants have been reported, often arising de novo or inherited in familial cases. Representative RDP-associated variants include c.1838C>T (p.Thr613Met) identified in multiple pedigrees (PMID:22534615).

Clinically, RDP presents with acute-onset asymmetric limb dystonia, prominent bulbar dysfunction, and bradykinesia without tremor. Physical or emotional triggers precipitate rapid deterioration (PMID:22534615), and nonmotor features including anxiety and mood disorders occur in up to half of mutation carriers (PMID:22933743).

Functional assays across diverse models confirm the pathogenicity of RDP variants. The D923N mutant exhibits a ~200-fold reduction in Na+ affinity at the third binding site (PMID:20576601), while patient iPSC-derived neurons carrying p.Gly947Arg show diminished ouabain-sensitive pump currents and depolarised membrane potentials (PMID:29567111). Moreover, a D801N knock-in mouse model displays motor dysfunction, seizures, and spreading depression akin to human disease (PMID:25523819).

Together, these genetic and functional lines of evidence establish a definitive association between ATP1A3 variants and RDP. Clinicians should pursue ATP1A3 sequencing in patients with acute dystonia–parkinsonism, as early molecular diagnosis can inform genetic counselling, anticipatory cardiac monitoring, and potential targeted therapies. Key take-home: ATP1A3-related RDP is a monogenic autosomal dominant disorder with >95 affected individuals reported, where Na+ pump dysfunction underlies the abrupt motor syndrome.

References

• Neuron • 2004 • Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. PMID:15260953
• The Journal of Biological Chemistry • 2010 • The rapid-onset dystonia parkinsonism mutation D923N of the Na+, K+-ATPase alpha3 isoform disrupts Na+ interaction at the third Na+ site. PMID:20576601
• Frontiers in Aging Neuroscience • 2022 • ATP1A3 mutation in rapid-onset dystonia parkinsonism: New data and genotype-phenotype correlation analysis. PMID:35978945
• Parkinsonism & Related Disorders • 2012 • New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. PMID:22534615
• Neurology • 2012 • Psychiatric disorders in rapid-onset dystonia-parkinsonism. PMID:22933743
• Neurobiology of Disease • 2018 • Direct evidence of impaired neuronal Na/K-ATPase pump function in alternating hemiplegia of childhood. PMID:29567111
• Epilepsia • 2015 • Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization. PMID:25523819

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