The expanding clinical and genetic spectrum of ATP1A3-related disorders

Hendrik Rosewich, Andreas Ohlenbusch, Peter Huppke, Lars Schlotawa, Martina Baethmann, Inês Carrilho, Simona Fiori, Charles Marques Lourenço, Sarah Sawyer, Robert Steinfeld, Jutta Gärtner, Knut Brockmann

Research output: Contribution to journalArticlepeer-review


Objective: We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation. Methods: We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses. Results: Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18. Conclusion: AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.

Original languageEnglish
Pages (from-to)945-955
Number of pages11
Issue number11
Publication statusPublished - Mar 18 2014

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)


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