Mutational and phenotypic expansion of ATP1A3-related disorders: Report of nine cases

Gene. 2020 Jul 30;749:144709. doi: 10.1016/j.gene.2020.144709. Epub 2020 Apr 25.


Background: Mutations in the ATP1A3 gene are known to be the cause of three distinct neurological syndromes including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP) and cerebellar ataxia, arefexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS). Recent studies have suggested the broader diversity of ATP1A3-related disorders. This study aimed to investigate the clinical spectrum in patients carrying causative mutations within the ATP1A3 gene.

Method: The medical histories of nine unrelated patients with diverse phenotypes harboring variants in ATP1A3 were retrospectively analyzed after they were referred to a tertiary epilepsy center in one of the two different health care systems (Germany or Thailand). Clinical features, neurophysiological data, imaging results, genetic characteristics and treatments were reviewed.

Results: Three patients harbor novel mutations in the ATP1A3 gene. Atypical clinical features and imaging findings were observed in two cases, one with hemiplegia-hemiconvulsion-epilepsy syndrome, and the other with neurodegeneration with brain iron accumulation. All nine patients presented with intellectual impairment. Alternating hemiplegia of childhood (AHC) was the most common phenotype (67%). Flunarizine and topiramate led to symptom reduction in 83% and 25% of AHC cases administered, respectively.

Conclusion: The present case series expands the clinical and genetic spectrum of ATP1A3-related disorders.

Keywords: ATP1A3; Alternating hemiplegia of childhood; Epilepsy; Epileptic encephalopathy; Hemiplegia-hemiconvulsion-epilepsy syndrome; Neurogeneration with brain iron accumulation.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Child
  • Dystonic Disorders / diagnosis
  • Dystonic Disorders / genetics
  • Electroencephalography
  • Female
  • Hemiplegia / diagnosis
  • Hemiplegia / genetics
  • Humans
  • Male
  • Mutation*
  • Nervous System Diseases / diagnosis
  • Nervous System Diseases / diagnostic imaging
  • Nervous System Diseases / genetics*
  • Neuroimaging
  • Phenotype*
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Young Adult


  • ATP1A3 protein, human
  • Sodium-Potassium-Exchanging ATPase

Supplementary concepts

  • Alternating hemiplegia of childhood
  • Dystonia 12