ATP1A2-related epileptic encephalopathy and movement disorder: Clinical features of three novel patients

Epileptic Disord. 2024 Jun;26(3):332-340. doi: 10.1002/epd2.20220. Epub 2024 Mar 21.


Objective: Variants in the ATP1A2 gene exhibit a wide clinical spectrum, ranging from familial hemiplegic migraine to childhood epilepsies and early infantile developmental epileptic encephalopathy (EIDEE) with movement disorders. This study aims to describe the epileptology of three unpublished cases and summarize epilepsy features of the other 17 published cases with ATP1A2 variants and EIDEE.

Methods: Medical records of three novel patients with pathogenic ATP1A2 variants were retrospectively reviewed. Additionally, the PUBMED, EMBASE, and Cochrane databases were searched until December 2023 for articles on EIDEE with ATP1A2 variants, without language or publication year restrictions.

Results: Three female patients, aged 6 months-10 years, were investigated. Epilepsy onset occurred between 5 days and 2 years, accompanied by severe developmental delay, intellectual disability, drug-resistant epilepsy, severe movement disorder, and recurrent status epilepticus. All individuals had pathogenic variants of the ATP1A2 gene (ATP1A2 c.720_721del (p.Ile240MetfsTer9), ATP1A2c.3022C > T (p.Arg1008Trp), ATP1A2 c.1096G > T (p.Gly366Cys), according to ACMG criteria. Memantine was p) rescribed to three patients, one with a reduction in ictal frequency, one with improvement in gait pattern, coordination, and attention span, and another one in alertness without significant side effects.

Significance: This study reinforces the association between ATP1A2 variants and a severe phenotype. All patients had de novo variants, focal motor seizures with impaired awareness as the primary type of seizure; of the 11 EEGs recorded, 10 presented a slow background rhythm, 7 multifocal interictal epileptiform discharges (IED), predominantly temporal IEDs, followed by frontal IED, as well as ten ictal recordings, which showed ictal onset from the same regions mentioned above. Treatment with antiseizure medication was generally ineffective, but memantine showed moderate improvement. Prospective studies are needed to enlarge the phenotype and assess the efficacy of NMDA receptor antagonist therapies in reducing seizure frequency and improving quality of life.

Keywords: ATP1A2; NMDA receptor antagonists; drug‐resistant epilepsy; encephalopathies; genetic epilepsy.

Publication types

  • Case Reports

MeSH terms

  • Child
  • Child, Preschool
  • Drug Resistant Epilepsy / drug therapy
  • Drug Resistant Epilepsy / genetics
  • Drug Resistant Epilepsy / physiopathology
  • Female
  • Humans
  • Infant
  • Intellectual Disability / genetics
  • Intellectual Disability / physiopathology
  • Memantine / therapeutic use
  • Movement Disorders* / drug therapy
  • Movement Disorders* / etiology
  • Movement Disorders* / genetics
  • Movement Disorders* / physiopathology
  • Retrospective Studies
  • Sodium-Potassium-Exchanging ATPase* / genetics
  • Spasms, Infantile / drug therapy
  • Spasms, Infantile / genetics
  • Spasms, Infantile / physiopathology


  • Sodium-Potassium-Exchanging ATPase
  • ATP1A2 protein, human
  • Memantine

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy