ATP1A3-related Epilepsy: Report of Six Cases and Literature-based Analysis of Treatment Response

Objectives: Since the first linkage of the ATP1A3 gene to phenotypes with neurologic disorders such as Alternating hemiplegia of Childhood or Rapid-onset Dystonia-Parkinsonism from 2012 on, it became apparent, that a remarkable subgroup of patients was suffering from epilepsy. The treatment of seizures is an ongoing and often problematic issue. The aim of the present study was to assess the prevalence and efficacy of the commonly used anti-epileptic-drugs in ATP1A3 patients.

Study Design: To gather a cohort for our investigation, we combined data of own patients with the results of a literature research in PubMed. Mandatory inclusion criteria were 1) a verified mutation within ATP1A3, 2) an epileptic phenotype and 3) information about the response to AED treatment. If available, additional clinical information (e.g. MRI, EEG) was collected, too. The acquired data were checked for plausibility and completeness and were entered in a database.

Results: The literature review yielded in 188 epileptic ATP1A3 patients published since 2012. 14 of them provided information about anti-epileptic treatment. Combined with our own six patients with pathogenic ATP1A3 variants identified by Next Generation Sequencing, a sample size of 20 patients could be reached. The most used antiepileptic drugs (AED) were levetiracetam (n = 8), phenobarbital (n = 8), valproic acid (n = 7) and topiramate (n = 5). Seizure reduction was declared in 55% of the patients. However, most of the authors hardly specified the degree of seizure reduction. For none of the individual AEDs used (either alone or in combination) success rate exceeded 50% and there was not a special AED performing remarkably better than the rest. Ketogenic diet proved effective in 2/4 patients. 45% of the patients (n = 10) did not show any seizure relief.

Discussion: The most surprising finding was the fact that even though epilepsy tends to be a significant clinical issue in ATP1A3 patients, only a minority of case publications (7.4%) provided any information about the patients’ anti-epileptic treatment. Another problem was the missing specification of the seizure reduction in cases that actually mentioned therapy. Here, an orientation to an overall binding standard could help to make case reports more transparent and results comparable. Apart from that, both, the finding of treatment effectiveness in only 55% (or even lower) and the non-existence of a clear first choice AED in ATP1A3 related epilepsy stress the need for further research.

No conflict of interest has been declared by the author(s).