Rationale:
The ATP1A3 gene, located on chromosome 19q13.2, comprises 23 exons and encodes the α3 subunit of the Na⁺/K⁺-ATPase, a 1013-amino acid membrane-bound ATP-dependent ion transporter predominantly expressed in neurons. This pump plays a pivotal role in maintaining neuronal excitability and electrochemical gradients across the plasma membrane. Pathogenic variants in ATP1A3 have been increasingly implicated in a spectrum of neurological disorders, including epilepsy, Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia-Parkinsonism (RDP), and CAPOS syndrome.
Methods:
In this study, we describe five patients with distinct epilepsy phenotypes, ranging from febrile seizures to drug-resistant epilepsy, all harboring heterozygous missense variants in ATP1A3: c.1022T >A (p.Met341Lys), c.1829G >A (p.Arg610His), chr19:42474634G >A (p.Pro788Leu), c.2443G >A (p.Glu815Lys), and c.2482G >A (p.Glu828Lys). Two of the variants were confirmed to be de novo. Notably, 4 of 5 patients also presented with comorbidities involving psychiatric, orthopedic, or ophthalmologic domains.
Results:
From a genotype–phenotype perspective, two patients exhibited alternating hemiplegia , although missense mutation was found in proximity, the mutation leading to p.Glu815Lys which involves TM6 transmembrane domain had global developmental delay and treatment resistent epilepsy, while the mutation in p.Glu828Lys which located near TM6 had epilepsy manged with monotheraphy and mild cognitive decline. more over, patient with drug-resistant epilepsy also carried a TM6-region mutation (p.Pro788Leu), while a patient with a TM3-region mutation was well managed on monotherapy without multisystem involvement.
Conclusions:
Our findings underscore the heterogeneity of ATP1A3-related epilepsy and highlight the importance of regional mutation impact within transmembrane domains, particularly TM6.
Despite phenotypic variability, most ATP1A3-associated epilepsies appear responsive to treatment, reinforcing the need for early recognition and tailored therapeutic strategies.
Funding: no