ATP1A3: Uncommon and wavering epilepsy phenotype in a rare variant

ATP1A3 encodes the Na+/K+‐ ATPase α3 catalytic subunit, selectively expressed in the central nervous system. ¹ Pathogenic variants cause a wide spectrum of neurological syndromes, including alternating hemiplegia of childhood, rapid‐onset dystonia–parkinsonism, early infantile epileptic encephalopathy, fever‐induced paroxysmal weakness and encephalopathy, recurrent cerebellar ataxia, CAPOS syndrome, early “profound” epileptic encephalopathy with polymicrogyria. ² Epilepsy associated with ATP1A3 is highly heterogeneous and often poorly responsive to antiseizure medications. ² , ³ We describe a child with the rare p.Pro775Leu variant showing a dynamic, progressive epilepsy with evolving clinical and electroencephalographic patterns, emphasizing the need for longitudinal monitoring and adaptable treatment strategies.

The proband is a 5‐year‐3‐month‐old male with an unremarkable perinatal and family history, carrying a pathogenic heterozygous ATP1A3 variant (NM_152296.5 c. 2324C>T, p.Pro775Leu).

Global developmental delay was apparent from early infancy: head control was achieved at 7 months, independent sitting five months later.

At 12 months, he developed a first prolonged left‐hemiclonic febrile seizure. Valproate (20 mg/kg/day) was introduced six months later for recurring febrile and afebrile events, with only partial efficacy. By 30 months, he could crawl only with support. Neurological examination revealed axial hypotonia and distal limb spasticity. EEG showed isolated right posterior sharp wave in sleep (Supporting Information). Brain MRI showed a thin splenium of the corpus callosum, and cognitive assessment (Bayley‐III) revealed moderate‐to‐severe impairment. Levetiracetam was added, yet despite titration to 30 mg/kg/day, seizures persisted—now featuring impaired consciousness, left head and eye deviation, sialorrhea, vomiting, and diaphoresis, with progression to bilateral tonic–clonic events.

At age 3, examination disclosed spastic paraparesis with axial hypotonia and appendicular dystonic–dyskinetic movements; trunk control during sitting remained limited, and crawling required support. EEG demonstrated sub‐continuous 2–2.5 Hz anterior spike‐and‐wave discharges (Supporting Information). Levetiracetam was replaced by ethosuximide (20 mg/kg/day), which brought meaningful EEG improvement and seizure freedom sustained over two years. At age 5, the neurological picture was largely unchanged, but prolonged focal hemiclonic seizures recurred alongside a marked increase in epileptiform discharges over the posterior vertex and centro‐parietal regions, which became near‐continuous during sleep (Supporting Information). Given ethosuximide's theoretical limitations for focal seizures, it was discontinued in favor of perampanel (4 mg/day) and nitrazepam (2.5 mg/day); both were withdrawn within the year due to excessive drowsiness and hypotonia. Cannabidiol was then initiated at 5 mg/kg twice daily. Within three months, focal motor seizures ceased – though motor skills declined further, with loss of crawling. EEG continued to show synchronous and asynchronous epileptiform discharges over the posterior and sagittal/parasagittal regions, significantly activated by sleep (Supporting Information), and also captured atypical absence seizures (Video 1), retrospectively recognized by caregivers. Despite worsening motor autonomy, quality of life improved in the Impact domain of the Epi‐Ped‐EM scale (64.4 vs. 53.3), ⁴ reflecting the meaningful reduction in daily seizure burden.

VIDEO 1.

Download video file ^{(5.9MB, mp4)}

Atypical absence seizure recorded during video‐EEG monitoring (10–20 International System; time constant 1 Hz; low‐pass filter 70 Hz; sensitivity 200 μV/cm). The ictal EEG shows generalized slow spike‐and‐wave discharges with frontal predominance at approximately 2.5–3 Hz, with gradual onset and termination, temporally associated with progressive impairment of awareness and psychomotor arrest. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/epd2.70263.

Variants in ATP1A3 give rise to a wide spectrum of neurological disorders, most commonly characterized by paroxysmal manifestations, although more static or progressive phenotypes may also occur. Recurrent variants mostly promote paroxysmal movement disorders or less often developmental and epileptic encephalopathies possibly associated with malformations of cortical development. ² The rare p.P775L variant has been reported in only nine patients to date. These individuals typically exhibit a phenotype characterized by progressive spasticity and intellectual disability, and lack non‐epileptic paroxysmal episodes, consistent with our observations. ⁵ Seizures have been described in only 3 of these 9 patients, as febrile and afebrile tonic–clonic seizures with an apparently favorable long‐term outcome. ²

In contrast, our patient displayed a markedly aggressive and waxing‐and‐waning course. Despite multiple therapeutic strategies, seizure control fluctuated. Eventually, cannabidiol interrupted focal motor seizures and partially ameliorated quality of life, as formerly reported in epileptic encephalopathies. ⁶ This benefit represents a meaningful clinical improvement that complements seizure management. However, insidious atypical absence seizures emerged—a finding reported in only three patients with ATP1A3‐related disorders and in none with the p.P775L variant. ⁵ , ⁷

Our experience suggests that electroclinical features in ATP1A3‐related disorders may evolve dynamically over time. We recommend careful monitoring for subtle absence seizures and for sleep‐activated epileptiform discharges. Recognizing these features is essential and supports the need for longitudinal surveillance and an adaptive therapeutic approach.

AUTHOR CONTRIBUTIONS

Conceptualization, D.C., G.V., E.B.; methodology, E.B.; data curation, E.B. and G.V.; writings – original draft preparation, D.C., G.V., E.B; writing – review and editing, G.V., R.S., E.B. All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no other conflict of interest to disclose.

PATIENT CONSENT

Written informed consent was obtained from the patient's parents for the publication of this clinical vignette.

Test yourself.

1. Which pathophysiological mechanism is considered most relevant in encephalopathies associated with ATP1A3 mutations?

   1. Altered myelination secondary to oligodendrocyte dysfunction
   2. Dysfunction of the neuronal Na⁺/K⁺‐ATPase pump with impairment of excitability and ionic homeostasis
   3. Primary defect of synaptic GABAergic transmission
   4. Mitochondrial respiratory chain failure leading to cerebral energy depletion
   5. Immune‐mediated neuronal injury triggered by autoantibody production
2. What characteristics do epileptic seizures show in ATP1A3‐related disorders?

   1. Late‐onset focal seizures with good pharmacological response
   2. Marked semiological homogeneity of seizures
   3. Early onset with high clinical variability and variable therapeutic response
   4. Exclusively generalized tonic–clonic seizures with spontaneous remission
   5. Reflex seizures triggered specifically by sensory stimuli
3. Which of the following statements is most consistent with current knowledge about the p.Pro775Leu variant?

   1. Epileptic seizures are always the predominant clinical feature
   2. Spastic paraparesis and intellectual disability are central features, while epilepsy is variable
   3. The clinical picture is always stable over time and shows no electroclinical evolution
   4. The phenotype is limited to episodic neurological symptoms without chronic deficits
   5. The variant is consistently associated with normal neurodevelopment and absence of motor impairment

Answers may be found in the supporting information .

Supporting information

Data S1.

Appendix S2.

Data S2.

Camussi D, Vega G, Scalise R, Bartolini E. ATP1A3: Uncommon and wavering epilepsy phenotype in a rare variant. Epileptic Disord. 2026;28:1319–1322. 10.1002/epd2.70263

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.