Rationale: Sodium/potassium-transporting ATPase subunit alpha-2 (ATP1A2) is a subunit of the Na/K-ATPase transmembrane protein that plays a critical modulatory role in the electrochemical gradient at neuronal plasma membranes. Heterozygous pathogenic variants in
ATP1A2 have been implicated in several conditions such as familial hemiplegic migraine, alternating hemiplegia of childhood, and even polymicrogyria. Additionally, these conditions may present with or without epilepsy. We report the first novel phenotype with the constellation of focal epilepsy, persistent hemiparesis, and hemispheric cerebral atrophy in a cognitively normal child.
Methods:
We describe a young girl with a novel heterozygous likely pathogenic variant of the ATP1A2 gene (c.835delC). She presented at age two with focal seizures, left-sided hemiparesis and was found to have right-sided hemispheric cerebral atrophy. A comprehensive epilepsy gene panel revealed the molecular diagnosis. We describe seizure semiology, EEG, and MRI findings and subsequent successful treatment of epilepsy with the Modified Atkins Diet.
Results: The patient presented at age two with recurrent seizures and left-sided hemiparesis with onset of seizures at 15 months of age. The semiology of her seizures was described as left-sided focal clonic seizures evolving into bilateral tonic-clonic seizures. She was also found to have hypertonia, hyperreflexia, and hemiparesis on the left. Video EEG revealed abundant pleomorphic right-sided epileptiform discharges and diffuse right-sided slowing. Brain MRI revealed cortical thinning of the right hemisphere with resultant asymmetry. She was initiated on oxcarbazepine therapy although she continued to have monthly breakthrough seizures. Gene sequencing with an epilepsy gene panel revealed a likely pathogenic missense variant in the
ATP1A2 gene.
Non-pharmacologic treatment with the Modified Atkins Diet was started. Patient remained completely seizure free after initiation of dietary therapy and was successfully weaned off of medication. On subsequent visits, she was noted to have normal cognitive development and improving left-sided paresis.
Conclusions:
ATP1A2 related disorders are known to have phenotypic pleiotropy, the spectrum of which includes familial hemiplegic migraine type two, alternating hemiplegia of childhood with/without epilepsy, and cortical brain malformations. Our patient is the first described case in the literature of a novel phenotype associated with focal epilepsy, persistent hemiparesis, and hemispheric cortical atrophy in a cognitively normal child. This further expands the known phenotypic spectrum of
ATP1A2 related disorders. Additionally, we demonstrate a strong therapeutic response when treating the patient's epilepsy with use of the Modified Atkins Diet, implicating this as a possible future direction of treatment for patients with refractory epilepsy and disease causing variants in the
ATP1A2 gene.
Funding: Funding was received from the section of Child Neurology at the University of Chicago Comer Children's Hospital.