Abstracts

Rationale: Mutation in the ATP1A2 gene has a wide clinical spectrum. Most common presentations are familial hemiplegic migraine, unprovoked ataxia, unprovoked acute onset of encephalopathy and less commonly, febrile or complex febrile seizures.  We describe a patient with a known heterozygous ATP1A2 mutation, with a differing clinical presentation as compared to the described cases. This patient’s specific mutation is:Novel de novo heterozygous 2563 G>A substitution in exon 18 resulting in an amino acid change from glycine to arginine at position 855 in the ATP1A2 FHM2 gene that encodes the a2 subunit of Na⁺, K⁺-ATPase pumps has been described in a family with Familial hemiplegic migraine with febrile seizures, unprovoked episodes of ataxia and rapidly progressive drowsiness without any focal neurologic deficits. The mutation was not identified in 300 control chromosomes. A challenge assay for the mutant p.Gly855Arg construct showed complete loss of cell survival, indicating the mutation has functional consequences. Methods: Case report on a patient who is now a 4-year-old female child with a novel heterozygous mutation of ATP1A2 gene.  Results: After first febrile seizures, she had afebrile seizures, which responded partially to Keppra. She developed acute onset truncal ataxia, thought to be post viral cerebellitis. She was on Keppra and Trileptal at 1 year of age. She had prolonged breakthrough seizures lasting up to 25 minutes. Diagnosis of ATP1A2 mutation was made. Lamictal was added and Trileptal was stopped. She was seizure free for 7 months. Speech delay was noted by 26 months of age with largely normal motor skills. Seizures recurred after 9 months seizure free when Keppra was reduced for insomnia. Lamictal was increased. Two months later she presented in status epilepticus with repetitive seizures. This led to prolonged encephalopathy with dystonia, chorea, and loss of development and oral skills. Diagnostic work up for metabolic, infectious and imaging were unremarkable. She was started on verapamil while hospitalized to bridge to flunarizine.Development improved on flunarizine and she was seizure free for 4 months. She then developed epileptic spasms. Sabril was ineffective. She did not tolerate ketogenic diet due to impaired GI motility and fat intolerance. Despite 70% decrease in spasms within a month, the diet was discontinued. 6 week course of ACTH was added and spasms resolved. Developmental skills improved. She smiled, laughed, walked and was saying more words. Epileptic spasms recurred 3 months later. A repeat 6 week ACTH regimen failed. Oral prednisone and Zonisamide were added. She continued to improve developmentally in all areas despite spasms and new onset of myoclonic seizures.Felbamate was added and Lamictal was stopped which resolved spasms and myoclonic seizures. She remains seizure free after 12 months. Conclusions: This case demonstrates atypical presentation of this genetic mutation with predominant speech delay and epileptic spasms. The stress/corticotropin-releasing hormone (CRH) hypothesis proposes the common mechanism in all of the etiologies of epileptic spasms causes an increase in the release of stress-activated mediators in the brain, especially the neuropeptide CRH in limbic and brainstem regions. It is possible the functional ramification of this mutation also affects the corticotropin releasing hormone pathway directly, leading to epileptic spasms. It is possible stress related to the encephalopathy lead to changes in the CRH pathway. Epileptic spasms would be expected more frequently in the second scenario. It is important to note that patients with ATP1A2 mutation can also present with epileptic spasms, and in an older age group as compared to the common age of less than 2 years. Funding: Not applicable