Abstracts

Rationale: The SCN8A gene encodes a voltage-gated sodium channel involved in action potential generation. Mutations result in various neurodevelopmental disorders, including epilepsy. There is an established SCN8A patient registry using data entered by caregivers (SCN8A.net, Michael Hammer) that has already yielded important information, but no large natural history study performed to date. Natural history studies are a critical component in understanding disease pathophysiology and informing drug development. We endeavored to evaluate a cohort of patients diagnosed with epilepsy due to mutations in SCN8Ain a multi-disciplinary clinic, incorporating an epileptologist, physiatrist, movement disorder specialist, speech and language pathologist, cardiologist, and neuropsychology at Children's National Health System (CNHS). Methods: We recruited patients with epilepsy due to mutations in SCN8A at CNHS, through family organizations, or SCN8A.net. Study procedures included medical record review, review of EEG and MRI data when available, clinical evaluation, specialized echocardiogram, EKG, and administration of the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Comprehensive Parent/Caregiver Form. Results: Twelve patients with epilepsy and known or suspected mutations in SCN8A completed the study. Median age was 6 years (range 2-19 years). Four subjects were female. Known or likely pathogenic mutations were present in 8 patients; 4 had variants of unknown significance (VUS). One VUS, R1904C, was found to be paternally inherited. Another VUS was de novo, and one parent was unavailable for testing for the other two VUS.  Seizure onset was 1 day to 4 years old (median age 4 months). Current epilepsy type is variable, comprising 5 with generalized motor epilepsies, 4 focal or mutifocal, 2 atypical absence, and 1 unknown. Five have a history of status epilepticus. No patients had a history of infantile spasms. Eight were administered anti-seizure medications that target the voltage-gated sodium channel at the time of evaluation. Three had seizures completely controlled for at least 6 months on oxcarbazepine and lamotrigine alone or in combination. Three had worsening in seizures on levetiracetam, while one was currently administered levetiracetam. Neuroimaging was typically normal. Initial EEG was also reported as normal in the 5/10 in whom the report was available. One child had typical development. Developmental delay was evident in 11. Parent-rated abilities were widely variable, ranging from the average to severely impaired range (Vineland-3 Communication Standard Score [SS] range 20-98,mean SS=48; Daily Living Skills range 20-95, mean 56; Socialization range 23-101, mean 65; Motor Skills range 20-100, mean 58; Adaptive Behavior Composite range 21-97, mean 58). Two with a mild epilepsy phenotype where seizures were controlled with medications (one N1877S and one L257V) had the highest Vineland-3 scores. However, another with the N1877S mutation and controlled seizures had SS in the moderate to borderline deficient function. Conclusions: This is the first report of a large series of patients with epilepsy due to mutations in SCN8A evaluated in a single multi-disciplinary clinic. Epilepsy phenotypes are variable, with both focal/ multifocal and generalized epilepsies. Response to medication and development also vary widely, and may correspond to the specific mutation, to some degree. This study establishes the basis for a larger natural history study of epilepsy due to mutations in SCN8A, a critical step in establishing more effective treatments. Funding: This clinic was supported financially by Motivated for Mav and Wishes for Elliot, with additional logistical support from The Cute Syndrome Foundation.