Abstracts

Rationale: Mutations in the GATOR1 complex genes (NPRL2, NPRL3, and DEPDC5) account for approximately 10% of focal epilepsy cases in the general population (Baldassari et al. J Med Genet 2016; 53:503-510). NPRL3-related epilepsy is an autosomal dominant disease with variable penetrance that is prevalent in the Old Order Mennonite Population of North America with an incident rate of 1.7%.  A better understanding of the phenotypic spectrum of NPRL3-related epilepsy is necessary in order to provide robust historical control data for future disease modifying therapy trials. Methods: We used medical records and structured interviews to collect retrospective data on 50 of 60 NPRL3 c.349delG mutation heterozygotes from the Mennonite community identified at the Clinic for Special Children between 2016 and 2018. Results: Only 43% of NPRL3 mutation heterozygotes had seizures.  Of those with seizures, the median age of onset was 6 years and ranged from 1 day to 37 years.  The peak seizure frequency ranged from 0.1 to 100 seizures per day with median of 10 seizures per day. Seizure type based on semiology was 48% focal, 9% generalized, and 43% mixed focal and generalized seizures.  Infantile spasms and status epilepticus occurred in 9% of subjects.  5% of subjects had only febrile seizure. 86% of subjects were treated with medications alone, and carbamazepine was the most widely used medication. 14% of subjects were treated with epilepsy surgery, vagal nerve stimulator, and/or ketogenic diet. MRI findings were reviewed and correlated to seizure phenotype, with abnormalities ranging from focal cortical dysplasia to hemimegalencephaly. Conclusions: To date, this is the largest natural history study of NPRL3-related epilepsy.  Understanding the phenotypic variability of NPRL3 mutation heterozygotes is necessary in order to assess the efficacy of future treatments. In addition, this study lays the foundation for discovery of biomarkers that segregate with disease phenotype. Funding: None