Explosive onset focal epilepsies without cortical malformation: A review of a pediatric cohort with pathogenic variations in the GATOR1 complex (DEPDC5, NPRL3 and NPRL2)

Abstract

GATOR1 complex genes (DEPDC5, NPRL2, NPRL3) are associated with focal epilepsies, often without cortical malformations or intellectual disabilities. Our study focused on 10 children, with GATOR1 pathogenic variation and negative MRIs, all experiencing focal epilepsy onset between ages 1 and 7 years. Three were initially misdiagnosed with immune encephalitis, with seizure frequencies ranging from 2 per week to 40 per day. The seizures were monofocal and stereotyped in the same child. No recurrent brain localization was found in EEG, clinical data, or MRI. After achieving early developmental milestones, some patients developed cognitive or psychiatric challenges during active seizures. Over 1 to 14 years, three experienced recurrent status epilepticus, triggered by infections or medication changes. Currently, two patients are seizure-free on antiepileptic medications, while six continue to have frequent seizures. Notably, only half showed concordance between EEG and PET scan anomalies. Pathogenic variations included five in DEPDC5, four in NPRL3, and one in NPRL2, with six inherited from parents 3 of them being unaffected. The timeline for genetic analysis requests has significantly shortened over time. In cases of pharmacoresistant monofocal epilepsy with normal MRIs, in children with normal development-especially with a family history-testing for GATOR1 variations should be prioritized.

Keywords: Depdc5; GATOR1; Genetic epilepsies; Immune encephalitis; Mtor pathway.