Targeted Therapy of GRIA1-Related Epilepsy and Intellectual Disability With Perampanel: A Case Report and Literature Review.

Abstract

Objectives: This report details a patient with a GRIA1 pathogenic variant presenting with intellectual disability (ID) and epilepsy. We describe clinical features, genetic findings, a personalized treatment approach, and a literature review of GRIA1-related disorders.

Methods: We describe clinical presentation, neuropsychological assessment, and genetic analysis. We conducted a literature review of published GRIA1-related disorders using PubMed, Simons Foundation Autism Research Initiative (SFARI) Gene, and ClinVar databases.

Results: An 8-year-old girl with ID, focal-to-bilateral tonic clonic seizure since age 5, and later atypical absences was diagnosed with a novel, de novo GRIA1 c.2530T > G, p.Leu844Val pathogenic variant. After genetic diagnosis, she was titrated to 4 mg of perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, which led to seizure control and improvements in cognition and school performance. Literature review identified 31 patients carrying 15 different pathogenic variants. The c.1906G > A, p.Ala636Thr variant was recurrent in 17 individuals. Intellectual disability and autism spectrum disorder were common while epilepsy was reported in approximately a quarter of patients. Two patients with gain-of-function missense variants in GRIA1 and GRIA2, successfully treated with perampanel, have also been reported.

Discussion: This case emphasizes the role of targeted interventions in the management of rare genetic disorders and underscores the potential of precision medicine in addressing GRIA1-related symptoms.