GRIA2 Variant Associated With Paradoxical Response to Perampanel Expanding the Spectrum of GRIA2 ‐Related Epileptic Encephalopathy: Case Report and Literature Review
Sai Srihitha Dommata, Chhitij Tiwari, Zheng Fan, Muge Gucsavas‐Calikoglu, Yael Shiloh‐Malawsky, Kimberly S. Foss, Stephanie N. Peck, Erin L. Heinzen, Chon Lee, Senyene E. HunterABSTRACT
Introduction
GRIA2 encodes the GluA2 ionotropic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit. Pathogenic GRIA2 variants cause epilepsy, developmental delay, and neurobehavioral disorders. Characterizations of clinical features, including seizure types and their treatments, in patients with GRIA2 ‐related disorders remain limited.
Methods
We describe a child with a de novo GRIA2 variant causing developmental epileptic encephalopathy and a previously unreported paradoxical response to perampanel. We include a comprehensive literature review of 42 patients with disease‐causing GRIA2 variants.
Results
There are 39 unique GRIA2 variants described across 43 patients. Our patient is the first report of a disease‐causing GRIA2 c.1565C>G (p.Ser522Cys) variant. Of those reported, 40/43 (93%) have global developmental delay, 21/43 (49%) have seizures, and 13/21 (62%) have drug‐resistant epilepsy. Common features include autism spectrum disorder (24/43, 56%), brain atrophy (11/30 with reported imaging, 37%), and behavioral and psychiatric comorbidities (14/43, 33%). Notably, ours is the only patient with paradoxically worsened seizures following perampanel initiation, a non‐competitive AMPA receptor antagonist.
Conclusion
We expand the clinical spectrum of GRIA2 ‐related epileptic encephalopathy and highlight a previously unreported adverse response to perampanel, offering insight into AMPA receptor function, disease pathophysiology, and potential clinical implications. This paradoxical response to an AMPA antagonist underscores the need for further study of GRIA2 ‐related phenotypes and targeted therapies.