GRIN1-related epilepsy in a neonate with response to memantine and vigabatrin

Abstract

Objective

A newborn with GRIN1-related early infantile developmental and epileptic encephalopathy (DEE) with striking pharmacoresistance is described with emphasis on potential therapy with memantine and vigabatrin.

Methods

The term neonate manifested electrographic and electroclinical seizures from the first day of life with focal tonic seizures with apnea, bradycardia, and desaturations and later developed epileptic spasms and a hyperkinetic movement disorder. Multiple antiseizure medication trials were unsuccessful. Brain magnetic resonance imaging displayed extensive malformations of cortical development.

Results

Whole-exome sequencing demonstrated a de novo novel GRIN1 variant (1916T > G,p.Phe639Cys), which can be associated with NMDA receptor dysfunction. Gain-of-function mutation was suspected based on phenotype correlation. Seizures markedly improved after initiation of memantine, an NMDA-receptor antagonist. Memantine was complemented by the concurrent use of vigabatrin, initiated 4 days earlier due to emergence of epileptic spasms. Significant reduction in seizures facilitated discharge from neonatal intensive care unit.

Interpretation

GRIN1-related disorders occur due to NMDA receptor dysfunction. Patients with gain-of-function GRIN1 mutations who present with the phenotype of DEE with extensive bilateral polymicrogyria may benefit from a trial of NMDA-receptor antagonist therapy and vigabatrin. Further research is warranted to better understand this markedly pharmacoresistant condition and to investigate targeted therapies in GRIN1 DEE.