Annals of the Child Neurology Society · 2024
GRIN1-related epilepsy in a neonate with response to memantine and vigabatrin.
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Eiler Isabella, Reecher Hope M, Carlton Katherine, Cabacungan Erwin, Cohen Susan, Adams Samuel, Jozwik Jenna, Singh Avantika
Аннотация
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.
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.