PP01.4 – 2720: Novel mutation in GRIN1 gene expressed as neonatal-onset drug-resistant epilepsy associated with microcephaly and polymicrogyria

Abstract

Objective A male infant with severe psychomotor retardation, congenital progressive microcephaly who presented in the first week of life with intractable neonatal seizures underwent genetic analysis. Brain MRI showed migration and sulcation disorder of the gray matter associated with bilateral fronto-parietal and temporal polymicrogyria. Genes mutations associated with abnormal cortical migration (such as CDX, LIS1, ARX, TUBBB1A, TUBB2A, TUBB2B, WDR62 and GPR56) were not detected. Methods Whole exome sequencing was employed and revealed 20,149 changes. Analysis of these mutations, filtration of nonspecific mutations and separation of alterations that were not present in the DNA samples of his parents provided us with one heterozygous mutation. Results We detected a novel mutation (c.2365 G> A p. D789N) in the GRIN1 gene. No single nucleotide polymorphisms were found in this region and its probability score was 1.0. The GRIN1 gene encodes the subunit 1 of the N-methyl D-aspartate (NMDA) ionotropic glutamate receptor which has an excitatory effect that may control synaptic plasticity in the central nervous system. Conclusion GRIN1 mutations were previously reported in children with “idiopathic” epilepsy, non-syndromic intellectual disabilities and recently with epileptic encephalopathy (such as infantile spasms) but not with malformations of cortical migration. The present report expands the clinical spectrum of GRIN1-associated neurological disorders, and suggests that early fetal NMDAR-induced exitotoxicity (during the late neuronal migration period) underlies neuronal damage which lead to microcephaly, polymicrogyria and intractable epilepsy.