GRIN2A Variant in A 3-Year-Old—An Expanding Spectrum?

Ioana Gheța,Daniel Mihai Teleanu,Eugenia Roza,Oana Vladacenco,Raluca Ioana Teleanu,Evelina Carapancea

doi:10.3390/neurolint13020018

Abstract

Glutamate, the major excitatory neurotransmitter, plays a ubiquitous role in most aspects of normal brain functioning. Its indispensable position is paradoxically doubled by a high excitotoxic potential following disruption of its dynamic equilibrium. Several lines of evidence have suggested the involvement of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) in learning, memory formation, and human cognition. Furthermore, NMDARs play a pivotal role in various neuropsychiatric disorders, recently being identified as an important locus for disease-associated genomic variation. The GRIN2A gene encodes the NMDAR’s GluN2A subunit. Genetic alterations of GRIN2A result in phenotypic pleiotropy, predisposing to a broad range of epilepsy syndromes, with an elusive and unpredictable evolution and response to treatment. The archetypal GRIN2A-related phenotype comprises the idiopathic focal epilepsies (IFEs), with a higher incidence of GRIN2A mutants among entities at the more severe end of the spectrum. We report the case of a patient heterozygous for GRIN2A, c.1081C>T, presenting with febrile convulsions and later superimposed atonic seizures, expressive language delay, and macrocephaly. As the number of reported GRIN2A variants is continuously increasing, the phenotypic boundaries gradually grow faint. Therefore, it is fundamental to maintain an acute critical awareness of the possible genetic etiology of different epilepsy syndromes. So far, therapeutic strategies rely on empirical observations relating genotypes to specific drugs, but the overall success of treatment remains unpredictable. Deciphering the functional consequences of individual GRIN2A variants could lead to the development of precision therapeutic approaches for patients carrying NMDAR mutations.

Highlights

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated cation channels activated by the “Jekyll and Hyde” molecule, glutamate, and co-agonist glycine
The characteristics of NMDAR-mediated synaptic transmission are dramatically altered during early postnatal development, which is consistent with a developmental change in the composition of the receptors from predominantly GluN1/GluN2B to GluN1/GluN2A
Correlating epileptic phenotype to genotype proves to be difficult in the context of polygenic interactions and multiple environmental and epigenetic factors involved in the expression of seizures

Summary

Introduction

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated cation channels activated by the “Jekyll and Hyde” molecule, glutamate, and co-agonist glycine They display a heterotetrameric structure, composed of two glycine-binding obligatory GluN1 subunits and two glutamate-binding regulatory subunits of either GluN2 or GluN3 type, expressed in several isoforms (GluN2A–D and GluN3A–B). These different subunits provide the central nervous system with a means of controlling NMDAR properties as a function of the brain region and developmental period. GRIN2A variants have been associated with a broad phenotypic spectrum, the canonical related presentation consisting of speech disorders and epilepsy syndromes. We report one clinical case that we encountered in our practice

Case Report

Discussion

Conclusions