Abstract
Background
N-methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that mediate excitatory
synaptic transmission and brain development in the central nervous system. Mutations
in GRIN2D encoding the NMDAR subunit GluN2D are associated with a wide spectrum of neurodevelopmental
disorders.
Methods
We report a novel de novo GRIN2D variant (NM_000836.2: c.2024C > T, p.Ala675Val) in an infant with severe developmental
and epileptic encephalopathy. Clinical characteristics and treatment outcomes of patients
with GRIN2D-related developmental and epileptic encephalopathy were summarized by reviewing the
literature.
Results
In silico analysis suggested this p.Ala675Val variant residing in the highly conserved M3 helix
of GluN2D would interfere with channel gating. Therapeutic options including multiple
anticonvulsants, oral corticosteroid therapy, and ketogenic diet failed to achieve
seizure control. Eventually, adjunctive therapy with perampanel led to marked electroclinical
improvement.
Conclusions
Perampanel can be beneficial adjuvant therapy for patients with GRIN2D-related intractable epilepsy. Mechanistic understanding and case-per-se analysis are required to enable more individualized treatment for the patients.
Keywords
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References
- Structure, function, and allosteric modulation of NMDA receptors.J Gen Physiol. 2018; 150: 1081-1105
- Glutamate receptor ion channels: structure, regulation, and function.Pharmacol Rev. 2010; 62: 405-496
- NMDA receptor subunits change after synaptic plasticity induction and learning and memory acquisition.Neural Plast. 2018; 2018: 5093048
- Structure, function, and pharmacology of NMDA receptor channels.Physiol Res. 2014; 63: S191-S203
- Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy.Brain. 2019; 142: 3009-3027
- Gene therapy repairs for the epileptic brain: potential for treatment and future directions.Curr GENE Ther. 2020; 19: 367-375
- GRIN2D variants in three cases of developmental and epileptic encephalopathy.Clin Genet. 2018; 94: 538-547
- GRIN2D recurrent De Novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers.Am J Hum Genet. 2016; 99: 802-816
- Conserved structural and functional control of N-Methyl-d-aspartate receptor gating by transmembrane domain M3.J Biol Chem. 2005; 280: 29708-29716
- Hodgkin–Huxley–Katz Prize Lecture: genetic and pharmacological control of glutamate receptor channel through a highly conserved gating motif.J Physiol. 2020; 598: 3071-3083
- From bedside-to-bench: What disease-associated variants are teaching us about the NMDA receptor.J Physiol. 2021; 599: 397-416
- Structural and functional insights into transmembrane AMPA receptor regulatory protein complexes.J Gen Physiol. 2019; 151: 1347-1356
- Genic intolerance to functional variation and the interpretation of personal genomes.PLoS Genet. 2013; 9: e1003709
- Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice.Brain J Neurol. 2020; 143: 2039-2057
- Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy.J Physiol. 2019; 597: 1691-1704
- A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca2+ permeability.Nat Commun. 2018; 9: 3748
- De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.Hum Mutat. 2019; 40: 2393-2413
- Identification of a novel GRIN2D variant in a neonate with intractable epileptic encephalopathy-a case report.BMC Pediatr. 2021; 21: 5
- Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: hippocampus and cortex.J Comp Neurol. 1998; 390: 75-90
- GluN2D-containing NMDA receptors-mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice.Front Cell Neurosci. 2015; 9: 95
- GRIN2D/GluN2D NMDA receptor: Unique features and its contribution to pediatric developmental and epileptic encephalopathy.Eur J Paediatr Neurol. 2020; 24: 89-99
- The efficacy of perampanel in young children with drug-resistant epilepsy.Seizure. 2020; 75: 82-86
- Perampanel: does it have broad-spectrum potential?.Epilepsia. 2019; 60: 22-36
Article info
Publication history
Published online: December 24, 2022
Accepted:
December 6,
2022
Received in revised form:
November 30,
2022
Received:
October 17,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
