Pierson TM , Yuan H , Marsh ED , Fuentes-Fajardo K , Adams DR , Markello T , Golas G , Simeonov DR , Holloman C , Tankovic A , Karamchandani MM , Schreiber JM , Mullikin JC , PhD for the NISC Comparative Sequencing Program , Tifft CJ , Toro C , Boerkoel CF , Traynelis SF , Gahl WA .

R01 NS036654 NINDS NIH HHS , R37 NS036654 NINDS NIH HHS , Z01 HG000215-05 Intramural NIH HHS

	Figure 1. Proband and neuroimaging. (A) The proband was nondysmorphic. (B–D) MRI of the brain at 9 years of age (B-Axial T1, C-Sagittal T1, D-Axial FLAIR) showed progressive cerebral atrophy and a thin corpus callosum associated with subtle abnormalities of the white matter including hypomyelination of the terminal zones and the temporal lobes.
	FIGURE 2. Genetic and protein changes of GRIN2A and GluN2A. (A) Family pedigree and genotypes reveal a de novo mutation (affected proband is indicated by arrow; parentage was confirmed by SNP array; data not shown). (B) Schematic representation of GluN2A subunit (asterisk notes the position of the L812M mutation). The L812 residue is highly conserved across vertebrate species. (C) A homology model of GluN2A subunit28 built from the GluA2 crystallographic data29 and shown as space fill. The red asterisk in the cartoon depicting the domain arrangement of an individual subunit shows the position of L812M in the linker region between the ligand-binding domain (S2, LBD) and the transmembrane domain (M4).
	Functional analysis of GluN1/GluN2A receptors, GluN1/GluN2A-N615K receptors, and GluN1/GluN2A-L812M receptors. (A) The composite glutamate (in the presence of 100 μmol/L glycine) and (B) glycine (in the presence of 100 μmol/L glutamate) concentration-response curves indicate an increased agonist potency in GluN1/GluN2A-L812M compared to wild-type and GluN1/GluN2A-N615K NMDA receptors. Fitted EC50 values are given in μmol/L in the symbol legend.
	Figure 4. Screening of NMDAR antagonists and personalized therapy. (A) Composite concentration-response curves for memantine inhibition of GluN1/GluN2A-L812M and wild-type current responses to 100 μmol/L glutamate and glycine determined by TEVC recordings from Xenopus oocytes. Memantine inhibits the wild-type and the mutant receptors with IC50 values of 4.6 μmol/L and 12 μmol/L, respectively. (B) Adjunct-AED treatment with memantine reduced seizure frequency. Seizures per week were compared against AED treatment. Lacosamide and rufinamide were fully weaned at weeks 50 and 58, respectively. Memantine was titrated up to its full dosage over weeks 50–55; valproate dosing remained unchanged. The average number of episodes and associated standard deviations over the full course of the study are represented by the labeled dashed lines.25 (C–D) Routine EEG segments before (C) and after (D) memantine treatment. Both demonstrate a poorly organized, diffusely slow background. However, the right frontal-predominant spike-wave discharges recorded in the prememantine EEG were not present in the postmemantine EEG.

Acker, Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators. 2011, Pubmed

Acker, Mechanism for noncompetitive inhibition by novel GluN2C/D N-methyl-D-aspartate receptor subunit-selective modulators. 2011, Pubmed
Akazawa, Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. 1994, Pubmed
Carvill, GRIN2A mutations cause epilepsy-aphasia spectrum disorders. 2013, Pubmed
Chez, Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. 2007, Pubmed
Choi, Glutamate receptors and the induction of excitotoxic neuronal death. 1994, Pubmed
de Ligt, Diagnostic exome sequencing in persons with severe intellectual disability. 2012, Pubmed
Endele, Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. 2010, Pubmed
Erickson, A retrospective study of memantine in children and adolescents with pervasive developmental disorders. 2007, Pubmed
Gahl, The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. 2012, Pubmed
Gahl, The NIH Undiagnosed Diseases Program: lessons learned. 2011, Pubmed
Ghasemi, The NMDA receptor complex as a therapeutic target in epilepsy: a review. 2011, Pubmed
Hamdan, Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. 2011, Pubmed
Hedegaard, Molecular pharmacology of human NMDA receptors. 2012, Pubmed
Küpfer, Pharmacogenetics of dextromethorphan O-demethylation in man. 1986, Pubmed
Lemke, Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. 2013, Pubmed , Xenbase
LePage, Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors. 2005, Pubmed
Lesca, GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. 2013, Pubmed
Lisman, A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. 2006, Pubmed
Monyer, Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. 1994, Pubmed
Pierson, Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. 2012, Pubmed
Pujar, Statistical process control (SPC)--a simple objective method for monitoring seizure frequency and evaluating effectiveness of drug interventions in refractory childhood epilepsy. 2010, Pubmed
Reutlinger, Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region. 2010, Pubmed
Sobolevsky, X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. 2009, Pubmed
Talukder, Specific sites within the ligand-binding domain and ion channel linkers modulate NMDA receptor gating. 2010, Pubmed , Xenbase
Tarabeux, Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. 2011, Pubmed
Traynelis, Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit. 1998, Pubmed , Xenbase
Traynelis, Glutamate receptor ion channels: structure, regulation, and function. 2010, Pubmed
Wollmuth, Adjacent asparagines in the NR2-subunit of the NMDA receptor channel control the voltage-dependent block by extracellular Mg2+. 1998, Pubmed , Xenbase
Yuan, Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. 2014, Pubmed