Excerpt
Clinical characteristics: GRIN2D-related developmental and epileptic encephalopathy (GRIN2D-related DEE) is characterized by mild-to-profound developmental delay or intellectual disability, epilepsy, abnormal muscle tone (hypotonia and spasticity), movement disorders (dystonia, dyskinesia, chorea), autism spectrum disorder, and cortical visual impairment. Additional findings can include sleep disorders and feeding difficulties. To date 22 individuals with GRIN2D-related DEE have been reported.
Diagnosis/testing: The diagnosis of GRIN2D-related DEE is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) missense variant in GRIN2D identified by molecular genetic testing
Management: Treatment of manifestations: There is no cure for GRIN2D-related DEE. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric neurology, pediatric ophthalmology, developmental pediatrics, feeding, orthopedics, physical medicine and rehabilitation, physical therapy, occupational therapy, and ethics.
Surveillance: In infancy: regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding. For all age groups: routine monitoring of developmental progress, educational needs, and behavioral issues.
Genetic counseling: GRIN2D-related DEE is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the proband represents a simplex case (i.e., the only affected family member) and the GRIN2D pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental mosaicism. Once the GRIN2D pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
XiangWei W, Kannan V, Xu Y, Kosobucki GJ, Schulien AJ, Kusumoto H, Moufawad El Achkar C, Bhattacharya S, Lesca G, Nguyen S, Helbig KL, Cuisset JM, Fenger CD, Marjanovic D, Schuler E, Wu Y, Bao X, Zhang Y, Dirkx N, Schoonjans AS, Syrbe S, Myers SJ, Poduri A, Aizenman E, Traynelis SF, Lemke JR, Yuan H, Jiang Y. Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy. Brain. 2019 Oct 1;142(10):3009-3027. doi: 10.1093/brain/awz232. PMID: 31504254; PMCID: PMC6763743.
Abstract
N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.
Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, Kosobucki GJ, Chen W, Schulien AJ, Chiavacci R, Tankovic A, Naase C, Brueckner F, von Stülpnagel-Steinbeis C, Hu C, Kusumoto H, Hedrich UB, Elsen G, Hörtnagel K, Aizenman E, Lemke JR, Hakonarson H, Traynelis SF, Falk MJ. GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. Am J Hum Genet. 2016 Oct 6;99(4):802-816. doi: 10.1016/j.ajhg.2016.07.013. Epub 2016 Sep 8. PMID: 27616483; PMCID: PMC5065652.
Abstract
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated cation channels that mediate excitatory synaptic transmission. Genetic mutations in multiple NMDAR subunits cause various childhood epilepsy syndromes. Here, we report a de novo recurrent heterozygous missense mutation-c.1999G>A (p.Val667Ile)-in a NMDAR gene previously unrecognized to harbor disease-causing mutations, GRIN2D, identified by exome and candidate panel sequencing in two unrelated children with epileptic encephalopathy. The resulting GluN2D p.Val667Ile exchange occurs in the M3 transmembrane domain involved in channel gating. This gain-of-function mutation increases glutamate and glycine potency by 2-fold, increases channel open probability by 6-fold, and reduces receptor sensitivity to endogenous negative modulators such as extracellular protons. Moreover, this mutation prolongs the deactivation time course after glutamate removal, which controls the synaptic time course. Transfection of cultured neurons with human GRIN2D cDNA harboring c.1999G>A leads to dendritic swelling and neuronal cell death, suggestive of excitotoxicity mediated by NMDAR over-activation. Because both individuals' seizures had proven refractory to conventional antiepileptic medications, the sensitivity of mutant NMDARs to FDA-approved NMDAR antagonists was evaluated. Based on these results, oral memantine was administered to both children, with resulting mild to moderate improvement in seizure burden and development. The older proband subsequently developed refractory status epilepticus, with dramatic electroclinical improvement upon treatment with ketamine and magnesium. Overall, these results suggest that NMDAR antagonists can be useful as adjuvant epilepsy therapy in individuals with GRIN2D gain-of-function mutations. This work further demonstrates the value of functionally evaluating a mutation, enabling mechanistic understanding and therapeutic modeling to realize precision medicine for epilepsy.
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