Dataset Information

GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

ABSTRACT:

Objective

Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband.

Methods

Three modern translational medicine tools were utilized: 1) high-throughput sequencing technology to identify a novel de novo mutation; 2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and 3) screening of existing drug libraries to identify potential therapeutic compounds.

Results

A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden.

Interpretation

This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.

SUBMITTER: Pierson TM

PROVIDER: S-EPMC4019449 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Publications

<i>GRIN2A</i> mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

Pierson Tyler Mark TM Yuan Hongjie H Marsh Eric D ED Fuentes-Fajardo Karin K Adams David R DR Markello Thomas T Golas Gretchen G Simeonov Dimitre R DR Holloman Conisha C Tankovic Anel A Karamchandani Manish M MM Schreiber John M JM Mullikin James C JC Tifft Cynthia J CJ Toro Camilo C Boerkoel Cornelius F CF Traynelis Stephen F SF Gahl William A WA

Annals of clinical and translational neurology 20140301 3

<h4>Objective</h4>Early-onset epileptic encephalopathies have been associated with de <i>novo</i> mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband.<h4>Methods</h4>Three modern translational medicine tools were utilized: 1) high-throughput sequencing technology to identify a novel <i>de novo</i> mutation; 2) <i>in vitro</i> ...[more]

PMID: 24839611

Similar Datasets

Project description:NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.

Dataset Information

GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

Objective

Methods

Results

Interpretation

Publications

<i>GRIN2A</i> mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

Objective

Methods

Results

Interpretation

Publications

&lt;i&gt;GRIN2A&lt;/i&gt; mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

<i>GRIN2A</i> mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.