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.

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

“…Mutations in GRIN2A have been found in a significant subset of patients with epilepsy-aphasia syndromes, comprising a phenotypic spectrum from atypical benign partial epilepsy to EEs with continuous spikes and waves during slow-wave sleep and LandauKleffner syndrome [Carvill et al, 2013b;Lemke et al, 2013;Lesca et al, 2013]. Furthermore, a few cases with severe early-onset EEs and severe ID as seen in the present case have been reported [Pierson et al, 2014]. The identified variant p.Asn614Ser is positioned directly at the tip of the re-entrant pore loop of GluN2A.…”

“…Variants of this domain have been shown to result in a significant loss of the Mg 2+ block resulting in a marked gain of channel function and severe neurodevelopmental delay [Endele et al, 2010]. Pierson et al [2014] recently reported that treatment with an NMDA receptor blocker, memantine, in a patient with intractable epilepsy and ID due to a GRIN2A gain-of-function mutation resulted in marked reduction of seizure frequency. However, the efficacy of memantine in patients with GRIN2A gain-of-function mutations remains to be confirmed in clinical trials.…”

Current Status of Treatments for Children with Electrical Status in Slow-Wave Sleep (ESES/CSWS)

“…Recently, GRIN2A mutations were found in a subset of patients. GRIN2A is involved in neural development and cell adhesion (7)/ Memantine, an (NMDA) receptor antagonist has been reported to improve seizures and CSWS (8).…”

Phenotypic Spectrum and Severity of Disease Depending on the Mutated Protein Domain of NMDA Receptor-Encoding Genes

“…The authors predict that individuals with developmental and epileptic encephalopathy due to misTMD+Linker SNVs are prone to having an underlying gain of NMDAR function. These patients represent promising candidates for treatment with NMDAR blockers, such as memantine [Pierson et al, 2014]. Conversely, patients with SNVs leading to complete or partial loss of channel function (misATD+LBD or null variants) may potentially respond to positive allosteric modulators of the NMDAR [Zhu and Paoletti, 2015;Addis et al, 2017].…”