The identification of this new gain-of-function mutation of Nav1.6 supports the inclusion of SCN8A as a causative gene in infantile epilepsy, demonstrates a novel mechanism for hyperactivity of Nav1.6, and further expands the role of de novo mutations in severe epilepsy.
Because the clinical phenotype associated with SCN8A mutations has previously been identified only in a few patients with or without epileptic seizures, these data together with our results suggest that mutations in SCN8A can lead to early infantile epileptic encephalopathy with a broad phenotypic spectrum.
Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy.
Our results demonstrate that variants in Scn2a, Kcnq2, and Scn8a can dramatically influence the phenotype of mice carrying the Scn1a-R1648H mutation and suggest that ion channel variants may contribute to the clinical variation seen in patients with monogenic epilepsy.
A small number of mutations have been found in SCN2A, SCN3A and SCN9A, and studies in the mouse suggest that SCN8A may also contribute to seizure disorders.
Mutations in SCN8A are associated with cognitive deficits and neuropsychiatric illness in humans and movement disorders in mice; however, a role for SCN8A (Na(v)1.6) in epilepsy has not been investigated.
Additionally, the downregulation of NR2B, p‑NR1 and p‑GluR1 in the miR‑34c agomir group demonstrated that miR‑34c may serve a negative role in cognitive function in epileptic seizures, by dysregulating NMDA and α-amino-3-hydroxy-5‑methyl‑4‑isoxazolepropionic acid receptors, which are associated with long‑term potentiation.
Our results suggest that the anti-GluN2B and anti-GluD2 antibodies may be associated with myoclonic atonic epileptic seizures and chronic cerebellitis.
Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function.
In this report, we provide a detailed clinical description of a sporadic male patient with early-onset epilepsy and epileptic encephalopathy in whom we performed complete exome sequencing (WES) and identified a GRIN2B mutation.
Tonic facilitation of glutamate release by presynaptic NR2B-containing NMDA receptors is increased in the entorhinal cortex of chronically epileptic rats.
We used coimmunoprecipitation and immunoblotting techniques to quantify and compare the numbers of coassembled PSD-95 with NR2B, PSD-95 with NR1, and NR2B with NR1 in the membrane proteins of brain tissues resected from four patients (aged 3.5, 6, 14, and 18 years) with medically intractable neocortical epilepsy associated with CD.
Further, for NF-κB p65, MDR1, P-gp and apoptosis-associated protein levels detection, miR-542-3p mimic showed a suppressive effect on these KA-induced protein levels, whereas TLR4 overexpression ameliorated the miR-542-3p-induced these protein levels in KA-treated epilepsy rats.
In mice and humans, epilepsy occurs only in heterozygous females who have a mixture of PCDH19 wild-type (WT) and mutant cells caused by random X-inactivation; it does not occur in hemizygous PCDH19 mutant males.
Our data provide key signaling steps underlying seizure-induced P-gp up-regulation and suggest that mPGES-1 inhibitors could potentially prevent P-gp up-regulation in epilepsy.-Soldner, E. L. B., Hartz, A. M. S., Akanuma, S.-I., Pekcec, A., Doods, H., Kryscio, R. J., Hosoya, K.-I., Bauer, B. Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier.
Neuroinflammation due to high levels of glutamate has been identified as one of the causes of P-gp upregulation, and several studies in animal models of epilepsy suggest that antiinflammatory drugs might prevent P-gp overexpression and, thus, avoid the development of refractory epilepsy.