Patients with Dravet syndrome were treated with varying doses of CBD. During the 48 weeks of treatment, monthly total seizure frequency reduced by 51%. After the 48 weeks of treatment, 85% of patients/caregivers reported improvement of the patient’s overall condition. Common adverse effects included diarrhea, pyrexia (fever), decreased appetite, and somnolence (strong desire to sleep).
We can obtain quantitative data of the expression of the sodium channel Nav 1.6 by choosing a certain protein sequence (DSLFPIR) and monitoring the amount of it being made by using multiple reaction monitoring (MRM), which measures concentrations of proteins in plasma. In the three types of mice studied, the wild type(+/+) and heterozygous mutant(D/+) had the same amount of expression, whereas the mutant null (+/-) had only 50% of this amount of expression of Nav 1.6.
SCN8A has a spectrum of phenotypes, a case of a seizures with an unclear origin has expanded the spectrum. The 14-month-old girl was originally diagnosed with episodes of reflex-anoxic seizures (non-epileptic) and breath-holding spells after cessation of crying. The girl was discovered to have a de novo mutation in the SCN8A gene, and a video-EEG suggests she was experiencing generalized seizures. She now takes a mixture of phenobarbital, levetiracetam, and oxcarbazepine, where the addition of oxcarbazepine caused a drastic reduction in episodes then an open-ended seizure-free period.
The activation of the R1872W, an SCN8A mutation, by several different factors was tested on mice. EIIa-Cre and Nestin-Cre resulted in early onset seizures and death, Emx1-Cre lengthened the life span of the mouse, while Gad2-Cre and D1x5/6-Cre did not induce seizures. These test show that lifelong treatments will be required for successful therapy.
Stem cell-derived GABAergic progenitor cells where introduced into the hippocampus in an animal model with early temporal lobe epilepsy. The model showed a suppression of seizures as well as an improvement in cognitive and mood function. In the future, with more research, this could be applied to patients.
An international study triples the amount of genetic associations for epilepsy that are currently known. Many anti-epileptic drugs in use target one or several of the genes that were found to be associated. With these new findings better seizure control will be able to be provided for patients.
Lennox-Gastaut syndrome patients were treated with low doses of ZX008 (fenfluramine HCl oral solution). Convulsive seizures in these patients reduced by more than 50% after 20 weeks of treatment. The adverse events of this treatment were decreased appetite and decreased alertness, however there are no signs of cardiac valvopathy or pulmonary hypertension.
A systematic literature review was conducted in October 2017 looking at evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. This included 6 randomized controlled trials (RCT) and 30 observational studies. Data suggests that cannabinoids may be an effective adjuvant treatment for reducing seizure frequency.
This paper is a review of nine published literature on the efficacy of vitamin D intervention on bone health in adults with epilepsy. While there did appear to be positive changes in bone turnover markers, the varying methodologies used in each study made the impact of vitamin D on bone mineralization inconclusive.
Using next generation sequencing, 74 patients with early-onset epilepsy were assessed with a panel that included 172 genes. The panel identified 28 patients with genetic abnormalities, one of them being an SCN8A mutation (p.Cys261Phe).
Due to missing codes in the International Classification of Diseases (ICD) system identification of rare epilepsy syndromes can be difficult. This group surveyed parent advocates, providers, and caregivers and found that emerging rare epilepsies, like SCN8A, were underrepresented. This illustrates the need for medical vocabularies to fill the gaps in representation of these rare epilepsies.
The sodium channels Nav1.2 and Nav1.6 are vitally important for the control of febrile seizures. When Nav1.2 is knocked out it is perinatal lethal in mice. A Nav1.6 knockout leads to a higher susceptibility to febrile seizures and lowers the temperature needed to induce the seizure.
The cause of developmental and epileptic encephalopathies is unknown in a majority of cases. The authors performed whole-genome sequencing in 197 individuals and performed meta-analysis to document de novo mutations in certain candidate genes.
While sodium channels are known to influence neuronal excitability, the exact role of each subtype is unclear. Johnson et al. investigated three main sodium channel subtypes (Nav 1.1, 1.2, and 1.6) and found selective pre- and postsynaptic expression of voltage-gated sodium channels in glutamatergic synapses.
Diagnostic exome sequencing identified a novel inherited mutation (p.Gly1476Asp) in the SCN8A gene. The paper reports the case of an infant and father with this mutation who had early onset benign familial infantile epilepsy but no cognitive impairment.
In this case study, a de novo mutation was reported in an EOEE patient who died from SUDEP. The data found help strengthen the association between SCN8A and EOEE and urge the screening for this mutation for early prevention of SUDEP.
Exome sequence data from 54 epilepsy patients and their unaffected parents to help identify the molecular diagnoses that were not initially provided. In the 54 trios, two de novo missense variants in SCN8A in the alternative exon 5A. This helps expand the range of SCN8A variants in epileptic encephalopathy.
A case-controlled study of patients ranging from 5-18 years old was completed to investigate the effects of antiepileptic drugs on bone development in young people. Researchers found that that those taking antiepileptic drugs had an increased prevalence of fractures, with the distal radius being the most common fracture site in this study.
It has been shown that cannabidiol (CBD) can alleviate certain epilepsies, however its pharmacological profile is unknown. The authors tested whether the anticonvulsant effects of CBD would be prevented by cannabinoid and vanilloid receptor blockers to help determine its pharmacological profile.
Action potentials initiate at the axon initial segment and influence action potential waveform, firing pattern, and rate. Motor function and behavior depend on the firing of substantia nigra pars compacta dopaminergic neurons, and so the axon initial segment of these neurons were characterized in the mouse. 1.6
The ketogenic diet has shown to be successful in reducing seizures in pharmaco-resistant epilepsy patients, however it is highly unpalatable and difficult to follow. A new diet which combines medium-chain fatty acids, polyunsaturated fatty acid, low glycemic index carbohydrates, and a high BCAA/AAA ratio has shown to reduce excitatory drive and produce results similar to the ketogenic diet.
Effects of the N1768D mutation on the neurons within the medial entorhinal cortex (mEC) were studied in this paper. mEC neurons are known to provide excitatory input to the dentate gyrus and hippocampus and are known to elevate the circuit excitability in animal models with temporal lobe epilepsy. It was found that unlike hippocampal or neocortical neurons, the mEC neurons are hyperexcitable and this increase in excitability precedes the onset of seizures by more than one month.
While it is unknown whether SCN8A mutations can lead to skeletal complications, there have been reports of children with SCN8A mutations who also suffer from skeletal fractures. Researchers analyzed skeletal phenotypes of 2-week-old SCN8A-null mice and revealed there was reduced bone mass as compared to control littermates.
Two SCN8A missense mutations (p.Gly964Arg and p.Glu1218Lys) were examined in this paper that present with intellectual disability and developmental delay but no seizures. Both these mutations completely prevented the generation of sodium currents within transfected cell lines. These observations extend the established phenotypic spectrum of SCN8A.
Carbamazapine and oxcarbazepine are some of the common choices for the treatment of focal epilepsy. One of the common side-effects from using these drugs is hyponatremia (low sodium levels in the blood). This study collected sodium blood levels of adults taking these drugs and looked at the prevalence for hyponatremia within this cohort.
A case report of a 5-year old boy with an SCN8A mutation (p.Val233Ile) is presented here. Initial treatment of the boy consisted of valproic acid and phenobarbital which granted seizure freedom for 1 year. After this status epilepticus events occurred once every 2-3 months so phenobarbital was switched out and other drugs were used as part of the child's drug therapy. Ketogenic diet, levetiracetam, zonisamide, and topiramate therapy all led to rapid deterioration. Phenytoin was found to be a reasonable rescue medication, but as a maintenance drug was found to cause severe side effects.
A cohort of 31 patients with severe infantile epileptic encephalopathy with seizure onset prior to 24 month was investigated in this paper. Next-generation sequencing was used for 430 epilepsy-associated genes to identify pathogenic variants in this cohort. One patient reported an SCN8A mutation (p.Arg1617Gln) with moderate intellectual disability and developmental regression.
The expression and distribution of Nav1.6 in rats in a stroke-like model was examined in this paper. The expression of Nav1.6 mRNA levels was decreased in these rats during the acute phase after reperfusion. Interestingly, the number of Nav1.6 positive cells was dramatically increased at 6 hours, and then decreased at 12 and 24 hours.
This article outlines recent findings in a variety of genetic mutations related to epilepsy, including SCN8A. It summarizes how precision medicine and gene discovery are facilitating rapid progress in the classification of epilepsy, as well as development of medications targeted toward patients with these specific genetic mutations.
Recent experimentation through mouse models suggests that a N1768D mutation in SCN8A results in hyperexcitability and an elevated persistent sodium current in hippocampal neurons. This data suggests that SCN8A plays a role in neural excitability, which could explain the mechanism through which early infantile epileptic encephalopathy (EIEE) causes severe seizures and cognitive impairment.
Patients 18 years of age or older were enrolled in this study to report the transitioning of patients with focal epilepsy from oxcarbazepine (OXC) to eslicarbazepine acetate (ESL). It was shown that patients who suffered from OXC-related adverse events had an improvement in tolerability after switching to ESL, and maintained seizure control.
Researchers identified a de novo missense SCN8A mutation (p.Leu267Ser, c.800T>C) in a 4 year old female. This case report provides information on the child's clinical presentation,family history, and genetic analysis.
De novo mutations in the SCN8A gene are at an increased risk for sudden unexpected death in epilepsy (SUDEP). In this study, the cardiac phenotype of a mouse model expressing the p.Asn1768Asp mutation in SCN8A was investigated for alterations in cardiac excitability. The authors observed prolongation of the early stages of action potential repolarization in mutated myocytes.
A summary of the clinical characteristics of SCN8A-related epilepsy. This complete review covers everything from available testing and diagnostic procedures available for SCN8A-related epilepsy, to the management of symptoms, in order to serve as a point-of-care resource for clinicians.
This paper describes the first reported case of a SCN8A mutation (p.Ile240Val) with clinical prenatal-onset seizures. Ultrasonography was found to be useful for identifying fetal seizures which may be treatable in utero. Finally the authors report that the clinical approach to fetal seizures should involve a multidisciplinary team.
IFracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. This study aimed to confirm the expression of voltage-gated sodium (NaV) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels.
In a recent study it was shown that high doses of phenytoin were effective in four patients with SCN8A encephalopathy. Researchers have created a cell line with a SCN8A mutation (p.Ile1327Val) to study the cell's response to phenytoin.
A retrospective study was conducted in five Israeli pediatric clinics examining the effect of cannabidiol (CBD) on children with intractable epilepsy. The results showed that CBD had a positive effect on seizure load and also was associated with improvements in behavior, language, communication, motor skills, and sleep. Some adverse events were also reported which included drowsiness, fatigue, gastrointestinal disturbances and irritability. Further clinical trials using CBD are warranted to validate these findings.
SCN1A was initially discovered in GEFS+, an autosomal dominant familial epilepsy syndrome. SCN2A was first identified in Benign Familial Neonatal-Infantile Seizures (BFNIS), also representing an autosomal dominant familial epilepsy syndrome. SCN8A, the third epilepsy-related sodium channel gene, has only...
In 2015, SCN8A has emerged as an important gene in epileptic encephalopathy. SCN8A encodes the voltage-gated sodium channel alpha subunit Nav1.6, and was first implicated in epileptic encephalopathy in 2012. Since then, approximately 100 cases of early-infantile...
For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome.
One of the commonly known pharmacoresistant epilepsy types is focal epilepsy, and many patients have no effective treatment options. In this paper, a chemical-genetic approach was taken to achieve localized suppression of neuronal excitability using viral expression in rats.
Only 10 years ago, deciphering the genetic information from one individual in a matter of weeks to find a certain disease-causing genetic mutation would have been written off as science fiction. It was the time of the Human Genome Project, and it had taken armies of sequencing robots working around the clock for almost a decade to unravel the complete sequence of the human genetic code – referred to as the genome.