Copy number variations (CNVs) have been related to developmental and epileptic encephalopathy (DEE). The 2q24.3 region includes a cluster of genes for voltage-gated sodium channels (SCN) and CNVs in this region cause DEE. However, the long-term course of DEE with a 2q24.3 duplication has not been described. A 20-year-old female developed epileptic encephalopathy in early infancy that was resistant to various antiseizure medications. Her seizures disappeared after starting vitamin B6 therapy. Therefore, her epilepsy was considered pyridoxine-dependent epilepsy. At 16 years old, whole exome sequencing revealed a 2q24.3 microduplication including SCN1A, SCN2A, SCN3A, SCN7A, and SCN9A. Quantitative PCR detected an increased copy number of 1.3 Mb on 2q24.3 involving these genes, but no gene mutation accounting for pyridoxine-dependent epilepsy. Considering that with this duplication she was reported to be seizure-free after infancy, she was able to be off antiseizure medications including vitamin B6. Our case involvingdrug-resistant epilepsy in early infancy had no recurrent seizures during long-term follow up. Detecting CNVs using whole exome sequencing data was useful to identify a 2q24.3 duplication unassociated with pyridoxine-dependent epilepsy, leading to cessation of unnecessary medications.

UNASSIGNED: Epilepsy is a neurological disease characterized by sudden, abnormal, and hyper- discharges in the central nervous system (CNS). Valproic acid (VPA) is commonly used as a broad-spectrum antiepileptic therapeutic. However, in many cases, patients develop resistance to VPA treatment due to overwhelming oxidative stress, which in turn might be a major catalyst for disease progression. Therefore, antioxidants can potentially become therapeutic agents by counteracting reactive oxygen species (ROS)-mediated damage. The present study is aimed to evaluate the potential antiepileptic effect of astaxanthin (ASTA) in pentylenetetrazol (PTZ) induced epileptic model rats that are chronically treated with VPA for 8 weeks.
UNASSIGNED: Fifty-male Wistar rats were randomly divided into five groups: Non-PTZ group, PTZ, PTZ/VPA, PTZ/ASTA, and PTZ/VPA/ASTA treated groups.
UNASSIGNED: PTZ/VPA treated group showed a neuroprotective effect with improvement in antioxidant levels, behavioral test, and histopathological changes induced by PTZ. VPA also exhibited an anti-inflammatory effect as its treatment resulted in the reduction of tumor necrosis factor-α (TNF-α). ASTA exhibited an anticonvulsant effect and enhanced anti-inflammatory effect as compared to VPA. During the combined therapy, ASTA potentiated the antiepileptic effect of the VPA by reducing the oxidative stress and TNF-α as well as increased the glutathione (GSH) levels. Also, there were substantial improvements in the behavioral and histopathological changes in the VPA/ASTA treated group as compared to the VPA treated group.
UNASSIGNED: ASTA could have an antiepileptic and anti-inflammatory effect by reducing ROS generation. Therefore, co-administration of both the therapeutics (VPA/ASTA) has a synergistic effect in treating epilepsy and could potentially minimize recurrence and/or exacerbation of seizures.

UNASSIGNED: Angelman syndrome (AS) is neurodevelopmental disorder, causal gene of which is maternally expressed UBE3A. A majority of patients results from the large deletion of relevant chromosome which includes GABAA receptor subunit genes (GABARs) as well as UBE3A (AS Del). We previously reported aberrantly desynchronized primary somatosensory response in AS Del by using magnetoencephalography. The purpose of this study is to estimate cortical and subcortical involvement in the deficit of primary somatosensory processing in AS.
UNASSIGNED: We analyzed short-latency somatosensory-evoked potentials (SSEPs) in 8 patients with AS Del. SSEPs were recorded on a 4-channel system comprising of two cortical electrodes which were placed on the frontal and centro-parietal areas. The peak and onset latency of each component were measured to compare latency and interval times.
UNASSIGNED: The first-cortical peak latency (N20, P20), and N13-N20 peak interval times were significantly prolonged in AS Del compared to healthy controls. In contrast, there was no difference in latencies between subcortical components up to N20 onset or for N11-N20 onset interval times.
UNASSIGNED: Highly desynchronized first-cortical SSEP components and normal latencies of subcortical components indicated cortical dysfunction rather than impairment of afferent pathways in AS Del patients, which might be attributed to GABAergic dysfunction due to loss of UBE3A function and heterozygosity of GABARs.

Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, is a genetic disorder with several neurological, cutaneous and skeletal manifestations. Epilepsy has been previously reported as a finding in Gorlin-Goltz syndrome but remains ill-described in the context of this disease. We report two new patients with Gorlin-Goltz syndrome featuring epilepsy and review the existing literature on the topic.

Evidence of the involvement of epigenetics in pathologies such as cancer, diabetes, and neurodegeneration has increased global interest in epigenetic modifications. For nearly thirty years, it has been known that cancer cells exhibit abnormal DNA methylation patterns. In contrast, the large-scale analysis of histone post-translational modifications (hPTMs) has lagged behind because classically, histone modification analysis has relied on site specific antibody-based techniques. Mass spectrometry (MS) is a technique that holds the promise to picture the histone code comprehensively in a single experiment. Therefore, we developed an MS-based method that is capable of tracking all possible hPTMs in an untargeted approach. In this way, trends in single and combinatorial hPTMs can be reported and enable prediction of the epigenetic toxicity of compounds. Moreover, this method is based on the use of human cells to provide preliminary data, thereby omitting the need to sacrifice laboratory animals. Improving the workflow and the user-friendliness in order to become a high throughput, easily applicable, toxicological screening assay is an ongoing effort. Still, this novel toxicoepigenetic assay and the data it generates holds great potential for, among others, pharmaceutical industry, food science, clinical diagnostics and, environmental toxicity screening. •There is a growing interest in epigenetic modifications, and more specifically in histone post-translational modifications (hPTMs).•We describe an MS-based workflow that is capable of tracking all possible hPTMs in an untargeted approach that makes use of human cells.•Improving the workflow and the user-friendliness in order to become a high throughput, easily applicable, toxicological screening assay is an ongoing effort.

Breast carcinoma is one of the most common malignancies in women. Previous studies have reported that 500 μM valproic acid can sensitize breast tumor cells to the anti-neoplastic agent hydroxyurea. However, the dose requirements for valproic acid is highly variable due to the wide inter-individuals clinical characteristics. High therapeutic dose of valproic acid required to induce anti-tumor activity in solid tumor was associated with increased adverse effects. There are attempts to locate suitably high-efficient low-toxicity valproic acid derivatives. We demonstrated that lower dose of 2-hexyl-4-pentynoic acid (HPTA; 15 μM) has similar effects as 500 μM VPA in inhibiting breast cancer cell growth and sensitizing the tumor cells to hydroxyurea on MCF7 cells, EUFA423 cells, MCF7 cells with defective RPA2-p gene and primary culture cells derived from tissue-transformed breast tumor cells. We discovered HPTA resulted in more DNA double-strand breaks, the homologous recombination was inhibited through the interference of the hyperphosphorylation of replication protein A2 and recombinase Rad51. Our data postulate that HPTA may be a potential novel sensitizer to hydroxyurea in the treatment of breast carcinoma.

We observed that cannabidiol supplements were highly effective in treating an infant boy with drug-resistant early infantile epileptic encephalopathy, eliminating his intractable tonic seizures. The infant began suffering clusters of brief tonic seizures from birth at 39 weeks gestation. EEG showed burst-suppression and seizures could not be controlled by trials of phenobarbital, zonisamide, vitamin B6, clobazam, levetiracetam, topiramate, phenytoin, valproate, high-dose phenobarbital, and ACTH therapy. The boy was discharged from hospital at 130 days of age still averaging tonic seizures 20-30 times per day. We started him on a cannabidiol supplement on day 207, increasing the dosage to 18 mg/kg/d on day 219. His seizures reduced in frequency and completely disappeared by day 234. These effects were maintained, with improved EEG background, even after his other medications were discontinued. Cannabidiol\'s effectiveness in treating drug-resistant epilepsy has been confirmed in large-scale clinical trials in Europe and the United States; however, no such trials have been run in Asia. In addition, no reports to date have documented its efficacy in an infant as young as six months of age. This important case suggests that high-dose artisanal cannabidiol may effectively treat drug-resistant epilepsy in patients without access to pharmaceutical-grade CBD.

Patients with mutations in the POLG-1 gene often are afflicted with drug-resistant seizures at an early age and have an increased risk of valproic acid-induced acute liver failure. Severe valproate hepatotoxicity most commonly arises in children within the first 3 months of treatment with an overall estimated incidence of 1 in 40,000 treated patients. Due to high mortality rates among transplanted children, many experts consider valproic acid-induced acute liver failure in patients with mitochondrial disorders to be a contraindication to liver transplant. We report the successful use of liver transplantation in a young man with valproic acid-associated acute liver failure harboring a previously unrecognized POLG-1 mutation.

Ictal syncope is a rare phenomenon that occurs in association with 0.002-0.4% of seizures. In the absence of other symptoms, seizures presenting with syncope may be challenging to diagnose. We report a case of a previously healthy male who developed recurrent episodes of syncope with postictal confusion and was later diagnosed with temporal seizures. The patient was successfully treated with anti-seizure drugs and placement of a cardiac pacemaker. In a systematic review of literature, we summarize the clinical characteristics of patients with ictal asystole and isolated syncope. Seizures should be considered in patients with syncope of uncertain etiology.

Chemical modifications to nucleosomal DNA and histone tails greatly influence transcription of adjacent and distant genes, a mode of gene regulation referred to as epigenetic control. Here, the authors summarize recent findings that have illustrated crucial roles for epigenetic regulatory enzymes and reader proteins in the control of cardiac fibrosis. Particular emphasis is placed on epigenetic regulation of stress-induced inflammation and fibroblast activation in the heart. The potential of developing innovative small molecule \"epigenetic therapies\" to combat cardiac fibrosis is highlighted.