Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to ...the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%–6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders.
Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated ...with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.
We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.
The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval CI, 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).
The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).
Acetazolamide: Old drug, new evidence? Shukralla, Arif Ali; Dolan, Emma; Delanty, Norman
Epilepsia open,
September 2022, Volume:
7, Issue:
3
Journal Article
Peer reviewed
Open access
Acetazolamide is an old drug used as an antiepileptic agent, amongst other indications. The drug is seldom used, primarily due to perceived poor efficacy and adverse events. Acetazolamide acts as a ...noncompetitive inhibitor of carbonic anhydrase, of which there are several subtypes in humans. Acetazolamide causes an acidification of the intracellular and extracellular environments activating acid‐sensing ion channels, and these may account for the anti‐seizure effects of acetazolamide. Other potential mechanisms are modulation of neuroinflammation and attenuation of high‐frequency oscillations. The overall effect increases the seizure threshold in critical structures such as the hippocampus. The evidence for its clinical efficacy was from 12 observational studies of 941 patients. The 50% responder rate was 49%, 20% of patients were rendered seizure‐free, and 30% were noted to have had at least one adverse event. We conclude that the evidence from several observational studies may overestimate efficacy because they lack a comparator; hence, this drug would need further randomized placebo‐controlled trials to assess effectiveness and harm.
Neuroinflammation is thought to contribute to the pathogenesis and maintenance of temporal lobe epilepsy, but the underlying cell and molecular mechanisms are not fully understood. The P2X7 receptor ...is an ionotropic receptor predominantly expressed on the surface of microglia, although neuronal expression has also been reported. The receptor is activated by the release of ATP from intracellular sources that occurs during neurodegeneration, leading to microglial activation and inflammasome-mediated interleukin 1β release that contributes to neuroinflammation. Using a reporter mouse in which green fluorescent protein is induced in response to the transcription of P2rx7, we show that expression of the receptor is selectively increased in CA1 pyramidal and dentate granule neurons, as well as in microglia in mice that developed epilepsy after intra-amygdala kainic acid-induced status epilepticus. P2X7 receptor levels were increased in hippocampal subfields in the mice and in resected hippocampus from patients with pharmacoresistant temporal lobe epilepsy. Cells transcribing P2rx7 in hippocampal slices from epileptic mice displayed enhanced agonist-evoked P2X7 receptor currents, and synaptosomes from these animals showed increased P2X7 receptor levels and altered calcium responses. A 5 d treatment of epileptic mice with systemic injections of the centrally available, potent, and specific P2X7 receptor antagonist JNJ-47965567 (30 mg/kg) significantly reduced spontaneous seizures during continuous video-EEG monitoring that persisted beyond the time of drug presence in the brain. Hippocampal sections from JNJ-47965567-treated animals obtained >5 d after treatment ceased displayed strongly reduced microgliosis and astrogliosis. The present study suggests that targeting the P2X7 receptor has anticonvulsant and possibly disease-modifying effects in experimental epilepsy.
Temporal lobe epilepsy is the most common and drug-resistant form of epilepsy in adults. Neuroinflammation is implicated as a pathomechanism, but the upstream mechanisms driving gliosis and how important this is for seizures remain unclear. In our study, we show that the ATP-gated P2X7 receptor is upregulated in experimental epilepsy and resected hippocampus from epilepsy patients. Targeting the receptor with a new centrally available antagonist, JNJ-47965567, suppressed epileptic seizures well beyond the time of treatment and reduced underlying gliosis in the hippocampus. The findings suggest a potential disease-modifying treatment for epilepsy based on targeting the P2X7 receptor.
Objectives
The current coronavirus disease 2019 (COVID‐19) pandemic stresses an urgency to accelerate much‐needed health service reform. Rapid and courageous changes being made to address the ...immediate impact of the pandemic are demonstrating that the means and technology to enable new models of health care exist. For example, innovations such as electronic patient portals (ePortal) can facilitate (a) radical reform of outpatient care; (b) cost containment in the economically constrained aftermath of the pandemic; (c) environmental sustainability by reduction of unnecessary journeys/transport. Herein, the development of Providing Individualised Services and Care in Epilepsy (PiSCES), an ePortal to the Irish National Epilepsy Electronic Patient Record, is demonstrated. This project, which pre‐dates the COVID‐19 crisis, aims to facilitate better patient‐ and family‐centered epilepsy care.
Methods
A combination of ethnographic research, document analysis, and joint application design sessions was used to elicit PiSCES requirements. From these, a specification of desired modules of functionality was established and guided the software development.
Results
PiSCES functional features include “My Epilepsy Care Summary,” “My Epilepsy Care Goals,” “My Epilepsy Clinic Letters,” “Help Us Measure Your Progress,” “Prepare For Your Clinic Visit,” “Information for Your Healthcare Provider.” The system provides people with epilepsy access to, and engages them as co‐authors of, their own medical record. It can promote improved patient‐clinician partnerships and facilitate patient self‐management.
Significance
In the aftermath of COVID‐19, it is highly unlikely that the healthcare sector will return to a “business as usual” way of delivering services. The pandemic is expected to accelerate adoption of innovations like PiSCES. It is therefore a catalyst for change that will deliver care that is more responsive to individual patient needs and preferences.
Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit ...development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)‐treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR‐129‐5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo. Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR‐129‐5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX‐treated neurons. Furthermore, we characterized a functional crosstalk between miR‐129‐5p and the RNA‐binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR‐129‐5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity‐dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.
Synopsis
A systematic approach using small RNA and mRNA profiling in combination with proteomics is used to delineate post‐transcriptional regulatory pathways involved in synaptic scaling. This led to the identification of a pathway consisting of the miRNA miR‐129‐5p and the RNA‐binding protein Rbfox that controls excitatory synapse function in neurons and epileptic seizure activity in the brain.
8 microRNAs, including miR‐129‐5p, are upregulated during homeostatic synaptic downscaling in hippocampal neurons.
miR‐129‐5p inhibition blocks synaptic downscaling in vitro and kainic acid‐induced epileptic seizures in vivo.
A combination of transcriptomics, proteomics and bioinformatics was used to identify miR‐129‐5p target mRNAs, including Atp2b4, Dcx and Rbfox1/3.
Activity‐dependent downregulation of Rbfox1 by miR‐129‐5p is required for the repression of synaptic genes during homeostatic synaptic downscaling.
Combining miRNA and mRNA profiling with proteomics reveals roles for miR‐129‐5p and the RNA‐binding protein Rbfox in excitatory synapse function and epileptic seizure.
•Valproate therapy can result in reduced sperm count, motility and abnormal morphology.•Valproate’s adverse effects on male fertility are reversible in some patients.•Abnormalities may be dependent ...on the dose and the duration of Valproate treatment.
Sodium valproate is a broad spectrum anti-seizure medication useful in the treatment of both generalized and focal epilepsies. The association between valproate and female reproductive disorders is well understood and delineated. Male infertility however is an under-recognised adverse effect of Valproate therapy.
Previous case reports have detailed reversible male infertility secondary to valproate. One report demonstrated a relationship between valproate dose and abnormal sperm parameters. We submit a case report suggesting a dose dependent effect of valproate on sperm parameters and a possible relationship between the duration of valproate therapy and its deleterious effect on male fertility.
Men on valproate should be counselled about the possibility of progressive but reversible infertility. Valproate should be stopped and replaced by an alternative agent in those men who are infertile and where the couple are trying to conceive, particularly if there are associated abnormal sperm parameters while on the drug.
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