New Therapeutic Target for Rare Type of Childhood Epilepsy Identified 

Article published by Medical Xpress

Researchers have identified a potential treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy. CDD causes seizures and impaired development. To date, there are no disease-targeting antiseizure medications. Recently, researchers have identified calcium channel Cav2.3 as a potential therapeutic target for CDD. Cav2.3 allows calcium to enter nerve cells, exciting the cells and allowing them to pass on electrical signals. This process is needed for the nervous system to function properly, but too much calcium coming into nerve cells can result in over-excitability and seizures. The researchers recorded calcium channel function and observed that a process called phosphorylation which changes the function of the channel was not occurring. Specifically, the channels were able to open, but were taking longer to close, leading to larger and more prolonged calcium currents flowing into cells. This implies that CDKL5 is needed to limit calcium entry into cells. Genetic mutations that enhance channel activity are already known to cause severe early-onset epilepsy in a related condition called DEE69 which shares similar symptoms as CDD. These results suggest that over-activity of nerve cells is a common feature of both disorders and that inhibiting the channel could help with symptoms like seizures. Marisol Sampedro-Castañeda, postdoctoral researcher, said, “Our research highlights for the first time a CDKL5 target with a link to neuronal excitability. There is evidence that this calcium channel could be involved in other types of epilepsy too, so we believe that Cav2.3 inhibitors could eventually be tested more widely. Our findings have implications for a large group of people, from the families affected by these conditions to researchers working in the rare epilepsy field.” 

Alternate Origin Discovered for Brain Mosaicism and Focal Epilepsy

Article published by Drug Target Review

Most people have the same genetic information in every cell of their body. However, during fetal development, two or more genetically diverse sets of cells can develop. These genetically diverse or ‘mosaic’ cells may cause disorders or diseases including epilepsy. Scientists have recently discovered an alternate origin of brain mosaicism in some children with focal epilepsy. The scientists performed a genetic analysis of brain tissue, blood and buccal cells (cells derived from the inside of the cheek). Tissue samples were taken from six patients, aged two months to seven months, who underwent epilepsy surgery. Analyses of the tissues showed that some of the cells in the brain tissue had extra copies of chromosome 1q compared to the normal tissue. The blood and buccal cells did not have any cells with extra copies of chromosome 1q. “This work is incredibly exciting for two reasons,” noted a study author. “First, it links a recently identified cause of epilepsy to a pathological finding, furthering our understanding of how chromosome 1q causes unrelenting seizures. Second, it opens the door to new mechanisms of how brain tissue may be impacted by genetic problems differently than the rest of the body. Now, we have to reconsider how we look at genetic causes of epilepsy.”

A New Fruit Fly Model to Probe an Epileptic Brain Disorder

Article published by Baylor College of Medicine

Developmental and epileptic encephalopathy (DEE) refers to a group of neurodevelopmental conditions characterized by developmental delay, cognitive impairment and seizures in children. In 2016, the first case linking variants in both copies of the UBA5 gene to DEE44 was reported. Since then, twelve distinct missense variants in the UBA5 gene have been identified. Recently, Dr. Hugo J. Bellen and his team at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital generated a new fruit fly model to assess the severity of symptoms caused by each of these variants. The severity and the type of symptoms varied widely among different variants. For instance, five variants caused progressive motor defects, three of which also caused developmental delays or seizure-like symptoms. Their systematic analysis lays the foundation for better evaluation of the variants, which is important for DEE44 patients in the future and for the development of drugs and gene therapy to treat this rare disorder. The study was published in the journal eLife.

Epilepsy Research News: September 2023

This issue of Epilepsy Research News includes summaries of articles on:



The Cerebellum as a Source of Generalized Convulsive Seizures

A recent study provides new insights into how convulsive seizures happen, implicating a “circuit” in the brain, specifically a connection of neurons between the cerebellum and thalamus, in driving convulsive seizures. To investigate the importance of this circuit in causing seizures, the team utilized a technique called optogenetic imaging to record the activity of neurons in the brain before, during, and after convulsive seizures. The team found that a group of neurons in a specific area of the thalamus called the ventral posteromedial nucleus were initiating convulsive seizures. The team then found that neurons in the cerebellum that connect to this area of the thalamus not only significantly contribute to the seizures, but that blocking activity from the cerebellum to the thalamus blocked seizures from occurring. The team noted that the findings not only deepen the understanding of how seizures originate but also create the possibility of targeting this cerebellum-thalamus circuit to treat convulsive seizures.

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Examining the Benefit of Rapid Genome Sequencing for Infantile Epilepsy

A recent study shows that rapid genome sequencing (a process that looks for changes across the entire genome) can provide a rapid diagnosis of genetic mutations and influence clinical care of infants with new-onset epilepsy. As part of this study, researchers sequenced the genomes of 100 infants with unexplained seizures along with their parents to better understand the potential diagnostic value of this approach for infantile epilepsy. The researchers found that across all children enrolled in the study, 43% received a diagnosis within weeks, and that diagnosis impacted the medical outcomes in nearly 90% of those cases, guiding treatment options for over half. This study provides an initial framework for further investigation of the long-term benefits of early genetic diagnosis in infants, and the potential use of targeted “precision” treatments that are specific to an infant’s genetic diagnosis.

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Large Genetic Study Provides Insights on Why Epilepsy Develops and Potential Treatments

The largest genetic study of its kind has discovered specific changes in our DNA that increase the risk of developing epilepsy. The research advances our knowledge of why epilepsy develops and may inform the development of new treatments for the condition. The researchers identified 26 distinct areas in our DNA that appear to be involved in epilepsy. This included 19 which are specific to a particular form of epilepsy called genetic generalized epilepsy. They were also able to identify 29 genes within these DNA regions that probably contribute to epilepsy. The researchers also showed that many of the current medications for epilepsy work by targeting the same epilepsy risk genes that were highlighted in the study. Furthermore, based on their data, the researchers were able to propose some potentially effective alternative drugs. The researchers noted that these discoveries, only achieved through international collaboration, help us to better understand the genetics of this type of epilepsy and potential treatments.

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Preventive Epilepsy Treatment with Vigabatrin Does Not Improve Neurocognitive Development in Infants with Tuberous Sclerosis Complex (TSC)

In new study results, researchers found that administering the preventive epilepsy treatment vigabatrin (Sabril ®) prior to seizure onset did not improve neurocognitive outcomes in TSC infants at two years of age. In the original results, this study (known as the PREVeNT trial) showed that preventative treatment delayed the start and lowered the number of infantile spasms in infants with TSC. This study enrolled 84 infants with TSC between 2016 and 2020, who had been diagnosed with TSC either through prenatal testing, physical examination, or genetic testing, but had yet to have any seizures. Infants who developed a specific EEG biomarker that indicates a risk of developing seizures were then placed in two groups, one receiving preventative vigabatrin treatment and one receiving a placebo. In this new study, the researchers found that infants who received vigabatrin still had drug-resistant epilepsy at 24 months, that focal seizures remained prominent in the infants, and there was no benefit in cognitive outcomes. The researchers state that these findings indicate the need to develop more effective therapies to treat cognitive and behavioral dysfunction in TSC.

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Advances in Cannabidiol (CBD) for Epilepsy Treatment and Prevention

A series of recently published articles details new breakthroughs in the field of medical cannabinoids for epilepsy and seizure disorders. Two publications review the effectiveness of CBD, a compound found in cannabis, in treating epilepsy and seizures. Another publication in the series describes the results of a meta-analysis (a type of study that reviews and combines the results of multiple other studies) to determine the overall effectiveness and safety of CBD treatment in children with genetic epilepsies such as Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. This analysis revealed that CBD was effective in managing these genetic epilepsies, albeit with an increase in adverse events such as diarrhea, somnolence, sedation, and potential drug interactions. A separate publication showed potential effects of CBD as a prevention against seizures that are similar to those associated with temporal lobe epilepsy. Together, these publications provide information on the use of CBD in the treatment of epilepsy and open up the possibility of utilizing CBD in individuals at risk for developing epilepsy.

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CDKL5-Mediated Developmental Tuning of Neuronal Excitability and Concomitant Regulation of Transcriptome

Abstract found on PubMed

Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase enriched in the forebrain to regulate neuronal development and function. Patients with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition caused by mutations of CDKL5 gene, present early-onset epilepsy as the most prominent feature. However, spontaneous seizures have not been reported in mouse models of CDD, raising vital questions on the human-mouse differences and the roles of CDKL5 in early postnatal brains. Here, we firstly measured electroencephalographic (EEG) activities via a wireless telemetry system coupled with video-recording in neonatal mice. We found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges, accompanied with increased burst activities and ictal behaviors, specifically at postnatal day 12 (P12). Intriguingly, those epileptic spikes disappeared after P14. We next performed an unbiased transcriptome profiling in the dorsal hippocampus and motor cortex of Cdkl5 null mice at different developmental timepoints, uncovering a set of age-dependent and brain region-specific alterations of gene expression in parallel with the transient display of epileptic activities. Finally, we validated multiple differentially expressed genes (DEGs), such as glycine receptor subunit 2 and cholecystokinin, at the transcript and/or protein levels, supporting the relevance of these genes to CDKL5-regulated excitability. Our findings reveal early-onset neuronal hyperexcitability in mouse model of CDD, providing new insights into CDD etiology and potential molecular targets to ameliorate intractable neonatal epilepsy.

Largest Genetic Study of Epilepsy to Date Provides New Insights on Why Epilepsy Develops and Potential Treatments 

Article published by Medical Xpress


The largest genetic study of its kind, coordinated by the International League Against Epilepsy, including scientists from FutureNeuro at RCSI University of Medicine and Health Sciences, has discovered specific changes in our DNA that increase the risk of developing epilepsy.


The research, published in Nature Genetics, greatly advances our knowledge of why epilepsy develops and may inform the development of new treatments for the condition.


Epilepsy, a common brain disorder of which there are many different types, is known to have genetic component and to sometimes run in families. Here, researchers compared the DNA from diverse groups of almost 30,000 people with epilepsy to the DNA of 52,500 people without epilepsy. The differences highlighted areas of our DNA that might be involved in the development of epilepsy.


The researchers identified 26 distinct areas in our DNA that appear to be involved in epilepsy. This included 19 which are specific to a particular form of epilepsy called ‘genetic generalized epilepsy’ (GGE). They were also able to point to 29 genes that are probably contributing to epilepsy within these DNA regions.


The scientists found that the genetic picture was quite different when comparing distinct types of epilepsy, in particular, when “focal” and “generalized” epilepsies were compared. The results also suggested that proteins that carry electrical impulse across the gaps between neurons in our brain make up some of the risk for generalized forms of epilepsy.


“Gaining a better understanding of the genetic underpinnings of epilepsy is key to developing new therapeutic options and consequently a better quality of life for the over 50 million people globally living with epilepsy,” said Professor Gianpiero Cavalleri, Professor of Human Genetics at RCSI School of Pharmacy and Biomolecular Science and Deputy Director of the SFI FutureNeuro Research Center.

Study Investigates the Impact of Rapid Genome Sequencing for Infantile Epilepsy

Article published by News Medical Science

Epilepsy in infants ranges in severity and can leave caregivers with questions about their child’s health. While genetic testing to help determine the cause of epilepsy is possible, comprehensive testing does not always happen routinely and it can take a long time, leaving families waiting for answers.

Published in The Lancet Neurology, this international study sequenced the genomes of 100 infants with unexplained seizures, along with their parents, from four countries (England, USA, Canada and Australia) to better understand the potential strengths of early, broad genome sequencing (a process which looks for changes across the entire genome) for infantile epilepsy.

The researchers used rapid genome sequencing (rGS) to investigate the impact of an expedited genetic diagnosis on care for the first time. Across all children enrolled in the study, 43 per cent received a diagnosis within weeks, and that diagnosis impacted prognosis in nearly 90 per cent of those cases, guiding treatment options for over half.

HCN1 epilepsy: From Genetics and Mechanisms to Precision Therapies

Abstract found on PubMed

Pathogenic variation in HCN1 is now an established cause of epilepsy and intellectual disability. Variation in HCN1 causes a spectrum of disease with a genotype-phenotype relationship emerging. De novo pathogenic variants that occur in the transmembrane domains of the channel typically cause a cation ‘leak’ that associates with severe developmental and epileptic encephalopathy (DEE). Genotype-phenotype associations for variants that fall outside of the transmembrane domains are less well established but do include milder forms of epilepsy that can be either de novo or inherited. HCN1 DEE mouse models have been generated which recapitulate the seizures and learning difficulties seen in human patients. These mice have also acted as powerful preclinical models which share pharmacoresponsiveness with human HCN1 DEE patients. Data from these mouse models support the conclusion that anti-seizure medications with sodium channel block as their primary mechanism of action should be used with caution in HCN1 DEE. Other comorbidities of HCN1 DEE including retinal dysfunction have also been modelled in HCN1 DEE mice, suggesting HCN1 variants can cause a dramatically reduced sensitivity to light with limited ability to process temporal information. Our understanding of the genetics and pathophysiological mechanisms underlying HCN1 epilepsy has progressed significantly and is already influencing therapy. However, more research effort is needed to fully understand the natural histories of HCN1 epilepsies and to develop precision therapeutic approaches.

Epilepsy Research News: July 2023

This issue of Epilepsy Research News includes summaries of articles on:


Beating Seizures by Jamming the Cellular Circuitry

Researchers have shown for the first time how the commonly prescribed antiseizure and pain medication gabapentin (Neurontin®) acts to affect cell function, potentially opening the door to new, more effective treatments for diseases like epilepsy. This research shows how gabapentin interacts with proteins called voltage-gated calcium channels, which are critical to the function of the brain. Voltage-gated calcium channels control the flow of calcium in and out of the cell and regulate brain excitation. By utilizing a technique called cryo-electron microscopy, the researchers confirmed the site where gabapentin binds to the channel to affect its function. The researchers also discovered that gabapentin interferes with the actions of a protein known as EMC. This interference could inhibit the actions of the ion channel, possibly decreasing the amount of calcium that gets into brain cells, in turn reducing brain activity and seizures. The study authors noted that by showing how gabapentin binds to calcium channels, there may be the opportunity to design a new generation of therapies.

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Identifying Seizures that Occur While Driving, Before Epilepsy Diagnosis

Five percent of people with focal epilepsy had a seizure while driving prior to being diagnosed with epilepsy, according to a new study. Researchers looked at clinical descriptions from study participants’ seizure diaries and medical records to classify types of seizures, seizure occurrence, and information about seizures while driving. They found 23 out of 447 participants, or 5% of participants, experienced one or more seizures while driving, for a total of 32 seizures while driving prior to diagnosis. Of these 23 people, seven people, or 30%, had more than one seizure while driving prior to diagnosis. The consequences of these seizures while driving included 19 motor vehicle accidents and 11 hospitalizations for injuries ranging from a tongue bite and a dislocated thumb to a near drowning. “From our study, we estimate nearly 6,500 people per year may experience pre-diagnosis seizures while driving in the United States alone, leading to nearly 4,000 possible motor vehicle accidents and over 2,200 hospitalizations,” stated the study authors. “Much of this may be preventable by earlier diagnosis.”

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Understanding Autism and Epilepsy

A study has increased our understanding and identified a possible treatment target for people with autism and epilepsy due to a lack of the ANK2 gene. This study showed that mice lacking the ANK2 gene in certain brain cells that contribute to brain excitation have autism spectrum disorder-like behaviors and juvenile seizure-related death. The researchers identified increased excitability of cortical neurons in these ANK2-deficient mice. These changes were accompanied by decreases in the function of a particular type of potassium channel in the brain. When the researchers used retigabine, an antiseizure medication, to enhance potassium channel function in the mice, they were able to restore neuronal excitability to normal levels and reduce seizure-induced deaths, suggesting that activation of potassium channels may be effective in treating epilepsy caused by ANK2 defects.

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Brain Inflammation and Drug-Resistant Epilepsy

New research investigated how inflammation contributes to the development of drug-resistant epilepsy. To study this, researchers examined brain tissue obtained during resective epileptic brain surgery. The researchers used a genetic sequencing technique called cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), which gathers information on RNA and surface proteins in single cells. They uncovered a proinflammatory microenvironment in drug-resistant epilepsy lesions that resembles brain autoimmune diseases, such as multiple sclerosis. They found that the drug-resistant epilepsy microenvironment includes activated microglia and other proinflammatory immune cells, and they captured cellular interactions with additional molecular analyses. The researchers noted that these results provide insight into the immune microenvironment in epileptic tissue, which may aid the development of new therapeutics.

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Reducing Seizures After Brain Tumor Treatment

According to a recent study, inhibiting a mutated gene can reduce seizure activity in adult-type diffuse gliomas, which are the most common type of malignant tumors arising in the central nervous system and which commonly cause seizures that are difficult to control with medication. Previous research has shown that gliomas with mutations in the IDH (IDHMut) gene are more likely to cause seizures because the mutated gene produces D-2-hydroxyglutarate (D2HG), a chemical which excites neurons and leads to an increase in seizure activity. In the recent study, scientists found that AG881, a newly discovered small molecule inhibitor that can cross the blood-brain barrier, can reduce seizure activity in mice with IDHmut gliomas by more than 50 percent. IDHmut inhibition also inhibited the production of D2HG by IDHmut glioma cells. The researchers stated that these findings provide a potential basis for treating seizures in human glioma patients.

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New Findings Expand the Genotypic Spectrum of NPRL3-associated Focal Epilepsy 

Article published by News Medical Life Sciences 


Science China Life Sciences magazine recently reported on the research results of Tang Beisha’s team from Xiangya Hospital of Central South University, Liu Jing Yu’s team from the Institute of Neurology of the Chinese Academy of Sciences, and Zhang Luoying’s team from Huazhong University of Science and Technology, including Du Shiyue, Zeng Sheng, and Song Li. Epilepsy has a complex etiology with 80% owing a genetic basis. A small portion of epilepsy is inherited in Mendelian mode. Exploring the causative genes and pathogenesis of epilepsy will improve the clinical understanding and facilitate precise medicine of epilepsy. GATOR1 which consists of DEPDC5, NPRL2 and NPRL3 protein and inhibits the pathway of mTORC1, was first identified to be related to genetic epilepsy in 2013. However, its pathogenic mechanism remains unclear. 


The Beisha Tang’s team, collaborated with the Jingyu Liu’s team, collected three families of focal epilepsy. Using techniques including linkage analysis and whole exome sequencing, they identified three NPRL3 mutations in patients from these three families: c.319_629del, c.937_ 945del and c.1514dupC. 


This study also generated nprl3 RNA interference (RNAi) flies, and epilepsy-like behavior was induced in the flies. Moreover, knocking down any component of the GATOR1 complex (nprl3, nprl2, and iml1) in fruit flies can cause epilepsy-like behavior, further supporting the contribution of GATOR1 signaling defects in epileptogenesis. At the same time, this study also found that the number of synaptic boutons and the expression level of excitatory glutamate receptors increased in nprl3 RNAi flies. The results may be the pathological basis for epilepsy-like behavior, suggesting that NPRL3-asscociated epilepsy is a development-related disease.