Gene Linked to Epilepsy, Autism Decoded in New Study

Article published by Brain

A new Northwestern Medicine study helps explain how changes in the SCN2A gene affect whether a child will develop autism or epilepsy, the age at which seizures start for those with epilepsy, and the severity of the child’s other impairments. The study represents a collaboration between an academic laboratory at Northwestern and the FamilieSCN2A Foundation, a parent-led rare disease advocacy group. The SCN2A Clinical Trials Readiness Study (SCN2A-CTRS) recruited 81 families from around the world and collected detailed clinical data and information to identify their SCN2A variants. The Northwestern team extensively analyzed the functional effects of each SCN2A variant on sodium channels—tiny gates in the membranes of nerve cells that control the flow of sodium ions into the cell and help neurons in the brain fire properly. Variants in the SCN2A gene alter how the sodium channel functions. Depending on the individual variant, the channel may be hyperactive or completely inactive. The study found that the clinical condition of the child varied with the functional impact on the channel. Hyperactive channels were generally associated with seizure onset in the first week of life. More impaired channel function was more common when the age of seizure onset was older. In fact, almost all of those without seizures had completely inactive sodium channels. As age at seizures-onset increased and channels became less active, severe neurological impairments in the child tended to be less severe. “Our new study clarifies the relationship between the functional consequences of SCN2A mutations, the primary phenotype (autism versus epilepsy and age at seizure onset in those with epilepsy), and the overall severity of the child’s impairments (mobility, etc.),” said co-corresponding author Dr. Alfred George, chair of pharmacology at Northwestern University Feinberg School of Medicine. Dr. Anne Berg, adjunct professor of neurology at Feinberg, lead investigator of the SCN2A-CTRS and the co-corresponding study author, emphasized that “this collaboration between a family foundation and a large NIH-funded project is an exemplar of the new partnerships that are needed and increasingly being developed to provide rapid answers to critical questions and lay foundation for successful drug development for severe neurodevelopmental disorders such as those associated with SCN2A.”

Study Reveals Key Mechanisms of a Rare Form of Epilepsy

Article published by MedicalXpress

*Featuring work by CURE Epilepsy Grantees, Drs. Edward Cooper and Jeffrey Noebels

New research is advancing the understanding of KCNQ2 encephalopathy. “KCNQ2 encephalopathy is a rare neurodevelopmental disorder caused by variants in the KCNQ2 gene, which provides the recipe for a type of brain potassium channel,” explains lead author Timothy Abreo, a student in the Genetics and Genomics Graduate Program at Baylor College of Medicine, Houston, Texas, US. “The disorder usually manifests as seizures beginning within days after birth and developmental delays which are lifelong and without effective current treatment.” Newly identified variants in the KCNQ2 gene are hard to assess because not every variant is disease-causing, and the reasons some variants lead to illness have been poorly understood. The research team closely examined a specific genetic variant of the KCNQ2 gene involving a single amino acid change—glycine 256 changed to tryptophan (G256W)—on one copy of the KCNQ2 gene. They examined the structure and pathogenicity of the G256W variant using molecular, cellular, and in vivo approaches and uncovered evidence that G256 helps form a network of hydrogen bonds that serve to stabilize the structure of the pore-forming region of the potassium channel. “Taken together, our study reveals that the presence of KCNQ2 G256W variants affects both molecular and cellular aspects of KCNQ channel activity, including their ion-carrying capacity, expression, and placement within cells,” explains senior author Edward Cooper, Associate Professor of Neurology, Neuroscience, and Molecular and Human Genetics at Baylor College of Medicine. “Selective KCNQ2 openers, which counter the effects of G256W mutations should be tested in additional laboratory models and if effective, in humans with KCNQ2 disease-causing variants,” says Dr. Cooper.

Genotype–Phenotype Associations in Individuals with SCN1A-Related Epilepsies

Article published by Wiley Online Library

A recent study assesses data from a retrospective cohort of 1,018 individuals with SCN1A-related epilepsies, exploring how seizure characteristics, genetic variant type, position, and in silico scores relate to the epilepsy phenotype. Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. Pathogenic variants in SCN1A, the gene coding for the alpha-1 subunit of the voltage-gated sodium channel, are associated with a range of epilepsy syndromes from relatively mild phenotypes in the genetic epilepsy with febrile seizures plus (GEFS+) spectrum to Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. DS usually presents at approximately five–six months of age with prolonged, febrile and afebrile, hemiclonic or generalized clonic seizures. From age nine months to four years, other seizure types, including myoclonic, absence, and focal seizures, develop. Typical antiseizure medications have limited efficacy, and sodium channel blockers are associated with worse outcomes. From age two years, cognitive, behavioral, and motor development becomes significantly impaired. Epilepsies within the less severe GEFS+ spectrum also present early in life; however, cognitive development is normal. This large cohort study of patients with SCN1A variants provides evidence of associations between gene variant features and phenotype. This includes differences in age at seizure onset associated with different variant types, identification of specific regions within SCN1A associated with specific presentations, and initial status epilepticus as a predictive phenotypic marker for DS.

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.