The Seizure-Associated Genes Across Species (SAGAS) Database Offers Insights into Epilepsy Genes, Pathways and Treatments

Abstract found on Wiley Online Library

Objective: Decades of genetic studies on people with many different epilepsies, and on many non-human species, using many different technologies, have generated a huge body of literature about the genes associated with seizures/epilepsy. Collating this data can help uncover epilepsy genes, pathways and treatments that would otherwise be overlooked. We aimed to collate and structure these data into a database, and use the database to identify novel epilepsy genes and pathways, and to prioritise promising treatments.

Methods: We collated all the genes associated with all types of seizures/epilepsy in all species, and quantified the supporting evidence for each gene, by manually screening ~10,000 publications, and by extracting data from existing databases.

Results: The largest published dataset of epilepsy genes includes only 977 genes, whereas our database ( includes 2876 genes, which demonstrates that the number of genes that can potentially contribute to seizures/epilepsy is much higher than previously envisaged. We use our database to identify 12 hitherto unreported polygenic epilepsy genes, and 479 high-confidence monogenic epilepsy genes, and 394 more biological pathways than identified using the previous largest epilepsy genes dataset. We use a unique feature of SAGAS—the number of citations for each gene—to demonstrate that a drug is more likely to affect seizures if there is more evidence that the genes it affects are associated with seizures, and we use these data to identify promising candidate antiseizure drugs.

Significance: This database offers insights into the causes of epilepsy and its treatments, and can accelerate future epilepsy research.

Genetic Variants in Epilepsy Gene Identified

Article published by Medical Xpress

Featuring the work of former CURE Epilepsy Grantee Dr. Gemma Carvill

Investigators have discovered a new method to determine whether individual genetic variants in the epilepsy-associated gene SZT2 cause a neurodevelopmental disorder, according to a Northwestern Medicine study published in the journal Brain.

Pathogenic variants in SZT2 have been associated with the development of different neurodevelopmental disorders, including early-onset epilepsy and developmental delays. Additionally, the SZT2 protein plays an essential role in the mTORC1 signaling pathway, which helps promote cell growth and proliferation.

Classifying these variants as either likely benign or pathogenic, however, has remained a challenge due the large size of SZT2—it contains more than 3,400 amino acids—as well as its lack of crystal structure and functional domains.

“There are many different amino acids that can be mutated and become missense variants, so it’s very challenging to tell which are pathogenic and which are benign. That’s why high-throughput studies like this are so important,” said Gemma Carvill, Ph.D., assistant professor in The Ken and Ruth Davee Department of Neurology Division of Epilepsy and Clinical Neurophysiology and senior author of the study.

For the current study, Carvill’s team recruited twelve individuals who carried biallelic SZT2 variants of which one or more were classified as variants of uncertain significance.

Using CRISPR-Cas9 genome editing, the investigators engineered cells to contain patient-specific missense SZT2 variants and performed a functional cell assay that separated cells based on whether the mTORC1 signaling pathway was active or inactive.

The investigators then used next-generation sequencing to determine which SZT2 missensevariants retained function and which lost function and were likely to be pathogenic.

Ultimately, they discovered a recurrent in-frame deletion—when one amino acid is deleted out of the protein—and was determined to be a loss-of-function variant and reclassified as likely pathogenic.

Common Risk Variants for Epilepsy are Enriched in Families Previously Targeted for Rare Monogenic Variant Discovery

Abstract found in The Lancet Discovery Science


Background: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies.

Methods: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry.

Findings: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5×10?9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5×10?11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases.

Interpretation: The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known genetic etiology.

Discovery of Genetic Variants Linked to Febrile Seizures

Article published in Statens Serum Institut News, original research published in Brain

A large-scale case-control study implicates genes critical for fever response and genes for communication between nerve cells.

It is usually an unexpected and frightening experience for parents when their child has a febrile seizure. Occurring in 3-5% of infants febrile seizures are the most common type of abnormal brain activity during childhood. While most febrile seizures are benign and self-limiting with no recurrence, about 7% of children with febrile seizures will later develop epilepsy.

Now, a new international genetic study led by researchers from Statens Serum Institut (SSI) in Copenhagen and conducted in collaboration with other research groups in Denmark and Australia have identified seven novel regions of the genome linked to febrile seizures in the largest case-control study reported for this common childhood disorder.

The research has just been published in the leading international neurological journal Brain.

Genes related to fever response

The researchers analyzed variants in the DNA of 7,635 children from Denmark and Australia, who had experienced one or more episodes of febrile seizures. They also analyzed a control group of 83,966 children without febrile seizures.

Almost 7 million genetic variants were interrogated and the study identified seven new gene regions robustly linked to increased risk of developing febrile seizures. The study also confirmed four previously known genetic associations for febrile seizures established by the same team in 2014.

Two of the new regions contained genes of major importance in the development of fevers in mammals. For one gene, called PTGER3, the mechanism has been elucidated in mouse experiments. When this gene was silenced in a specific brain region called the median preoptic nucleus, the mice were unable to develop fevers. Another gene called IL10 encodes a signaling molecule that normally functions to suppress fevers.

Dr. Bjarke Feenstra, a senior researcher and group leader at Statens Serum Institut in Denmark, who was the lead author of the study, said: “The connections to fever response are intriguing. We hypothesize that genetic changes that affect the way the PTGER3 and IL10 genes function may lead to a more pronounced fever response, which in turn could increase the susceptibility of children to febrile seizures”.

Genetic Testing Before Epilepsy Surgery – An Exploratory Survey and Case Collection From German Epilepsy Centers

Abstract, originally published in Seizure

Introduction: Genetic testing in people with epilepsy may support presurgical decision-making. It is currently unclear to what extent epilepsy centres use genetic testing in presurgical evaluation.

Methods: We performed an exploratory survey among members of the German Society for Epileptology to study the current practice of genetic testing in presurgical evaluation at the respective sites. Survey participants contributed educational case reports.

Results: The majority of participants consider genetic testing to be useful in individuals with familial syndromes or phenotypic features suggesting a genetic etiology. We report 25 cases of individuals with a confirmed genetic diagnosis that have previously undergone epilepsy surgery. Our cases demonstrate that a genetic diagnosis has an impact on both the decision-making process during presurgical evaluation, as well as the postoperative outcome.

Conclusion: Genetic testing as part of the presurgical work-up is becoming increasingly established in epilepsy centres across Germany. mTORopathies and genetic hypothalamic hamartomas seem to be associated with a generally favourable surgical outcome. Synaptopathies and channelopathies may be associated with a worse outcome and should be considered on a case-by-case level. Prospective studies are needed to examine the impact of an established genetic diagnosis on postsurgical outcome.

Gene Mutation Leads to Epileptic Encephalopathy Symptoms, Neuron Death in Mice

Abstract, originally published in University of Illinois News Bureau

Mice with a genetic mutation that’s been observed in patients with epileptic encephalopathy, a severe form of congenital epilepsy, exhibit not only the seizure, developmental and behavioral symptoms of the disorder, but also neural degeneration and inflammation in the brain, University of Illinois Urbana-Champaign researchers found in a new study. The findings highlight the mutation as an important part of the disease’s pathology and a potential target for treatment.

Patients with epileptic encephalopathy begin having seizures when they are born, and display progressive developmental delay, intellectual disability and autismlike behavior, said study leader Hee Jung Chung, a professor of molecular and integrative physiology.

“The dogma regarding epileptic encephalopathy has been that the epileptic seizures are driving the pathogenesis of intellectual disability and developmental delay. But we wanted to answer the question, is it really just the seizures driving the intellectual disability and developmental delay?” Chung said. “This study is the first to show that expressing this human epileptic encephalopathy mutation in mice can cause not only spontaneous seizure and intellectual disability, but also neural degeneration.”

In the new study, published in the Proceedings of the National Academy of Sciences, Chung’s group, in collaboration with psychology professor Justin Rhodes and molecular and integrative physiology professors Eric Bolton and Catherine Christian-Hinman, bred a population of mice with the gene mutation. The researchers studied the mice from birth to observe whether they developed symptoms and how the mutation affected the expression of the potassium channels as well as their brains.

The mice developed spontaneous seizures analogous to human patients, who begin having seizures as infants. The mice also had an increase in mortality – half of mice with the mutation died as juveniles. The surviving mice showed significant deficits in learning and memory, as well as repetitive behaviors associated with human autistic behavior.

Accelerated Long-Term Forgetting in Adult Patients with Genetic Generalized Epilepsy

Summary, originally published in Epilepsia

Objective: Accelerated long-term forgetting (ALF) has been demonstrated among children but not adults with genetic generalized epilepsy (GGE). We investigated (1) how forgetting patterns of verbal and visuospatial material differ between patients with GGE and healthy controls (HCs) and (2) whether ALF is associated with ictal or interictal epileptic activity.

Methods: Forty-two patients with GGE (39, 92.9% experiencing seizures) were compared to 57 HCs in word, logical story, and Rey–Osterrieth complex figure recall tasks by testing after intervals of 30 min and 4 weeks. Ambulatory electroencephalography (EEG) was performed before testing to detect generalized epileptic activity, and patients were asked to document the number of seizures during the 4-week interval.

Results: A two-way repeated measures ANOVA indicated that individuals with GGE have different forgetting patterns in comparison to HCs in tasks of word (delay by group interaction F1.5, 142.5 = 4.5, p = .02, ?2??p2 = .04) and figure (F2, 194 = 15.9, p < .001, ?2??p2 = .14) but not story (F1.6 151.1 = .5, p = .58, ?2??p2 = .005) recall. Last learning trial-adjusted scores of word recall were comparable between HCs and patients with epilepsy (PWEs) at 30 min (p = .21) but not at 4 weeks (p = .006). Individuals with GGE performed worse than HCs in figure recall at 30 min and 4 weeks (p < .001), with lower performance after the 4-week interval present only among seizure-positive and EEG-positive individuals (p < .001) during subgroup analysis. Performance on memory tests was unrelated to overall seizure frequency, the number of antiseizure drugs used, and epilepsy duration.

Significance: Our study supports the presence of accelerated long-term forgetting in a task of word recall among adult patients with genetic generalized epilepsy (GGE). The pattern of forgetting visuospatial information suggests greater forgetting of material before the first delay and ongoing deficits among patients with epilepsy with epileptic activity. Future studies should confirm our findings and investigate the functional or pathological mechanisms of memory dysfunction in GGE.

Defining Dravet syndrome: An Essential Pre-Requisite for Precision Medicine Trials

Abstract, originally published in Epilepsia

Objective: The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials.

Methods: Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome.

Results: Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5–20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ?30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months–25.4 years) and 15.5 months (range 4 months–8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%.

Significance: An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.

An Astounding Find Reveals a Rare Cause of Epilepsy

Research originally published in Cell Reports

Researchers at The University of Queensland, working to gain a better understanding of how brain cells work, have discovered the underlying mechanism of a rare genetic mutation that can cause epilepsy.

Dr. Victor Anggono from UQ’s Queensland Brain Institute said his team made the ground-breaking findings while researching nerve cell communications, which are an important process in normal brain function.

”We’re both excited and astounded to make such an important contribution to the field of cellular and molecular neuroscience,” Dr. Anggono said.

He stressed that the mutation was extremely rare, with only one reported case in the world to date.

Dr. Anggono’s team studied protein structures, called receptors, that are attached to cell surfaces to make the discovery.

”It turns out that this particular mutation causes receptors in brain cells to behave differently, resulting in an imbalance in brain cell communication – and that can lead to disorders,” he said.

”For example, cells that talk too much are associated with epilepsy and unwanted cell death – while cells that talk too little have negative impacts on learning and memory.

”There are also many examples of other mutations in the same gene that are known to be associated with epilepsy.

”What we know is that this receptor is critical for brain function and can lead to epilepsy when its function is misregulated.

”The findings point the way for further research to understand and potentially treat similar mutations.”

The imbalance in brain cell communications is also believed to be involved in neurological conditions including Alzheimer’s disease and autism spectrum disorders.

Dr. Anggono said the research provided a springboard for developing personalized medicines to target the mutation.

”Receptor blockers which have been approved by the US Food and Drug Administration (FDA), are already available for human treatment, but the challenge is to find the right ones and see how patients respond,” he said.

Genetic Associations of Neurodevelopmental Disorders with Epilepsy in Adults

Summary, originally published on

Often, genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) focus largely on children, leaving a scarcity of data regarding adult patients. A study published in Genetics in Medicine analyzed genetic associations of NDDE in adults and elderly patients.

A total of 150 patients with NDDE underwent conventional karyotyping, FMR1 testing, chromosomal microarray, and panel sequencing. When cases remained unresolved, exome sequencing was performed.

“Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE,” the study authors concluded.