Study ID’s Genetic Mutations Contributing to Adult Epilepsy

Article published by Harvard Medical School

Epilepsy affects approximately 1-in-26 people and the most common form, known as temporal lobe epilepsy (TLE), often cannot be adequately treated with anti-seizure medications. Patients with this form of epilepsy may require neurosurgery to provide relief from seizures. 

The condition’s origins and progression are not well understood, and it has been unclear if genetic mutations may contribute to TLE. 

A new study by Harvard Medical School investigators at Brigham and Women’s and Massachusetts General hospitals, in collaboration with colleagues at Boston Children’s Hospital, sheds new light on the role of somatic mutations in TLE — DNA alterations that occur after conception — and suggests the potential of using existing cancer therapies to treat TLE that is resistant to anti-seizure medications. The results are published in JAMA Neurology.  

“Somatic mutations are likely an underappreciated and significant cause of neurologic diseases, particularly for epilepsy,” said co-first author Sattar Khoshkhoo, HMS instructor in neurology at Brigham and Women’s Hospital. 

“And as an epileptologist who specifically focuses on epilepsy genetics in my clinical practice, my underlying assumption is that all epilepsy is due to genetic causes until proven otherwise. We are discovering more and more new genetic pathways in epilepsy, which is important because our goal is to offer more specific, targeted treatments for individual patients and offer guidance on who would benefit from one treatment versus the other,” he said. 

“Our results provide the first solid insight into this most common form of adult epilepsy,” said co-senior author Christopher A. Walsh, the Bullard Professor of Pediatrics and Neurology at Boston Children’s Hospital. 

“It shows that epilepsies that are not usually inherited can still be genetic in their mechanism. And the specific genetic pathway we have identified, RAS/MAPK, opens a whole new avenue of therapeutic possibilities, since anti-cancer drugs that target this pathway may have unexpected uses in epilepsy,” Walsh said.

CURE Epilepsy Discovery: CURE Epilepsy Funds Research to Investigate Mechanisms of Genetic Epilepsies

Key Points:

  •  As part of its quest to find a cure for the epilepsies, CURE Epilepsy has led initiatives, including one focused on genetic epilepsies.
  • The impact of CURE Epilepsy on epilepsy genetics over the years has been broad, ranging from the discovery of individual genes that are associated with epilepsy, to contributions in rare epilepsies, to the Epilepsy Genetics Initiative (EGI).
  • In this CURE Epilepsy Discovery, we highlight the efforts of EGI and the centralized database to store and analyze genetic signatures associated with epilepsy; we also summarize its impact on people living with genetic epilepsies and the epilepsy research community.
  • We then feature three recent CURE Epilepsy grants awardees who have contributed to numerous aspects of genetic epilepsies ranging from the development and application of new technology to study epilepsy genetics, to studying specific genes and their contributions to epilepsy, to exploring the epigenomic pattern associated with epilepsy.
  • The three CURE Epilepsy grants awardees are Dr. Heather Mefford at St. Jude Children’s Research Hospital, and Drs. Gemma Carvill and Jeff Calhoun, both at Northwestern University.
  • Adding to this work is a recent endeavor, the Rare Epilepsy Partnership Award to find cures for rare forms of epilepsies.


Deep Dive

Epilepsy occurs when the normal electrical signaling between brain cells (neurons) is disrupted; however, the exact causes of epilepsy are not fully understood. Broadly speaking, epilepsy can have several potential causes, and one of these causes is genetic. Epilepsy is said to have a genetic cause if the seizures are caused as a result of a genetic defect or mutation.[1] These epilepsies are very diverse and the underlying gene or genes involved are not always known. Having a genetic cause for the epilepsies does not necessarily mean that the gene mutation was inherited; sometimes, the genetic variant or mutation may occur spontaneously in a child without being present in either parent; these are called “de novo” mutations.[2] Some epilepsies that have a genetic cause may have additional environmental causes as well.

With the emergence of novel technologies, our knowledge about the genes impacting the epilepsies has grown substantially in the last several years. The increased availability and steadily decreasing costs of genetic technology to analyze one’s entire genetic makeup has meant that scientists can identify many more genes that may be associated with epilepsy. By identifying particular genes associated with epilepsy, we can create animal models to simulate epilepsy in the lab and answer questions regarding the mechanisms by which a particular genetic mutation gives rise to seizures. The ultimate goal of identifying genes associated with epilepsy is to develop targeted therapies for a particular gene.[3] An even more exciting prospect of understanding the genes associated with epilepsy is the prospect of targeting the genes to potentially stop the onset of seizures before it even begins! Understanding the genetic mechanisms of epilepsy is helped by continued advances in genetic technologies, sophisticated ways to store and analyze huge datasets, and the capability to perform experiments in animals and translate findings to the human condition, thus setting the scene for precision medicine in genetic epilepsy.[4]

CURE Epilepsy’s Epilepsy Genetics Initiative (EGI) was formed in 2015 and was instrumental in creating a centralized database that holds the genetic (whole exome sequence) data of people with epilepsy. Whole exome sequencing is a way to analyze a person’s unique DNA fingerprint pattern. By analyzing and re-analyzing genetic data as techniques advance, EGI aimed to advance our understanding of the genetic causes of epilepsy so that clinicians could better and more effectively diagnose, treat, and even prevent genetic epilepsies. Thanks to GI, new genes underlying epilepsy have been found; re-analysis of patient genetic materials has led to new diagnoses for those with genetic epilepsy. Additionally, there have been benefits to the epilepsy community as well. EGI is a community resource, and the whole exome data within the database is available to the research community. All the genetic data are de-identified; hence, there is no way for information to be linked back to a patient or the patient’s family.

In addition to the formation of a centralized database, CURE Epilepsy is also intently focused on identifying and funding cutting-edge research in epilepsy curing the epilepsies. This CURE Epilepsy Discovery article will also outline the work of three CURE Epilepsy grants awardees: Dr. Heather Mefford, her mentee Dr. Gemma Carvill, and Dr. Carvill’s mentee Dr. Jeff Calhoun. By funding these outstanding researchers investigating mechanisms underlying genetic epilepsies, CURE Epilepsy is actively supporting the development of the future generation of epilepsy researchers and scientists.

Dr. Heather Mefford is currently at St. Jude Children’s Hospital and received a CURE Epilepsy Award in 2019. As part of this grant, she investigated the causes of Developmental and Epileptic Encephalopathies (DEE). DEE are severe, early-onset epilepsy disorders that are associated with developmental delay and seizures that are resistant to treatment. A specific genetic cause can be correctly identified in about half of the cases of DEE, and this identification can be associated with a correct diagnosis and a favorable prognosis (course of the disease). Also, a proper diagnosis can help the clinician connect the family to appropriate support groups as well. However, about half of those with DEE are not accurately diagnosed, even with state-of-the-art genetic testing. Work done by Dr. Mefford’s team looked for a different cause in those with DEE that are not diagnosed. Her team looked at abnormal methylation – a type of chemical modification in the DNA structure – in individuals with DEE that did not have a diagnosis or cause. Methylation is considered an “epigenetic” modification – these modifications are not hardwired into one’s DNA, but turn genes “on” and “off.” [5]

Work done by Dr. Mefford’s team has led to the development of “methylation signature” analysis by which methylation patterns of individuals with DEE without a known diagnosis can be studied. Methylation patterns have been studied for other disorders, but not comprehensively for epilepsy. More work is needed to understand the precise methylation signature in DEE; however, the goal is that one day, by diagnosing methylation patterns, we will be able to improve the diagnosis of those with DEE. An accurate diagnosis could also improve the prognosis, and clinicians will be able to accurately offer genetic counseling services to patients and families. There is also the hope of being able to provide targeted precision therapies for these specific methylation patterns.

In addition to recognizing methylation patterns, Dr. Mefford’s team has also been instrumental in characterizing de novo mutations in a gene called PPP3CA and the role of these mutations in causing epilepsy. Since mutations in the PPP3CA gene are very rare, the scientists working on this gene pooled data from different sources including CURE Epilepsy’s EGI. By collecting and analyzing data in this way, Dr. Mefford and her collaborators were able to show that mutations in the PPP3CA gene were a lead factor in the development of specific childhood-onset epilepsy. Dr. Mefford and her collaborators were also able to understand how mutations in the PPP3CA gene cause epilepsy. This gene is responsible for the production of a protein in the brain known as calcineurin; this substance is responsible for key functions in the brain, including proper signaling between neurons. Mutations in PPP3CA interfere with the ability of calcineurin in electrical transmission in the brain leading to neurodevelopmental disorders and epilepsy.[6] Hence, Dr. Mefford’s work funded and supported by CURE Epilepsy is laying the foundation for the study of epigenetics, particularly methylation, in DEE.[7]

In addition to her work as a physician caring for pediatric patients living with severe epilepsy syndromes, and her work as an epilepsy genetics researcher (described above), Dr. Mefford is also passionate about supporting the next generation of epilepsy scientists. One of her trainees, Dr. Gemma Carvill is an independent epilepsy researcher and leads her research program at Northwestern University. Dr. Carvill received CURE Epilepsy’s Taking Flight Award in 2015. The Taking Flight Award was developed to foster and develop the careers of young epilepsy investigators by allowing them to develop a research focus independent of their mentor(s). The Taking Flight Award came at an opportune time in Dr. Carvill’s career and was instrumental in directing her scientific interests in the field of epilepsy genetics.

Dr. Carvill investigated the genetic causes of the most severe forms of epilepsy known as epileptic encephalopathy. Childhood epileptic encephalopathies are a group of epilepsy disorders that are profoundly treatment-resistant; children with this condition also have severe cognitive and neurological deficits.[8,9] Specifically, she was interested in exploring the epigenomic causes of epileptic encephalopathy, i.e., studying genes that turn the activity of other genes “on” or “off”. By using a new genome-editing technology called CRISPR-Cas9 to introduce mutations in a class of genes known as “chromatin remodelers”, she was able to study the mechanisms by which these genes cause seizures.

To study the epigenomic causes of epilepsy, she studied de novo mutations in the CUX2 gene. In an international study done with Dr. Gaetan Lesca of the Lyon University Hospital, Dr. Carvill found mutations in the CUX2 gene in nine patients who started having seizures early in life, had treatment-resistant epilepsy, and severe developmental delay. Since mutations such as the one in the CUX2 gene are rare, several research teams must come together to provide statistical rigor. By identifying mutations in the CUX2 gene in epileptic encephalopathy, this gene can potentially be targeted to develop therapies.[10]

Another work done by Dr. Carvill and her team looked at another epilepsy-associated gene called SZT2. Earlier studies have shown an association between mutations in the SZT2 gene and some neurodevelopmental disorders,[11] but the full extent of the impact of mutations in this gene and its link to epilepsy was not yet known. It is also known that the SZT2 gene plays a critical role in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway which is essential in cell growth and proliferation. By using state-of-the-art genetic technologies, Dr. Carvill’s team determined that mutations in the SZT2 gene were likely pathogenic and that the mutation is more prevalent in individuals of Ashkenazi Jewish ancestry. The direct implication of these findings is the knowledge that this gene should be included in prenatal gene panels. Given that the SZT2 gene interacts with the mTORC1 pathway, and since the mTORC1 pathway is implicated in other neurodevelopmental diseases as well, there are also implications for potential treatment strategies involving the mtORC1 signaling pathway.[12]

Since receiving the Taking Flight Award, Dr. Carvill has been awarded other accolades also; notably the prestigious Innovator’s Award from the NIH. As part of this award, she will continue her work on genetic epilepsies, specifically exploring if cell-free DNA (cfDNA) could be used as a non-invasive avenue for epilepsy diagnosis and perhaps as a biomarker.[13] At Northwestern University, she too is mentoring a Taking Flight grantee, Dr. Jeffrey Calhoun.

Carrying on the tradition, Dr. Jeffrey Calhoun received the Taking Flight Award in 2022 and his research will look at genetic variants that are linked to the risk for epilepsy. He is developing methods to determine which genetic variants near SCN1A, a gene implicated in epilepsy, alter SCN1A gene expression. This technique eventually could also be used to study variants that impact other genes associated with epilepsy. By understanding the pattern of gene expression and the variants that may cause variable expression, Dr. Calhoun’s work aims to impact the diagnosis and care of those with genetic epilepsies. 

Hence, the work of Drs. Mefford, Carvill, and Calhoun together aim to develop new technologies to better understand genetic epilepsies, which many times, can be catastrophic. In addition to funding Dr. Mefford and her mentees, CURE Epilepsy is making an incredible impact on rare epilepsies, having inaugurated the Rare Epilepsy Partnership Award this year. With this partnership award providing funding for the rare and devasting epilepsies, we can not only provide hope but more understanding that will one day be translated into a cure.


Literature Cited:

  1. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology Epilepsia. 2017 Apr;58:512-521.
  2. Steinlein OK. Genetics and epilepsy Dialogues Clin Neurosci. 2008;10:29-38.
  3. Szepetowski P. Genetics of human epilepsies: Continuing progress Presse Med. 2018 Mar;47:218-226.
  4. Knowles JK, Helbig I, Metcalf CS, Lubbers LS, Isom LL, Demarest S, et al. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress Epilepsia. 2022 Oct;63:2461-2475.
  5. What is Epigenetics? Available at: Accessed April 9, 2023.
  6. Myers CT, Stong N, Mountier EI, Helbig KL, Freytag S, Sullivan JE, et al. De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures Am J Hum Genet. 2017 Oct 5;101:516-524.
  7. Hebbar M, Mefford HC. Recent advances in epilepsy genomics and genetic testing F1000Res. 2020;9.
  8. Cross JH, Guerrini R. The epileptic encephalopathies Handb Clin Neurol. 2013;111:619-626.
  9. Jehi L, Wyllie E, Devinsky O. Epileptic encephalopathies: Optimizing seizure control and developmental outcome Epilepsia. 2015 Oct;56:1486-1489.
  10. Chatron N, Møller RS, Champaigne NL, Schneider AL, Kuechler A, Labalme A, et al. The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant Ann Neurol. 2018 May;83:926-934.
  11. Kariminejad A, Yazdan H, Rahimian E, Kalhor Z, Fattahi Z, Zonooz MF, et al. SZT2 mutation in a boy with intellectual disability, seizures and autistic features European Journal of Medical Genetics. 2019 2019/09/01/;62:103556.
  12. Calhoun JD, Aziz MC, Happ HC, Gunti J, Gleason C, Mohamed N, et al. mTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion Brain. 2022 Jun 30;145:1939-1948.
  13. Carvill GL. Cell-free DNA sequencing approaches to define the genetic etiology of unexplained epilepsy. Accessed April 9, 2023.

Epilepsy Research News: April 2023

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


Predicting Seizures in Temporal Lobe Epilepsy

Seizures can be predicted more than 30 minutes before they occur in patients with temporal lobe epilepsy, possibly opening the door to preventing seizures from happening, according to a new study. Researchers used electroencephalography (EEG), which measures electrical activity in the brain, to examine periods of potentially heightened risk for seizures known as “pro-ictal states.” The researchers were able to detect pro-ictal states in patients with temporal lobe epilepsy approximately 30 minutes or more before seizure onset. This information could lead to the development of electrical stimulation or drug therapies aimed at preventing seizures in people with this type of epilepsy. “The ability to predict seizures before they occur is a major step forward in the field of epilepsy research,” a study author stated.

Learn More


Altered Brain Signaling in People with Epilepsy Detected Through Non-Invasive Approach

New research has found that large-scale changes in the activation of neurons can be detected in the brains of people with temporal lobe epilepsy during a resting state (a state in which the brain is not stimulated by tasks or input), even when no seizure is occurring. The non-invasive approach uses EEG to detect changes in brain activity and could lead to a new method to aid in the diagnosis of epilepsy. While the brain is at rest, spontaneous waves of neuronal activation are constantly generated in a phenomenon called a “neuronal avalanche.” The researchers demonstrated that even during the resting state it is possible to detect a change in the neuronal avalanches in the brains of people with epilepsy. The researchers suggested that this method might be used as a preliminary diagnostic method, especially for difficult cases where standard scalp EEG fails to detect seizures, but additional investigations are necessary.

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Simple Blood Test Shows Potential Biomarker to Distinguish Epileptic from Non-Epileptic Psychogenic Seizures

Researchers have discovered higher levels of immune proteins in the blood before and after an epileptic seizure. In this study, researchers discovered that levels of five inflammation markers, or proteins, were elevated in people with temporal or frontal lobe epilepsy who had experienced a seizure. Among patients with psychogenic non-epileptic seizures (PNES), however, there was no change in the protein levels. These proteins, therefore, have the potential to be future biomarkers for a diagnosis of epilepsy. Diagnosing epilepsy from a simple blood draw would provide a significant advantage over the current diagnostic standards which may include admittance to a hospital for several days with constant video and EEG surveillance.

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Study Investigates Therapy for Treatment-Resistant Epilepsy

In a new study, researchers report that sodium selenate could be the first curative drug therapy for epilepsy. The study, conducted in an animal model of drug-resistant epilepsy, revealed sodium selenate to have a long-lasting effect (after months of stopping the medication) in reducing the frequency of seizures and in 30% of cases stopping them altogether. Sodium selenate also improved other aspects of epilepsy such as memory, learning, and sensor-motor functioning. The researchers will next begin a clinical trial of sodium selenate as a curative treatment in patients with drug-resistant epilepsy. “Despite the cost of the disease and the enormous amount of research into it, there has not been a single therapy developed to prevent the development of epilepsy,” stated a study author. “This Phase 2 clinical trial, if effective, has the potential to tackle a disease that is an enormous global burden as well as being truly transformative for people who are impacted by often daily seizures, with no respite.”

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Insights into the Drivers of Glioma-Related Epilepsy

Researchers at Baylor College of Medicine, including former CURE Epilepsy grantee Dr. Jeff Noebels, report that glioma tumors in the brain can interfere with the ability of surrounding neurons to handle potassium, an important ion in neuronal communication. The disruption of this normal neural function drives seizures and favors the progression of epilepsy. The team found that patients who have seizures have increased expression of genes involved in the formation of neuronal connections or synapses. In both humans with glioma and animal models, the researchers identified one of the genes, IGSF3, as the driver that mediated seizures in glioma-related epilepsy. The team found that IGSF3 suppresses the ability of these cells to take up potassium, which leads to its accumulation of this ion and then seizures. “Our studies reveal that tumor progression and seizures are triggered by disruption of potassium handling. The findings support further studies into novel strategies to control seizures and tumor growth,” stated one of the study’s authors.

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Association of FAT1 with Focal Epilepsy and Correlation Between Seizure Relapse and Gene Expression Stage

Abstract found on PubMed

Purpose: The FAT1 gene encodes FAT atypical cadherin 1, which is essential for foetal development, including brain development. This study aimed to investigate the relationship between FAT1 variants and epilepsy.

Methods: Trio-based whole-exome sequencing was performed on a cohort of 313 patients with epilepsy. Additional cases with FAT1 variants were collected from the China Epilepsy Gene V.1.0 Matching Platform.

Results: Four pairs of compound heterozygous missense FAT1 variants were identified in four unrelated patients with partial (focal) epilepsy and/or febrile seizures, but without intellectual disability/developmental abnormalities. These variants presented no/very low frequencies in the gnomAD database, and the aggregate frequencies in this cohort were significantly higher than those in controls. Two additional compound heterozygous missense variants were identified in two unrelated cases using the gene-matching platform. All patients experienced infrequent (yearly/monthly) complex partial seizures or secondary generalized tonic-clonic seizures. They responded well to antiseizure medication, but seizures relapsed in three cases when anti-seizure medication were decreased or withdrawn after being seizure-free for three to six years, which correlated with the expression stage of FAT1. Genotype-phenotype analysis showed that epilepsy-associated FAT1 variants were missense, whereas non-epilepsy-associated variants were mainly truncated. The relationship between FAT1 and epilepsy was evaluated to be “Strong” by the Clinical Validity Framework of ClinGen.

Conclusions: FAT1 is a potential causative gene of partial epilepsy and febrile seizures. Gene expression stage was suggested to be one of the considerations in determining the duration of anti-seizure medication. Genotype-phenotype correlation helps to explain the mechanisms underlying phenotypic variation.

Epilepsy Research News: March 2023

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


Epilepsy-Causing Neural “Hubs” in Children

A new method of determining which brain cells lead to seizures in children has been developed. The team used noninvasive techniques and advanced computational methods to measure the electric and magnetic signals generated by neural cells to identify brain “hubs” responsible for the generation of seizures in children with epilepsy. This team retrospectively analyzed electroencephalography (EEG) and magnetoencephalography data recorded from 37 children and young adults with drug-resistant epilepsy who had neurosurgery. They then created a virtual model of the brain and virtually implanted sensors at locations where invasive EEG contacts had been placed during neurosurgery. The researchers found that the virtual sensors could non-invasively identify highly connected hubs in patients with drug-resistant epilepsy. The authors stated that the discovery could help to identify areas of the brain that generate epileptic activity in children with drug-resistant epilepsy in a non-invasive way.

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Potential Cause of Infantile and Epileptic Spasms Syndrome

New research featuring the work of a former CURE Epilepsy grantee, Dr. Chris Dulla, and colleagues suggests that the timing of the death of a subset of neurons in the brain shortly after birth may be partly to blame for infantile and epileptic spasms syndrome (a form of which is also called infantile spasms (IS) or West syndrome), a childhood epilepsy with poor outcomes. These neurons are responsible for providing inhibitory input to the brain; the lack of these neurons may lead to too much excitation and epileptic spasms. The research suggests that it may be the timing of inhibitory neuron cell death which is important, not just the fact that it occurs. This research may suggest a potential target for the future development of treatments for infantile and epileptic spasms.

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Underreported Symptoms in Patients with Genetic Epilepsy

A new study increases our understanding of symptoms associated with changes in the STXBP1 gene, one of the most common genetic causes of childhood epilepsies and neurodevelopmental disorders. By systematically mapping symptoms and assessing their impacts on patients and their caregivers, the researchers identified previously underreported symptoms beyond just neurological symptoms. To understand these symptoms, the researchers performed more than 24 hours of interviews among 19 caregivers of 16 individuals with STXBP1-related disorders and seven healthcare professionals. In doing so, the researchers created a so-called “disease concept model,” which is meant to determine which outcomes are relevant in everyday clinical practice. These results may serve as an important foundation for future trials assessing the effectiveness of therapeutic interventions for all related symptoms.

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How Cannabidiol Counters Epileptic Seizures

A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy. The new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function but can also be hijacked by disease to promote seizures. The work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings suggest for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment. “Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” stated a study author. “The study also clarified, not just how CBD counters seizures, but more broadly how neural circuits are balanced in the brain.”

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How the Brain’s Immune System Response Worsens Epilepsy

In a new study using a fruit fly model of epilepsy, researchers describe a chain of events that link the brain’s immune system response to worsening seizures. The researchers used flies with a mutation in a gene known as the prickle gene, similar to the mutation in the PRICKLE gene found in humans with progressive myoclonus epilepsy with ataxia, and found that this particular mutation can lead to increases in a condition called oxidative stress. The researchers found that oxidative stress can activate the brain’s resident immune cells (called glia), which in turn triggers more severe seizures. “We have provided genetic proof that both oxidative stress and activation of the brain immune system make epilepsy worse,” stated a study author. “This is hugely significant because our data suggest that we can now repurpose exceedingly well-tolerated anti-inflammatory compounds as well as perhaps antioxidants to help control epilepsy progression.”

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Study Identifies Cause for Mysterious Cases of Epilepsy in Children

Article published by Science Daily

Epilepsy is present in 4% of the population, and is among the most common brain disorders in children. Modern medicine can prevent most seizure recurrences, but approximately 20% of patients do not respond to treatment. In these cases, the reason may originate in patches of damaged or abnormal brain tissue known as “malformations of cortical development” (MCD), which results in a diverse group of neurodevelopment disorders.

Surgical resection or removal of the patch can cure the seizures, and epilepsy surgery to improve neurological outcomes is now a key part of the modern medical armamentarium, but what causes the patches has largely remained a mystery.

Writing in the January 12, 2023 issue of Nature Genetics, researchers at University of California San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine, collaborating with an international consortium of more than 20 children’s hospitals worldwide, report a significant breakthrough in understanding the genetic causes of MCD.

The team conducted intensive genomic discovery using state-of-art somatic mosaic algorithms developed by the National Institutes of Health-sponsored Brain Somatic Mosaicism Network, of which UC San Diego is a member.

“We tried our best to detect mutations in as little as 1 percent of cells,” said co-first author Xiaoxu Yang, PhD, a postdoctoral scholar in Gleeson’s lab. “Initially we failed. To solve these problems, we needed to develop novel artificial intelligence methods to overcome barriers in sensitivity and specificity.”

The team ultimately identified 69 different genes carrying somatic brain mutations, the majority of which have never previously reported in MCD.

Epilepsy Research News: January 2023

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


Genetic Testing for Epilepsy Improves Patient Outcomes

Genetic testing in patients with epilepsy can inform treatment and lead to better outcomes in many cases, according to a new study. The study, led and funded by the genetic testing company Invitae, included patients referred for genetic testing between 2016 and 2020 whose testing revealed a positive molecular diagnosis. The investigators asked the patient’s healthcare providers how the results of the genetic test impacted the patient’s treatment plan and outcomes. Of the 418 children and adults with epilepsy who were included in the study, nearly half saw changes in their treatment plans such as a change in medication or referral to a specialist, after genetic testing revealed new information about their condition. The study also found that of 167 patients with follow-up information available, treatment changes were associated with improved patient outcomes including a reduction or elimination of seizures. The authors concluded that results support the use of genetic testing to guide the clinical management of epilepsy to improve patient outcomes. Learn more about genetic testing for epilepsy here.

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New Tools to Map Seizures and Improve Epilepsy Treatment

A new “tool” – a statistical model – has been developed to help doctors find precisely where seizures originate in the brain to increase the possibility of treating that specific region. Localizing where seizures begin is usually a costly and time-consuming process that can often require days to weeks of invasive monitoring. In this study, researchers aimed to shorten the time it takes to locate the seizure onset zone by studying patients’ brains, both when they weren’t having seizures and when their brains were stimulated with quick electrical pulses, to quickly create maps predicting where seizures begin. In the 65 patients studied, the model predicted the location of the onset of seizures and the ultimate success of surgical intervention with 79% accuracy. The researchers noted that this tool might be used to help clinicians identify the area where seizures begin in a less time-consuming process.

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Gene Therapy for Epilepsy

A recently published study shows that a potential new treatment can prevent seizures in mice by clearing the accumulation of a protein in the brain known as the tau protein. Researchers at Macquarie University recently found that accumulation of tau protein can lead to neurons becoming hyperexcited. Hyperexcited neurons that fire continuously can result in seizures and cognitive decline. In the newly published study, the researchers developed a gene therapy that uses a brain enzyme known as p38y to prevent this accumulation. When treated with the new gene therapy, mice with uncontrolled epilepsy had a better chance of survival in addition to reduced seizure susceptibility. The researchers note that their next step is to conduct a more detailed study in the laboratory, in hopes of eventually preparing the treatment for a possible clinical trial.

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World Health Organization (WHO) Focuses on Improving the Lives of People with Epilepsy

A technical brief published by the World Health Organization (WHO) called Improving the Lives of People with Epilepsy sets out the actions required to deliver an integrated approach to epilepsy care and treatment with the goal of meeting the multifaceted needs of people with epilepsy. In summary, the brief highlights the importance of:


  • Integrated services across the life-course, particularly at the primary care level

  • Access to anti-seizure medicines

  • Resources and training for the health and social services workforce

  • Anti-stigma and discriminatory legislation and practices; promoting and respecting the human rights and full social inclusion of people with epilepsy, their families and caregivers.

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Memory Impairment in Those with Epilepsy

People with chronic epilepsy often experience impaired memory. Researchers have now found a mechanism using a mouse model of epilepsy that could explain this impairment. Porous channels called ion channels within the brain allow electrically charged particles (ions) to flow into neurons, allowing neurons to communicate with each other. However, the researchers found changes in sodium ion channels within neurons of the hippocampus – an area of the brain important in learning and memory – that could lead to changes in the activity of these neurons and affect their normal function. When the researchers administered substances to restore the normal function of these channels, the firing properties of the neurons normalized, and the animals were better able to remember places they had visited. The study provides insight into the processes involved in memory retrieval. In addition, it provides support for the idea that the development of new drugs may improve the memory of epilepsy patients.

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CURE Epilepsy Grantee Announcement Fall 2022

CURE Epilepsy is honored to announce our newest CURE Epilepsy grantees. Our research grants are awarded for cutting-edge, novel research projects that seek to accelerate treatments, improve outcomes, and get us to cures so that we can live in a world free of seizures. This year’s grantees’ research will focus on a wide range of epilepsies – sudden unexpected death in epilepsy (SUDEP), sleep and epilepsy, genetic causes of epilepsy, Lafora disease, post-traumatic epilepsy, pediatric epilepsy, and focal epilepsy.

TAKING FLIGHT AWARD GRANTEES – $100,000 for one year 

This award seeks to promote the careers of early-career epilepsy investigators to allow them to develop a research focus independent of their mentor(s).

Jeffrey Calhoun, PhD
Northwestern University – Chicago, Illinois

With this grant, funded by the Joseph Gomoll Foundation, Dr. Calhoun’s research will work to develop a new method to assess the functionality of variants of the SCN1A gene.
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William Tobin, PhD
The University of Vermont and State Agriculture  – Burlington, Vermont

With a grant co-funded by the KCNT1 Epilepsy Foundation, Dr. Tobin will test strategies to optimize cutting-edge gene therapy methods for the gene KCNT1.
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Gerben van Hameren, PhD
Dalhousie University– Nova Scotia, Canada

Dr. van Hameren will study a possible way to prevent the development of post-traumatic epilepsy.
Learn More


CURE EPILEPSY AWARD GRANTEES – $250,000 over two years  

This award reflects CURE Epilepsy’s continued focus on scientific advances that have the potential to truly transform the lives of those affected by epilepsy, with prevention and disease modification as critical goals.

Gordon Buchanan, MD, PhD
University of Iowa Medicine – Iowa City, Iowa

For this grant, generously funded by The Joanna Sophia Foundation, Dr. Buchanan’s group will examine whether a signaling molecule called serotonin drives a time-of-day vulnerability to SUDEP (Sudden Unexpected Death in Epilepsy).
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Annaelle Devergnas, PhD
Emory University – Atlanta, Georgia

The hypothesis for Dr. Devergnas’ project is that frontal seizures disrupt the normal function of the brain structure called the pedunculopontine nucleus (PPN), leading to changes in sleep, and that manipulating PPN activity might restore normal sleep activity.
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Juliet Knowles, MD, PhD
Stanford School of Medicine – Palo Alto, California

For this project, Dr. Knowles and her team will study the therapeutic potential for targeting myelin plasticity in Lennox-Gastaut syndrome.
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CATALYST AWARD GRANTEES – $250,000 over two years 

The CURE Epilepsy Catalyst Award stimulates and accelerates the development of new, transformative therapies for epilepsy, moving promising preclinical and/or clinical research closer to clinical application.

James Pauly, PhD, Greg Gerhardt, PhD, and Matthew Gentry, PhD
University of Kentucky – Lexington, Kentucky

In collaboration with Enable Therapeutics, Drs. PaulyGerhardt, and Gentry developed a potential drug called VAL-1221 that can penetrate brain cells and degrade the aberrant sugar aggregates therein that cause LaFora disease. Having obtained promising initial results, this project will test the safety and brain distribution of this novel therapy.
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John Gledhill, PhD
Cognizance Biomarkers, LLC  – Philadelphia, Pennsylvania

Dr. Gledhill and the team at Cognizance will build upon their preliminary research showing that people with treatment-resistant epilepsy have differences in inflammation-associated proteins in the blood compared with those who do respond to treatment. For this project, the team proposes to extend their observations by assessing additional blood samples from treatment-resistant and treatment-responsive people with epilepsy and developing an algorithm to predict response to initial anti-seizure medications.
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Genetic Testing for Epilepsy Improves Patient Outcomes

Article published by Northwestern Medicine

Genetic testing in patients with epilepsy can inform treatment and lead to better outcomes in many cases, according to a new study published in JAMA Neurology.

Genetic causes are responsible for seizures in 30 percent or more of infants and toddlers and about 10 percent of adults with epilepsy, but genetic testing is not routinely done. Many insurers are hesitant to cover pricey genetic testing since there’s limited research demonstrating the benefits, which is why the findings of this study are significant, said Anne Berg, PhD, adjunct professor of Neurology in the Division of Epilepsy and Clinical Neurophysiology and co-author of the study.

“I think a lot of us have been really frustrated that there’s this highly effective diagnostic tool out there, genetic testing, that is very much underutilized or when it is utilized, it tends to be used very late in the disease course,” Berg said. “Epilepsy is not a single disease. It’s a symptom that is caused by a multitude of different diseases and a lot of these are genetic. With genetic testing, we now have that specificity in the diagnosis that can often lead to improvements in patient treatment and management. With this study, we looked at patients referred for genetic testing and received a positive molecular diagnosis to see if it made a difference for their care.”

The study, led and funded by genetic testing company Invitae, included patients referred for genetic testing between 2016 and 2020 whose testing revealed a positive molecular diagnosis. The investigators asked the patient’s healthcare providers how the results of the panel test impacted the patient’s treatment plan and outcomes.

New Tools Map Seizures in the Brain, Improve Epilepsy Treatment

Article published by John Hopkins University 

Two new models could solve a problem that’s long frustrated millions of people with epilepsy and the doctors who treat them: how to find precisely where seizures originate to treat exactly that part of the brain.

By helping surgeons decide if and where to operate, the tools developed by Johns Hopkins University researchers and newly detailed in the journal Brain, could help patients avoid risky and often-ineffective surgeries as well as prolonged hospital stays.

“These are underserved patients,” said Sridevi V. Sarma, associate director of Johns Hopkins Institute of Computational Medicine and head of the Neuromedical Control Systems Lab. “We want surgeries to go well, but we also want to prevent surgeries that may never go well.”

Using equations based on machine learning and calculus to reveal patterns in brain activity, the models identify where seizures begin in the brain. And they do it in just minutes.

Typically patients spend five to 14 days hospitalized with electrodes stuck to their heads, while doctors hope that they’ll have a seizure so that surgeons can map the brain, pinpoint the trouble spot, and plan how to remove it.

“This is a new paradigm,” said Joon-Yi Kang, a neurologist at Johns Hopkins Hospital, who co-authored the studies. “We’re getting more insights into specific brain networks. We’re not waiting around for seizures to happen.”