News Topics: Genetics

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.
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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. Pauly, Gerhardt, 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.”

De novo KCNA6 Variants with Attenuated KV1.6 Channel Deactivation in Patients with Epilepsy

Abstract found on Wiley Online Library

Objective: Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novosequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies.

Methods: Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two-electrode voltage-clamp.

Results: We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect pore lining S6 ?-helix of KV1.6. Prominent finding of functional characterisation in Xenopusoocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co-expressed with wild-type KV1.6 or KV1.1 subunits.

Significance: This is the first report of de novo non-synonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain-of-function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

One Type of Epilepsy Traced to a Mutation in a Single Person 800 Years Ago

Article published by Medical Xpress

A team of researchers affiliated with several institutions in Australia and the U.K. has found evidence that suggests one type of epilepsy people carry today can be traced back to a mutation that occurred in a single person approximately 800 years ago. In their paper published in The American Journal of Human Genetics, the group describes finding the genetic variant responsible for the disease in the U.K. Biobank.

Epilepsy is not just one disease, it is a group of diseases that have shared symptoms. The most common symptom is the periodic onset of a burst of abnormal brain activity, which presents as seizures. One type of the disease is called febrile epilepsy—it is notable because the seizures it causes are accompanied by a fever. Prior research has shown that it can be traced to the SCN1Bc.363C>G variant. It is less severe than other types of epilepsy; some people with the variant do not even know they have it.

In this new effort, the researchers sought to learn if the variant responsible for febrile epilepsy had arisen in multiple people over time or if it could be traced back to just one person. To find out, they traced the lineage of 14 people with the variant. Finding nothing that suggested multiple people had originally had the variant, they expanded their search to include data from the U.K. Biobank and found 74 people with the variant. A closer look showed that all of them had the same sort of patterns in their variants, which together made them a haplotype.

CURE Epilepsy Discovery: CURE Epilepsy Grantees Explore Genetic Determinants of Sudden Unexpected Death in Pediatrics (SUDP)

Key Points:

  • Sudden infant death syndrome (SIDS), sudden unexpected infant death (SUID), and sudden unexplained death in childhood (SUDC) are tragic conditions referring to the unexplained death of an infant or child. While previously thought of as separate entities, evidence suggests that there is an overlap between these conditions and that they may be considered under the overarching umbrella of sudden unexpected death in pediatrics (SUDP).
  • A previous study awarded by CURE Epilepsy and made possible by funding from the Isaiah Stone Foundation to Dr. Annapurna Poduri and colleagues suggested that genes associated with epilepsy may be involved in SUDP.[1]
  • A new study*, which was an outgrowth of the earlier CURE Epilepsy funded research, included 352 SUDP cases and employed state-of-the-art genetic techniques, in-depth analysis of family history and circumstances of death, and analysis of parental genetic information as well.[2]
  • The study showed evidence for genetic factors that may play a role in SUDP; while some genes were already potentially associated with sudden death in children, several variants in genes previously not associated with SUDP were identified.
  • In addition to providing genetic information about SUDP, the group’s work is proof of concept that a multidisciplinary lens to study SUDP is not only feasible, but necessary to advance the field.

 

Deep dive

The sudden death of a child is a tragic occurrence. Of all the child and infant deaths in the United States, more than 10% occur without any apparent cause, compounding the grief of families who have lost their children.[3] These sudden, unexpected deaths typically impact seemingly healthy children and are classified as sudden infant death syndrome (SIDS), sudden unexpected infant death (SUID), or sudden unexplained death in childhood (SUDC). Together, these three entities are thought of as sudden unexpected death in pediatrics (SUDP).[4] Through the generous support of the Isaiah Stone Foundation, CURE Epilepsy funded Dr. Annapurna Poduri and colleagues Rick Goldstein, Hannah Kinney, and Ingrid Holm in Robert’s Program** at Boston Children’s Hospital to explore the genetic basis of SUDP; the hypothesis for this work is that there are common, underlying, genetic mechanisms behind the three entities of sudden childhood death, epilepsy and sudden unexpected death in epilepsy (SUDEP).

Earlier work from these researchers had highlighted a link between SIDS and variants in a gene called SCN1A, which is associated with epilepsy and SUDEP.[1, 5, 6] What was notable is that while this gene is traditionally thought to be related to epilepsy, the children who died suddenly and unexpectedly had no history of seizures or epilepsy. This and other studies have suggested that SUDP is an overarching disorder consisting of rare and yet-undiagnosed diseases with potentially overlapping genetic mechanisms.[1, 7, 8]

To build on the previous work supported by CURE Epilepsy, Dr. Poduri and colleagues conducted a larger, more extensive study* to explore genetic risk factors for SUDP.[2] The ultimate goal was to find more accurate ways of diagnosing children at risk of sudden death and eventually prevent such incidences. The current study led by Dr. Poduri and her colleagues Drs. Hyunyong Koh and Alireza Haghighi included 352 SUDP cases.[2] This study looked at “trio-based” cohorts; meaning they studied the child and the child’s parents. This is a stronger approach to studying genetic contributions to a disease process, especially for SUDP, where a genetic link is suspected.[9, 10] Additionally, since the mechanisms underlying SUDP are complex and not yet fully known, the team took a “multidisciplinary undiagnosed diseases approach”[11] that combined genetic analysis, autopsy data, and in-depth study of the child’s phenotype (or observable characteristics). Parents agreed to all analyses performed. 

The genetic analysis included a candidate-gene approach where scientists have some information to suggest that a certain gene may be associated with a certain disease. In this case, 294 genes plausibly related to SUDP, called SUDP genes were studied, many of which were associated with neurologic disorders, cardiac disorders, or systemic/syndromic conditions. [12, 13] Systemic conditions and associated genes affect the entire body, and syndromic conditions include genes for metabolism and those responsible for the functioning of multiple body systems. The team performed a genetic technique called exome sequencing, where the parts of genes that eventually become functional proteins were analyzed for variants that may have caused or contributed to sudden death.[2]

The multidisciplinary team at Robert’s Program on SUDP, directed by Dr. Rick Goldstein, characterized fully the conditions surrounding the death of the child, performed an in-depth analysis of the child’s medical and family history, and conducted exome sequencing. The study showed that SUDP was associated with specific genetic factors, some of which were previously known, but many of which were novel. Detailed analysis showed that the majority of the children were between two and six months old, and 57% were male. Out of the 352 cases, death was associated with sleep in an overwhelming majority (346 children).[2] Genetic analysis revealed variants in genes related to cardiac disease, neurologic diseases, and systemic/syndromic diseases. Most variants were de novo, or new, while some were inherited. Burden analysis, in which the trios were compared to controls, showed that there were more SUDP trio cases with rare, damaging de novo variants as compared to controls. There were also clues as to the presence of febrile seizures, a family history of SIDS or SUDC, and a family history of epilepsy and cardiac disease in several cases. When the genes implicated in SUDP were classified by the age of death of the child, a pattern emerged. Specifically, variants in neurological and syndromic genes appeared in the age ranges associated with SIDS (the child being less than one year old) and SUDC (the child is greater than one year old), and variants in cardiac genes were preferentially seen only in the earlier age range, i.e., associated with SIDS.[2]

Overall, the study found that there was a genetic contribution to SUDP in 11% of the cases and suggests that these genetic variants may increase susceptibility to sudden death. Many genes that were previously not linked with SUDP were able to be reclassified as being associated with SUDP. The power of this study is that the genes for SUDP that were investigated were not the ones previously examined. A few specific genes found to be implicated in SUDP are SCN1A and DEPDC5, which have also been shown to be relevant in SUDEP. Other genes were associated with cardiac issues such as arrhythmia and cardiomyopathy (a condition that makes it harder for the heart to pump blood).[2]

The study also shows the importance of looking at trio data, as in this case, it led to the reclassification of several genetic variants. SUDP is a particularly difficult condition to study because unfortunately, a genetic condition may never have been diagnosed or suspected. Hence, the trio approach was instrumental in the success of the current study. The study also adds to evidence [7, 8] that conditions such as stillbirth, SIDS, and SUDC are not separate entities, but represent a continuum of events associated with unexplained death from fetal life to childhood.[14] It is possible and even likely that there are overlapping genetic variants (SCN1A being one) common to these conditions. Notably, another study from a different group also performed genetic analysis from trios and found de novo mutations associated with sudden unexplained death in childhood.[15]

Future studies will look at more trio data and an even more detailed genetic analysis. While many genetic risk factors were found in the current study, it does not mean that they were necessarily the cause of death; more work will be needed to look at specific neurologic mechanisms. In addition to the scientific findings, the study also sets the scene for a model where a multidisciplinary team engages with parents who have lost their children to unexplained death. In addition to providing scientific answers, a multidisciplinary team also can help provide counseling for family members at a much-needed time.

 

Footnotes:

*Supported by funds from the Robert’s Program on Sudden Unexpected Death in Pediatrics, the Cooper Trewin Memorial SUDC Research Fund, CURE Epilepsy through the Isaiah Stone Foundation Award, Three Butterflies SIDS Foundation, The Florida SIDS Alliance, Borrowed Time 151, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development under grant numbers R21 HD096355 and R01 HD090064.

**Robert’s Program at Boston Children‘s Hospital provides comprehensive clinical care to those that have lost a child suddenly and unexpectedly and performs research to better understand SUDP.

 

Literature Cited:

  1.      Brownstein CA, Goldstein RD, Thompson CH, Haynes RL, Giles E, Sheidley B, et al. SCN1A variants associated with sudden infant death syndrome Epilepsia. 2018 Apr;59:e56-e62.
  2.      Koh HY, Haghighi A, Keywan C, Alexandrescu S, Plews-Ogan E, Haas EA, et al. Genetic Determinants of Sudden Unexpected Death in Pediatrics Genet Med. 2022 Apr;24:839-850.
  3.      About Underlying Cause of Death, 1999-2020. Available at: https://wonder.cdc.gov/ucd-icd10.html. Accessed October 4.
  4.     Goldstein RD, Nields HM, Kinney HC. A New Approach to the Investigation of Sudden Unexpected Death Pediatrics. 2017 Aug;140.  
  5.     Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms Epilepsia. 2010 Sep;51:1650-1658.
  6.    Goldman AM. Mechanisms of sudden unexplained death in epilepsy Curr Opin Neurol. 2015 Apr;28:166-174.
  7.    Perrone S, Lembo C, Moretti S, Prezioso G, Buonocore G, Toscani G, et al. Sudden Infant Death Syndrome: Beyond Risk Factors Life (Basel). 2021 Feb 26;11.
  8.    Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM. Sudden Infant Death Syndrome: review of implicated genetic factors Am J Med Genet A. 2007 Apr 15;143a:771-788.
  9.    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med. 2015 May;17:405-424.
  10.   Rehm HL. A new era in the interpretation of human genomic variation Genet Med. 2017 Oct;19:1092-1095.
  11.   MacNamara EF, D’Souza P, Tifft CJ. The undiagnosed diseases program: Approach to diagnosis Transl Sci Rare Dis. 2020 Apr 13;4:179-188.
  12.   An Online Catalog of Human Genes and Genetic Disorders (OMIM). Available at: https://www.omim.org/. Accessed October 4.
  13.   The Human Gene Mutation Database (HGMD®). Available at: https://www.hgmd.cf.ac.uk/ac/index.php. Accessed October 4.
  14.   Goldstein RD, Kinney HC, Willinger M. Sudden Unexpected Death in Fetal Life Through Early Childhood Pediatrics. 2016 Jun;137.
  15.   Halvorsen M, Gould L, Wang X, Grant G, Moya R, Rabin R, et al. De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca(2+) regulation Proc Natl Acad Sci U S A. 2021 Dec 28;118.

Gene Tied to Childhood Epilepsy

Article published by VUMC Reporter

In the mammalian brain, the chief inhibitory neurotransmitter is called GABA. The gene SLC6A1 encodes the GABA transporter GAT1, and in Neurobiology of Disease, Felicia Mermer, Sarah Poliquin, Jing-Qiong Kang, MD, PhD, and colleagues report experiments — in silico, in vitro and in mice-o — tying novel variants in SLC6A1 to a childhood syndrome called myoclonic atonic epilepsy (MAE).

Among data drawn from four unrelated MAE patients were seizure phenotypes (including EEG patterns) and whole-exome sequences (drawn also from the parents). Four different de novo SLC6A1 variants were found in the four patients, and for two of these, machine learning predicted destabilized forms of GAT1.

In murine and in human astrocytic glial cell cultures (the latter generated from induced pluripotent stem cells), the four variants posed reduced expression of GAT1 (measured in mouse cells) and reduced GABA uptake (measured in mouse and human cells). In a mouse model these deficits posed seizure activity of both MAE and childhood absence epilepsy varieties.

Epilepsy Research News: September 2022

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

 

Recent Advances in Precision Medicine for Genetic Epilepsy

The genetic basis of many epilepsies is increasingly understood. This gives rise to the possibility of precision treatments that can be tailored to a person’s specific genetic epilepsy. CURE Epilepsy Taking Flight grantee Juliet Knowles, MD, PhD, led a collection of prominent stakeholders within the epilepsy community, including CURE Epilepsy’s Dr. Laura Lubbers, in authoring a critical review that describes recent progress, new or persistent challenges, and future directions of precision medicine for genetic epilepsies, among other things. The article states that though current medical therapy for most epilepsies remains imprecise, the epilepsy community is ready to make big steps forward in precision therapy tailored to a person’s specific genetic epilepsy because of increased access to genetic testing and counseling and advances in the ability to diagnose genetic epilepsies. The authors conclude that the future of precision medicine for genetic epilepsy looks bright if progress in this area continues in a strategic and coordinated manner.
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Mortality Rates are Higher Among Veterans with Drug Resistant Epilepsy, Prompting Need for Improved Management

According to data from an observational cohort study, US veterans with drug-resistant epilepsy have higher rates of mortality than the general population, suggesting a critical need for appropriate management of epilepsy in this population. The findings showed that lower mortality was associated with increased utilization of medical care, especially when utilizing a Veterans Affairs Epilepsy Center of Excellence compared to a neurology clinic alone. The study authors noted that the higher mortality risk might be lowered by appropriate referrals for comprehensive evaluation, adequate diagnostic testing, and optimal medication management and that adequate resources should be allocated to care for this patient group.
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Seizures and Epilepsy Risk Still High Two Years After Delta, Omicron Infections

A recent study found an increased risk among adults for epilepsy or seizures two years after COVID-19 infection. Researchers used data collected as part of a two-year retrospective cohort study to investigate the neurological and psychiatric impact of SARS-CoV-2 infections. The researchers discovered that participants who had been infected with the Delta COVID-19 variant had an increased risk for epilepsy or seizures (amongst other risks) when compared to participants who had been infected with the Alpha variant. They also found that while the death rate decreased after the emergence of the Omicron variant, the virus still carried about the same risks for psychiatric or neurological problems, including epilepsy or seizures, compared to the Delta variant. The authors note that these findings emphasize there is a need for further research into the long-term impact of COVID-19.
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Study of Potassium Channels Reveals Novel Mechanism Behind Epilepsy

Epilepsy can have a variety of causes, including genetic variants in a family of proteins that regulate potassium ions in the brain. A research team is examining the mechanisms behind the function and dysfunction of two of these proteins, the potassium ion channels KCNQ2 and KCNQ3, as well as their interactions with an antiseizure medication, to develop a new strategy to treat epilepsy. The team identified a set of mutations in these ion channels associated with early infantile epileptic encephalopathy, a severe form of childhood epilepsy, that specifically disrupts the function of these channels. The researchers took advantage of the antiseizure drug retigabine, given its mechanism of action on neuronal KCNQ channels, and demonstrated that the function of these mutated KCNQ channels can be restored. Their studies suggest that targeting the function of KCNQ channels may be an effective strategy for developing more effective therapies for epilepsy.
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Brain Abnormalities in Epilepsy Detected by New AI Algorithm

An artificial intelligence (AI) algorithm to detect subtle brain abnormalities that cause epileptic seizures has been developed. The abnormalities, known as focal cortical dysplasias (FCDs), can often be treated with surgery but are difficult to visualize on an MRI. The new algorithm is expected to give physicians greater confidence in identifying FCDs in patients with epilepsy. To develop the algorithm, the team quantified features of the brain cortex—such as thickness and folding—in more than 1,000 patient MRI scans from 22 epilepsy centers around the world. They then trained the algorithm on examples labeled by expert radiologists as either being healthy or having FCD. The study’s authors state that the algorithm automatically learns to detect lesions from thousands of MRI scans of patients and can reliably detect lesions of different types, shapes, and sizes. The algorithm can even detect many of those lesions that were previously missed by radiologists. Ultimately, the team would like this AI algorithm to help doctors confidently identify FCDs, and then use surgery to remove them, in hopes of providing a cure for epilepsy.
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CURE Epilepsy Discovery: Developing Precision Medicine Treatments for Genetic Epilepsies: Present Challenges, Recent Scientific Advances, and Future Prospects

Key Points:

  • Epilepsy is a serious neurological disorder with many possible causes, and those directly linked to genetic abnormalities have undergone significant scientific breakthroughs in recent years.
  • Precision medicine is “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”. This concept is being applied to genetic epilepsies, but significant challenges have limited the rate at which basic science has translated into new treatments.
  • New strategies and scientific techniques may hasten the process. A recent publication in Epilepsia highlights some of them, along with the basic science that has fostered the hope for the eventual realization of precision medicine [1]. The authors suggest that greater coordination of efforts by scientists, physicians, patient advocates, and the federal government will accelerate effective, ethical, and equitable precision medicine for genetic epilepsy.
  • This publication stems from discussions at the Epilepsy Precision Medicine conference, funded in part by CURE Epilepsy and held in Washington, DC in 2019. This conference brought together the many stakeholders involved in developing precision therapies for epilepsy including researchers, physicians, funding agencies, and people with lived experience to share their experiences of epilepsy. The publication’s writing team was led by recent CURE Epilepsy Taking Flight grantee Juliet Knowles, MD, PhD.

 

Deep Dive:

Epilepsy is a debilitating but surprisingly common neurological disorder, with 1 in 26 people in the United States developing it over the course of their lives [2]. Despite the availability of numerous antiseizure medications (ASMs), one-third of people with epilepsy have seizures that remain treatment-resistant [3]. There are many possible causes of epilepsy, ranging from traumatic brain injuries to specific genetic mutations. Regardless of the cause, treatment remains primarily empirical or based on observation, with patients and their epileptologists often trying different and multiple ASMs in an attempt to eliminate the seizures while managing unwanted side effects. Ideally, treatments for epilepsy would precisely target the underlying biological mechanism, control seizures, and reduce the occurrence of negative side effects.

Optimism for this approach of “precision medicine” for epilepsy grew following the complete sequencing of the human genome and fueled the hope that individual genetic information could be used to develop more specific ways to treat epilepsy. Precision medicine, also known as personalized medicine, is the “tailoring of medical treatment to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.” Unfortunately, for most types of genetic epilepsy, the individual genetic makeup of a patient has not yet translated to clinical application of precision medicines for epilepsy. This has been due, in part, to the complexity of the underlying biological mechanisms as well as limitations in the technologies needed to advance genetic discovery to appropriate treatments.

However, the authors describe how epilepsy research is entering an exciting new phase that may enable new precision therapies for many more types of genetic epilepsy. Over the last decade, significant progress in advancing precision medicine approaches has been achieved for epilepsies caused by discrete mutation(s) in a single gene. This work has involved 1) acceleration and efficiency of gene sequencing technology and identification of epilepsy-causing, including the location and type of specific mutations in the DNA sequence of these genes, and 2) clarification of the neuronal function(s)/dysfunction of the corresponding protein and underlying biochemical pathways. In addition, the development of specific laboratory methods such as cell-based models that replicate aspects of the structure and function of the human brain and the use of zebrafish that are sensitive to ASMs have accelerated the testing of novel epilepsy treatments. Finally, new epilepsy gene-targeted technologies, for example, antisense oligonucleotides, are being tested in clinical trials, and there is active discussion about changes in clinical trial design that could enable smaller clinical trials needed for rare genetic epilepsies.

Despite these successes, multiple challenges remain for the future development and accessibility of precision therapies for epilepsy. First, genetic testing and counseling remain inaccessible to many groups, including the elderly and the poor, across the world. Second, nearly 70% of epilepsy cases involve more than one gene and thus require an improved understanding of disease risk in the context of multiple genetic mutations, overall genetic background, and environmental exposure. Third, although gene therapy is conceptually encouraging there are challenges related to large-scale development of safe, ethical, and equitable delivery of gene-based therapies to overcome. It will be critical for the research community to work together to overcome these challenges to ensure the delivery of new precision therapies for genetic epilepsies.

An important driver for the advancements that have been made toward the development of precision therapies are the many new stakeholders calling for action. Numerous patient advocacy groups, professional societies such as the American Epilepsy Society, government and non-profit funding agencies such as the National Institute of Neurological Disorders and Stroke and CURE Epilepsy, respectively, have collectively called for a coordinated and systematic approach to developing new epilepsy treatments. Progress stemming from this call to action could bring a new age of treatments for those with epilepsy, shifting from observational experience to data-driven and patient-centered precision therapy.

 

Literature Cited:

  1. Knowles JK, Helbig I, Metcalf CS, Lubbers LS, Isom LL, Demarest S, Goldberg EM, George AL, Lerche H, Weckhuysen S, Whittemore V, Berkovic SF, Lowenstein DH. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia 2022
  2. Hesdorffer D, Logroscino G, Benn E, Katri N. Cascino G, Hauser W. Estimating risk for developing epilepsy. A population-based study in Rochester, Minnesota. Neurology 2011; 76:23–27
  3. Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs. A 30-Year Longitudinal Cohort Study. JAMA Neurology 2018 75:279-286.

Precision Medicine for Genetic Epilepsy on the Horizon: Recent Advances, Present Challenges, and Suggestions for Continued Progress

Featuring the work of CURE Epilepsy Chief Scientific Officer Dr. Laura Lubbers, CURE Epilepsy Advisors Dr. Daniel Lowenstein and Dr. Vicky Whittemore, and CURE Epilepsy grantees Dr. Juliet Knowles, Dr. Lori Isom and Dr. Ethan Goldberg

Abstract found on PubMed

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.