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.
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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. 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.”

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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