‘Missing Mutation’ Found in Severe Infant Epilepsy

Researchers have discovered a “missing mutation” in severe infant epilepsy — long-suspected genetic changes that might trigger overactive, brain-damaging electrical signaling leading to seizures. They also found early indications that specific anti-seizure medications might prevent disabling brain injury by controlling epilepsy during a crucial period shortly after birth.

“These are still early days, but we may be able to use this knowledge to protect the newborn brain and improve a child’s long-term outcome,” said study leader Ethan M. Goldberg, MD, PhD, a pediatric neurologist at Children’s Hospital of Philadelphia.

Goldberg collaborated with European and American researchers in this neurogenetic study of early infantile epileptic encephalopathy, published online Feb. 21, 2018 in Annals of Neurology.

The study focused on mutations in the gene SCN3A. Scientists already knew that the gene had a pattern of high expression in the brain, before and shortly after birth. Variants in SCN3A had also been previously linked to less severe forms of epilepsy, but the current research solidified this link and was the first to establish that SCN3A mutations cause the severe infantile form.

Translating these findings into potential clinical treatments, Goldberg stressed, will require considerable further research — both in nerve cells and in future animal models, in which neurologists can test possible precision-medicine treatments for safety and efficacy before they can be investigated in patients. In addition, the current research allowed the SCN3A gene to be added to an existing diagnostic test, CHOP’s Epilepsy Panel, which uses next-generation sequencing to rapidly test for over 100 genetic causes of childhood epilepsy.

Precise, early diagnosis, added Goldberg, will be crucial, because of the highly regulated timetable of early-life neurological events. “The mutation’s activity in the Nav1.3 sodium ion channel occurs during a short period in newborns, but if we can intervene during that window, we may be able to help prevent long-term neurological injury and benefit patients,” he said.

Variants in one gene account for 7% of juvenile myoclonic epilepsy cases

An extremely rare genetic variant that affects the maturation, migration, and death of neurons appears to be responsible for about 7% of cases of juvenile myoclonic epilepsy.

Variants of the intestinal-cell kinase gene (ICK) occurred in 12 members of a family affected by the disorder and were confirmed in 22 of 310 additional patients, Julia N. Bailey, PhD , of the University of California, Los Angeles, and her colleagues reported in the March 15 issue of the New England Journal of Medicine .

But among these 34 patients, the variant manifested as different epileptic phenotypes, suggesting genetic pleiotropism, the investigators said.

The investigators drew data from the GENESS (Genetic Epilepsies Studies) consortium, which has study sites in the United States, Mexico, Honduras, Brazil, and Japan. The current study from the databank analyzed information from 334 families with genetic generalized epilepsies. Among these, 310 patients had adolescent-onset myoclonic seizures and polyspike waves, or had a diagnosis of JME.

Woman sitting at a laptop participating in a CURE webinar.

Genetic Testing to Develop Personalized Medicine for Epilepsy

This webinar recorded at Columbia University in New York City, focuses on “Genetic Testing to Develop Personalized Medicine in Epilepsy”. In this webinar, learn more about the importance of genetic testing in epilepsy, the different diagnoses you can receive from genetic testing, and what options are available after your testing results. Also, learn how CURE’s Signature Program, the Epilepsy Genetics Initiative or EGI, is helping push the precision medicine movement in epilepsy forward.

The webinar is presented by Dr. David Goldstein, Director of the Institute of Genomic Medicine at Columbia, and also features a Q&A portion. Some of the questions you might hear addressed include:

  • What is the value of genetic testing?
  • How do I go about getting testing ordered for me and/or my child?
  • What type of results can I expect if I do have genetic testing completed?
  • How can knowing the cause of my/my child’s epilepsy help with the available treatment options?
  • How is epilepsy research, like that involved in EGI, helping end the diagnostic odyssey that many patients face?

PPP3CA Gene Mutations Cause a Severe Neurodevelopmental Disease and Seizures

The discovery is credited to data from CURE’s Epilepsy Genetics Initiative

De novo mutations in the PPP3CA gene lead to a severe form of neurodevelopmental disease characterized by seizures. These mutations are not inherited from an individual’s parents.

The discovery was based on genomic data from CURE’s Epilepsy Genetics Initiative.

The identification of PPP3CA as an epilepsy-associated gene provides new insight into the possible causes and mechanisms behind epilepsy, opening a new research target for potential PPP3CA-related therapeutics.

The discovery also provides much-needed information to the individuals and families affected by PPP3CA-associated epilepsies because that diagnosis can potentially be used to inform decisions regarding treatments.

Identifying the genes in which mutations can lead to epilepsy can be challenging, especially for the severe and rare forms. The rarity of these disorders is often associated with a lack of sufficient data. However, in pooling genetics data from several different sources, including those from CURE’s Epilepsy Genetics Initiative, Principal Investigator Dr. Erin L. Heinzen and senior co-author Dr. Heather Mefford had the statistical power to successfully identify mutations in the PPP3CA gene as a lead factor in the development of one severe type of PPP3CA-associated neurodevelopmental disease characterized by childhood-onset epilepsy.

The PPP3CA gene is typically responsible for the production of a protein called calcineurin, which is an essential component of proper signaling between neurons in the brain.[1] As the results of the current study demonstrate, mutations interfering with proper neuronal transmission, such as mutations in PPP3CA, can lead to neurodevelopmental disorders and epilepsy. Using a combined genomic dataset, Dr. Heinzen and her team found de novo mutations in PPP3CA in six individuals: 6/6 of these individuals had developmental delays, 5/6 had childhood-onset epilepsy, and 3/6 had an atypical physical appearance.

According to Dr. Laura Lubbers, Chief Scientific Officer at CURE, “The powerful discovery that mutations in the PPP3CA gene can lead to this severe form of disease with childhood-onset epilepsy paves the way for the creation of new treatments for epilepsy, and hopefully, a cure.”

This research, recently published in The American Journal of Human Genetics, was led by Dr. Heinzen from the Institute of Genomic Medicine at Columbia University, and involved the efforts of several other Epilepsy Genetics Initiative researchers including Dr. David B. Goldstein, also from the Institute of Genomic Medicine at Columbia University.

At its core, the CURE Epilepsy Genetics Initiative is a program created to use genetic information from people with epilepsy to uncover the causes of epilepsy and advance precision medicine.

Through the Epilepsy Genetics Initiative, individuals with epilepsy undergo Trio Whole Exome Sequencing – a test that analyzes approximately 20,000 genes simultaneously to identify changes in the person’s DNA that are related to their epilepsy.

The results of this powerful study highlight the importance of the continued work of projects like CURE’s Epilepsy Genetics Initiative in advancing towards a better understanding of the genetic causes of epilepsy. “Begun in 2014, CURE’s Epilepsy Genetics Initiative is already helping people understand the cause of their epilepsy” says CURE CEO Kate Carr. “We are excited about this advance in our search for the genetic causes of epilepsy and will continue in our quest for new treatments and our pursuit of a cure.”
[1] Lai MM, Hong JJ, Rugiero Am et al. The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis. J Biol Chem 1999; 274:25963-25966.

Congenica and FutureNeuro unite to deliver more accurate diagnoses for genetic epilepsy

New software to deliver faster and more accurate diagnoses in genetic epilepsies is the ambition of a ground-breaking partnership between Congenica, a global provider of clinical genomics interpretation software, and FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological Diseases, supported by Science Foundation Ireland. The software will be designed to work with electronic health record (EHR) systems, including the Irish electronic health record for Epilepsy, so that the entire diagnostic process, from initial DNA sequencing to determining treatment options, is available to clinicians and patients through their electronic records.

The partnership, operating out of the FutureNeuro Human Genetics lab of Professor Gianpiero Cavalleri in RCSI, Dublin, will build on Congenica’s clinical genomics analysis software, Sapientia™, to assist clinicians in making more tailored treatment decisions for certain types of genetic epilepsy. At the moment, epilepsy is diagnosed using EEGs, CT scans or MRIs, which only provide a limited picture of a person’s epilepsy. Genomics, which focuses on the structure, function, mapping, and editing of genomes, is a new and powerful tool for reaching a molecular diagnosis, which in turn can inform and improve treatment options.

“Genomics is changing clinical medicine,” said Dr Norman Delanty, Clinical Neurologist with FutureNeuro, “neurologists need to embrace it as a new powerful diagnostic tool to allow us to understand the many challenging faces of epilepsy, and lead us to individualising treatment and prognosis in the clinic.”

Gene playing major role in neurological condition found

This genetic discovery included the efforts of CURE grantee Minghsan Xue.

Researchers are closer to solving the puzzle of a complex neurological condition called 15q13.3 microdeletion syndrome. Individuals with this condition are missing a small piece of chromosome 15 that usually contains six genes, but which one of the genes is responsible for the clinical characteristics of patients has not been clear. In this study, a multidisciplinary team of researchers at Baylor College of Medicine and Texas Children’s Hospital has identified in a mouse model OTUD7A as the gene within the deleted region that accounts for many characteristics of the human condition. The researchers also discovered that mice deficient in the gene Otud7a have fewer dendritic spines, small protrusions involved in neuron communication, which might be related to the neurological deficits.

The report appears in the American Journal of Human Genetics.

“Identifying the gene within a deleted region of a chromosome that accounts for the clinical characteristics we see in patients is very important,” said senior author Dr. Christian Schaaf, assistant professor of molecular and human genetics at Baylor College of Medicine and the Joan and Stanford Alexander Endowed Chair for Neuropsychiatric Genetics at Texas Children’s Hospital. “If we want to get to the point where we can treat patients, we need to know which gene or genes to target. That is the big picture question behind this study.”

MicroRNAs as Biomarkers Clinical Trial: Circulating microRNAs as Biomarkers of RESPIratory Dysfunction in Patients With Refractory epilePSY (MIRESPILEPSY)

Sudden and unexpected death in epilepsy (SUDEP) has become a major issue for patients with epilepsy and their physicians. SUDEP is a nontraumatic and non-drowning death in patients with epilepsy, unrelated to a documented status epilepticus, in which postmortem examination does not reveal a toxicologic or anatomic cause of death. It primarily affects young adults with drug-resistant epilepsy, with an incidence of about 0.5%/year. A recent study reported that up to 20% of patients with childhood onset drug resistant epilepsy will die of a SUDEP by the age of 45. Apart from optimizing antiepileptic drugs, no preventive treatment is available to prevent SUDEP. As underscored by the World Health Organization (WHO), there is an urgent need to develop specific therapeutic approaches to tackle this issue.

The primary objective of the proposal is to evaluate the diagnostic value of a set of circulating microRNAs pre-selected because of their implication in the regulation of molecular pathways involved in the respiratory regulation to identify patients with seizure-related respiratory dysfunction, as defined by occurrence ictal/peri-ictal pulse oxymetry < 90%.

A total of 50 patients will be included over a period of one year. Patients undergoing long-term video-EEG/SEEG monitoring will be recruited in the epilepsy monitoring unit of the Department of Functional Neurology and Epileptology, Hospices Civils de Lyon, Lyon, France.

It will be a case-control study in a cohort of patients with drug-resistant focal epilepsy undergoing long-term video-EEG monitoring, in which patients who demonstrate ictal/post-ictal hypoxemia (cases) will be compared with those without seizure-related respiratory dysfunction (controls).

Elibibility Criteria

Inclusion Criteria

For the patients:

  • Adult patient (? 18 years) suffering from drug-resistant focal epilepsy or from drug-resistant generalized epilepsy according to ILAE classification
  • Patient undergoing long-term video-EEG monitoring in Epilepsy unit of Lyon to record and characterize her/his seizure
  • Patient who gave her/his written informed consent to participate to the study
  • Patient affiliated to the French health care system


For the healthy volunteers:

  • Adult (? 18 years)
  • Without history of neurological disorders and/or psychiatric disorders, and/or general medical disorders
  • Subject who gave her/his written informed consent to participate to the study
  • Subject affiliated to the French health care system


Exclusion Criteria

For the patients:

  • Ongoing major depressive episode as defined by a score ? 15 at the French version of the NDDI-E scale*
  • Current panic disorder as defined by a score ? 7 at the French version of the GAD-7 scale*
  • Ongoing treatment with selective serotonin reuptake inhibitor
  • Patient who benefit from a protective measure


For the healthy volunteers:

  • Presence of the symptoms of anxiety and/or depression as defined by a score ? 11 at the French version of the Hospital Anxiety and Depression Scale (HADS)
  • Ongoing treatment with selective serotonin reuptake inhibitor
  • Subjects with these psychiatric comorbidities and/or treatment will be excluded in order to limit risk that the relation previously reported between miR-135a, miR-16, miR-1202 and depression and/or panic disorder and/or response to selective serotonin

Isaiah’s story inspires us to do more

“I have never felt so powerless as when I watched Isaiah’s first seizure.”
–C. Renzi Stone, Isaiah’s father

Isaiah had his first seizure when he was just four months old. For ten excruciating minutes, his father cradled Isaiah’s rigid body as his eyes fluttered to the back of his head and his legs jerked uncontrollably.

It soon became clear that Isaiah, like one-third of epilepsy patients, was unresponsive to current treatments. On the 333rd day of Isaiah’s life, he had a fatal seizure and died.

At the time of his passing in 2010, there was no known cause for Isaiah’s epilepsy. However, last December, his parents received a call from his neurologist. A periodic re-screening by the lab that conducted Isaiah’s original genetic testing found the faulty gene. Isaiah’s had Dravet Syndrome, a rare, catastrophic form of genetic epilepsy that starts in the first year of life and is characterized by frequent, prolonged seizures.

IsaiahIt’s hard to say if Isaiah’s story would have had a different outcome if he had received the diagnosis sooner. But thanks to CURE’s Epilepsy Genetics Initiative (EGI), families may not have to wait years to find out the truth. Please help us continue these efforts with a year-end gift to CURE.

First-of-its-Kind Initiative Aims to Unlock the Genetic Secrets of Epilepsy

Three million Americans currently live with epilepsy and 30-40 percent have uncontrollable seizures – of which genetics is proving to be a major cause. Citizens United for Research in Epilepsy (CURE) today announced the launch of its new signature program, the Epilepsy Genetics Initiative (EGI) – a first-of-its-kind database for epilepsy that aims to unlock the genetic secrets of the disease, driving research into its causes and treatments to ultimately find a cure for epilepsy.

The John and Barbara Vogelstein Foundation is the principal sponsor of EGI, having generously committed $1 million to the project over 3 years. “We think that genetics are the next frontier for epilepsy treatment,” said John Vogelstein. “We know firsthand how devastating epilepsy can be. We’re confident that with CURE’s leadership, EGI can provide families with answers, and researchers with the tools to find a cure.”
For patients diagnosed with epilepsy, initial analysis of their DNA may not identify a cause for the disease. EGI will permit for reanalysis as breakthrough genetic discoveries are made, linking patients, physicians and scientists together to better customize treatment for different forms of epilepsy.

“We now know that finding the genetic cause of a patient’s epilepsy can tell us how best to treat that patient. Getting the diagnosis right depends on a thorough and comprehensive analysis of each patient’s genetic data and being able to directly compare data against the largest possible number of patients with a similar diagnosis,” said David B. Goldstein, director of the Institute of Genomic Medicine at Columbia University Medical Center. “EGI will help to ensure that every patient benefits from the remarkable advances in epilepsy genetics and the emerging paradigm of targeting treatments to the exact underlying causes of epilepsy.”

“The primary idea behind EGI is to capture and centralize genetic data for repeat analysis with the most cutting-edge methods and the most current knowledge,” explained Dr. Tracy Dixon-Salazar, associate research director at CURE and mother of a child with severe epilepsy whose condition has been improved by exome sequencing. “Nearly one-third of all those living with epilepsy deal with uncontrolled seizures, living day-to-day at the hand of epilepsy. For these one million people, they come in unannounced and uninvited and rock your world – EGI can get us closer to identifying treatments and cures to help these and others living with epilepsy.”
EGI will allow for the discovery of additional genetic mutations that cause epilepsy, which can lead to better patient care. Knowing a person’s genetic makeup can better inform a physician’s diagnosis and treatment of epilepsy, in addition to a better understanding of why some epilepsy patients experience other conditions such as depression, autism or cognitive challenges.

“EGI has the potential to accelerate our understanding of the genetic causes of epilepsy by leaps and bounds,” said Susan Axelrod, founding chair of CURE. “Through this initiative, we can truly transform the way we diagnose and, most importantly, treat patients with epilepsy. EGI is paving the way for a future of personalized, precision medicine with the support of an unprecedented team.”

EGI is open to anyone who has epilepsy and has access to one of the official or remote enrollment sites. There are two ways to enroll – directly at one of the eight official EGI enrollment locations or by contacting CURE, who will help guide patients to a site that does remote enrollment in the program. Current EGI enrollment sites and academic partners include:

• Ann & Robert H. Lurie Children’s Hospital of Chicago
• Boston Children’s Hospital
• Duke University
• Columbia University
• New York University School of Medicine
• The Children’s Hospital of Philadelphia
• The University of Melbourne
• University of California San Francisco

EGI has been established in partnership with the National Institute of Neurological Disorders and Stroke.

Industry Partners include Ambry Genetics, Transgenomic, GeneDX, Courtagen Life Sciences and Inc, B Braun | CeGaT.


To learn more and view a video on how EGI works, please visit: www.cureepilepsy.org/egi.

Questions? Please contact the CURE office at (312) 255-1801 or 844-EGI-CURE, egi@www.cureepilepsy.org.

CURE Conversations: Dr. Avtar Roopra

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Can you share some details about what you do?
I run a lab in the Department of Neuroscience at the University of Wisconsin at Madison. We study the role of genes in epilepsy and breast cancer. We focus on one master regulator of genes called REST. My lab uses computational approaches to study how large patterns of gene expression in disease can be used to predict how patients will fare. We use insights from these studies to guide experiments in mouse models of cancer and epilepsy and to test novel treatments.

What motivated you to become interested in this area of research?
I have been interested in how genes are controlled since I was a graduate student. It became clear that a key controller of many genes, REST, plays a major role in epilepsy. Later we found that it also played a role in cancer. So the lab split into two subgroups to chase both these findings. The subgroups synergize very well together, such that findings in the brain color how we look at cancer, and vice versa.

What is your current research focus?
Genes are stretches of DNA that encode information required by cells to perform certain tasks. A major focus of our lab is the study of how genes in the brain are controlled by neuronal activity. How do seizures alter the patterns of genes in neurons and how do these changes alter the brain functions after a seizure? Are there long-term alterations in gene patterns after a seizure that make the brain prone to further seizures in the future? Can this long-term alteration (a process called “epigenetics”) be controlled to prevent the development of epilepsy?

Can you share some of the latest findings?
Some epilepsies are caused by environmental factors such as a head trauma. These are acquired or evoked epilepsies. Other forms of epilepsy are caused by gene mutations and are termed genetic epilepsies. We have found that we can control seizures in both genetic and acquired epilepsies with drugs that control epigenetic processes. Whereas some work has already been published showing a role for epigenetics in acquired epilepsies, our findings with genetic epilepsies were totally unexpected, novel, and exciting.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
Ultimately, it is hoped that tools will be invented that can repair or fix mutated genes and cure epilepsy. However, that goal is still far in the future. Our goal is to find ways to leave the mutations alone but use epigenetics to cover up and hide the effects of the mutation. We predict that this goal can be achieved with currently available drugs and in a much shorter time frame that genetic engineering.

What accomplishment—personal or professional—are you most proud of?
I get to hang out and speak with some of the brightest people on the planet on a daily basis. I have friends across the globe who lead their fields in the sciences and humanities. As a scientist, I have achieved the position of being paid to work on my very favorite hobby! I get to witness the uncovering and discovery of new knowledge, totally unseen to any other human in the history of mankind, everyday. As a teacher, I have altered the course of young peoples’ trajectories into science. My lab has generated findings that could change clinical practice in the fields of epilepsy and breast cancer.