Epilepsy Research Findings: March 2020

This month’s research highlights feature promising work by former CURE Grantees and CURE partners.

Former CURE Grantee Dr. Kristina Simeone’s recent research has uncovered a potential predictive biomarker for Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Simeone’s work was supported by the Benninghoven family in memory of Cameron Benninghoven.

We also feature research by another former CURE Grantee, Dr. Angelique Bordey, who along with her research team published exciting findings showing that targeting a particular protein in the brain can reduce or prevent seizures in mouse models of difficult-to-treat epilepsy.

We are also highlighting research by Dr. Daniel Correa and his work through the EpiBioS4Rx Public Engagement Core, a project in which CURE participates. Dr. Correa’s research indicates that greater efforts should be made to ensure online epilepsy health education materials are more easily understandable to the general population to increase epilepsy literacy.

These findings, as well as others, can be found below:

Research Discoveries & News

  • SUDEP: Research featuring the work of former CURE Grantee Dr. Kristina Simeone found a potential time-based biomarker of impending SUDEP. Dr. Simeone found cardiac and respiratory dysfunction that changed over time in mice at risk for SUDEP and may serve as a biomarker to indicate who is at risk for SUDEP. She also found that this dysfunction could be lessened by blocking a particular type of receptor in the brain, the orexin receptorLearn More

    This research was supported by the Benninghoven family in memory of Cameron Benninghoven.

  • Uncontrolled Epilepsy Treatment: Former CURE Grantee Dr. Angelique Bordey and her research team utilized an experimental drug to reduce seizures in mouse models of tuberous sclerosis complex (a rare genetic epilepsy) and a subset of focal cortical dysplasia type II (a brain malformation causing epilepsy). The team found that seizures can be prevented or reduced by targeting a protein called actin-cross linking protein filament A which is often elevated in the brains of humans with these epilepsies. Learn More
  • Online Epilepsy Education: Researcher Dr. Daniel Correa found that the majority of online health education materials related to traumatic brain injury (TBI), epilepsy, and post-traumatic epilepsy (PTE) do not meet the sixth-grade reading level recommendation from most health organizations. This study was published as part of the CURE-supported EpiBioS4Rx Public Engagement Core, an NINDS initiative focused on ensuring successful future clinical trials to prevent the development of PTE following TBI. This study suggests that improving the readability of health education materials may increase epilepsy-related health literacy, leading to more effective recruitment efforts for future clinical trials, as well as better patient-centered results. Learn More
  • New Treatment: Valtoco (diazepam), a nasal spray intended to treat seizure emergencies in patients 6 years of age and older, is now commercially available in the US. Learn More
  • Clinical Trial: Engage Therapeutics announced that its Phase 2b StATES study of Staccato® alprazolam, an orally inhaled therapy designed to terminate an active epileptic seizure, met its primary endpoint. This endpoint was a proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours. Learn More
  • Post-Traumatic Epilepsy: Research suggests that rats treated with certain drugs within a few days of a traumatic brain injury have a dramatically reduced risk of developing epilepsy later in life. Researchers found that suppressing an immune system receptor called Toll-like receptor 4 shortly after brain injury reduces seizure susceptibility and neuronal excitability in an important part of the brain called the hippocampus. Learn More
  • SCN8A Encephalopathy: A therapy that enables researchers to control gene expression in the brain, called antisense oligonucleotides (ASOs), has been utilized to stop seizures in a mouse model of SCN8A encephalopathy, a rare childhood epilepsy. By using ASOs, researchers delayed seizure activity and increased the lifespan of these mice. Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Professor Ji Won Um (left) as well as combined master's and doctoral dual degree program students Seungjoon Kim (front), and Hyeonho Kim (back) in the Department of Brain and Cognitive Sciences at DGIST

Discovery of GABAergic synaptic regulations inside the brain for a new epilepsy treatment

DGIST joint research team identified the roles of ‘Somatostatin,’ which mediates the functions of GABAergic synaptic protein

DGIST announced on February 12 that the joint research team of Professor Jaewon Ko and Professor Ji Won Um in the Department of Brain and Cognitive Sciences found a new candidate target to treat epilepsy by regulating GABAergic synaptic functions. This research achievement is expected to set a milestone to develop new treatments such as epilepsy, one of the intractable brain diseases.

Epilepsy is one of the intractable brain diseases with a high prevalence of 1% in South Korea’s population, as more than 30% of the central nervous system does not respond well to the conventional medications. In particular, the number of patients with epilepsy convulsions that occur with high blood pressure, diabetes, hemorrhage, etc., due to various causes, account for 10-15% of the total population. However, no specific mechanisms have been known clearly on how epilepsy begins in which parts of the brain, how it spreads to other parts of the brain, and how its symptoms are controlled, are largely unknown.

Professor Um’s research team had been steadily discovering and researching key molecules that mediate the development of GABAergic synapse associated with brain diseases and discovered IQSEC3, a GABAergic synapse-specific protein, for the first time in 2016. In this research, her research team uncovered a new molecular mechanism that mediates the GABAergic synaptic development by regulating neural circuit activity in the hippocampal dentate gyrus, in which IQSEC3 mediates higher brain functions such as memory and learning.

To determine this, the research team produced a knockdown virus which eliminates IQSEC3 and injected it into the hippocampal dentate gyrus of mice, which showed a decrease in GABAergic synapse numbers and neurotransmission with severe seizures. This revealed that IQSEC3 protein was a key factor in mediating the GABAergic synaptic structure and function.

The researchers found that the amount of somatostatin peptide, originally known to be secreted from hypothalamus, in the hippocampal dentate gyrus, was dramatically decreased. They confirmed that injecting somatostatin peptides into the specific type of GABAergic interneurons also completely restored the GABAergic synaptic deficits and increased frequency of seizures caused by IQSEC3 deficiency.

Professor Um said, “We found a key clue that somatostatin, which is a key for regulation of synaptic transmission between nerve cells, directly mediates the development of GABAergic synapses. This can be used as a novel treatment strategy for epilepsy and various refractory brain diseases caused by a breakdown of the excitatory-GABAergic balance at synapses and neural circuits.”

Epilepsy Research Findings: February 2020

Among the articles featured this month, we highlight the work of former CURE Grantee Dr. Annapurna Poduri, whose recent study argues for early use of whole exome sequencing and repeated analysis to identify the genetic cause of epilepsy in children. Dr. Poduri’s study supports the idea that reanalysis can aid in diagnosis. We also highlight Dr. Tristan Shuman, whose CURE-funded work sheds light on how epilepsy can affect cognition.

You can find more detail about our CURE Grantees’ work, as well as additional intriguing studies, below.

Research Discoveries & News

  • Epilepsy Genetics: In a study featuring the work of past CURE Grantee Dr. Annapurna Poduri, authors argue that use of whole exome sequencing with reanalysis of genetic data can, in some cases, more quickly lead to the identification of genetic variants associated with epilepsy in patients. Learn More
  • Epilepsy and Cognition: A study partially funded by CURE investigated the ways epilepsy affects navigation in mice. CURE Grantee Dr. Tristan Shuman and collaborators report that a particular feature of epilepsy – namely the “desynchronization” of neurons in the brain that are important in cognition – causes deficits in spatial information coding. Learn More
  • Dravet Syndrome: Researchers report that treating a mouse modeling Dravet syndrome with a small molecule reduces abnormal brain activity and improves cognitive function. The study states that the molecule enhances the function of a particular type of brain receptor found at the connection points between neurons. Learn More
  • Epilepsy and Technology: Smartphone videos taken by witnesses could help physicians diagnose seizures. Researchers concluded that patient-generated smartphone videos can help predict inpatient video-EEG diagnosis of epilepsy and add valuable information to the patient’s history and physical examination. Learn More
  • Angelman Syndrome: Using human nerve cells and three-dimensional “mini brains,” researchers have found that dysfunctional potassium channels may underlie the development of seizures associated with Angelman syndrome. Learn More
  • Epilepsy Benchmarks: These articles review the NINDS Epilepsy Benchmarks, examining progress made in epilepsy research and identifying priorities for the next phases of research. This is a process that continues to evolve to reflect scientific advances and community research priorities over time. Learn More
    • The Benchmarks: Progress and Emerging Priorities in Epilepsy Research – Learn More
    • Epilepsy Benchmarks Area I: Understanding the Causes of Epilepsies and Epilepsy-Related Neurologic, Psychiatric and Somatic Conditions – Learn More
    • Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression – Learn More
    • Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions without Side Effects – Learn More
    • Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequences of Seizures and Their Treatment Across the Life Span – Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Genetic Diagnoses in Epilepsy: The Impact of Dynamic Exome Analysis in a Pediatric Cohort

Featuring the work of par CURE-Grantee Dr. Annapruna Poduri

Objective: This research team evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

Methods: The team identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. The team analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

Results: Overall, the researchers identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were “unsolved” through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%).

Significance: The data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

Epilepsy Research Findings: January 2020

This past month of research advances include the finding that “silencing” certain populations of neurons may stop seizures and the uncovering of a possible cause of memory impairments in individuals with epilepsy. In addition, a study found that one in every four children in the US with epilepsy has anxiety and/or depression, emphasizing the importance of investing resources into epilepsy and mental health.

Other exciting news for the epilepsy community includes the approval of a new nasally administered rescue medication called VALTOCO and the expanded availability of the no-cost epilepsy gene panel testing program Behind the Seizure® to a wider age range of children who have had an unprovoked seizure.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • Seizure Control: Seizures can be “switched off” in an animal model of epilepsy by silencing one particular set of neurons located in the brainstem, specifically in an area called the substantia nigra, according to research from the Georgetown University Medical Center. Zeroing in on specific neurons suggests that treatment for epilepsy can be improved, researchers say. Learn More
  • Epilepsy and Memory: A new Cedars-Sinai study reveals how memory and abnormal brain activity are linked in patients with epilepsy. The data show that abnormal electrical pulses from specific brain cells are associated with a temporary kind of memory disruption called transient cognitive impairment. Learn More
  • Epilepsy and Depression: A study utilizing data from the 2009-2010 National Survey of Children with Special Health Care Needs found that one in four US children with epilepsy has depression and/or anxiety. The study authors concluded that physicians should consider the various factors that are related to depression and anxiety in children with epilepsy so that at-risk children can be screened and managed appropriately. Learn More
  • Treatment Approval: Neurelis, Inc. announced that the FDA has approved VALTOCO® (diazepam nasal spray) as an acute treatment of intermittent, stereotypic episodes of frequent seizure activity (seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in people with epilepsy 6 years of age and older. Learn More
  • Genetic Testing: The no-cost epilepsy gene panel testing program Behind the Seizure®, which aims to provide faster diagnosis for young children with epilepsy, is being extended to any child under the age of eight who has an unprovoked seizure. Learn More

The CURE Epilepsy Research Mobile App delivers research news to the palm of your hand! With frequent updates, you’ll always be in-the-know about the latest in epilepsy science. Download today. iOS | Android

Behind the Seizure® Program Further Expands Access to Genetic Testing for Children to Speed the Diagnosis of Genetic Epilepsy

BioMarin Pharmaceutical Inc. and Invitae Corporation announced that Biogen, Encoded Therapeutics, Neurogene, Praxis Precision Medicines, and PTC Therapeutics joined Behind the Seizure®, an innovative, cross-company collaboration that aims to provide faster diagnosis for young children with epilepsy. The program will also be expanded to make no-charge testing available for healthcare providers to order for any child under the age of eight who has an unprovoked seizure.

“Behind the Seizure is one of the longest-running cross-company collaborations aimed at increasing access to genetic testing. It has been shown to decrease time to diagnosis for children experiencing unprovoked seizures by one to two years from reported averages, and as more companies have joined the program, more children have been helped,” said Robert Nussbaum, chief medical officer of Invitae. “Earlier diagnosis enables clinicians to focus on providing disease-specific care sooner, which is particularly important in neurodegenerative diseases. We applaud these companies for their commitment to expanding this unique effort to help children.”

Phenotypic Spectrum and Genetics of SCN2A-Related Disorders, Treatment Options, and Outcomes in Epilepsy and Beyond

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy.

There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.

Key Points

  • SCN2A-related disorders can present with epilepsy and/or intellectual disability with autism
  • Mutation type and associated functional effects (gain vs loss of function) may predict phenotype and medication response
  • Sodium channel blockers may be effective in early onset cases associated with gain of function mutations
  • Insights into SCN2A-related functional effects offer a target for novel specific therapies
Locations of SCN2A variants within the NaV1.2 channel.

SCN2A Channelopathies: Mechanisms and Models

Variants in the SCN2A gene, encoding the voltage-gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self-limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype-phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain-of-function variants. Here, researchers sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A-related disorders.

Key Points

  • SCN2A variants cause a variety of syndromes with different severities
  • There is a correlation between the severity of the clinical phenotype and the nature of the SCN2A variants
  • Patients carrying gain-of-function SCN2A variants can be treated with sodium channel blockers

Overview of STXBP1-Related Developmental and Epileptic Encephalopathy

Researchers from the University of Antwerp, Belgium, and numerous international collaborators report a comprehensive overview of the phenotypic and genetic spectrum of Syntaxin-binding protein 1 (STXBP1) encephalopathy.

COMMENTARY. This paper provides a comprehensive phenotypic and genetic analysis of individuals with STXBP1 pathogenic variants. Although most patients with STXBP1-related disease present with epilepsy, others may have primarily movement disorders such as an ataxia-tremor-retardation syndrome. In some selected patients with drug resistant epilepsy, surgical intervention has been reported to successfully reduce seizure frequency. Although profound intellectual disability is highly associated with STXBP1 variants, autism spectrum disorder is rarely seen. Management typically includes anticonvulsants for seizure control and early intervention with physiotherapy, occupational, speech and or behavioral therapy to treat the complex neurodevelopmental aspects of the disorder.

Age Is Just a Number: Adults Deserve the Same Access to Genetic Testing as Children

At what point in the course of chronic epilepsy is finding the etiology no longer worthwhile? Is it fair to assume there comes a point where knowing the cause is no longer beneficial to the patient? If that time exists, is it the medical equivalent of waving the white flag?

Understanding the genetic basis of epilepsy has changed the way treatment is delivered, particularly for patients with epileptic encephalopathies. For the majority of people with seizures, regardless of severity, understanding the etiology of their epilepsy brings an end to the diagnostic odyssey that for many has included years of testing and uncertainties about the future. Multigene panels and whole-exome sequencing have primarily been used in pediatric populations where the downstream value of accurate diagnosis is likely highest and programs providing free testing make the early identification of syndromes where the course of treatment may be altered easier. Genetic testing has particularly high yield for children with early-life epilepsy and epileptic encephalopathies where the diagnostic hit rate can exceed 25%, approaching the yield of imaging and surpassing that of metabolic testing. Unfortunately, for adults with chronic epilepsy of childhood onset, the bus has often left the station, and they are not afforded the same advances in gene testing. The question is whether that matters and the answer is we don’t really know.

The limited use of genetic testing in adults is likely multifactorial. Essentially, all of the genetic epileptic encephalopathies have onset in childhood where the majority of research interest in diagnosis and treatment of these disorders exists. Unfortunately, this fails to acknowledge the undiagnosed adult patients who could benefit if afforded the same advances in treatment. For many of these conditions, early mortality has been the rule, thus many may consider testing low yield in older individuals. However, most of these conditions represent a phenotypic spectrum that is only now becoming more obvious as increasing numbers of individuals are diagnosed, thus we truly have no handle on the number of individuals with more favorable courses. Many adults with epilepsy and intellectual disabilities may no longer have strong advocates in the search for a diagnosis as they would have had as children, thus no voice to push for genetic testing. Finally, many question whether the outcome is altered in an adult who has suffered so many years with these conditions. This is a question that will remain unanswered if we don’t identify adults living with these disorders now. Ultimately, the goal of care should likely be to decrease the burden of disease for every individual with epilepsy and having a precise diagnosis to provide the most effective care would be the obvious path to consider.