UBE3A Gene Reactivation in Inhibitory Neurons May Prevent Seizures, Angelman Mouse Study Shows

Epileptic seizures caused by disturbances in the activity of a specific type of nerve cell called an inhibitory neuron were prevented by the reactivation of the UBE3A gene in young mice with Angelman syndrome features, a study shows.

The study, “Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice,” was published in The Journal of Clinical Investigation.

The disorder is frequently associated with epileptic seizures — estimated to affect between 80% and 95% of patients — that usually fail to respond to anti-epileptic medications. However, the reason why genetic mutations in UBE3A seem to increase patients’ risk of developing epileptic seizures is not yet fully understood.

Although there is no cure for Angelman syndrome, recent studies in mouse models based on UBE3A gene replacement or reactivation in neurons hold great therapeutic potential, including for the treatment of epilepsy.

Reanalyzing Gene Tests Prompts New Diagnoses in Kids

A new study from UT Southwestern quantifies for the first time how quickly rapid advancements in genomics may benefit patients. Research published in JAMA Pediatrics includes a five-year review of more than 300 epilepsy cases that showed nearly a third of children had a change in diagnosis based on new data.

Based on these data, scientists are calling for parents to review gene tests done in children with epilepsy at least every two years to ensure their diagnoses and treatments are based on the latest discoveries. This finding is significant because the leading genome societies have suggested periodic checks but have not recommended how frequently these should be made.

Much remains unknown about the human genome. One widely used database contains about 175,000 “variants of uncertain significance” – approximately double the number of genetic variants believed to cause disease.

Still, the new research shows how quickly scientists are piecing the puzzle together. The study found that 31 percent of the patients received a diagnosis based on a new understanding of their genetic variant within the five-year window. In patients who received a genetic test result as recently as two years prior, researchers still found 25 percent had a disease-causing variant reclassified.

New Causative Gene Found in Severe Childhood Epilepsy

A large international research team has discovered a new genetic cause for a severe, difficult-to-treat childhood epilepsy syndrome. Spontaneous mutations in one gene disrupt the flow of calcium in brain cells, resulting in epileptic overactivity. The team’s research in patients also found clues to potential medical treatments for the rare condition.

“Even though variants in this gene were only just discovered to cause disease, we already have a good understanding of how changes in the gene’s associated protein affect brain function–causing neural overactivity in epilepsy,” said first author Katherine L. Helbig, MS, CGC, a research genetic counselor in the Neurogenetics Program in the Division of Neurology at Children’s Hospital of Philadelphia (CHOP). “Furthermore, although much follow-up research remains to be done, we found that there is a possibility that specific anti-seizure medications could reduce this overactivity in some patients.”

The research team focused on disease-causing changes in the CACNAIE gene, long suspected to play a key role in how neurons regulate their electrical activity, but not previously known to cause human disease. This study was the first to link the gene to human epilepsy.

Genome Sequencing Identifies Cause of Early Infantile Epileptic Encephalopathy

Scientists at University of Utah (U of U) Health report that they have developed high-tech tools to uncover the genetic cause of early infantile epileptic encephalopathy (EIEE). Their study (“Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy”) appears online in Nature Genomic Medicine.

“Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE,” write the investigators.

“The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, three of the 12 patients received nondiagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.”

“These tools let us peek in the dark corners and under the rug of the genome that other methods do not,” says Aaron Quinlan, Ph.D., associate professor of human genetics and biomedical informatics at U of U Health and senior author on the paper. “With this approach rather than undergoing multiple tests, families can receive results faster, limiting their medical odyssey, at ultimately a lower cost.”

Establishing a Plan to Return Individual Results is Important in Epilepsy Genomic Research

Genomic findings are emerging rapidly in 2 large, closely related epilepsy research consortia: the Epilepsy Phenome/Genome Project and Epi4K. Disclosure of individual results to participants in genomic research is increasingly viewed as an ethical obligation, but strategies for return of results were not included in the design of these consortia, raising complexities in establishing criteria for which results to offer, determining participant preferences, managing the large number of sites involved, and covering associated costs. Here, researchers describe the challenges faced, alternative approaches considered, and progress to date.

Experience from these 2 consortia illustrates the importance, for genomic research in epilepsy and other disorders, of including a specific plan for return of results in the study design, with financial support for obtaining clinical confirmation and providing ongoing support for participants. Participant preferences for return of results should be established at the time of enrollment, and methods for allowing future contacts with participants should be included. In addition, methods should be developed for summarizing meaningful, comprehensible information about findings in the aggregate that participants can access in an ongoing way.

Epilepsy Research Findings: July 2018

This month’s promising epilepsy news includes the FDA approval of the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with Dravet Syndrome and Lennox-Gastaut Syndrome, two forms of epilepsy that are challenging to treat. This decision brings hope to families facing these difficult diagnoses. In addition, a report discusses epilepsy genetics and the utility of next-generation sequencing in the diagnosis of early-life epilepsies.

In more sobering news, a study shows that the incidence of Sudden Unexpected Death in Epilepsy (SUDEP), once thought to be greater in adults than in children, may be the same in both populations. However, we have included a report discussing the recent discovery of a potential biomarker for SUDEP, which could lead to preventative measures for this devastating occurrence.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome 

The US Food and Drug Administration (FDA) approved EPIDIOLEX® (cannabidiol/CBD) for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients two years of age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of antiepileptic drugs.

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New Technique Fine-Tunes Treatment for Severe Epilepsy Cases 

An advance by researchers will enable surgeons to more precisely target areas of the brain which cause debilitating symptoms in a subset of epilepsy patients. The technology, called magnetoencephalography or MEG, measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and researchers have developed a novel way to employ it.

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Treating Refractory Epilepsy with Transcutaneous Vagal Nerve Stimulation 

This study found that transcutaneous vagal nerve stimulation (t-VNS) had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients.

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Sunovion Announces Health Canada Approval of Aptiom (eslicarbazepine acetate) as Monotherapy to Treat Partial-Onset Seizures in Adults with Epilepsy

Health Canada approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy.

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Diagnostic Advances

Next-Generation Sequencing May Improve Pediatric Epilepsy Treatment

Next-generation sequencing can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy, according to a study published in CNS Neuroscience & Therapeutics.

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Prediction Method for Epileptic Seizures Developed 

Scientists have proposed a generalized, patient-specific seizure-prediction method that can alert epilepsy sufferers of the likelihood of a seizure within 30 minutes, according to a paper published in Neural Networks.

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Research Discoveries

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

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Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk. This would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

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Also Notable

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

This study reports that levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

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Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report. NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

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Generic Antiepileptic Drugs — Safe or Harmful in Patients with Epilepsy?

Sufficient evidence indicates that most generic antiepileptic drugs (AEDs) are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. This report recommends administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

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Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

Epilepsy is common among elderly individuals, and health care expenditures among this growing group are two times higher than in those without epilepsy.

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Mechanism Leading to Cortical Malformation from Brain-Only Mutations Identified

Focal malformations of cortical development (FMCDs) are a heterogeneous group of brain cortical abnormalities. These conditions are the most common causes of medically refractory epilepsy in children and are highly associated with intellectual disability, developmental delay, and autism-spectrum disorders. Despite a broad spectrum of cortical abnormalities in FMCDs, the defective migration of neuronal cells is considered a key pathological hallmark.

A Korean research team led by [CURE grantee] Professor Jeong Ho Lee at the Korea Advanced Institute of Science and Technology (KAIST) has recently investigated the molecular mechanism of defective neuronal migration in FMCDs.

The research team previously demonstrated that brain-only mutations in the mechanistic target of rapamycin (MTOR) gene causes focal cortical dysplasia, one major form of FMCDs leading to intractable epilepsy in children. However, the molecular mechanisms by which brain-only mutations in MTOR lead to cortical dyslamination and defective neuronal migration in FMCDs remain unclear.

Next-Generation Sequencing May Improve Pediatric Epilepsy Tx

Next-generation sequencing (NGS) can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy (DRE), according to a study published CNS Neuroscience & Therapeutics.

Jing Peng, Ph.D., from Central South University in China, and colleagues conducted genetic testing on 273 pediatric DRE patients with no obvious acquired etiology; 74 underwent whole-exome sequencing (WES), 141 had epilepsy-related gene panel testing, and 58 had clinical WES gene panel testing. Frequency of seizures, outpatient visits, and hospitalization was also assessed.

The researchers found that a genetic diagnosis was made in 86 patients (31.5 percent; 93 likely disease-causing mutations in 33 genes). By testing type, detection rates were 32.6% for the epilepsy-related gene panel, 44.8% for the clinical WES gene panel, and 17.3% for WES. Also, 34 patients accepted therapy based on their mutant genes, after which 52.9% became seizure-free and 38.2% experienced seizure reduction. Hospitalization incidents were significantly lower for patients after testing than before regardless of positive or negative genetic results.

CURE Discovery: New Cause of Severe Childhood Epilepsy Found – Genetic Mutation in the CUX2 Gene

CURE Grantee Dr. Gemma Carvill has identified a new cause of epilepsy: a mutation in the gene CUX2. Dr. Carvill’s discovery was recently published in the Annals of Neurology.[1]

The discovery provides an important advance in our understanding of the causes of a class of severe childhood epilepsies. This class includes childhood epileptic encephalopathy, an aggressive and severe group of treatment-resistant epilepsy disorders in which children can have profound cognitive and neurological deficits.[2,3]

Dr. Carvill began her research into the ways specific genetic mutations lead to childhood epileptic encephalopathy in 2015 as the result of a 1-year CURE Taking Flight Award. This award program encourages young investigators to conduct independent research which could lead to a cure for epilepsy. When Dr. Carvill recieved the CURE Taking Flight Award, she was a Postdoctoral Fellow at the University of Washington.

Dr. Carvill studied the ways genetic mutations lead to epilepsy. Her initial findings suggested that mutations in a class of genes important in determining the structure of DNA could impact several genes involved in epilepsy, making this class of genes a potential target of future epilepsy therapy development.

Since receiving her CURE award, Dr. Carvill’s career has certainly “taken flight” – she is now Assistant Professor of Neurology and Pharmacology at Northwestern University. Still, Dr. Carvill has remained committed to her quest to understand the genetic mechanisms behind severe childhood epilepsy. In her latest study, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital, located in France, to identify de novo mutations in the gene CUX2 as a new cause of epilepsy. De novo mutations are changes present only in the affected patient and not in their healthy parents. CUX2 is important in binding DNA and promoting the expression of certain target genes. Mutations in CUX2 cause errors in this process that can lead to epilepsy.

Dr. Carvill’s report details her international study of 9 patients aged 6 months to 21 years who first began having seizures early in life. To identify the mutation in the CUX2 gene, Dr. Carvill and her team used, among other techniques, a test called whole exome sequencing. This test analyzes a person’s genes to identify changes in their DNA. All 9 patients had the same CUX2 mutation. The team found that the majority of these patients had severe treatment-resistant epilepsy that started early in life, severe intellectual disability, and did not have speech appropriate for their age.

Besides finding an important genetic cause of severe childhood epilepsy, which can now be targeted for the development of therapeutic interventions, Dr. Carvill’s collaboration with Dr. Lesca highlights the importance of international efforts to identify new genes important in epilepsy. As Dr. Carvill notes, these genetic mutations are very rare and therefore collaborative efforts with multiple patient populations make it more likely that a rare genetic mutation can be identified and studied.

In the future, Dr. Carvill plans to further explore the genetic mechanisms behind these devastating childhood epilepsies. Her goal, which we at CURE share, is that treatments and cures can be found for all of the amazing children affected by epilepsy and their wonderful families, too.

Citations

[1] Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol2018; 6 [Epub ahead of print]
[2] Cross H and Guerrini R. The epileptic encephalopathies. Handb Clin Neurol 2013; 111:619-626.
[3] Jehi L, Wylie E, Devinsky O. Epileptic encephalopathies: Optimizing seizure control and developmental outcome. Epilepsia 2015; 56(10):1486-1489.

The adult motor phenotype of Dravet syndrome is Associated with Mutation of the STXBP1 Gene and Responds Well to Cannabidiol Treatment

Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult; that is why Cannabidiol emerged as valid option for treatment of this condition.