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

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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.

New Genetic Cause of Epilepsy Found

Researchers from the Walter and Eliza Hall Institute have contributed to a decades-long global effort that has revealed two new gene mutations that cause a rare type of epilepsy, familial adult myoclonic epilepsy.

The Institute research team also traced one genetic mutation back to its origin; an individual with the spontaneous mutation who lived more than 5000 years ago. The team developed technologies that can detect the specific mutations – called repeat expansions – even in small sample groups, and the tools to trace the ancestry of a mutation to its origin.

The discoveries were published in back-to-back papers in Nature Communications. Dr Mark Bennett, Dr Haloom Rafehi and Professor Melanie Bahlo from the Institute were part of the international consortium, which included clinicians, bioinformaticians and biologists from Australia, Germany, France and the Netherlands.

Re-Annotation of 191 Developmental and Epileptic Encephalopathy-Associated Genes Unmasks De Novo Variants in SCN1A

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis. Here, researchers explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. These annotations increase the transcriptional “footprint” of these genes by over 674 kb.

Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, the team screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now – through improved gene annotation – are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications.

Furthermore, the team identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. These findings suggest the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

Epilepsy Research Findings: November 2019

Among the interesting research published this past month are advances in epilepsy genetics that may help predict who is at risk for developing epilepsy and a novel gene therapy concept for treating temporal lobe epilepsy. Research has also furthered our understanding of how epilepsy may impact cognition – even when seizures are controlled by medication.

In this update, we also feature the results of the “Seize the Truth about Epilepsy Perceptions” survey. This national survey of adult epilepsy patients, caregivers, and healthcare professionals explores the physical, social, emotional, and financial consequences associated with epilepsy.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • Epilepsy Genetics: Risk scores are being used to investigate the genetic risk of epilepsy in a large sample of people with and without epilepsy. The international team led by the Cleveland Clinic is using this model to work towards a more personalized method of epilepsy diagnosis and treatment. Learn more
  • Epilepsy Gene Therapy: A new gene therapy concept has been developed for the treatment of temporal lobe epilepsy. In a “proof-of-concept” study, the researchers demonstrated that strategically delivering a specific gene to the place in the brain where seizures start can suppress them on demand in animal models. Learn more
  • Understanding Epilepsy: A new, national survey of adult epilepsy patients, caregivers, and healthcare professionals (HCPs) revealed a wide range of challenges in the management of the condition. The findings range from significant disconnects that occur in conversations among patients, caregivers, and HCPs to revelations about the far-reaching impact of epilepsy. Learn more
  • Epilepsy and Cognition: A study by Stanford University School of Medicine investigators may help explain why even people benefiting from medications for their epilepsy often continue to experience bouts of difficulty thinking, perceiving, and remembering clearly. The cause is a pathological buzz of electrical brain activity, called a high-frequency oscillation, that interferes with the brain’s normal activity. Learn more
  • Seizures in Newborns: Utilizing a mouse model of hypoxic-ischemic seizures has shed light on why seizures in newborns may lead to behavioral issues and learning disabilities much later, according to a study from University of Virginia Children’s Hospital. This research suggests that the brain’s learning and memory centers are among the regions most affected by seizures caused by inadequate oxygen and blood flow. Learn more

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Variants in the Gene GNB5 Associated with Seizures and Profound Impairment

Pathogenic variants in [the gene] GNB5 cause an autosomal recessive neurodevelopmental disorder with neonatal sinus bradycardia.

Seizures or epilepsy occurred in 10 of 22 previously reported cases, including 6 children from one family. This research team delineate the epileptology of GNB5 encephalopathy. The nine patients, including five new patients, were from seven families. Epileptic spasms were the most frequent seizure type, occurring in eight of nine patients, and began at a median age of 3 months (2 months to 3 years). Focal seizures preceded spasms in three children, with onset at 7 days, 11 days, and 4 months. One child presented with convulsive status epilepticus at 6 months. Three children had burst suppression on electroencephalography (EEG), three had hypsarrhythmia, and one evolved from burst suppression to hypsarrhythmia. Background slowing was present in all after age 3 years. Magnetic resonance imaging (MRI) showed cerebral atrophy in one child and cerebellar atrophy in another. All nine had abnormal development prior to seizure onset and ultimately had profound impairment without regression. Hypotonia was present in all, with contractures developing in two older patients. All individuals had biallelic pathogenic variants in GNB5, predicted by in silico tools to result in protein truncation and loss-of-function.

GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment.