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.

A female researcher with a silver ponytail looks through a microscope.

CURE Discovery: Understanding and Treating NMDA Receptor-Associated Epilepsy

Key Takeaways:

  • Researchers are studying whether off-label treatment with certain FDA-approved drugs can improve seizure control for individuals whose epilepsy is caused by over-activation of NMDA-R.
  • The CURE-funded team is researching previously unstudied mutations in GRIN genes and using this information to determine who might benefit from off-label treatment with NMDA-R blockers.
  • Interested families with a genetic diagnosis of a GRIN mutation and epilepsy can enroll in this important study. Contact Jenifer Sargent at Jenifer.Sargent@childrenscolorado.org for more information.

Deep Dive:

Dr. Stephen Traynelis

Can off-label use of certain FDA-approved drugs which reduce NMDA-R function

improve seizure control in patients with epilepsy caused by over-activation of NMDA-R? That is the question a CURE-funded study by Dr. Stephen Traynelis at Emory University and his team aims to answer.

Dr. Traynelis and his collaborators, Drs. Sooky Koh, Ann Poduri, and Tim Benke, will assess if epilepsy caused by over-activation of a protein in the brain, called the N-methyl-D-aspartate receptor (NMDA-R), can be improved when patients with GRIN mutations are treated off-label by their clinicians with certain FDA-approved NMDA-R blockers. They also hope to determine if treatment with these drugs has any positive effects on developmental progress in addition to improved seizure control.

NMDA-R is an essential component of electrical signaling in the brain and is made from proteins encoded by the GRIN family of genes.1 Because GRIN genes provide the blueprint for NMDA-R, mutations in these genes can impact how the NMDA-R works. Not all of these mutations cause over-activation of the NMDA-R, so in the first part of this project, the researchers are investigating each human GRIN mutation that has not been studied before by re-creating them in the laboratory and evaluating how they affect NMDA-R activity. This information will then be used to determine who might benefit from off-label treatment with drugs that reduce NMDA-R function.

People with GRIN variants that data suggest produce a strong over-activation of the NMDA-R might be candidates for treatment by their physician with NMDA-R blockers. Those with GRIN variants that reduce activity of the NMDA-R or produce complex actions which are difficult to clearly categorize would not be expected to benefit from treatment.

The investigators have created a registry where families affected by GRIN mutations can sign up to participate. The registry collects medical history data and records that are stored without any identifying information to protect the privacy of each participant. Following analysis of a patient’s mutation status, a report is shared with their clinician who will judge whether it is in the patient’s best interest to be considered for off-label treatment. Treatment could then be offered to the family and is based on treatment guidelines Dr. Traynelis and his collaborators have developed.

The team will follow up with a retrospective analysis of treatment efficacy. That is, the investigators will go back and analyze medical records, EEG data, seizure history, and other relevant data for people who received off-label treatment from their physicians to understand how well the treatment worked. This data will also allow an assessment of whether particular GRIN mutations may benefit more from the treatment than others.

This study is expected to provide data for a clinical trial that could lead to new therapies for these difficult to treat epilepsies. In a previously published study, the investigators treated a child with early-onset epileptic encephalopathy associated with a mutation in GRIN2A with the drug memantine and found a substantial reduction in his seizure burden after treatment for a year.2 Additional studies provided more mixed results, creating a need to better understand the utility of this approach.

The team is looking to enroll additional families in this important study. If you or anyone you know with a genetic diagnosis of a GRIN mutation and epilepsy are interested in participating, please contact Jenifer Sargent at Jenifer.Sargent@childrenscolorado.org to learn more about the study.

1 Hansen KB, Feng Y et. al., J Gen Physiol. 2018 Aug 6; 150(8): 1081–1105
2 Pierson TM, Yuan H et. al., Ann Clin Transl Neurol. 2014 Mar 1;1(3):190-198

New Genetic-Based Epilepsy Risk Scores

An international team of researchers led by Cleveland Clinic has developed new genetic-based epilepsy risk scores which may lay the foundation for a more personalized method of epilepsy diagnosis and treatment. This analysis is the largest study of epilepsy genetics to date, as well as the largest study of epilepsy using human samples.

The research team, led by Dennis Lal, Ph.D., calculated for the first time quantitative scores that reflect overall genetic risk for epilepsy, called polygenic risk scores. They showed that these scores can accurately distinguish on a cohort level between healthy patients and those with epilepsy, as well as between patients with generalized and focal epilepsies.

After the first seizure, it can be difficult for clinicians to predict which patients will go on to develop epilepsy. Development of these novel genetic risk scores could help clinicians to intervene and treat patients earlier.

“The fact that we can now identify people at high risk for epilepsy, and even start to distinguish between the two main types of epilepsy, based on genetic scores is really exciting,” said Lal, the study’s lead author. “These landmark results set the stage for an entirely new direction of epilepsy research.”

New Report Shows Rare Disease More Common Than Previously Thought

Approximately one in forty-two thousand children are born with a disease called CDKL5 Deficiency Disorder, according to a new medical report recently published in the journal Brain and presented last month at the 13th European Paediatric Neurology Society Congress in Athens, Greece. This means that each year there are over 100 new children born with the disease in the EU alone, and over 3,000 in the world.

The disease leads to frequent seizures shortly after birth and severe impairment in neurological development, with most affected people being unable to walk, talk or care for themselves. “When our daughter was diagnosed in 2009 they told us there were approximately 200 cases in the world”, says Carol-Anne Partridge, chair of CDKL5 UK and the International CDKL5 Alliance, which represents patient organizations from 18 countries. “Today we know that these children were simply not being diagnosed correctly,” she adds.

The study, by a medical team from the Royal Hospital for Children in Glasgow, kept track of all births in Scotland during three years and applied genetic testing to all children under 3 years of age who developed epilepsy. “We found that as many as 1 in 4 children with epilepsy have a genetic syndrome”, explains Professor Sameer Zuberi, corresponding author for the study, “and a small group of genes explains most of the cases.”

Among these genes is CDKL5, which encodes a protein necessary for proper brain functioning. Mutations in the CDKL5 gene produce CDKL5 Deficiency Disorder, with one of the first symptoms being early-onset epilepsy. There is no therapy approved for treating the disease now known to affect thousands of people.

Complex Neurocognitive Skills Delayed in Youth With SCN8A Variant Epilepsy

Complex neurocognitive skills, typically acquired later in development, are the most delayed skills in youth with SCN8A?related epilepsy, according to results published in Epilepsia.

Researchers analyzed 91 patients with SCN8A-related epilepsy. Analyses were conducted to identify correlations between age at seizure onset and neurodevelopmental growth. Parents and guardians provided information pertaining to their child’s medications, seizure history, comorbidities, and developmental skills based on Denver II items. Twenty-five skills were chosen, six to seven from each category (fine motor, gross motor, social motor, and language).

Researchers carried out a retrospective analysis of data from an online SCN8A community registry and used the canonical transcript to map all genetic variants collected. Spearman rank tests were used to evaluate pairwise relationships between certain seizure characteristic variables and development score.

A limitations of this study included the potential for recall error in questionnaires completed by parents and guardians. Further, cohort included was not large enough to produce statistically significant tests and prevented further stratification based on subphenotypes or mutational type.

Researchers concluded that variants of uncertain significance should be taken into consideration when evaluating children with SCN8A-related epilepsy. Researchers believe these findings provide “a clinical context at initial presentation that may be prognostic for developmental outcome.”