Study Shows Genetic Testing Program Lowered Age of Molecular Diagnosis in Children

Summary, originally published in Dravet Syndrome News

By implementing a free-of-charge epilepsy genetic testing program, it is possible to lower the average age of molecular diagnosis of children with epileptic disorders caused by mutations in the SCN1A gene, such as Dravet syndrome, from more than 6 to less than 2 years of age.

The study with that finding, “Reducing the Time to Diagnosis and Increasing the Detection of Individuals With SCN1A-Related Disease Through a No Cost, Sponsored Epilepsy Genetic Testing Program,” was presented during the American Epilepsy Society (AES) 2020 Virtual Annual Meeting.

Genetic mutations in the SCN1A gene have been associated with a wide spectrum of epileptic disorders, including Dravet syndrome, generalized epilepsy with febrile seizures plus (GEFS+), and early infantile epileptic encephalopathy (EIEE).

According to a previous study, from 2011 to 2015, the average age of molecular diagnosis of patients with forms of epilepsy associated with SCN1A mutations was 6.2 years.

“As precision medicine therapies emerge, it is becoming increasingly important to diagnose SCN1A-related disorders before disease progression,” the researchers wrote.

Research Grant of Over 2 Million Euros ($2.5 Million) Offers New Hope for Children with Rare Epilepsy

Summary, originally published by Schinzel-Giedion Syndrome Foundation

Funding from two major European grants has been awarded to an international group of researchers to find treatments for the devastating rare genetic disease Schinzel-Giedion Syndrome (SGS).

The grants are the first major funding awarded for SGS research.

Nuala Summerfield, Founder and Chair of UK based patient group The Schinzel-Giedion Syndrome Foundation said: “My daughter Ophelia has Schinzel-Giedion Syndrome and has battled her entire short life with multiple daily seizures and many other severe health and developmental problems. There are no effective treatments currently available for SGS, so it is wonderful news that SGS is now receiving such commitment from the scientific community. Our patient advocacy group and our international SGS community will now have the unique opportunity to collaborate closely with these world class scientists to help them to develop new treatments for rare epilepsies.”

The funding comes from the European Joint Program on Rare Diseases (EJP RD), co-funded by the European Commission. The TREAT-SGS project was selected from 173 eligible proposals and will receive 1.6 million Euros. The focus of the TREAT-SGS project is the development and preclinical testing in human cell models and transgenic mice of novel treatments for Schinzel-Giedion Syndrome. The project is a collaboration between the UK based patient group The Schinzel-Giedion Syndrome Foundation and academic researchers in Canada, Italy, Sweden and Germany, facilitated by Dr. Carl Ernst.

Screening of Genetically Diverse Mice Identifies Novel Rodent Models of Diverse Epilepsy Outcomes

Funded by the generosity of families who have experienced a loss due to SUDEP.

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Bin Gu and colleagues used genetically diverse mouse strains to identify those that vary in seizure susceptibility, seizure spread, seizure development, and sudden unexpected death in epilepsy (SUDEP).
  • Initial screening of these mice identified four different genetic strains that suddenly and unpredictably died after inducing a single seizure, suggesting these mice may represent novel models for studying SUDEP.
  • Further genetic characterization of these four mouse strains should provide valuable insights into the underlying genetic risk factors for SUDEP.

Deep Dive:

Dr. Bin Gu, PhD

Dr. Bin Gu, PhD

SUDEP is the sudden, unexpected death of someone with epilepsy who otherwise appears healthy. To facilitate an understanding of the complex genetic basis of SUDEP, studies need to use genetically diverse mouse populations [1,2], such as the “Collaborative Cross” [3,4], which can help identify different genetic risk factors that control SUDEP susceptibility.

With the help of a CURE Epilepsy Taking Flight Award, Dr. Bin Gu and his colleagues in the laboratories of Drs. Ben Philpot and Fernando Pardo-Manuel de Villena at the University of North Carolina at Chapel Hill used Collaborative Cross mice to identify mouse strains that were more likely to have seizures, were more prone to having subsequent seizures, were more susceptible to having their seizures spread throughout the brain and were especially vulnerable to SUDEP [5].

The researchers screened mice from this population to identify candidate genes and genetic variants linked to many key symptoms of epilepsy. For example, within this population of mice, when Dr. Gu induced epilepsy, he observed that some mouse strains were resistant to developing epilepsy, whereas others were more susceptible. Identifying the genetics of the resistant strains is important for understanding the mechanisms underlying seizures and developing new ways of stopping seizures before full-blown epilepsy develops.

Among the groups of mice that Dr. Gu studied, four strains of mice died suddenly after a single seizure that was not fatal in “normal” mice. Although the precise cause of sudden death in these mice is currently unknown, the specific strains may eventually provide important clues to the causes of SUDEP in humans.

Dr. Gu’s upcoming research will focus on characterizing these “pro-SUDEP” strains, identifying those genes that control SUDEP susceptibility and resistance and studying the biological causes, including cardiac and respiratory events, that can provoke SUDEP. Such an understanding will hopefully lead to effective strategies to prevent SUDEP.

By providing Dr. Gu with critical initial funding for his research through a Taking Flight Award, CURE Epilepsy has also helped advance Dr. Gu’s career. He will soon establish his own independent lab as an Assistant Professor of Neuroscience at Ohio State University, where he will continue to pursue his passion for epilepsy research.

Dr. Bin Gu is a postdoctoral fellow at the University of North Carolina at Chapel Hill.


Literature Cited
[1] Saul, M.C. et al. High-diversity mouse populations for complex traits. Trends Genet. 2019; 35(7): 501-514.
[2] Bogue, M.A. et al Collaborative cross and diversity outbred data resources in the mouse phenome database. Mamm. Genome 2015; 26(9-10): 511-520.
[3] Churchill, G.A. et al. Complex Trait Consortium. The collaborative cross, a community resource for the genetic analysis of complex traits. Nature Genetics 2004; 36(11): 1133-1137.
[4] Srivastava, A. et al. Genomes of the mouse collaborative cross. Genetics 2017; 206(2): 537-556.
[5] Gu, B. et al. Collaborative cross mice reveal extreme epilepsy phenotypes and genetic loci for seizure susceptibility. Epilepsia 2020; 61(9): 2010-2021.

Inflammation in Genetic Epilepsy

Summary, originally published in Epilepsia

Brain inflammation plays a role in human epilepsy, but most studies have focused on acquired epilepsies, such as those due to head trauma, viral infection or other insults. Neuroinflammation has never been reported in genetic epilepsy associated with ion channel gene mutations.

Jing-Qiong (Katty) Kang, MD, PhD, and colleagues previously characterized how mutations in the gene encoding a GABA-A receptor subunit — part of an ion channel that blunts excitatory signaling — contribute to epileptogenesis in mouse models.

They now report in the journal Epilepsia that mice with a particular GABA-A receptor subunit mutation (a model for the genetic epilepsy Dravet syndrome) have increased levels of proinflammatory factors in the brain, but not in the plasma. They found increased neuroinflammation in multiple brain regions and throughout different developmental stages and showed that it was independent of seizure occurrence.

This research was supported by grants from Citizens United for Research in EpilepsyDravet Syndrome Foundation, Vanderbilt Brain Institute, and National Institutes of Health (NS082635, TR002243). 

CHOP Researchers Characterize Shared Pathways in Epilepsy and Autism

Summary, originally published in CHOP News

In a new paper published in Scientific Reports, researchers at Children’s Hospital of Philadelphia (CHOP) have identified and characterized genetic pathways shared by epilepsy and autism spectrum disorder (ASD), two heterogenous brain disorders. Further exploration of the findings could lead to better, more personalized treatments for both conditions.

Epilepsy and ASD are two broad categories of brain disorders that overlap with surprising frequency. For example, some 30% of patients with ASD also have epilepsy, whereas the seizure disorder occurs in only 2-3% of the general population. While the reason for this overlap has not been identified, one hypothesis is that both conditions involve the disruption of shared neurodevelopmental pathways implicated by the relatively high number of genes associated with both disorders.

Certain biological pathways are involved in both disease processes, such as transcription regulation, cellular growth, and synaptic regulation, though the specific mechanisms involved are still unknown. Although previous studies have used network-based approaches to identify pathways and genes implicated in epilepsy and ASD, those studies have largely focused on protein-protein interactions or other types of biological networks in each condition in isolation, rather than examining how the conditions relate to one another. Prior studies also have not focused on networks based on gene-phenotype associations – that is, how the implicated genes relate to how the disease presents clinically.

Mechanism Connects Epilepsy and Enzyme Deficiency

Summary, originally published in JCI Insight

Researchers from Kyushu University’s Medical Institute of Bioregulation in collaboration with Nihon University, Yasuda Woman’s University, and Nagoya University now report a better understanding of a mechanism causing epilepsy in infants as the result of a deficiency of an enzyme known as inosine triphosphatase, or ITPA.

The new study could also give insight into possible risks for the 2% of the Japanese population in which both copies of the gene for ITPA produce versions with reduced activity.

Using mice that were genetically engineered such that ITPA production is disrupted only in the nervous system, the researchers found that ITPA deficiency led to a reduction in the negative charge inside the neurons when signals are not being sent, a phenomenon known as depolarization. This depolarization in turn results in frequent excitation of neurons and epileptic seizures in the mice.

The new results indicate that Early Infantile Epileptic Encephalopathy 35 (EIEE35), a neurological disorder characterized by epileptic seizures and associated with deficiency of ITPA, may involve cell membranes becoming more excitable because of depolarization caused by ITPA deficiency.

Epilepsy Research News: January 2021

This month’s research news includes announcements about CURE Epilepsy’s Frontiers in Research seminar series, and an announcement from the CDC about an incidence and etiology funding opportunity.

We also share that the NINDS Clinical Trials Methodology Course is accepting applications, and that the deadline to apply to the National Science Foundation Enabling Discovery Through Genomics (EDGE) Program is March 16.

These news items are summarized below.

Research Highlights

CURE Epilepsy’s Frontiers in Research Seminar Series has gone virtual!

As part of our on-going commitment to supporting the research community through these difficult times, we are conducting our research seminar series virtually with the topics below. Mark your calendars!

The virtual Frontiers in Research Seminar Series is sponsored by the Nussenbaum-Vogelstein Family.

Learn more

CDC Epilepsy Incidence and Etiology Funding Opportunity Announcement
Projects are intended to inform incidence and social determinants of epilepsy including risk factors and protective factors that affect epilepsy incidence. Information about epilepsy incidence will provide invaluable information to help better guide interventions or services for preventing epilepsy, treating and rehabilitating people with epilepsy, and minimizing their health disparities and adverse outcomes.

Click here for details. Search opportunity number by RFA-DP-21-004 and SIP 21-007.

Learn More

NINDS Clinical Trials Methodology Course-Application Deadline February 28
The NINDS Clinical Trials Methodology Course (CTMC) is accepting applications for the 2021 cohort. The overarching goal of the CTMC is to help investigators develop scientifically rigorous, yet practical clinical trial protocols. The focus is on investigators who have not previously designed their own prospective, interventional clinical trials.

Learn More

National Science Foundation Enabling Discovery Through Genomics (EDGE) Program-Application Deadline March 16
The goal of the EDGE program is to provide support for genomic research and associated theory, approaches, tools, and infrastructure development to address the mechanistic basis of complex traits in diverse organisms within the context (environmental, developmental, social, and/or genomic) in which they function.

Learn More

Girls With Rett Have Higher Rate of Menstrual Seizures, Study Says

Summary, originally published in the Journal of Pediatric and Adolescent Gynecology

Girls and women with Rett syndrome may have increased rate of menstrual seizures, also known as catamenial seizures, compared to healthy females, a study reports.

Age of onset, and duration and flow of menstruation in girls and women with Rett were similar to healthy girls. Bone health concerns was one of the most common reasons for discontinuing hormonal treatment among those with Rett.

The study “Features of menstruation and menstruation management in individuals with Rett syndrome” was published in the Journal of Pediatric and Adolescent Gynecology.

Epilepsy Research News: December 2020

This month’s research news includes announcements about the Curing the Epilepsies 2021 Conference, and a reminder about the Cure Epilepsy and Taking Flight grant letters of intent (LOIs).

We also share that the Health Disparities Research Institute will be accepting applications, and that the TESS Research Foundation is hiring.

These news items are summarized below.

Research Highlights

Curing the Epilepsies 2021 Conference–January 4-6, 2021

Please join the epilepsy community from around the world to discuss the progress made in understanding the biological mechanisms underlying the epilepsies, and the inroads being made towards potential cures.

The main outcome and priority of the meeting will be to identify transformative research priorities that will accelerate development of cures and improve outcomes for people with epilepsy. The meeting takes place from January 4-6, 2021. It will be open to the public and freely available via livestream.

Learn more

Understanding & Treating Temporal Lobe Epilepsy
A team of researchers has found that an amino acid produced by the brain could play a crucial role in preventing cell loss and seizures associated with temporal lobe epilepsy. Utilizing an animal model of temporal lobe epilepsy, the research team found that administration of the amino acid D-serine prevented cell loss characteristic of temporal lobe epilepsy and reduced the number and severity of seizures.

Learn More

CURE Epilepsy and Taking Flight Grant Timeline–Letter of Intent (LOI) due January 11, 2021 9 PM EST
Reminder, CURE Epilepsy is accepting LOIs for both the CURE Epilepsy and Taking Flight grant awards now through Monday, January 11, 2021 at 9 PM ET. Don’t miss your opportunity to be considered!

  • CURE Epilepsy Award, $250,000 over two years: This award reflects CURE Epilepsy’s continued focus on scientific advances that have potential to truly transform the lives of those affected by epilepsy.
  • Taking Flight Award, $100,000 for one year: This award seeks to promote the careers of young epilepsy investigators, allowing them to develop a research focus independent of their mentors.
  • Research areas: Sudden unexpected death in epilepsy (SUDEP), acquired epilepsy, treatment-resistant epilepsy, pediatric epilepsy, and sleep and epilepsy

Learn More

2021 Health Disparities Research Institute–Accepting Applications February 1-March 8, 2021The next Health Disparities Research Institute–featuring lectures on minority health and health disparities research, mock grant review, seminars and more–will be held virtually August 9-13, 2021.

The program’s intent is to support early-career minority health/health disparities research scientists and stimulate research in the disciplines supported by health disparities science. Admission to this program is by application only. The application cycle is open February 1-March 8, 2021.

Learn More

Job Opportunity: Research Program Manager Position with TESS Research Foundation
Looking for an opportunity to make a difference in the area of rare epilepsies? The TESS Research Foundation is seeking a Research Program Manager to oversee all scientific research focused on SLC13A5 Epilepsy, including research coordination, grant program oversight, community outreach, and scientific communication and cultivation.

Learn More

Exploring Quality of Life in Individuals with a Severe Developmental and Epileptic Encephalopathy, CDKL5 Deficiency Disorder

Abstract, originally published in Epilepsy Research

Background: CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder caused by a mutation in the cyclin-dependent kinase-like 5 (CDKL5) gene. It is now considered to be a developmental and epileptic encephalopathy because of the early onset of seizures in association with severe global delay. Other features include cortical visual impairment, sleep and gastro-intestinal problems. Progress in clinical understanding, especially regarding the spectrum of functional ability, seizure patterns, and other comorbidities was initially slow but accelerated in 2012 with the establishment of the International CDKL5 Database (ICDD). Our aim was to use this data source to investigate quality of life (QOL) and associated factors in this disorder.

Method: A follow-up questionnaire was administered in 2018 to parents of children registered with the ICDD who had a pathogenic CDKL5 variant. QOL was assessed using QI Disability, an instrument, specifically developed to measure total and specific domains of QOL (physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors (leisure) and independence) in children with intellectual disability. Associations with functional abilities, physical health, mental health and family factors were investigated, initially using univariate analyses followed by multivariate analyses for each of these groups with a final composite model which included the important variables identified from previous models.

Results: Questionnaires were returned by 129/160 families with a child aged >3 years. Functional impairment, including lack of ability to sit, use hands and communicate had the greatest adverse impact on QOL. There were also some relationships with major genotype groupings. Individuals using three or more anti-epileptic medications had poorer QOL than those on one or no medication, particularly in the physical health domain. There was also variation by geographical region with those living in North America typically having the best QOL and those living in middle or lower income countries poorer QOL.

Conclusion: Although lower functional abilities were associated with poorer quality of life, further research is needed to understand how environmental supports might mitigate this deficit. Comprehensive care and support for both the child and family have important roles to play in helping families to thrive despite the severity of CDD.