Article published by Medical Xpress

Featuring the work of former CURE Epilepsy Grantee Dr. Gemma Carvill

Investigators have discovered a new method to determine whether individual genetic variants in the epilepsy-associated gene SZT2 cause a neurodevelopmental disorder, according to a Northwestern Medicine study published in the journal Brain.

Pathogenic variants in SZT2 have been associated with the development of different neurodevelopmental disorders, including early-onset epilepsy and developmental delays. Additionally, the SZT2 protein plays an essential role in the mTORC1 signaling pathway, which helps promote cell growth and proliferation.

Classifying these variants as either likely benign or pathogenic, however, has remained a challenge due the large size of SZT2—it contains more than 3,400 amino acids—as well as its lack of crystal structure and functional domains.

“There are many different amino acids that can be mutated and become missense variants, so it’s very challenging to tell which are pathogenic and which are benign. That’s why high-throughput studies like this are so important,” said Gemma Carvill, Ph.D., assistant professor in The Ken and Ruth Davee Department of Neurology Division of Epilepsy and Clinical Neurophysiology and senior author of the study.

For the current study, Carvill’s team recruited twelve individuals who carried biallelic SZT2 variants of which one or more were classified as variants of uncertain significance.

Using CRISPR-Cas9 genome editing, the investigators engineered cells to contain patient-specific missense SZT2 variants and performed a functional cell assay that separated cells based on whether the mTORC1 signaling pathway was active or inactive.

The investigators then used next-generation sequencing to determine which SZT2 missensevariants retained function and which lost function and were likely to be pathogenic.

Ultimately, they discovered a recurrent in-frame deletion—when one amino acid is deleted out of the protein—and was determined to be a loss-of-function variant and reclassified as likely pathogenic.

Abstract, originally published in Seizure

Introduction: Genetic testing in people with epilepsy may support presurgical decision-making. It is currently unclear to what extent epilepsy centres use genetic testing in presurgical evaluation.

Methods: We performed an exploratory survey among members of the German Society for Epileptology to study the current practice of genetic testing in presurgical evaluation at the respective sites. Survey participants contributed educational case reports.

Results: The majority of participants consider genetic testing to be useful in individuals with familial syndromes or phenotypic features suggesting a genetic etiology. We report 25 cases of individuals with a confirmed genetic diagnosis that have previously undergone epilepsy surgery. Our cases demonstrate that a genetic diagnosis has an impact on both the decision-making process during presurgical evaluation, as well as the postoperative outcome.

Conclusion: Genetic testing as part of the presurgical work-up is becoming increasingly established in epilepsy centres across Germany. mTORopathies and genetic hypothalamic hamartomas seem to be associated with a generally favourable surgical outcome. Synaptopathies and channelopathies may be associated with a worse outcome and should be considered on a case-by-case level. Prospective studies are needed to examine the impact of an established genetic diagnosis on postsurgical outcome.

Abstract, originally published in University of Illinois News Bureau

Mice with a genetic mutation that’s been observed in patients with epileptic encephalopathy, a severe form of congenital epilepsy, exhibit not only the seizure, developmental and behavioral symptoms of the disorder, but also neural degeneration and inflammation in the brain, University of Illinois Urbana-Champaign researchers found in a new study. The findings highlight the mutation as an important part of the disease’s pathology and a potential target for treatment.

Patients with epileptic encephalopathy begin having seizures when they are born, and display progressive developmental delay, intellectual disability and autismlike behavior, said study leader Hee Jung Chung, a professor of molecular and integrative physiology.

“The dogma regarding epileptic encephalopathy has been that the epileptic seizures are driving the pathogenesis of intellectual disability and developmental delay. But we wanted to answer the question, is it really just the seizures driving the intellectual disability and developmental delay?” Chung said. “This study is the first to show that expressing this human epileptic encephalopathy mutation in mice can cause not only spontaneous seizure and intellectual disability, but also neural degeneration.”

In the new study, published in the Proceedings of the National Academy of Sciences, Chung’s group, in collaboration with psychology professor Justin Rhodes and molecular and integrative physiology professors Eric Bolton and Catherine Christian-Hinman, bred a population of mice with the gene mutation. The researchers studied the mice from birth to observe whether they developed symptoms and how the mutation affected the expression of the potassium channels as well as their brains.

The mice developed spontaneous seizures analogous to human patients, who begin having seizures as infants. The mice also had an increase in mortality – half of mice with the mutation died as juveniles. The surviving mice showed significant deficits in learning and memory, as well as repetitive behaviors associated with human autistic behavior.

Summary, originally published in Epilepsia

Objective: Accelerated long-term forgetting (ALF) has been demonstrated among children but not adults with genetic generalized epilepsy (GGE). We investigated (1) how forgetting patterns of verbal and visuospatial material differ between patients with GGE and healthy controls (HCs) and (2) whether ALF is associated with ictal or interictal epileptic activity.

Methods: Forty-two patients with GGE (39, 92.9% experiencing seizures) were compared to 57 HCs in word, logical story, and Rey–Osterrieth complex figure recall tasks by testing after intervals of 30 min and 4 weeks. Ambulatory electroencephalography (EEG) was performed before testing to detect generalized epileptic activity, and patients were asked to document the number of seizures during the 4-week interval.

Results: A two-way repeated measures ANOVA indicated that individuals with GGE have different forgetting patterns in comparison to HCs in tasks of word (delay by group interaction F1.5, 142.5 = 4.5, p = .02, ?2??p2 = .04) and figure (F2, 194 = 15.9, p < .001, ?2??p2 = .14) but not story (F1.6 151.1 = .5, p = .58, ?2??p2 = .005) recall. Last learning trial-adjusted scores of word recall were comparable between HCs and patients with epilepsy (PWEs) at 30 min (p = .21) but not at 4 weeks (p = .006). Individuals with GGE performed worse than HCs in figure recall at 30 min and 4 weeks (p < .001), with lower performance after the 4-week interval present only among seizure-positive and EEG-positive individuals (p < .001) during subgroup analysis. Performance on memory tests was unrelated to overall seizure frequency, the number of antiseizure drugs used, and epilepsy duration.

Significance: Our study supports the presence of accelerated long-term forgetting in a task of word recall among adult patients with genetic generalized epilepsy (GGE). The pattern of forgetting visuospatial information suggests greater forgetting of material before the first delay and ongoing deficits among patients with epilepsy with epileptic activity. Future studies should confirm our findings and investigate the functional or pathological mechanisms of memory dysfunction in GGE.

Research originally published in Cell Reports

Researchers at The University of Queensland, working to gain a better understanding of how brain cells work, have discovered the underlying mechanism of a rare genetic mutation that can cause epilepsy.

Dr. Victor Anggono from UQ’s Queensland Brain Institute said his team made the ground-breaking findings while researching nerve cell communications, which are an important process in normal brain function.

”We’re both excited and astounded to make such an important contribution to the field of cellular and molecular neuroscience,” Dr. Anggono said.

He stressed that the mutation was extremely rare, with only one reported case in the world to date.

Dr. Anggono’s team studied protein structures, called receptors, that are attached to cell surfaces to make the discovery.

”It turns out that this particular mutation causes receptors in brain cells to behave differently, resulting in an imbalance in brain cell communication – and that can lead to disorders,” he said.

”For example, cells that talk too much are associated with epilepsy and unwanted cell death – while cells that talk too little have negative impacts on learning and memory.

”There are also many examples of other mutations in the same gene that are known to be associated with epilepsy.

”What we know is that this receptor is critical for brain function and can lead to epilepsy when its function is misregulated.

”The findings point the way for further research to understand and potentially treat similar mutations.”

The imbalance in brain cell communications is also believed to be involved in neurological conditions including Alzheimer’s disease and autism spectrum disorders.

Dr. Anggono said the research provided a springboard for developing personalized medicines to target the mutation.

”Receptor blockers which have been approved by the US Food and Drug Administration (FDA), are already available for human treatment, but the challenge is to find the right ones and see how patients respond,” he said.

Summary, originally published on docwirenews.com

Often, genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) focus largely on children, leaving a scarcity of data regarding adult patients. A study published in Genetics in Medicine analyzed genetic associations of NDDE in adults and elderly patients.

A total of 150 patients with NDDE underwent conventional karyotyping, FMR1 testing, chromosomal microarray, and panel sequencing. When cases remained unresolved, exome sequencing was performed.

“Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE,” the study authors concluded.