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.”

Scientific Method Called “dCas9-Based Scn1a Gene Activation” Lessens Febrile Seizures in Dravet Syndrome Mice

Dravet syndrome (DS) is a severe epileptic encephalopathy caused mainly by heterozygous loss-of-function mutations of the SCN1A gene, indicating haploinsufficiency as the pathogenic mechanism.

Here, researchers tested whether catalytically dead Cas9 (dCas9)-mediated Scn1a gene activation can rescue the decrease in Scn1a gene in a mouse DS model and restore physiological levels of its gene product, the Na v 1.1 voltage-gated sodium channel. The team screened single guide RNAs (sgRNAs) for their ability to stimulate Scn1a transcription in association with the dCas9 activation system.

This study identified a specific sgRNA that increases Scn1a gene expression levels in cell lines and primary neurons with high specificity. Na v 1.1 protein levels were augmented, as was the ability of wild-type immature GABAergic interneurons to fire action potentials. A similar enhancement of Scn1a transcription was achieved in mature DS interneurons, thus rescuing their ability to fire. To test the therapeutic potential of this approach, the team delivered the Scn1a-dCas9 activation system to DS pups using adeno-associated viruses. Parvalbumin interneurons recover their firing ability and febrile seizures were significantly attenuated.

The research team claims that their results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach in Dravet syndrome and other disorders resulting from altered gene dosage.

New Candidate Gene for Periventricular Nodular Heterotopia, a Disorder Characterized by Seizures, is Discovered

Study featuring the work of former CURE Grantee Dr. Alica Goldman

Periventricular nodular heterotopia (PNH) is a common structural malformation of cortical development.

Mutations in the filamin A gene are frequent in familial cases with X-linked PNH. However, many cases with sporadic PNH remain genetically unexplained. Although medically refractory epilepsy often brings attention to the underlying PNH, patients are often not candidates for surgical resection. This limits access to neuronal tissue harboring causal mutations.

This research team evaluated a patient with PNH and medically refractory focal epilepsy who underwent a presurgical evaluation with stereotactically placed electroencephalographic (SEEG) depth electrodes. Following SEEG explantation, we collected trace tissue adherent to the electrodes and extracted the DNA. Whole-exome sequencing performed in a Clinical Laboratory Improvement Amendments–approved genetic diagnostic laboratory uncovered a de novo heterozygous pathogenic variant in novel candidate PNH gene MEN1 (multiple endocrine neoplasia type 1; c.1546dupC, p.R516PfsX15). The variant was absent in an earlier exome profiling of the venous blood–derived DNA. The MEN1 gene encodes the ubiquitously expressed, nuclear scaffold protein menin, a known tumor suppressor gene with an established role in the regulation of transcription, proliferation, differentiation, and genomic integrity.

This study contributes a novel candidate gene in periventricular nodular heterotopia generation and a novel practical approach that integrates electrophysiological and genetic explorations of epilepsy.

Possible Role of SCN4A Skeletal Muscle Mutation in the Loss of Breathing During Seizure

SCN4A gene mutations cause a number of neuromuscular phenotypes including myotonia. A subset of infants with myotonia-causing mutations experience severe life-threatening episodic laryngospasm [a spasm of the vocal cords that makes it difficult to speak or breathe] with apnea.

This research team recently identified similar SCN4A mutations in association with sudden infant death syndrome. Laryngospasm has also been proposed as a contributory mechanism to some cases of sudden unexpected death in epilepsy (SUDEP). The team reports an infant with EEG-confirmed seizures and recurrent apneas. Whole-exome sequencing identified a known pathogenic mutation in the SCN4A gene that has been reported in several unrelated families with myotonic disorder.

This study proposes that the SCN4A mutation contributed to the apneas in our case, irrespective of the underlying cause of the epilepsy. They suggest this supports the notion that laryngospasm may contribute to some cases of SUDEP, and implicates a possible shared mechanism between a proportion of sudden infant deaths and sudden unexpected deaths in epilepsy.

Epilepsy Research Findings: August 2019

The past month has been filled with interesting research discoveries, including work done by CURE Grantee Dr. William Nobis and colleagues to advance our understanding of the areas of the brain that may be important in Sudden Unexpected Death in Epilepsy (SUDEP). In the field of epilepsy genetics, a large-scale study identified new epilepsy-associated genetic variants by examining the genetic make-up of more than 17,000 people with epilepsy. There is also intriguing research news looking at why cilantro, used in traditional medicine, may work to combat seizures.

Summaries of these research discoveries are below.

Plus, get epilepsy research news all month by downloading the new CURE mobile app! Find the details here.

Research Discoveries

  • SUDEP: A study featuring the work of CURE Grantee Dr. William Nobis and colleagues suggests that an area of the brain called the amygdala plays a role in dysfunctional breathing during seizures and possibly SUDEP. Learn More
  • Epilepsy Genetics: In one of the largest studies of its kind to examine the genetic make-up of individuals with epilepsy, scientists discover rare genetic variants associated with epilepsy. Learn More
  • Herbal Treatments: A study examines how the molecular action of cilantro, which is used as a traditional anticonvulsant medication, can help combat seizures. Learn More
  • Dementia and Epilepsy: Patients with dementia who are registered in the Swedish dementia registry were found to have increased rates of epilepsy. Learn More
  • Multiple Sclerosis and Epilepsy: Patients with multiple sclerosis have a higher risk of developing seizures compared with the general population. Learn More
  • SCN8A-Related Epilepsy: A study featuring the work of CURE Grantee Dr. Gemma Carvill and colleagues identified a set of neurons in the brains of mice that have a SCN8A gene mutation similar to humans that may be critical targets for therapeutic intervention. Learn More

Introducing the CURE Epilepsy Research Mobile App for research updates in the palm of your hand! Download today. iOS | Android

Seizures Associated With Cardiac Disease: What Role Does Genetics Play?

Most people with a medical condition called long QT syndrome have a mutation in a gene that causes bouts of fast, chaotic heartbeats. They also experience fainting spells and seizures. The clinical approach has largely assumed that when the heart beats erratically, the brain eventually does not get enough oxygen — which in turn causes the seizures.

Research from Washington University in St. Louis finds that mutations of a gene implicated in long QT syndrome in humans may trigger seizures because of their direct effects on certain classes of neurons in the brain — independent from what the genetic mutations do to heart function. The new work from Arts & Sciences was conducted with fruit flies and is published in PLOS Genetics.

“This gene seems to be a key factor in the physiological process that protects neurons from starting to fire uncontrollably in response to a rapid increase in temperature, which could lead to paralysis and death,” said Yehuda Ben-Shahar, associate professor of biology in Arts & Sciences.

Alexis Hill, recently a postdoctoral fellow in the Ben-Shahar laboratory, discovered this unexpected relationship as she probed the nervous system response to acute environmental stress.

Scientists Discover Rare Genetic Variants Associated with Epilepsy in Large-Scale Study

For the first time, scientists have mapped out the genes associated with epilepsy. The study is one of the largest of its kind to look into the genetic make-up of people with epilepsy. The research, which was conducted by scientists from Austin Health and the University of Melbourne was published in the latest issue of the journal American Journal of Human Genetics.

The team of researchers included patients from different nations and included around 18000 persons. Rare genetic variants within these patients pointed at their association with epilepsy. The team writes that there have been genetic sequencing studies before that have noted genetic association with severe epilepsies.

Even certain gene deletions have been found to be associated with less severe forms of epilepsy. This study looked at the “ultra-rare genetic risk factors for different types of epilepsies,” they wrote.

A Partnership to Make New Medicines: MaRS Innovation Launches New Drug Discovery Program Based on UHN Discovery

MaRS Innovation is partnering with Dr. James Eubanks at the University Health Network (UHN) to develop a new treatment for Rett syndrome, a rare developmental disorder found almost exclusively in girls and women.

Infants with Rett syndrome develop and grow normally until the age of 8 to 12 months when symptoms begin appearing. Although the symptoms vary in type and severity, most of the girls and women with the disorder cannot speak or use their hands purposefully. Many also experience seizures that are difficult to control with medications. Presently, there is no cure for Rett syndrome, and the available treatments can only help alleviate symptoms.

Researchers have known for many years that most cases of Rett syndrome are caused by mutations in the MECP2 gene; however, the mechanisms that link these genetic changes to the syndrome’s diverse symptoms are not well understood.

“We believe that we have discovered an important piece of the puzzle,” says Dr. Eubanks, a Senior Scientist at the Krembil Research Institute (UHN) who has been studying the disorder for over 20 years.

MaRS Innovation will initially invest up to $400,000 to help translate Dr. Eubanks’ discovery into a new treatment for Rett syndrome. The funds will support the creation and evaluation of drug-like compounds that target TRPM2, dampening its activity, in the brain of Rett patients. Dr. Mark Reed, a medicinal chemist and head of Krembil’s Centre for Medicinal Chemistry and Drug Discovery, will oversee the work, which will be split between the Centre and the Charles River Discovery site in the United Kingdom. The new partnership will also give Drs. Eubanks and Reed access to MaRS Innovation commercialization services to support further development of any promising treatments.

Large Epilepsy Genetics Study Compares Severe and Less-severe Epilepsies in 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry.

The research team focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE).

The team observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; they saw the strongest enrichment in individuals with severe developmental and epileptic encephalopathies and the least strong in individuals with non-acquired focal epilepsy. Moreover, the research team found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G,EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, andGABRG2 for NAFE.

The research team’s study, the largest epilepsy whole-exome sequencing study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Study Examines Most Common Type of Seizures Found in CDKL5 Deficiency Disorder

OBJECTIVE: The cyclin-dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). This study sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure-free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones.

METHODS: This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit.

RESULTS: Ninety-two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0-11.0). Eighty-one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor-tonic-spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty-three percent of patients experienced a seizure-free period ranging from 1 to >12 months, but only 6% were still seizure-free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia.

SIGNIFICANCE: The most common seizure types in CDKL5 deficiency disorder (CDD) are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. Cortical visual impairment is a common feature in CDD and is correlated with achieving fewer milestones.