Defining Dravet syndrome: An Essential Pre-Requisite for Precision Medicine Trials

Abstract, originally published in Epilepsia

Objective: The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials.

Methods: Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome.

Results: Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5–20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ?30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months–25.4 years) and 15.5 months (range 4 months–8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%.

Significance: An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.

An Astounding Find Reveals a Rare Cause of Epilepsy

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.

Genetic Associations of Neurodevelopmental Disorders with Epilepsy in Adults

Summary, originally published on

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.

Genome-Wide Association Study of Epilepsy in a Japanese Population Identified an Associated Region at Chromosome 12q24

Abstract, originally published in Epilepsia

Objective: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population.

Methods: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data.

Results: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10-10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24.

Significance: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.

Reproductive Decision-Making in Families Containing Multiple Individuals With Epilepsy

Abstract, originally published in Epilepsia

Objective: This study evaluated factors influencing reproductive decision-making in families containing multiple individuals with epilepsy.

Methods: One hundred forty-nine adults with epilepsy and 149 adult biological relatives without epilepsy from families containing multiple affected individuals completed a self-administered questionnaire. Participants answered questions regarding their belief in a genetic cause of epilepsy (genetic attribution) and estimated risk of epilepsy in offspring of an affected person. Participants rated factors for their influence on their reproductive plans, with responses ranging from “much more likely” to “much less likely” to want to have a child. Those with epilepsy were asked, “Do you think you would have wanted more (or any) children if you had not had epilepsy?”

Results: Participants with epilepsy had fewer offspring than their unaffected relatives (mean = 1.2 vs. 1.9, p = .002), and this difference persisted among persons who had been married. Estimates of risk of epilepsy in offspring of an affected parent were higher among participants with epilepsy than among relatives without epilepsy (mean = 27.2 vs. 19.6, p = .002). Nineteen percent of participants with epilepsy responded that they would have wanted more children if they had not had epilepsy. Twenty-five percent of participants with epilepsy responded that “the chance of having a child with epilepsy” or “having epilepsy in your family” made them less likely to want to have a child. Having these genetic concerns was significantly associated with greater genetic attribution and estimated risk of epilepsy in offspring of an affected parent.

Significance: People with epilepsy have fewer children than their biological relatives without epilepsy. Beliefs about genetic causes of epilepsy contribute to concerns and decisions to limit childbearing. These beliefs should be addressed in genetic counseling to ensure that true risks to offspring and reproductive options are well understood.

Adult Phenotype of KCNQ2 Encephalopathy

Abstract, originally published in Neurogenetics

Background: Pathogenic KCNQ2 variants are a frequent cause of developmental and epileptic encephalopathy.

Methods: We recruited 13 adults (between 18 years and 45 years of age) with KCNQ2 encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.

Results: While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individuals (46%) remained unable to walk independently, six (46%) had limb spasticity and four (31%) tetraparesis/tetraplegia. Six (46%) remained non-verbal, 10 (77%) had autistic features/autism, 4 (31%) exhibited aggressive behavior and 4 (31%) destructive behavior with self-injury. Four patients had visual problems, thought to be related to prematurity in one. Sleep problems were seen in six (46%) individuals.

Conclusion: Seizure frequency declines over the years and most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are common during childhood and adolescence. Most adult patients have severe ID. Motor, language and behavioral problems are an issue of continuous concern.

Mutations in the Neurochondrin Gene Linked to Epilepsy

Summary, originally published by Uppsala University

Mutations in the neurochondrin (NCDN) gene can cause epilepsy, neurodevelopmental delay and intellectual disability. The gene mutation significantly impairs contacts and signaling between neurons in the brain. This is the conclusion of a study led from Uppsala University and published in the American Journal of Human Genetics.

“The mutation may provide an additional explanation as to why people suffer from these conditions, making it easier to diagnose affected individuals. These are common ailments that are often diagnosed in preschool-age children. They raise concerns and questions among the parents of the affected children: Is this due to something going wrong during pregnancy, childbirth or infancy? Was there something wrong with our germ cells and is it hereditary? The mutations we have identified sometimes arise in individual germ cells prior to conception itself. It is then a matter of chance that they happen upon the neurochondrin gene to produce these effects,” says Niklas Dahl, senior consultant and professor of clinical genetics at Uppsala University’s Department of Immunology, Genetics and Pathology.

The study, which was led from Uppsala University, began by analyzing a worldwide database of genetic analyses of entire genomes. Researchers and physicians from around the world report genome abnormalities that they come across in patients or while conducting research, making it possible to see if any similar cases have been reported anywhere in the world. In Uppsala, researchers initially identified three cases of mutation in the NCDN gene.

Researchers Provide Complete Clinical Landscape for Gene Linked to Epilepsy and Autism

Summary, originally published by Children’s Hospital of Philadelphia

Researchers from Children’s Hospital of Philadelphia (CHOP) affiliated with the CHOP Epilepsy Neurogenetics Initiative (ENGIN) have compiled a complete genetic and clinical analysis of more than 400 individuals with SCN2A-related disorder, which has been linked to a variety of neurodevelopmental disorders, including epilepsy and autism. By linking clinical features to genetic abnormalities in a standardized format, the researchers hope their findings lead to improved identification and clinical intervention.

The study was published online by the journal Genetics in Medicine.

Pathogenic variants in the SCN2A gene can lead to a wide range of clinical features – or phenotypes – associated with neurodevelopmental disorders. Several studies have described the genetic information collected on individuals with disease-causing changes in this gene. However, while genetic information is collected in a standardized manner, data on phenotypes is not standardized, and prior to this study, the available data on clinical features of these patients had not been thoroughly analyzed, meaning that many correlations between the genotypes and phenotypes of these patients were often anecdotal.

UVA Scientist Developing Gene Therapy to Help Girls With Rett Syndrome

A University of Virginia School of Medicine scientist is developing an innovative gene therapy she hopes will slow disease progression and improve movement, coordination and communication in children with Rett syndrome. The approach also may be useful for battling other genetic disorders involving the X chromosome.

UVA researcher Sanchita Bhatnagar discovered that tiny bits of RNA, called microRNAs, play an important role in Rett, a rare genetic disorder that can impair children’s ability to speak, move and even breathe. Based on that finding, she is seeking to sop up those RNA bits, called microRNA, using absorbent particles called microRNA sponges.

Early work in lab models has produced promising results, and she hopes the approach could lead to a better quality of life for children with Rett.

“We are seeing that lab animals treated with this gene therapy are more mobile. They’re moving faster, they’re smarter,” Bhatnagar said. And if that translates into even modest improvements for children, it could make a big difference, she said: “If we can help a child to move more independently, or improve their ability to communicate, I think for a parent, that’s a big win.”

World-Leading Children’s Hospitals Partner to Find New Treatments for Pediatric Diseases

Summary, originally published by University College London

Four leading children’s research institutions on three continents are joining forces to decipher pediatric illnesses, including rare diseases, and find better treatments.

The four pediatric hospitals — Boston Children’s Hospital; UCL Great Ormond Street Institute for Child Health and Great Ormond Street Hospital (London); the Murdoch Children’s Research Institute with The Royal Children’s Hospital (Melbourne); and The Hospital for Sick Children (SickKids) in Toronto — are working together to evaluate genomic data, clinical data from patients, and scientific and medical expertise to accelerate discovery and therapeutic development.

The partnership, known as the International Precision Child Health Partnership (IPCHiP), is the first major global collaboration around genomics and child health. The founding partners anticipate that additional institutions will join the collaboration in the future.

IPCHiP’s first project will involve epilepsy in infants, bringing together efforts already underway at the four hospitals.

Investigators at each site will enroll babies under age one with epilepsy, sequence their genomes, change treatment based on the findings when appropriate, and follow the children’s development long term. No patient will be identifiable from the data used, and no patient data will be shared across international borders.