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.

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.

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.

In this study, researchers identify a set of neurons in the brain as critical targets for therapeutic intervention, utilizing a mouse model mimicking a mutation of the sodium channel gene SCN8A found in 14 individuals with epilepsy. These individuals had seizures that began in the prenatal or infantile period as well as severe verbal delays. The researchers report that this mutation resulted in seizures in both juvenile and adult mice, suggesting that successful therapy would require lifelong treatment.

2017 ERUK Fellow Dr Gabriele Lignani, has been awarded a New Investigator Research Grant, worth nearly £700,000 by the Medical Research Council (MRC), to investigate the potential use of gene therapy in Dravet syndrome. This research project will build on Dr Lignani’s ongoing fellowship research – GeneLoop, which is currently investigating the potential of gene therapy as a treatment for acquired intractable epilepsy.

Dravet Syndrome is a severe and extremely rare but catastrophic neurological disorder affecting young children (approximately 1 in 19,000 people). Every day 3 or 4 children are diagnosed with Dravet syndrome worldwide, with symptoms including epilepsy, autism, movement disorders, and sleep disturbances. To date, the majority of therapies are ineffective or poorly tolerated. Sodium channel drugs, which are some of the most commonly prescribed and effective antiepileptic drugs may even worsen Dravet syndrome.

Dr Lignani said: “This research will be useful not only to understand if a permanent general treatment for Dravet syndrome is achievable, but will also give insight into the potential of the techniques to cure other neurological conditions caused by similar mutations in different genes.”

He continued “This research will be useful not only to understand if a permanent general treatment for Dravet syndrome is achievable, but will also give insight into the potential of the techniques to cure other neurological conditions caused by similar mutations in different genes.”

Dr Lignani’s ERUK Fellowship officially began in 2018 but is already showing promising results. His team’s work thus far has focused on developing and testing their gene therapy tools, and they have found that this tool is able to subdue neurons during epileptic activity. The following stages of the fellowship will involve trialing these tools in models of acquired intractable epilepsy.