The numerous presentations on the genetics of epilepsy at AES2020 indicate the further development of an important and promising era in the testing, diagnosis, and treatment of epilepsy. Historically, epilepsy has been classified according to electroclinical features based on correlations between seizure manifestations and electroencephalogram findings. Genetic research is providing new insights that might ultimately redefine or reclassify epilepsy phenotypes, with important implications for the development of new treatments and the more precise use of currently available treatments.

One example is a pharmacokinetic and safety study of a possible precision medicine intervention, STK-001, for Dravet syndrome (DS). Laux et al noted in abstract 344 that approximately 85% of DS cases are caused by spontaneous heterozygous loss of function mutations in the SCN1A gene; this gene encodes the voltage-gated sodium channel α subunit Nav1.1. The investigational antisense oligonucleotide treatment STK-001 uses a unique platform, Targeted Augmentation of Nuclear Gene Output technology, to exploit naturally occurring, nonproductive splicing events to upregulate Nav1.1 protein expression. It is thought that this upregulation of Nav1.1 protein expression may restore normal function to neurons and prevent the occurrence of seizures and significant nonseizure comorbidities in patients with DS. While current treatments address seizure control, STK-001 would be the first disease-modifying therapy to address the specific functional cause of DS.

Progress is also being made on the treatment of genetic epilepsies using nonprecision therapies. The development of fenfluramine, for instance, was not targeted or based on knowledge of the SCN1A gene, but fenfluramine was nonetheless observed to be highly effective in DS. An international, phase 3, clinical trial found a 64.8% greater reduction in mean monthly convulsive seizure frequency with fenfluramine 0.7 mg/kg/day vs placebo; median reduction from baseline in monthly convulsive seizure frequency was 73.7% with fenfluramine 0.7 mg/kg/day compared with 7.6% for placebo (abstract 853). The authors concluded that fenfluramine was generally well tolerated. In fact, no patient developed valvular heart disease or pulmonary hypertension. Continued observation is necessary to better understand the safety of this agent, as this trial included a small patient population; however, the findings are encouraging.

Some of the genetically linked epilepsies may be quite heterogeneous, and abstract 735 from AES2020 highlights heterogeneity within tuberous sclerosis complex (TSC). The observation that TSC may be milder in adults also points to the questions of when and how TSC epilepsy develops (ie, what is the mechanism for its development on the individual level?). This abstract is a good reminder that the genetic cause of an epilepsy is not necessarily the epilepsy and that the epilepsy may ultimately manifest because of heterogeneity in how the genetic abnormality affects function, which may be due to the influence of other genes or some environmental factors. TSC is another example of precision medicine in epilepsy, as targeted treatment is possible through mammalian target of rapamycin (mTOR) inhibition; however, the epilepsy-generating mechanisms appear to remain intact despite seizure response by targeting mTOR in a mouse model (abstract 862).

Several analyses sought to better characterize the yield of genetic testing for epilepsy, particularly in the pediatric and young adult populations. Although studies on the diagnostic yield of genetic testing have generally focused on early onset epilepsies (ie, in those younger than 2 years of age), a program that included 541 children with seizure onset after 2 years of age found a genetic cause in approximately 21% of patients, which is a meaningfully high proportion (abstract 178). Moreover, the authors reported that 62.6% of those who received a molecular diagnosis had a disorder that has a targeted treatment. Another study presented at AES2020 compared patients under 18 years of age with those 18 years of age and older and found that 15% of patients aged under 18 years and approximately 11% of those aged 18 years and older had genetic abnormalities linked to epilepsy (abstract 1069). These findings suggest that many adult patients might benefit from genetic testing. Further, there is the suggestion that the onset of epilepsy in adults may be more often associated with important environmental influences in addition to genetically defined causes when compared with the onset of epilepsy in children. 

While not all patients with epilepsy should be considered for genetic testing, these studies presented at AES2020 raise the questions of whether more patients should be tested for genetic causes and which patients are most likely to benefit from such testing. Taken together, these studies indicate a clear movement toward clinical genetics in the treatment of epilepsy.