Introduction

There is a rising number of epilepsies that have been associated with genetic mutations called genetic variants (see Blog 14) .  For example, some of these epilepsies result from gene variants in ion channels that produce a loss of function or a gain of function.  Such changes promote seizures and other neurological deficits.  Specifically, the common gene variants account for 30% of adult general epilepsies. As more genetic expertise is developed, this number is expected to significantly increase.  Ongoing research from Ingo Helbig and collaborators at the Children’s Hospital of Philadelphia, Perelman School of Medicine and other University neurological departments) suggests that precision medicine is the promising future therapy of genetic-based epilepsies.

Precision Medicine

As reviewed by Knowles et al., (2022), precision medicine is an encompassing approach to optimal treatment.  In particular, it is based on classifying patients according to measurable biology, susceptibility to disease, and response to treatment to assure an efficacious intervention for those who would benefit and avoid those who would not.  For genetic epilepsies, “ideal precision treatment would correct a well-defined genetic mechanism in the context of individualized factors, to impart freedom from seizures and comorbidities” (Knowles et al., 2022).  However, this calls for integration of genetic analysis, natural history and clinical data into searchable databases.  Already, genetic testing alone yields better treatment and less hospitalizations.  Adding natural history and clinical data to genetic analysis would achieve considerably more treatment success.

Achievements Toward Precision Medicine

Identification of genetic variants in certain epilepsies allows for the application of molecular biology techniques to interfere with unwanted mRNA produced by genetic variants.  Therefore, appropriately designed oligonucleotides as well as vector-promoter-gene complexes successfully treat animal models of epilepsy. Currently, evaluation of the latter is ongoing in a clinical trial (NCT05419492) (https://clinicaltrials.gov/ct2/show/) for a genetic epilepsy. 

The discovery of the gene termed SCN8A exemplifies the feasibility of  rapid trajectory from gene identification to precision medicine.  Specifically, SCN8A (voltage-gated sodium channel gene) was discovered in 1995 in mice. Later, its pathological variants were associated with epileptic encephalopathies (seizures with neurological pathology).  By 2019, following intense research, the testing of a specific sodium channel inhibitor (NBI-921352) for the genetic variant was initiated.  Presently, “NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures” (Johnson et al., 2022).  Although this is impressive, “coordinated and systematic streamlining of the epilepsy precision medicine pipeline” from gene discovery to effective therapy is the essential goal (Knowles et al., 2022).

Challenges for Precision Medicine

Technological improvements in genome-wide association studies (GWAS) have facilitated the ability to screen large groups of patients to detect genetic variants associated with disease.  The result is the creation of large available, searchable databases of genetic variants.  However, not only must the gene variant associated with the disease be considered but more importantly, the unique expression of the gene variant in a particular patient must be defined. 

The expression of a gene variant is termed the phenotype of the disease. The phenotype includes all of the clinical observations and measurements in the patient relevant to the epilepsy. Therefore, gene expression may take many forms creating multiplicities and complexities of expression (heterogeneity) from patient to patient. Hence, the correct association of a gene variant with a defined phenotype poses a serious challenge.  According to Helbig and Tayoun, (2016) accurately defining the phenotype of a rare genetic variant, e.g. STXBP1 producing an epileptic encephalopathy represents a “hurdle” due to the phenotypic spectrum that it produces. 

To address this challenge, Helbig et al., (2019) characterized the phenotype of patients with “missense variant in AP2M1” (coding a protein needed for uptake mechanisms on the cell membrane).  The use of the searchable database, Human Phenotype Ontology, set up in 2008 to formalize the phenotypes of all diseases, enhanced this work.  More recently, the International League Against Epilepsy added neurological data and guidelines to it (Kohler et al., 2021).  This database presents “a standardized format to provide both terminology and semantics to a broad range of phenotypic features, including neurological features” (Helbig and Tayoun, 2016).  Consequently, with this type of analysis, researchers (Helbig and Tayou) were able to show “significant phenotypic overlap in individuals with the recurrent AP2M1”. 

Conclusions

To successfully treat epilepsy and its comorbidities both the genotype and phenotype of the epilepsy requires accurate assessment.  Researchers at Children’s Hospital of Pennsylvania and the Perelman School of Medicine and their collaborators are focused on this assessment.  The challenge lies in the interpretation of the epilepsy phenotype since both severe and less severe epilepsies are driven by the same genetic variants.  Sorting out this phenotypic heterogeneity will be worthwhile and lead to benefits of precision medicine for all patients.

References (pubmed)

Clatot J et al., SCN1A gain-of-function mutation causing an early onset epileptic encephalopathy. Epilepsia.64(5):  1318-1330, 2023.

Ganesan S, et al., A longitudinal footprint of genetic epilepsies using automated electronic medical record interpretation. Genet Med. 22(12):  2060-2070, 2020.

Helbig I et al., A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy.  Am J Hum Genet .104(6):  1060-1072, 2019.

Helbig I, Tayoun ANA. Understanding Genotypes and Phenotypes in Epileptic Encephalopathies. Mol Syndromol  7:  172–181, 2016.

Kohler S et al.,  Human Phenotype Ontology in 2021, Nucleic Acids Research  49, Database issue D1207–D1217, 2021.

Knowles JK et al., Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia. 63(10):   2461–2475, 2022.

Lewis-Smith D et al., Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data. Eur J Hum Genet. 29(11):  1690-1700, 2021.

Seiffert S et al., KCNC2 variants of uncertain significance are also associated to various forms of epilepsy. Front Neurol. 14: 1212079, 2023.

Xian J et al., Delineating clinical and developmental outcomes in STXBP1-related disorders. medRxiv. 2023 May 11;2023.05.10.23289776. doi: 10.1101/2023.05.10.23289776. Preprint