The relationship between genes affecting the development of epilepsy and approaches to epilepsy therapy

Abstract

The epilepsies are a clinically heterogeneous group of common brain diseases which are refractory to pharmacotherapy in up to one-third of patients. The discovery of DNA variants that cause or predispose to epilepsy has the potential to lead to new treatments that are based on the protein products or functional pathways of implicated genes. Overlap of gene classes involved in several broad phenotypic categories of epilepsy provides a means to prioritize various genetic leads for therapy development. In cases of epilepsy that are influenced strongly by single genetic defects, treatments may be personalized based upon the structural nature of the DNA alteration rather than on the function of the defective gene(s) or pathway(s). However, since most cases of epilepsy may be polygenic, the extent to which this approach may be widely applicable is unclear, thus creating a need for development of new target-based medications as well as further refinement of currently effective therapies.

Keywords::

• anti-sense nucleotide pharmacotherapy
• common variant
• ion channel
• monogenic epilepsies
• multifactorial epilepsies
• pleiotropy
• polygenic epilepsies
• rare variant
• RNA import
• SCN1A
• stop-codon read-through

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Epilepsy is a common, multifactorial disease in which genetic factors play a major etiological role; however, many of the genes involved in epilepsy remain unknown. Better understanding of these factors will facilitate the identification of new molecular targets for therapy.

• Advances in biotechnology have led to an increase in the discovery of both common genetic variants, which generally have minor effects in a large fraction of cases, and rare genetic variants, which may have large effects, and can even cause epilepsy, but in a small fraction of cases. Particularly with regard to rare variants, new methods of DNA sequence analysis have greatly expanded the number of documented epilepsy-related genes. A key issue is how best to translate genetic discoveries into potential treatments.

• Regardless of whether a given genetic variant is rare, and has a large impact on disease in a small number of cases, or whether it is common, and has small impact on a large number of cases, discovering its identity is nonetheless important since any epilepsy gene can reveal molecules and molecular pathways that are associated with abnormal electrical activity in the brain, and can thus be used as leads for therapy development.

• One of the genes involved in both common and rare forms of epilepsy is SCN1A. This gene encodes a subunit of the major brain sodium channel NaV1.1, a molecular target for a number of standard anti-epileptic drugs including phenytoin, carbamazepine and valproic acid. SCN1A serves as a prototype in linking anti-epilepsy drug action with epilepsy-related genes.

• There is considerable overlap in the classes of genes involved in both common and rare forms of epilepsy and indeed there are a number of specific genes that have been documented to play a role in both forms. In addition to SCN1A, these genes include CACNA1H, CHRNA4, GABRB3, GABRG2, KCNJ10, KCNQ2, KCNQ3 and SLC2A1. The products of these genes and the pathways in which they function are logical targets for anti-epilepsy therapy development programs.

• Epilepsy co-occurs in monogenic syndromes that involve other complex, diverse and severe clinical phenotypes. Further, causative genes have been identified for many of these syndromes, and in many cases they come from the same classes as those associated with pure epilepsy syndromes, and with genetically complex epilepsies. However, the pleiotropic gene effects documented in these phenotypically complex syndromes present an additional challenge in terms of translating such discoveries into leads for therapy development.

• Advances in technology will allow screening of individual epilepsy patients for rare or private variants that may have a large effect on development of disease. In those cases where potentially deleterious structural DNA changes are documented, personalized therapies may be devised, which are based specifically on the nature of the genetic alteration rather than on the nature of the gene product or its functional pathway.

Notes