Review articleIdentifying mutations in epilepsy genes: Impact on treatment selection
Introduction
Since the historical finding of a CHRNA4 mutation causing autosomal dominat sleep-related hypermotor epilepsy (formerly known as autosomal dominant nocturnal frontal lobe epilepsy) in 1995 (Steinlein et al., 1995), discoveries of epilepsy genes have advanced greatly and accelerated further with the advent of next generation sequencing (Helbig et al., 2016; Perucca, 2018). Initially, identification of a pathogenic variant in an individual with epilepsy was considered to have primarily implications for diagnosis, prognosis, and counseling (Weber et al., 2014). Increasingly, however, evidence is emerging that characterizing specific gene mutations is relevant for treatment selection. To some extent, this relates to accumulation of studies assessing genotype-phenotype correlations and providing empyrical observations on how certain genotypes influence response to specific treatments. More relevantly, however, therapeutic implications emerge from understanding the function of the mutated gene, a crucial step which permits the selection, or the development, of treatments which target the molecular defect or its consequences (EpiPM Consortium, 2015). We are now entering the era of genomics-driven personalized medicine, whereby novel treatments can be designed which are not solely symptomatic, but address the underlying cause of the epilepsy in the individual person and offer opportunities for truly disease modifying effects (Delanty and Cavelleri, 2017).
The present article will discuss several examples of how identifying the mutated gene or, more precisely, the specific gene variant permits rational treatment selection, either by prescribing the most appropriate intervention or by avoiding medications which can paradoxically worsen the disease. To illustrate the broad therapeutic impact of genetic knowledge, the chosen examples are drawn from epilepsies caused by mutations affecting a wide variety of targets, from ion channels to genes controlling cellular metabolism and cell signaling pathways. While this article will focus on treatments for Mendelian epilepsies, it should be emphasized that important therapeutic clues or opportunities to develop novel treatments may also derive from improved understanding of polygenic epilepsies, and epilepsy susceptibility genes (Ferraro, 2012; International League against Epilepsy Consortium on Complex Epilepsies, 2018).
Section snippets
Epilepsies due to mutations in sodium channel genes
Voltage-gated sodium channels are involved in action potential generation and propagation, and their antagonism is a primary mechanism of action of many currently available antiepileptic drugs (AEDs). Mutations in sodium channel genes, including SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, and SCN9A are collectively responsible for a considerable proportion of cases of drug-resistant genetic epilepsies with onset in infancy and childhood (Parrini et al. (2017)). The three most common among these genes,
Epilepsies due to mutations in potassium channel genes
Potassium channels play an important role in regulation of neuronal excitability. Not surpringly, mutations in several potassium channel genes (KCNA2, KCNB1, KCNC1, KCND2, KCND3, KCNH1, KCNH2, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) have been associated with a variety of epilepsy phenotypes. Activation of potassium channels is expected to reduce neuronal excitability, which explains why many of these epileptogenic mutations are loss-of-function (Wei et al., 2017). Yet, as best
Epilepsies due to mutations in N-methyl-D-aspartate (NMDA) receptor genes
Glutamate-mediated excitatory neurotransmission is partly mediated by activation of NMDA receptors. These cation channel-receptors are made up of two GluN1 subunits (obligatory), together with auxiliary GluN2(A–D) or GluN3(A,B) subunits. Mutations of GRIN1, GRIN2A, GRIN2B, and GRIN2D genes, which encode the GluN1, GluN2A, GluN2B, and GluN2D subunits, respectively, have all been associated with epileptic phenotypes (Wei et al., 2017).
Much attention has been given to the association between GRIN2A
Epilepsies related to mTOR pathway mutations
The mechanistic target of rapamycin (mTOR) signalling pathway is involved in the modulation of many functions, including lipid and protein synthesis, cell growth and survival, cell motility and cell proliferation. It plays a key role in brain development, and its hyperexpression can lead to epileptogenic malformations of cortical development, such as tuberous sclerosis complex (TSC), focal cortical dysplasias, and hemimegalencephaly. The molecular genetics of these disorders have been reviewed,
Epilepsies due to inborn errors of metabolism
Mutations affecting genes that control the intermediary metabolism of carbohydrates, lipids, amino acids, vitamins, and energy metabolism, result in a many rare syndromes associated with early-onset seizure disorders. Prompt identification of the underlying cause is important, because the clinical manifestations, including long-term outcome, can be managed succesfully with precision treatments. A detailed review of the pathophysiological, diagnostics and therapeutic aspects of these epilepsies
Conclusions and future perspectives
As discussed above, an increasing body of evidence indicates that identifying the pathogenic variant in individual patients with genetic epilepsies is relevant not only for diagnosis and prognosis, but also for treatment selection (Mei et al., 2017; Reif et al., 2017). This finding is not surprising, because responses to specific treatments can vary depending on the disease’s underlying mechanisms which, in turn, may differ even across individuals sharing the same phenotype (McTague et al., 2016
Conflicts of interest
EP received speaker’s or consultancy fees from Axovant, Biogen, Eisai, GW Pharma, Sanofi, Takeda, UCB Pharma and Xenon Pharma. PP has received honoraria from Eisai.
Author contributions
Both authors contributed equally to this work.
Acknowledgments
This work was not supported by any funding source.
PP is supported by an Early Career Fellowship from the National Health and Medical Research Council (NHMRC), and by the Viertel Clinical Investigator Award from the Sylvia and Charles Viertel Charitable Foundation.
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