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Genetic Determinants of Seizures and Epilepsy
As AED tolerability is also critical, there is hope that pharmacogenetic SCN1A, KCNQ2, and CLCN2, but also in genes not directly related to
advances will be able to identify patients likely to experience ion channel function such as CSTB, has helped to guide research but
idiosyncratic side effects. Thus, certain AEDs could be avoided in has not led to breakthroughs in understanding or treating the disease.
susceptible patients. A very strong association between human Identification of susceptibility genes for the vast majority of epilepsy
leukocyte antigen (HLA) allele B*1502, carbamazepine (CBZ), and cases is a matter of ongoing investigation. To date, only a small
Stevens-Johnson syndrome (SJS) in Han Chinese patients
54
has limited number of susceptibility genes have been confirmed, including
new use of CBZ in patients of Asian descent. This finding could KCNJ10, which was nominated as a candidate from a mouse model of
become a model of the potential for pharmacogenetics to influence seizure susceptibility. Utilization of translational strategies, such as
AED choice and benefit patients. However, it should be noted that genetic animal models, in combination with advances in technology
confirming such associations in a more ethnically diverse population such as those facilitating comprehensive genome-wide association,
may be challenging. The timing and severity of more chronic AED side mutation screening, and gene expression studies in large numbers of
effects, such as weight gain, weight loss, decreased bone density, patients, will help to elucidate the complex genetic determinants
cognitive dysfunction, and mood alteration, may also be influenced by underlying the risk for developing epilepsy and identify new targets
genotype. Identification of patients likely to develop side effects could for AED pharmacotherapy. Furthermore, the establishment and
impact specific AED choice. Better understanding of the mechanisms application of well-defined clinical criteria for determining the
involved in the development of these adverse effects could lead to resistance and responsiveness of patients to AEDs will permit
strategies to circumvent their occurrence if certain AEDs must be analysis of the genetic determinants that influence successful
prescribed for particular patients. treatment outcome. Such pharmacogenetic studies can be conducted
in parallel with those designed to discover susceptibility genes, thus
There is hope that better understanding of AED pharmacogenetics maximizing the value of the large amount of genetic data that will be
will explain why some patients are refractory to multiple AEDs. generated. Despite current limitations in the practical value of genetic
Emphasis has been placed on analyzing polymorphisms in genes data with regard to diagnosing and treating epilepsy, the future holds
encoding drug efflux transporters, which transport AEDs and other much promise for patients and clinicians alike. n
drugs out of cells. Such work has the potential to identify patients
who could be early candidates for non-AED treatments such as brain
Dennis J Dlugos, MD, MSCE, is an Associate Professor of Neurology and Pediatrics at
stimulation or surgery. With improved understanding of AED transport
The Children’s Hospital of Philadelphia (CHOP) at the University of Pennsylvania
mechanisms, it may also be possible to develop methods of School of Medicine. He is Director of the Pediatric Regional Epilepsy Program and the
circumventing drug efflux transporters and improve access of AEDs to
Epilepsy and Clinical Neurophysiology Fellowship at CHOP. Dr Dlugos is a co-
investigator on National Institutes of Health (NIH) grants involving epilepsy genetics,
critical sites of action in the brain.
pharmacogenetics, and epilepsy surgery.
Although it is not yet possible to make general recommendations for
Thomas N Ferraro, PhD, is a Research Associate
the incorporation of genetic data into the decision-making process for
Professor of Pharmacology in Psychiatry at the University
AED therapy, recent studies are beginning to provide a foundation for of Pennsylvania School of Medicine in Philadelphia. He is
the future establishment of treatment guidelines.
also a member of the Center for Neurobiology and
Behavior and the Penn Institute for Neurological
Sciences. Dr Ferraro’s research program is funded by the
Conclusion National Institutes of Health (NIH) to study genetic
Epilepsy is a genetically complex group of CNS disorders that affects
influences on epilepsy in humans through utilization of
genetic mouse models of seizure susceptibility.
about 1% of the population globally. Identification of a variety of rare,
causative epilepsy mutations, primarily in ion channel genes such as
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US NEUROLOGY 67
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