Ethical, Legal, and Social Dimensions of Epilepsy Genetics Sara Shostak* and Ruth Ottman��� * Department of Sociology, Brandeis University, Waltham, Massachusetts ��� G. H. Sergievsky Center and Department of Neurology, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, and Epidemiology of Brain Disorders Research Department, New York State Psychiatric Institute, New York, New York, U.S.A. Summary Purpose��� Emerging genetic information and the availability of genetic testing has the potential to increase understanding of the disease and improve clinical management of some types of epilepsy. However, genetic testing is also likely to raise significant ethical, legal, and social issues for people with epilepsy, their family members, and their health care providers. We review the genetic and social dimensions of epilepsy relevant to understanding the complex questions raised by epilepsy genetics. Methods��� We reviewed two literatures: (a) research on the genetics of epilepsy, and (b) social science research on the social experience and social consequences of epilepsy. For each, we note key empiric findings and discuss their implications with regard to the consequences of emerging genetic information about epilepsy. We also briefly review available principles and guidelines from professional and advocacy groups that might help to direct efforts to ascertain and address the ethical, legal, and social dimensions of genetic testing for epilepsy. Results��� Genetic information about epilepsy may pose significant challenges for people with epilepsy and their family members. Although some general resources are available for navigating this complex new terrain, no guidelines specific to epilepsy have yet been developed to assist people with epilepsy, their family members, or their health care providers. Conclusions��� Research is needed on the ethical, legal, and social concerns raised by genetic research on epilepsy and the advent of genetic testing. This research should include the perspectives of people with epilepsy and their family members, as well as those of health care professionals, policymakers, and bioethicists. Keywords Epilepsy Genetics Genetic testing Stigma Discrimination The conceptualization of epilepsy as an inherited condition dates at least to 400 B.C., the approximate date of On the Sacred Disease, attributed to Hippocrates (Temkin, 1971). In the many centuries following, clinicians and scientists have articulated varying notions of its heritability (Temkin, 1971 Schneider and Conrad, 1983). Currently, genetic researchers are attempting to identify both genes that cause epilepsy via monogenic inheritance and genes associated with increased susceptibilities to epilepsy, including possible genetic predispositions to developing epilepsy after central nervous system trauma. Pharmacogenetic research also is being done to ascertain the genetic bases for differential responses to medications used to treat epilepsy. Address correspondence and reprint requests to Dr. S. Shostak at Department of Sociology, Brandeis University, MS 071, Waltham, MA 02454-9110, U.S.A. E-mail: sshostak@brandeis.edu. NIH Public Access Author Manuscript Epilepsia. Author manuscript available in PMC 2007 February 21. Published in final edited form as: Epilepsia. 2006 October 47(10): 1595���1602. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Advances in research on epilepsy genetics have the potential to improve the quality of life of people in families affected by epilepsy by offering new means of preventing, controlling, and curing the disease, its symptoms, and its sequelae. At the same time, the ethical, legal, and social dimensions of genetic information about epilepsy require careful consideration. Some aspects of the experience of having epilepsy, as documented in social scientific research, are particularly important to understanding the ethical, legal, and social dimensions of genetic testing for epilepsy. Therefore this review considers the current state of the field of epilepsy genetics alongside social scientific analyses of the experience of having epilepsy. It draws on these two literatures as a means of highlighting areas for future empirical research and for efforts to develop guidelines for genetic testing. GENETICS AND EPILEPSY In the last decade, substantial progress has been made in the identification of genes that influence risk for some forms of epilepsy. To date, almost all of this progress has come from analysis of rare families with autosomal dominant patterns of transmission. As of August 2005, 12 genes have been identified in autosomal dominant forms of eight nonsymptomatic epilepsy syndromes. All but two of these genes encode voltage-gated or ligand-gated ion channels. In families with autosomal dominant nocturnal lobe epilepsy, mutations have been found in the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor (CHRNA4 and CHRNB2) (Steinlein et al., 1995 De Fusco et al., 2000). In families with benign familial neonatal seizures, mutations have been found in the potassium channel genes KCNQ2 and KCNQ3 (Charlier et al., 1998 Singh et al., 1998). Mutations in the genes encoding three sodium channel subunits, SCN1A, SCN1B, and SCN2A, have been found in different families with generalized epilepsy with febrile seizures plus (GEFS+) (Wallace et al., 1998 Singh et al., 1999 Escayg et al., 2000 Sugawara et al., 2001a Sugawara et al., 2001b), and mutations in SCN2A have been found in families with a different phenotype, benign familial neonatal��� infantile seizures (Heron et al., 2002). Mutations in GABRG2, the gene encoding the gamma 2 subunit of the ��-aminobutyric acid subtype A (GABAA) receptor, have been found in families with GEFS+ (Baulac et al., 2001 Harkin et al., 2002) and in families with childhood absence epilepsy with febrile seizures (Scheffer et al., 2001 Kananura et al., 2002). In a large French Canadian family with an autosomal dominant form of juvenile myoclonic epilepsy (JME), a mutation was identified in GABRA1, encoding the ��1 subunit of the GABAA receptor (Cossette et al., 2002). Mutations in EFHC1, encoding a protein with an EF-hand motif that appears to influence calcium currents, were identified in another set of families with JME (Suzuki et al., 2004). In three families with an autosomal dominant form of idiopathic generalized epilepsy (IGE) with a range of different syndromes, mutations were identified in the chloride channel gene CLCN2 (Haug et al., 2003). In families with autosomal dominant partial epilepsy with auditory features (ADPEAF), mutations have been found in the leucine-rich glioma inactivated 1 gene (LGI1), which encodes a leucine-rich repeat protein (Kalachikov et al., 2002 Morante- Redolat et al., 2002 Ottman et al., 2004). The mechanism by which LGI1 influences epilepsy risk is still not well understood, but based on protein homology, it appears likely to be involved in development of the central nervous system (Kalachikov et al., 2002). In addition to these gene discoveries in nonsymptomatic epilepsies, genes have been identified in a number of Mendelian symptomatic epilepsy syndromes. These include progressive myoclonic epilepsies [e.g., Unverricht���Lundborg disease, Lafora disease, and the neuronal ceroid lipofuscinoses (Shahwan et al., 2005)], X-linked myoclonic epilepsy with mental retardation (Stromme et al., 2002), and cortical malformation syndromes such as polymicrogyria, pachygyria, and periventricular nodular heterotopia (Guerrini, 2005 Mochida, 2005). In addition, mutations in SCN1A have been identified in many patients with severe myoclonic epilepsy of infancy (SMEI) (Claes et al., 2001 Ohmori et al., 2002 Sugawara et al., 2002 Wallace et al., 2003). Shostak and Ottman Page 2 Epilepsia. Author manuscript available in PMC 2007 February 21. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript