Comment
with much debate concerning the finding of human papillomavirus affecting the development of focal cortical dysplasia type IIB.8 But what about the molecular landscape of the malformed cortical tissue itself? Each cortical neuron has around 1500 SNVs that differentiate it from the rest of an individual’s tissues.5 Therefore, these somatic variants might explain the marked variable penetrance seen in families with malformations and familial mutations, as well as the variability in the severity of the PIK3R2 phenotype demonstrated by Mirzaa and colleagues.2 Many genes are now implicated in malformations of cortical development with increasing overlap in their phenotypic range. Genetic insights are blurring the boundaries of a classification based on the developmental processes of cell proliferation, neuronal migration, and subsequent cortical organisation.1 These stages of development are increasingly recognised to be genetically and functionally interdependent.1 The implication of PIK3R2 in polymicrogyria emphasises the burgeoning importance of the mTOR pathway in malformations of cortical development with the promise that therapeutic convergence, targeting a pathway rather than a protein, might enable a precision medicine approach to be more widely and readily applicable in future.
Ingrid E Scheffer Florey Institute, University of Melbourne, Austin Health and Royal Children’s Hospital, Melbourne, VIC, Australia scheff[email protected] I report grants from National Health and Medical Research Council of Australia and the National Institutes of Health, during the conduct of the study, and personal fees from UCB, Athena Diagnostics, Transgenomic, GlaxoSmithKline, Sanofi, and Eisai, outside the submitted work. I also have a patent Diagnostic and Therapeutic Methods for EFMR (Epilepsy and Mental Retardation Limited to Females) with royalties paid. 1 2
3
4 5
6
7
8
Guerrini R, Dobyns WB. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol 2014; 13: 710–26. Mirzaa GM, Conti V, Timms AE, et al. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study. Lancet Neurol 2015; published online Oct 29. http://dx.doi.org/10.1016/S14744422(15)00278-1. Kheradmand Kia S, Verbeek E, Engelen E, et al. RTTN mutations link primary cilia function to organization of the human cerebral cortex. Am J Hum Genet 2012; 91: 533–40. Jamuar SS, Lam AT, Kircher M, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med 2014; 371: 733–43. Lodato MA, Woodworth MB, Lee S, et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 2015; 350: 94–98. Scheffer IE, Heron SE, Regan BM, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol 2014; 75: 782–87. Scerri T, Riseley JR, Gillies G, et al. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol 2015; 2: 575–80. Chen J, Tsai V, Parker WE, et al. Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol 2012; 72: 881–92.
Epilepsy treatment: precision medicine at a crossroads See Personal View page 1219
1148
In this issue of The Lancet Neurology, David Goldstein and colleagues of the EpiPM Consortium1 provide a challenging view of how genetic and molecular biological tools could advance the search for therapeutic targets in epilepsy that are specific for each patient’s genetic constitution. Despite the various structures and mechanisms of action of currently available antiepileptic drugs, many patients are still not seizure-free or have adverse drug reactions. Guidelines exist for drugs of first and second choice on the basis of current epilepsy classifications, yet the added therapeutic value of most new compounds is somewhat limited, and antiepileptic drug treatment is still typically a matter of trial and error. This situation might improve with better insight into the individual genetic determinants of disease and therapeutic responses, thus driving research into individually tailored treatments for patients with epilepsy.1
Medical treatment of disease—with cure of disease and relief of symptoms in the absence of side-effects being the ultimate goals—is a balance between expectations of therapeutic effects and side-effects and between costs and benefits. Individual patients differ in their reaction to treatment, not only in terms of therapeutic response but also adverse reactions. Adverse drug reactions are common and can be chronic or irritating, affect quality of life, or sometimes lead to life-threatening complications; they might include paradoxical effects, other CNS sideeffects, or side-effects outside the CNS. A substantial proportion of the variation in adverse effects probably depends on genetic factors related to the disease or on genetic factors that determine pharmacokinetic pathways and pharmacodynamic targets of therapeutic compounds. We are at a crossroads in epilepsy drug development, and future research on optimum personalised, or precision, medicine needs to take all of these factors into account. www.thelancet.com/neurology Vol 14 December 2015
Comment
Once monogenic or polygenic causes of epilepsy are identified, drugs could be targeted towards the genetic defect or molecular pathways that might compensate for that defect, or could be used to bypass the pathway disturbed by the genetic variant or variants causing the disease. New functional test systems measuring singlegene targets as well as multicomponent pathways and neuronal networks will be indispensable to make breakthroughs in precision medicine in epilepsy, and a small number of case reports have already provided proof of principle.1,2 Identification and development of a drug with a specific molecular genetic target does not imply that such a drug will be effective in clinical practice and not cause side-effects. Preclinical testing for potential side-effects is highly relevant, also for drugs of high specificity or potency. Preclinical testing is even more important for drugs that are expected to be used by women at reproductive age, which represent a substantial proportion of patients with epilepsy. Most, if not all, drugs cross the placenta, and even well designed drugs with specific targets might have specific or potent adverse effects on the developing embryo and fetus. Retinoic acid embryopathy is an example of how well targeted vitamin A analogues can induce specific fetal defects and functional abnormalities in human offspring.3 Genetic factors are also likely to have a role in conferring susceptibility of the fetus towards teratogenesis, which cannot be entirely explained by maternal factors. Drugs with therapeutic precision also interact with pharmacokinetic pathways, and might have other unexpected pharmacodynamic targets that mediate paradoxical or adverse effects. Such off-target effects are recognised by Goldstein and colleagues1 when they refer to POLG-associated, valproate-induced hepatotoxicity and HLA B*15:02 allele-associated, carbamazepine-induced Stevens–Johnson syndrome. However, researchers are still missing a robust roadmap for the discovery of genes underlying adverse drug reactions in epilepsy treatment and for the development of molecular biological tools to predict their side-effects and identify patients and embryos at risk. Research into adverse drug reactions and their genetic determinants has generally not been prioritised during drug development. For example, why did it take more than 30–40 years before valproate was uncovered as a neurocognitive teratogen?4 Why is it not possible www.thelancet.com/neurology Vol 14 December 2015
to predict who in pregnancy is susceptible to having a fetus with valproate-induced spina bifida, despite hundreds of fatal cases and fetal terminations?5,6 Why was loss of seizure control due to lamotrigine-induced glucuronidation by pregnancy steroids not predictable despite previous evidence of decreased clearance of lamotrigine in genetic Gilbert’s syndrome?7,8 Why is there still no test to identify patients at risk of developing visual field defects with vigabatrin,9 hyponatraemia with carbamazepine and oxcarbazepine,10 or psychiatric sideeffects of many antiepileptic drugs? These examples clearly suggest that the epilepsy research community needs two roadmaps to restore the balance: a roadmap to guide the search for targeted therapeutics, as set out by Goldstein and colleagues,1 and—in collaboration with (reproductive) toxicological and pharmacological disciplines—a roadmap to guide the identification and investigation of the potential side-effects of new compounds. Without prediction of side-effects, there will be no precision medicine! Dick Lindhout Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, NL-3508, Utrecht, Netherlands; and Stichting Epilepsie Instellingen Nederland (SEIN), PO Box 540, NL2130 AM Hoofddorp, Netherlands [email protected] I declare no competing interests. 1
2
3 4 5
6
7
8
9 10
EpiPM Consortium. A roadmap for precision medicine in the epilepsies. Lancet Neurol 2015; published online Sept 21. http://dx.doi.org/10.1016/ S1474-4422(15)00199-4. Boerma RS, Braun KP, van den Broek MPH, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics 2015; published online Aug 9. http://dx.doi.org/10.1007/s13311-015-0372-8 (accessed Oct 22, 2015) Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837–41. Baker GA, Bromley RL, Briggs M, et al. IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology 2015; 84: 382–90. Charlton RA, Weil JG, Cunnington MC, Ray S, de Vries CS. Comparing the General Practice Research Database and the UK Epilepsy and Pregnancy Register as tools for postmarketing teratogen surveillance: anticonvulsants and the risk of major congenital malformations. Drug Saf 2011; 34: 157–71. Lindhout D, Omtzigt JG, Cornel MC. Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992; 42 (4 suppl 5): 111–18. Posner J, Cohen AF, Land G, Winton C, Peck AW. The pharmacokinetics of lamotrigine (BW430C) in healthy subjects with unconjugated hyperbilirubinaemia (Gilbert’s syndrome). Br J Clin Pharmacol 1989; 28: 117–20. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171–75. Kinirons P, Cavalleri GL, Singh R, et al. A pharmacogenetic exploration of vigabatrin-induced visual field constriction. Epilepsy Res 2006; 70: 144–52. Kim YS, Kim DW, Jung KH, et al. Frequency of and risk factors for oxcarbazepine-induced severe and symptomatic hyponatremia. Seizure 2014; 23: 208–12.
1149
with much debate concerning the finding of human papillomavirus affecting the development of focal cortical dysplasia type IIB.8 But what about the molecular landscape of the malformed cortical tissue itself? Each cortical neuron has around 1500 SNVs that differentiate it from the rest of an individual’s tissues.5 Therefore, these somatic variants might explain the marked variable penetrance seen in families with malformations and familial mutations, as well as the variability in the severity of the PIK3R2 phenotype demonstrated by Mirzaa and colleagues.2 Many genes are now implicated in malformations of cortical development with increasing overlap in their phenotypic range. Genetic insights are blurring the boundaries of a classification based on the developmental processes of cell proliferation, neuronal migration, and subsequent cortical organisation.1 These stages of development are increasingly recognised to be genetically and functionally interdependent.1 The implication of PIK3R2 in polymicrogyria emphasises the burgeoning importance of the mTOR pathway in malformations of cortical development with the promise that therapeutic convergence, targeting a pathway rather than a protein, might enable a precision medicine approach to be more widely and readily applicable in future.
Ingrid E Scheffer Florey Institute, University of Melbourne, Austin Health and Royal Children’s Hospital, Melbourne, VIC, Australia scheff[email protected] I report grants from National Health and Medical Research Council of Australia and the National Institutes of Health, during the conduct of the study, and personal fees from UCB, Athena Diagnostics, Transgenomic, GlaxoSmithKline, Sanofi, and Eisai, outside the submitted work. I also have a patent Diagnostic and Therapeutic Methods for EFMR (Epilepsy and Mental Retardation Limited to Females) with royalties paid. 1 2
3
4 5
6
7
8
Guerrini R, Dobyns WB. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol 2014; 13: 710–26. Mirzaa GM, Conti V, Timms AE, et al. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study. Lancet Neurol 2015; published online Oct 29. http://dx.doi.org/10.1016/S14744422(15)00278-1. Kheradmand Kia S, Verbeek E, Engelen E, et al. RTTN mutations link primary cilia function to organization of the human cerebral cortex. Am J Hum Genet 2012; 91: 533–40. Jamuar SS, Lam AT, Kircher M, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med 2014; 371: 733–43. Lodato MA, Woodworth MB, Lee S, et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 2015; 350: 94–98. Scheffer IE, Heron SE, Regan BM, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol 2014; 75: 782–87. Scerri T, Riseley JR, Gillies G, et al. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol 2015; 2: 575–80. Chen J, Tsai V, Parker WE, et al. Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol 2012; 72: 881–92.
Epilepsy treatment: precision medicine at a crossroads See Personal View page 1219
1148
In this issue of The Lancet Neurology, David Goldstein and colleagues of the EpiPM Consortium1 provide a challenging view of how genetic and molecular biological tools could advance the search for therapeutic targets in epilepsy that are specific for each patient’s genetic constitution. Despite the various structures and mechanisms of action of currently available antiepileptic drugs, many patients are still not seizure-free or have adverse drug reactions. Guidelines exist for drugs of first and second choice on the basis of current epilepsy classifications, yet the added therapeutic value of most new compounds is somewhat limited, and antiepileptic drug treatment is still typically a matter of trial and error. This situation might improve with better insight into the individual genetic determinants of disease and therapeutic responses, thus driving research into individually tailored treatments for patients with epilepsy.1
Medical treatment of disease—with cure of disease and relief of symptoms in the absence of side-effects being the ultimate goals—is a balance between expectations of therapeutic effects and side-effects and between costs and benefits. Individual patients differ in their reaction to treatment, not only in terms of therapeutic response but also adverse reactions. Adverse drug reactions are common and can be chronic or irritating, affect quality of life, or sometimes lead to life-threatening complications; they might include paradoxical effects, other CNS sideeffects, or side-effects outside the CNS. A substantial proportion of the variation in adverse effects probably depends on genetic factors related to the disease or on genetic factors that determine pharmacokinetic pathways and pharmacodynamic targets of therapeutic compounds. We are at a crossroads in epilepsy drug development, and future research on optimum personalised, or precision, medicine needs to take all of these factors into account. www.thelancet.com/neurology Vol 14 December 2015
Comment
Once monogenic or polygenic causes of epilepsy are identified, drugs could be targeted towards the genetic defect or molecular pathways that might compensate for that defect, or could be used to bypass the pathway disturbed by the genetic variant or variants causing the disease. New functional test systems measuring singlegene targets as well as multicomponent pathways and neuronal networks will be indispensable to make breakthroughs in precision medicine in epilepsy, and a small number of case reports have already provided proof of principle.1,2 Identification and development of a drug with a specific molecular genetic target does not imply that such a drug will be effective in clinical practice and not cause side-effects. Preclinical testing for potential side-effects is highly relevant, also for drugs of high specificity or potency. Preclinical testing is even more important for drugs that are expected to be used by women at reproductive age, which represent a substantial proportion of patients with epilepsy. Most, if not all, drugs cross the placenta, and even well designed drugs with specific targets might have specific or potent adverse effects on the developing embryo and fetus. Retinoic acid embryopathy is an example of how well targeted vitamin A analogues can induce specific fetal defects and functional abnormalities in human offspring.3 Genetic factors are also likely to have a role in conferring susceptibility of the fetus towards teratogenesis, which cannot be entirely explained by maternal factors. Drugs with therapeutic precision also interact with pharmacokinetic pathways, and might have other unexpected pharmacodynamic targets that mediate paradoxical or adverse effects. Such off-target effects are recognised by Goldstein and colleagues1 when they refer to POLG-associated, valproate-induced hepatotoxicity and HLA B*15:02 allele-associated, carbamazepine-induced Stevens–Johnson syndrome. However, researchers are still missing a robust roadmap for the discovery of genes underlying adverse drug reactions in epilepsy treatment and for the development of molecular biological tools to predict their side-effects and identify patients and embryos at risk. Research into adverse drug reactions and their genetic determinants has generally not been prioritised during drug development. For example, why did it take more than 30–40 years before valproate was uncovered as a neurocognitive teratogen?4 Why is it not possible www.thelancet.com/neurology Vol 14 December 2015
to predict who in pregnancy is susceptible to having a fetus with valproate-induced spina bifida, despite hundreds of fatal cases and fetal terminations?5,6 Why was loss of seizure control due to lamotrigine-induced glucuronidation by pregnancy steroids not predictable despite previous evidence of decreased clearance of lamotrigine in genetic Gilbert’s syndrome?7,8 Why is there still no test to identify patients at risk of developing visual field defects with vigabatrin,9 hyponatraemia with carbamazepine and oxcarbazepine,10 or psychiatric sideeffects of many antiepileptic drugs? These examples clearly suggest that the epilepsy research community needs two roadmaps to restore the balance: a roadmap to guide the search for targeted therapeutics, as set out by Goldstein and colleagues,1 and—in collaboration with (reproductive) toxicological and pharmacological disciplines—a roadmap to guide the identification and investigation of the potential side-effects of new compounds. Without prediction of side-effects, there will be no precision medicine! Dick Lindhout Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, NL-3508, Utrecht, Netherlands; and Stichting Epilepsie Instellingen Nederland (SEIN), PO Box 540, NL2130 AM Hoofddorp, Netherlands [email protected] I declare no competing interests. 1
2
3 4 5
6
7
8
9 10
EpiPM Consortium. A roadmap for precision medicine in the epilepsies. Lancet Neurol 2015; published online Sept 21. http://dx.doi.org/10.1016/ S1474-4422(15)00199-4. Boerma RS, Braun KP, van den Broek MPH, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics 2015; published online Aug 9. http://dx.doi.org/10.1007/s13311-015-0372-8 (accessed Oct 22, 2015) Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837–41. Baker GA, Bromley RL, Briggs M, et al. IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology 2015; 84: 382–90. Charlton RA, Weil JG, Cunnington MC, Ray S, de Vries CS. Comparing the General Practice Research Database and the UK Epilepsy and Pregnancy Register as tools for postmarketing teratogen surveillance: anticonvulsants and the risk of major congenital malformations. Drug Saf 2011; 34: 157–71. Lindhout D, Omtzigt JG, Cornel MC. Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992; 42 (4 suppl 5): 111–18. Posner J, Cohen AF, Land G, Winton C, Peck AW. The pharmacokinetics of lamotrigine (BW430C) in healthy subjects with unconjugated hyperbilirubinaemia (Gilbert’s syndrome). Br J Clin Pharmacol 1989; 28: 117–20. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171–75. Kinirons P, Cavalleri GL, Singh R, et al. A pharmacogenetic exploration of vigabatrin-induced visual field constriction. Epilepsy Res 2006; 70: 144–52. Kim YS, Kim DW, Jung KH, et al. Frequency of and risk factors for oxcarbazepine-induced severe and symptomatic hyponatremia. Seizure 2014; 23: 208–12.
1149
