The lacking evidence for the heritability of drug response – and why nobody cares about it

Seizure disorders Hughlings Jackson, one of the pioneers of epileptology, commented that “man is built to seize”.  Seizures, pathological synchronisation of network activity in the Central Nervous System, are the final common pathway of different pathogenic processes within the brain.  Whereas fever is the most common provoking factor in children, provoking factors in adults are metabolic derangements, head trauma or brain tumours. Epilepsy, in contrast to seizures, is defined as the occurence of more than one unprovoked seizure.  This reflects an inherent hyperexcitability of the Central Nervous System.  Seizure disorders are common with up to 2% of the population affected and have a strong genetic component.

Drug response in epilepsy A significant proportion of seizure disorders can be controlled with antiepileptic medication and up to 30% of all patients are seizure free on medication.  Novel antiepileptic medications are constantly developed which harbour the potential of providing a broad spectrum for the physician and the patient to choose from.  However, many medications carry common and rare, potentially lethal side effects.  Finding the medication that provides the best seizure control while having the fewest side effects is the ultimate goal in each patient. Furthermore, up to one third of all patients in specialised epilepsy centre are pharmacoresistant [1].  Accordingly, there is an urgent need to understand factors that influence drug response in patients with epilepsy.

Pharmacogenetics Identifying genetic variations that predict response to particular antiepileptic medications has received much attention in recent years [2, 3].  This research is mainly motivated by particular drug responses in rare genetic epilepsy syndromes such as Dravet syndrome [4] and animal studies on selective inbreeding [5].  Several candidate genes have been suggested that determine drug response in patients with epilepsy, but most studies so far lack replication and draw upon a biased patient population [2].  Accordingly, the potential for pharmacogenetics is difficult to estimate.  Epidemiological methods such as the analysis of familial aggregation are inadequate to answer the question as to how much of the response to antiepileptic medication is due to genetics factors and whether the field of pharmacogenetics is built upon a reasonable hypothesis.

Response to medication in twins with epilepsy Twins have traditionally been the flagship of epilepsy genetics.  Ever since the first report of a concordant twin pair with Temporal Lobe Epilepsy by Wolfson in 1929 and the historical studies by William Lennox in the 1950’s [6],  twins have been crucial in demonstrating a genetic impact on a variety of epilepsy syndromes [7].  Particular the Idiopathic Generalised Epilepsies are considered to be almost essentially genetic nowadays with a heritability of more than 80% [8].  Constance and Kathryn, an identical (monozygotic) twin pair with Childhood Absence Epilepsy, have become the well-recognized face of twin research in epilepsy genetics.  Constance and Kathryn both suffered from Childhood Absence Epilepsy and the EEG recordings showed virtually identical traces.  However, it is commonly not known that Constance and Kathryn were discordant for drug response [9].  Whereas seizures could easily be controlled in one twins, the other twin required multiple medications to gain control of the epilepsy.  Apparently, factors other than genetics influenced the response to medication in this pair. However, there is also evidence for striking similarities in response to medication between twins, such as identical concordant twin pairs with severe Childhood Absence Epilepsy and an concordant unusual response to steroid treatment. In summary, little is known about similarities and differences between drug response in identical twins except for anecdotal evidence and the heritability of drug response is not known. What is the consequence of this lack of information on the genetics of drug response? As strange as it might sound at first glance, researchers are not particularly concerned about the lack of clinical genetic evidence and even look for genetic factors in the absence of clinical evidence. In fact, common genetic variants might actually be prevalent in conditions that do not seem to be heritable at first glance [10], a topic that will be addressed in a future blog.


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1.           Kwan, P. and M.J. Brodie, Early identification of refractory epilepsy. N Engl J Med, 2000. 342(5): p. 314-9.

2.                 Szoeke, C.E., et al., Update on pharmacogenetics in epilepsy: a brief review. Lancet Neurol, 2006. 5(2): p. 189-96.

3.                 Sisodiya, S.M., Genetics of drug resistance. Epilepsia, 2005. 46 Suppl 10: p. 33-8.

4.                 Mulley, J.C., et al., Channelopathies as a genetic cause of epilepsy. Curr Opin Neurol, 2003. 16(2): p. 171-6.

5.                 Cramer, S., U. Ebert, and W. Loscher, Characterization of phenytoin-resistant kindled rats, a new model of drug-resistant partial epilepsy: comparison of inbred strains. Epilepsia, 1998. 39(10): p. 1046-53.

6.                 Lennox, W.G., The heredity of epilepsy as told by relatives and twins. J Am Med Assoc, 1951. 146(6): p. 529-36.

7.                 Berkovic, S.F., et al., Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol, 1998. 43(4): p. 435-45.

8.                 Berkovic, S.F., et al., Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci, 2006. 29(7): p. 391-7.

9.                 Lennox, W.G.L., M. A., Epilepsy and Related Disorders. 1960, Boston: Little, Brown & Co. 548-574.

10.                 Visscher, P.M., W.G. Hill, and N.R. Wray, Heritability in the genomics era–concepts and misconceptions. Nat Rev Genet, 2008. 9(4): p. 255-66.

Ingo Helbig

Child Neurology Fellow and epilepsy genetics researcher at the Children’s Hospital of Philadelphia (CHOP), USA and Department of Neuropediatrics, Kiel, Germany

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