Textbook of Personalized Medicine - Second Edition [2015]

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(SCN1A) and drug transport (ABCB1) proteins can infl uence the effi cacy of AEDs
as shown in Table 12.5.
The common SCN1A splice-site polymorphism rs3812718 (IVS5N + 5 G > A)
may contribute to the pathophysiology underlying genetic generalized epilepsies
and is associated with electrophysiological properties of the channel and the effect
of AEDs that block Na-channels. Studies associating other genes and their variants
with seizure control have inherent weaknesses and have not provided unifying con-
clusions. A better understanding of the genetic infl uences on epilepsy outcome is the
key to developing the much needed new therapeutic strategies for individual patients
with epilepsy.
Control of epilepsy with phenytoin can be a diffi cult and lengthy process because
of the wide range of doses required by different patients and the drug’s narrow
therapeutic index. Similarly, appropriate doses of carbamazepine take time to deter-
mine because of the drug’s variable effects on patient metabolism and its potential
neurologic side effects. People with epilepsy are genetically different from one
another, and some of those differences affect their responses to drugs in a predict-
able manner. A variant of the gene SCN1A, which is found more frequently in
patients on the highest doses of phenytoin, has been implicated in many inherited
forms of epilepsy. Detection of these gene variants might identify in advance, which
patients will need the higher dose and enable a more optimal dose schedule at the
start. Otherwise it could take months to get the seizures under control. These new
fi ndings provide a direction for a dosing scheme that could be tested in a clinical
trial to assess whether pharmacogenetic testing can improve dosing decisions.
Transcranial magnetic stimulation is useful for investigating the effects of genetic
variants on cortical excitability and pharmacoresponse.

Table 12.5 Infl uence of gene polymorphisms on effi cacy of antiepileptic drugs

Gene/polymorphism Infl uence on action of antiepileptic drug Reference
ABCB1/T allele of
G2677T

Resistance to carbamazepine as a single drug therapy

in the treatment of complex partial seizures in

Malaysian patients

Subenthiran

et al. ( 2013 )

ABCC2/G1249A Decreased risk of resistance to antiepileptic drugs in
metaanalysis of studies involving Chinese as well
as Caucasian patients

Chen

et al. ( 2014 )

ABCC2/T allele of
rs3740066

Resistance to effect of carbamazepine in Mexican

patients

Escalante-
Santiago
et al. ( 2014 )
ABCC2/
1249G > A SCN1A/
IVS5-91G > A

Prediction of drug response due to signifi cant

association with carbamazepine/oxcarbamazepine

resistant epilepsy in Han Chinese patients

Ma et al. ( 2014 )

SCN1A/rs3812718 The frequency of the AA genotype was signifi cantly
higher in carbamazepine-resistant Japanese
patients

Abe et al.

( 2008 )

SCN1A/rs3812718 In healthy European volunteers GG homozygotes
showed increased carbamazepine- induced cortical
silent period compared to AA homozygous subjects

Menzler

et al. ( 2014 )

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12 Personalized Management of Neurological Disorders