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testing for risk assessment and personalized treatment (Kearney 2012 ). Personalized
WES is already available and WGS is likely to be routinely available within next
few years.
Breakthroughs are needed in the identifi cation of new molecular targets that will
translate to novel intervention approaches. Discovering genetic variants that
increase the susceptibility to disease is a promising avenue to identifying such tar-
gets. However, early candidate gene-based studies in epilepsy proved ineffective in
identifying genetic risk factors for the non-Mendelian, complex epilepsies, which
represent >95 % of clinically encountered epilepsy. Furthermore, genome wide
association studies (GWAS) of epilepsy patients have been largely negative, with
the exception of several putative susceptibility loci discovered in Han Chinese focal
epilepsy and European Caucasians. Results of these GWAS suggest that, similar to
other common diseases, associations with SNPs appear likely to account for a small
fraction of the heritability of epilepsy, thus fueling the effort to also search for alter-
native genetic contributors, with a recent increased emphasis on rare variants with
larger effects. It is possible that both common and rare variants contribute to an
increased susceptibility to common epilepsy syndromes.
Examples where genetic factors play a role in epilepsy are Dravet syndrome,
febrile seizures, and epileptic encephalopathies. Dravet syndrome is a rare form of
infantile epilepsy that is associated with a high incidence of developmental delays
and even (sudden unexplained death in epilepsy. Dravet is caused by a genetic
defect in the SCN1A gene-affecting sodium channel. Also, there is a rare mutation
in the GABARG2 and SCN1B genes (Al-Baradie 2013 ). The condition can be man-
aged if diagnosed. A combination therapy of stiripentol, valproic acid, clobazam,
and topiramate is promising.
Proline-rich transmembrane protein 2 (PRRT2) gene is related to paroxysmal
kinesigenic dyskinesia (PKD), infantile convulsions with PKD, and PKD with
benign familial infantile epilepsy. A study that screened PRRT2 exons in a cohort of
epileptic patients with febrile seizures identifi ed PRRT2 genetic mutations in 18.4 %
of patients (He et al. 214). PRRT2 may provide a new drug target for personalized
treatment of febrile seizures.
Epileptic encephalopathy (EE) is a heterogeneous group of severe epilepsy dis-
orders characterized by early onset of seizures and cognitive as well as behavioral
features associated with ongoing epileptic activity. Two classical forms are infantile
spasms and Lennox-Gastaut syndrome. An exome sequencing study has revealed
several de novo mutations of which GABRB3 and ALG13 genes show clear statisti-
cal evidence of association with epileptic encephalopathy (Epi4K and EPGP
Investigators 2013 ). Other genes with de novo mutations in this cohort include
CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2,
MTOR and NEDD4L. It may be diffi cult to predict with confi dence the responsible
gene, and the genetic diagnostics in EE in the future will focus on the genome as a
whole rather than single genes or even gene panels. Genomic studies of EE have
implications for drug development and personalized treatment of EE because many
of these mutations appear to converge on specifi c biologic pathways.
12 Personalized Management of Neurological Disorders