Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy

Abstract

Objective Determine if common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short term seizure outcome in Childhood Absence Epilepsy (CAE). Methods 446CAEchildren in a randomized double blind trial of ethosuximide, lamotrigine and valproate had short term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥15%)in four genes andseizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of one variant on T-type calcium channel responsiveness to ethosuximide. Results 80% (357/446) of subjects had informative short term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, two polymorphisms (CACNA1Hrs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not seizure free participants (p=0.011; Odds Ratio(OR):2.63; 95% Confidence limits(CL):1.25–5.56, p=0.026; OR:2.38; 95%CL:1.11–5.00). In lamotrigine subjects, one ABCB1 missense polymorphism (rs2032582/S893A, p=0.015; OR:2.22; 95%CL:1.16–4.17) was more common in not seizure free participants, two CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure free participants (p=0.038; OR:0.52; 95%CL:0.28–0.96). In valproate subjects, no common polymorphisms associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in ethosuximide’s absence. Ethosuximide’s effect on rate of decay of CaV3.2was significantly less for P640L channel compared to wild type channel. Interpretation Four T-type calcium channel variants and one ABCB1 transporter variant were associated with differential drug response in CAE. The in vivoP640L variant’s ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests genetic variation plays a role in differential CAE drug response.

Ictal connectivity in childhood absence epilepsy: Associations with outcome

“…ETX is presumed to have its major therapeutic effect by reducing low threshold T‐type calcium channel currents in the thalamus . A pharmacogenetic study of ETX efficacy in CAE identified 2 polymorphisms of the T‐type calcium channel (CACNA1H rs61734410/P640L, CACNA1I rs3747178) that were more common in patients who were not seizure‐free, and in vitro studies showed that ETX's rate of calcium current decay was reduced for the P640L polymorphism seen in treatment nonresponders, compared to the wild‐type channel . The link between these genetic findings and the pretreatment ictal network that we have identified in this study is unclear; however, we speculate that if a child has a network driven by the frontal cortex, where ETX may not work as effectively as in the thalamus, then this may provide a mechanistic explanation for their poor response to the treatment (Figure ).…”

“…Phenotypic groups of patients with CAE have been proposed based on differences in their pretreatment seizure semiology, electroencephalography (EEG), presence of attention deficits, and treatment response . Clinical outcome is clearly variable, with 19.5% of patients failing to respond to the first‐line treatment, ethosuximide (ETX) . This individual variability also extends to the brain networks responsible for absence seizures.…”

The absence of NIPA2 enhances neural excitability through BK (big potassium) channels

“…Electroencephalography shows generalized 2.5‐3.5 Hz spike‐and‐wave discharges. Susceptible CAE genes, such as CACNA1H , a Ca v 3.2 T‐type calcium channel gene, are primarily associated with ion channels . CAE is also related to nonion channel genes, such as NIPA2 , a highly selective magnesium transporter gene …”

“…channel gene, are primarily associated with ion channels. 5 CAE is also related to nonion channel genes, such as NIPA2, a highly selective magnesium transporter gene. 6 NIPA2 encodes nonimprinted Prader-Willi/Angelman syndrome region protein 2.…”

DRD3 Ser9Gly Polymorphism and Its Influence on Risperidone Response in Autistic Children

“…As a means of targeted treatment and personalized medicine, pharmacogenetics has currently drawn a lot of attention in many neurologic and psychiatric diseases (36)(37)(38)(39)(40). Although many studies have focused on the contribution of genetic factors in autism (41,42), their role as therapeutic elements stays illusive.…”