Executive functioning in children with epilepsy: Genes matter.

Pediatric epilepsy has emerged as a chronic medical disease with a characteristic behavioral and cognitive phenotype, which includes compromised executive functioning (EF) and attention-related deficits. However, considerable interindividual variability exists; children often display very different or even opposite outcomes, and some children are more likely than others to develop neurocognitive problems in the face of similar individual and disease-related problems. The factors responsible for this interindividual variability are still largely unknown, but we do know that some genetic factors render the developing brain more susceptible to damage or traumatic experiences than others. Dopamine availability has a neuromodulatory function in the prefrontal cortex (PFC) and especially affects EF. Dopamine availability relates to polymorphisms in the gene encoding catechol-O-methyltransferase (COMT Val158Met), which in turn is affected by the methylation state of its promoter. Allelic variation of the methylenetetrahydrofolate reductase (MTHFR C677T) gene, alters methylation and may influence the methylation state of the COMT promoter. Given this, we tested the hypothesis that these polymorphisms interact in children with epilepsy, and that variability in allelic expression is associated with variability in cognitive phenotype. Executive function was tested directly and indirectly (parent-rated) in 42 children between 5 and 12 years of age. The MTHFR T allele carriers performed worse than MTHFR homozygous CC carriers on indirect EF, and a significant decline was observed when T allele carriers had at least one met allele of the COMT gene, especially on Working Memory. Direct EF was significantly compromised in COMT Val/Val carriers where reduced dopamine availability seems to confer a higher risk in a test that requests a high degree of executive attention and planning. This finding suggests that in children with epilepsy, genes that influence methylation and dopamine availability affect PFC-related EF. Therefore, we should consider genetic vulnerability as a polygenic risk, which might predispose for a particular phenotype and include specific genetic signatures as part of each patient's behavioral and cognitive profile from the moment that we start to take care of the child.