Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the KCNB1 gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-month-old fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individuals fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a de novo variant in KCNB1 [c.1154C > T/p.Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the probands heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of KCNB1 developmental encephalopathies.

Objectives

Children with temporal lobe epilepsy (TLE) exhibit executive dysfunction on traditional neuropsychological tests. However, there is limited evidence of neural network alterations associated with this clinical executive dysfunction. The objective of this study was to characterize working memory deficits in children with TLE via activation of the executive control network on functional magnetic resonance imaging (fMRI) and determine the relationships to fMRI behavioral findings and traditional neuropsychological tests.

Experimental design

Functional magnetic resonance imaging was conducted on 17 children with TLE and 18 healthy control participants (age 8-16 years) while they performed the N-back task in order to assess activation of the executive control network. N-back accuracy, N-back reaction time, and traditional neuropsychological tests (Delis-Kaplan Executive Function System [D-KEFS] color-word interference and card-sort test) were also assessed.

Principal observations

Children with TLE exhibited executive dysfunction on D-KEFS testing, reduced N-back accuracy, and increased N-back reaction time compared with healthy controls; D-KEFS and N-back behavioral findings were significantly correlated. Children with TLE also exhibited significant reduction in activation of the frontal lobe within the executive control network compared to healthy controls. These alterations were significantly correlated with N-back behavioral findings and D-KEFS testing.

Conclusions

Children with TLE exhibit executive dysfunction, which correlates with executive control network alterations. This lends validity to the theory that the executive control network contributes to working memory function. The findings also indicate that children with TLE have network alterations in nontemporal brain regions.