Heterozygous Mutation in the KCNMA1 Gene with “Loss of Function” Phenotype in a Patient with Generalized Epilepsy
Background: The KCNMA1 gene encodes the BK channels pore forming α subunit. BK channels (Big Kalium) are potassium channels characterized by their large conductance of potassium ions. These channels are activated by changes in membrane potential and by increase in the concentration of intracellular calcium ions. BK channels play a pivotal role in the regulation of membrane potential. Mutations in the KCNMA1 gene cause generalized epilepsy and/or paroxysmal dyskinesia in an autosomal dominant pedigree pattern (GEPD, OMIM #609446). In all cases, a “gain of function” effect was reported. It is suggested that BK channel blocking agents might be used in the therapy for GEPD: Ethosuximide inhibits neuronal BK channels in addition to its primary effect of blocking t-type calcium channels.
Case Report: We report the case of a 4-year-old girl suffering from dialeptic and myoclonic seizures starting at the age of 2 years. The development was slightly retarded. The electroencephalography (EEG) was characterized by generalized spike wave activity, the cerebral MRI scan was normal. A molecular genetic panel analysis revealed a most probably pathogenic novel heterozygous mutation in the KCNMA1 gene (c.2984A > G; p.N995S exon 25). We treated our patient with ethosuximide, which resulted in a strong aggravation of seizure frequency. We presumed that in our patient a so far novel “loss-of-function” phenotype was identified. Therefore, we treated the girl with zonisamide. Zonisamide activates BK channels in addition to other mechanisms and contributes to enhanced activity of BK channels by increasing mean opened time. The myoclonic seizures deceased immediately; the frequency of dialeptic seizures was declining. Full freedom from seizures could not be reached yet.
Discussion: To our knowledge, this is the first case report to demonstrate that loss of function mutation in the KCNMA1 gene leads to generalized epilepsy and may be treated with zonisamide to activate BK channels. Electrophysiological analyses of the mutated channel are needed to verify this hypothesis.
Keywords: epilepsy, KCNMA1, BK-Channel, ethosuxumide, zonisamide.