KCNQ2 Potassium Channel Epileptic Encephalopathy Syndrome: Divorce of an Electro-Mechanical Couple?

Commentary The potassium channels expressed from the KCNQ genes are standouts for epileptologists, in that they are both mutated in human epilepsy and principal targets of an approved antiepileptic drug (ezogabine/retigabine) (1, 2). Mutations in two closely related subunits, KCNQ2 or KCNQ3, cause benign familial neonatal seizures (BFNS), an autosomal dominant syndrome characterized by seizures in the first weeks or months of life that remit and are followed by normal motor and cognitive development. Weckhuysen et al. now extend the KCNQ2 phenotypic spectrum, describing a set of seven novel mutations in eight patients with persistent epilepsy and psychomotor disability. The initial clinical presentation of KCNQ2 encephalopa-thy is instantly recognizable as akin to two severe neonatal epileptic encephalopathies, Early Myoclonic Encephalopathy (EME) and Ohtahara syndrome, which are characterized by tonic and myoclonic seizures with EEG burst suppression and onset within the first week of life (3). Patients with EME and Ohtahara syndrome typically undergo exhaustive evaluation for metabolic or structural etiologies. Treatment-resistant seizures usually continue throughout an evolution to other severe age-dependent encephalopathies such as West and Lennox-Gastaut syndromes. In contrast, the patients of Weck-huysen et al. largely became seizure-free (under anticonvul-sant treatment), after approximately 1 to 3 years but exhibited persistent cognitive and motor impairment. The EEG evolved to multifocal epileptiform discharges within weeks to months and was normal in four patients at the last follow-up test. The evidence that the new mutations are pathogenic in this novel syndrome is strong but would be enhanced through description of more patients and functional studies of the mutations. Even without such additional work, however, earlier studies suggest testable, potentially complementary, explanations why these mutations might cause severe phenotypes. Each of these hypotheses invokes a pathogenic " divorce " of components that are tightly coupled in the healthy state. The first such obligatory linkages are found within each KCNQ2 subunit protein. All voltage-gated channels are equipped to (1) sense the membrane potential, (2) open and close their pore in response to membrane voltage changes, and (3) selectively allow ions to pass. The connection between membrane voltage-sensing and the pore's gates is termed OBJECTIVE: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause …