HCN1 Gain-Of-Function Mutations - A New Cause of Epileptic Encephalopathy.

Commentary Early infantile epileptic encephalopathy (EIEE) refers to severe early onset epilepsy with associated neurodevelopmental abnormalities. The term was used initially to reflect EIEE with suppression-burst pattern on EEG, or Ohtahara syndrome, but it has been applied more widely to a larger and growing group of epileptic encephalopathies; patients with mutations in the EIEE genes display a range of epilepsy syndrome phenotypes , including infantile spasms, Lennox-Gastaut syndrome, Dravet syndrome, and migrating partial seizures of infancy. The formally designated EIEE genes in the Online Mendelian Inheritance in Man (OMIM) database now number 25, and many additional genes involved in severe early onset epilepsy have been identified in the era of next-generation sequencing (1–3). One such gene is HCN1 (EIEE25), encoding the hyperpo-lalization-activated, cyclic nucleotide-gated (HCN) channel (4). A group of four HCN channels mediates a cationic current (Ih). HCN channels possess an inherent negative feedback property – hyperpolarization activates HCN channels, whereas depo-larization deactivates them. The net effect of HCN channel activation is a decrease in membrane input resistance. Therefore , Ih tends to stabilize the neuronal membrane potential toward resting potential. HCN1 has been localized to neuronal dendrites, where it plays a major role in membrane potential stabilization (4). Thus, HCN channels might be expected to play a role in epilepsy (5). Nava and colleagues identify a novel gene for early onset epilepsy using a logical approach to patients with a known epilepsy syndrome. Their initial cohort of 39 cases was described as having many of the core features of Dravet syndrome, characterized by epilepsy with onset in infancy, an association of fever as a seizure trigger, a combination of seizure types typically involving GTCs and myoclonic seizures but also other generalized and sometimes focal seizure types, intractability, and intellectual impairment. The majority of patients with classic features of Dravet syndrome have mutations in the SCN1A gene that encodes the alpha subunit of the voltage-gated sodium channel (6). In girls with Dravet syndrome who do not have mutations (sequence changes or deletions), the current genetic differential diagnosis includes PCDH19, a gene that encodes proto-cadherin 19 and is associated with epilepsy in females with intellectual impairment (7). These two genes were evaluated in the first 39 cases using a clinical syndrome-guided approach to genetic diagnosis. When the results were negative, the authors performed whole exome sequencing of their cohort using a now well-established " trio " approach (2). Two cases …