Of fish and men.

Commentary Dravet syndrome (DS) is a severe pediatric epilepsy that presents with multiple seizure types commonly resistant to pharmacologic treatment, as well as intellectual disability, behavioral abnormalities, gait and motor dysfunction, and increased mortality (1). In most cases, the disease is caused by heterozygous de novo mutations or gene deletions of SCN1A, the gene encoding the pore-forming protein Na v 1.1 of the voltage-gated sodium channel (VGSC) (2). DS is considered an epileptic encephalopathy, meaning that seizures contribute to the progressive worsening of the neurologic condition (1). Unfortunately, most available anticonvulsants are ineffective in controlling the seizures; some anticonvulsants, such as phenytoin, carbamazepine, and lamotrigine, are sodium channel blockers and may worsen seizure control. Among the medications that have shown some efficacy are valproate, clobazam, clonazepam, topiramate, levetiracetam, bromides, and stiripentol (3). The ketogenic diet is also useful and may reduce seizure frequency in up to 75% of patients (4). These treatments are neither fully effective nor curative, however, and thus a need exists for finding better therapies for DS. The search for such new compounds would be greatly aided by the availability of a DS model amenable to high-throughput screening (HTPS). Available models of DS include Scn1a knockout mice (5), mice engineered with a human DS SCN1A mutation (6), and DS patient-induced pluripotent–stem cell (iPSC)-derived neurons (7, 8). While the murine models reproduce many of the behav-ioral and electrographic characteristics of the disease, breeding is often difficult and takes substantial time, seizure phenotypes vary considerably between different mouse genetic backgrounds, and screening techniques are not easily scalable. The DS iPSC model has the advantage of being patient derived and shows in vitro electrophysiological abnormalities, but at present no consensus exists on the best method to monitor responses to pharmacologic treatments in this model. The study by Baraban et al. aims to investigate the feasibility of using zebrafish as an animal model of DS to investigate disease mechanisms and the feasibility of HTPS of pharma-cologic compounds. Given the short breeding times and the possibility of simultaneously monitoring dozens of fish, this is an intriguing idea. The authors take advantage of a previously described mutant fish line carrying a homozygous mutation in the gene Scn1Lab (9), which shares 77% identity with the human SCN1A gene. Because the zebrafish genome underwent a duplication during evolution, the fish have two genes homologous to SCN1A: Scn1Lab and Scn1Laa. Thus, a homozy-gous mutation in one …