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The Expanding SCN8A-Related Epilepsy Phenotype

Commentary Larsen, Carvill, and colleagues report a spectrum of epileptic encephalopathy phenotypes associated with the gene SCN8A, relatively recently identified in the epilepsy genetics literature as a gene responsible for epilepsy and intellectual disability. As with many newly emerging genes associated with epilepsy and epileptic encephalopathy, the SCN8A spectrum is quite broad and still expanding. Since initial reports often reflect the most severe cases of epilepsy associated with a new gene, it is difficult to predict the full range of this spectrum. Thus, there is great value in the detailed characterization of cases from wellcurated cohorts of patients with epilepsy. Even though it is not a population study, the fact that the seven cases they report derive from an impressive cohort of 683 individuals with epileptic encephalopathy reflects the role of SCN8A as one of many important genes for early-onset epilepsy. To those outside the field, this 1% may not seem substantial, but epilepsy—even epileptic encephalopathy—is genetically heterogeneous, with a multitude of genetic causes collectively accounting for the growing list of epileptic encephalopathies with identifiable genetic etiology (1–4). To add to the phenotypic characterization of SCN8A encephalopathy, the authors also included ten additional cases referred for this study. The work thus represents the collaborative strength of some of the major groups who have been devoting their careers to epilepsy genetics. One feature of the genetics of SCN8A encephalopathy worth noting is that, as with other epilepsy genes and their mutations, the types and locations of SCN8A mutations are varied. The authors outline very reasonable criteria for their assumptions of pathogenicity for each case. Clinical neurologists should take heed that the mere mention of a variant in a gene associated with epilepsy does not necessarily mean that that gene is the cause of a patient’s epilepsy. The majority of the mutations are missense variants predicted to be pathogenic, including an apparent mutation hotspot at amino-acid position 1872 (more detail is available in a subsequent review by Wagnon and Meisler [5]). While there is already some functional evidence for gain of channel function and resultant neuronal hyperexcitability for some previously described mutations, additional functional work on some of the mutations is needed and can be correlated with the clinical data presented by these authors. The phenotypes of the 17 patients considered to have mutations in SCN8A are quite variable. While many began The Phenotypic Spectrum of SCN8A Encephalopathy.