SCN1A-related epileptic encephalopathy: Beyond Dravet syndrome

SCN1A phenotypes. Readers of Beyond the Ion Channel will know that we often post about SCN1A, one of the first discovered and most common genetic causes of epileptic encephalopathy. We more or less assume that we understand the phenotypes associated with pathogenic variants in SCN1A: most commonly Dravet syndrome, which is associated with de novo variants, and less commonly genetic epilepsy with febrile seizures plus (GEFS+), associated with inherited missense variants. However, a recent publication by Sadleir and colleagues suggests that the phenotypic spectrum of SCN1A-related disorders may be broader than we have previously appreciated. Are there SCN1A-related epileptic encephalopathies in addition to Dravet syndrome? Continue reading

SCN1A – what’s new in 2016?

The story of SCN1A. Variants in SCN1A were first reported in association with epilepsy in 2000, when familial heterozygous SCN1A missense variants were identified in two large families with GEFS+. The phenotype was characterized by incomplete penetrance and significant variable expressivity between family members, making it clear from the beginning that the SCN1A story would not be simple. Within the next few years, we learned that SCN1A variants could cause a wide spectrum of epilepsy phenotypes, including GEFS+, Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures, and, less frequently, infantile spasms and simple febrile seizures. As it became clear that SCN1A variants played an important role in genetic epilepsies, focus turned towards understanding the mechanism underlying seizure genesis, as well as identifying management and therapy options. Even after 15 years of study, our understanding of SCN1A-related epilepsy is still evolving. Keep reading to learn more about the most recent discoveries related to SCN1A. Continue reading

The story of the missed SCN1A mutations

Dravet Syndrome. In 2011, our EuroEPINOMICS-RES program was in full swing. We had recruited a cohort of 31 patients with Dravet Syndrome who had been previously tested negative for mutations in SCN1A with the aim to identify novel genes for this epileptic encephalopathy. Even though this cohort was crucial in our identification of CHD2, HCN1, and KCNA2 as novel genes for genetic epilepsies, the main finding in this cohort was something that we did not expect. Roughly one third of our 31 patients had mutations in SCN1A, even though they had previously been tested negative. In a recent publication in Molecular Genetics and Genomic Medicine, we tried to understand what had happened and joined forces with other groups who had made the same observation. Here is the story of the missed SCN1A mutations. Continue reading

The three twists in the SCN1A story that you didn’t know about

SCN1A. Finally, after various other epilepsy genes have been added, we are trying to put together a static website on SCN1A rather than updates only. SCN1A is by far the most prominent epilepsy gene and the first genetic etiology that comes to mind for anything relating to fever and seizures. While our Epilepsiome page will give you all the relevant facts regarding this gene, here is my personal view on the SCN1A story. Continue reading