GABRA1 and STXBP1 as novel genes for Dravet Syndrome

Beyond SCN1A. Dravet Syndrome is a severe fever-associated epileptic encephalopathy. While the large majority of patients with Dravet Syndrome carry mutations in the SCN1A gene, the genetic basis is unknown in up to 20% of patients. Some female patients with Dravet-like epilepsies have mutations in PCDH19, but other than this, no additional major gene for typical Dravet Syndrome is known. In a recent paper in Neurology, de novo mutations in GABRA1 and STXBP1 are identified as novel causes for Dravet Syndrome. In addition, several SCN1A-negative patients were shown to have mutations in SCN1A that were initially missed. Continue reading

CHD2 encephalopathy as a novel Dravet-like epilepsy syndrome

Negative for SCN1A. Today the first major paper by the EuroEPINOMICS-RES consortium was published in the American Journal of Human Genetics online. As you might recall from some of our previous posts, RES has worked on gene identification in patients with Dravet Syndrome negative for SCN1A using trio exome sequencing. A significant fraction of patients turned out to be positive for SCN1A with mutations initially missed using conventional sequencing techniques. However, there was also a second gene that we discovered in an initial cohort of patients with SCN1A-negative Dravet Syndrome. This gene was CHD2.  While working on the functional studies in zebrafish, CHD2 was also discovered as a novel gene for epileptic encephalopathies by both Carvill and collaborators and the Epi4K consortium. These parallel discoveries clearly highlight the relevance of this gene in human epilepsy and suggest that CHD2 mutations might be more common than mutations in many of the other candidate genes discovered in the last 12 months. In addition, when looking closer, the phenotype of the patients was not exactly Dravet Syndrome, but might represent a novel fever-related epileptic encephalopathy. Continue reading

Guilt by association: SCN1A in Temporal Lobe Epilepsy

GWAS. Genome-wide association studies investigate the association of common genetic variants with disease in large patient samples. While this approach has been very successful in many other diseases, the results in epilepsy research have been less convincing. Given the complexity of epilepsy phenotypes, selection of the right epilepsy phenotype has been an ongoing debate. Now, a recent study in Brain finds an intronic variant of the SCN1A gene that is associated with Temporal Lobe Epilepsy (TLE), the most common epilepsy in man. Interestingly, the association with SCN1A seems to be specific for only a particular subtype of focal epilepsies. Continue reading

The endozepine mystery

Compound unknown. GABA is the main inhibitory neurotransmitter in the Central Nervous System and its effect is mediated through GABA receptors. Benzodiazepines are compounds that reinforce the action of GABA in the brain, which gives them antiepileptic properties. Consequently, benzodiazepines are one of the most common groups of antiepileptic drugs used to interrupt acute epileptic seizures. Interestingly, benzodiazepines have their own binding site on the GABA receptor, suggesting that they might actually mimic the effect of another, yet unknown substance that is present in the brain. The identity of this mysterious substance, the endogenous benzodiazepine or endozepine, has been one the romantic mysteries of neuroscience. Now, a recent paper in Neuron provides strong evidence that products of the DBI gene are the long-sought endozepine. Continue reading

Traveling with Lennox – on my way to the Old New Land

On the road. For this week, the Channelopathist will be a travel blog. I am on my way to Israel where we will be busy recruiting and phenotyping epilepsy families for the EuroEPINOMICS project for the next seven days. This trip abroad gives me the opportunity to do something that I have been thinking about for quite some time: reading “Epilepsy and Related Disorders” by William G. Lennox, one of the pioneers of epilepsy genetics. I will try to put some thoughts on Lennox into words this week while spending my time down here in Israel. Continue reading