Glut1 deficiency and Myoclonic Astatic Epilepsy – reassessed

Ketogenic. Several patients with Myoclonic Astatic Epilepsy (MAE) have a surprisingly positive response to the ketogenic diet, even after failing several antiepileptic medications. Given this observation, it is obvious to assume that SCL2A1 mutations play a significant role in MAE, and some earlier studies seemed to suggest that up to 5% of MAE patients carry SLC2A1 mutations. However, in a recent study, we failed to demonstrate a connection between SLC2A1 mutations and Myoclonic Astatic Epilepsy (MAE) in a large cohort of patients. Read more on why the genetics of MAE is an ongoing mystery and why we need a new approach to “keto-genetics”. Continue reading

CHD2 myoclonic encephalopathy – delineating a novel disease

CHD2. In 2013, mutations in CHD2 were reported in various publications including two major studies on epileptic encephalopathies, reinforcing the notion that de novo mutations in this gene are a recurrent cause of epileptic encephalopathies. However, large-scale studies often cannot fully appreciate the complete phenotype of the patient behind the gene finding. Therefore, it is difficult to appreciate similarities between patients and assess whether phenotypes constitute a recognizable entity. In a recent publication in Neurology, the phenotype of CHD2 encephalopathy is explored in detail – it represents a distinct, recognizable disease entity. Continue reading

Heat at the synapse – STX1B mutations in fever-associated epilepsies

Febrile Seizures. The discovery of the genes for fever-associated epilepsies was one of the most relevant milestones in epilepsy genetics. Discovery of the underlying genes including SCN1A, SCN1B and GABRG2 was tightly linked to the development of the Genetic/Generalized Epilepsy with Febrile Seizures Plus (GEFS+) concept, describing the spectrum of epilepsy phenotypes seen in families with these mutations. Gene discovery in GEFS+, however, has slowed down in recent years, and no further causative genes had been identified for more than a decade. Now, in a recent paper in Nature Genetics, mutations in STX1B are found as a novel cause for fever-associated epilepsies. 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