Dynamin 1. De novo mutations in DNM1 coding for Dynamin 1 are increasingly recognized as a cause for epileptic encephalopathies. However, given the role of Dynamin 1 in endocytosis in a large number of cells, the precise mechanisms how mutations may result in seizures are poorly understood. Now two recent publications in PLOS Genetics and Neurology Genetics explore the functional effects of epilepsy-related DNM1 mutations. The publication of both manuscripts is also a timely reminder to announce our international DNM1 study group that has the aim to better understand the phenotype of this disease. Continue reading
Doose Syndrome. In the early 1970s, a group of children with severe childhood epilepsies was found to have comparable clinical features that consisted of quick jerks and subsequent drop attacks amongst other types of epileptic seizures. These seizures, myoclonic-astatic or myoclonic-atonic seizures, eventually became the defining feature of an epilepsy syndrome referred to as Myoclonic Astatic Epilepsy or Doose Syndrome. In the recent issue of the American Journal of Human Genetics, we report on the first true gene for Doose Syndrome. Here is the story of SLC6A1 (GAT-1). Continue reading
Update. As information on the epilepsies caused by SCN1A mutations are amongst our most frequently read posts, we thought that a quick update on the state-of-the art regarding SCN1A would be timely. These are the ten things about SCN1A that you should known in 2014. Continue reading
The other sodium channel gene. The week before Christmas, the Kiel group identified its first patient with SCN2A encephalopathy. At the same time, a questionably benign SNP in the same gene is haunting our Israel Epilepsy Family Project. Time to review the mysterious SCN2A gene that initially entered the scene as a candidate for a rare, benign familial epilepsy syndrome – only to return as one of the most prominent genes for autism, intellectual disability, and epileptic encephalopathies to date. Continue reading
Joining forces. The EuroEPINOMICS-RES consortium and Epi4K/EPGP are currently joining forces for genetic studies on epileptic encephalopathies. A first collaborative study focuses on de novo mutations in Infantile Spasms and Lennox-Gastaut-Syndrome. In the last two years, after decades of disappointment, we have finally managed to accomplish a breakthrough in understanding the genetic basis of epileptic encephalopathies. The method of trio-based exome sequencing works amazingly well to identify the genetic cause, and the field currently has the crucial momentum to reach the next level of research. Let’s briefly review why we need international collaborations to disentangle the genetic architecture of the epileptic encephalopathies. Continue reading
The de novo paradigm. De novo mutations play a significant role in many neurodevelopmental disorders including autism, intellectual disability and schizophrenia. In addition, several smaller studies have indicated a role for de novo mutations in severe epilepsies. However, unless known genes for human epilepsies are involved, findings from large-scale genetic studies are difficult to interpret. De novo mutations are also seen in unaffected individuals and only very few genes are observed more than once. Now, a publication in Nature by the Epi4K and EPGP collaborators uses a novel framework to tell pathogenic mutations from genomic noise. Their study provides very strong evidence for a predominant role of de novo mutations in Infantile Spasms and Lennox-Gastaut Syndrome. Continue reading
Quantum leap. At the Annual Meeting of the American Epilepsy Society, the Epi4K consortium presented the first data on exome sequencing in epileptic encephalopathies. This data is the most exciting finding in the field of epilepsy genetics in 2012 so far, as it provides a deep insight into the genetic architecture of Infantile Spasms (IS) and Lennox-Gastaut Syndrome (LGS). With the findings presented by the Epi4K collaborators, the epileptic encephalopathies are joining a group of neurodevelopmental disorders with a significant burden of de novo mutations. However, there are important differences that set both IS and LGS apart from diseases like autism, intellectual disability and schizophrenia. Continue reading
Taking the gloves off. Historically, epilepsy is called the falling sickness because of episodes when patients suddenly crash to the ground and lose their posture. These seizures are called atonic or astatic seizures and are often the most troubling events for patients. During these events, patients may seriously hurt themselves. From the epileptological point of view, there is a long debate regarding the nature of these events. Are they purely due to loss of posture or are they associated with a brief myoclonic seizure? Lennox quotes Pierce Clark who states bluntly that describing an astatic seizure without a preceding jerk is due to “faulty clinical observation”. This is when Lennox takes the gloves off.