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

Five things I learned at the FamilieSCN2a Annual Family and Professional Conference

FamilieSCN2A. On July 14th and 15th, Ingo and I had the pleasure of speaking at the FamilieSCN2a Annual Family and Professional Conference, which was hosted at the DuPont Children’s Hospital in Wilmington, Delaware. This meeting brings together families of children and young adults with SCN2A-related disorders and medical professionals and scientists working in the field, with the purpose of sharing information, learning from one another, and moving the field forward. This post won’t be a comprehensive recap of all that was discussed, since we heard from a broad range of professionals including therapists, electrophysiologists, epidemiologists, neurologists, and geneticists and it would be nearly impossible to sufficiently summarize everything. But I did want to share some of my impressions and thoughts. Here my five things I learned at the FamilieSCN2a Conference. Continue reading

Into the epilepsy phenome

Genome to phenome. Meaningful patterns in human diseases are often only revealed when looking at larger groups of patients. Over the last decade, we have figured out how to make genetics scalable to fit this need. High-throughput genetics can now be performed on an industrial scale with the possibility of assessing almost every base pair in the human genome in thousands of people. Phenotyping, however, has remained a non-scalable task, requiring repeated review, extraction, and interpretation of phenotypic data. In addition, there is no agreed-upon format for phenotypic data that parallels the standards we have in genetics. To overcome this problem, projects such as the Epilepsy Phenome/Genome Project (EPGP) have collected systematic, standardized phenotypic data upfront on every patient. In a recent study in Neurology that analyzed familial clustering of phenotypes within this dataset, we get a first view of what working with the epilepsy phenome may look like. We were asked to provide an editorial for this study where we emphasized that systematic phenotyping in large datasets can reveal phenotypic patterns that are beyond our understanding of disease genetics.  Basically, the phenome suggests patterns that are contradictory to what we think genes would do. Continue reading

DNM1 encephalopathy – a new disease of vesicle fission

Dynamin 1. Our recognition of DNM1 encephalopathy as a novel disease started out as a digital flicker. Deep inside some of the large-scale studies in epilepsy genetics, there were a few patients with de novo mutations in the gene coding for DNM1. However, amongst all the other likely and less likely candidates, it took a while for DNM1 to emerge as a true candidate. But even then, being a disease gene born out of large-scale studies with little information on clinical presentation and disease course, we had learned little about how patients with DNM1 encephalopathy actually present and how they develop over time. In our recent publication in Neurology, we describe the spectrum of DNM1 encephalopathy, including an unusual mutational landscape and the first genetic cause in a patient with FIRES. Continue reading

Three things I learned about focal epilepsies on the Faroe Islands

Focal to genetic. While there was little interest in the genetics of focal epilepsies only five years ago, the field has gained significant momentum since the discovery of DEPDC5 and the subsequent new appreciation of the mTOR pathway. This finding resulted in several gene discoveries and linked traditional genetic epilepsies with the emerging field of somatic mutations. In May 2017, the European epilepsy genetics community met on the Faroe Islands for the international conference on focal epilepsy. Here are the three things that I learned about focal epilepsies on the Faroe Islands. Continue reading

Absence of evidence – where are the recessive epilepsy genes?

E2. When we work up a new-onset epileptic encephalopathy in clinical practice, there is a discrepancy between what we know and what we do. While we know that we have an almost 30% chance to find a causative de novo mutation in any of the known epilepsy genes, we usually think about a possible underlying inherited metabolic disorder when we order our first round of tests. However, the full phenotypic spectrum is often unknown and the question remained how many of these inherited metabolic disorders are missed. In our recent publication of the E2 consortium, we looked for evidence of inherited genetic disorders in patients with epileptic encephalopathies. Follow us on our journey that led to a negative answer, but uncovered a complexity in finding inherited diseases that we did not anticipate. Continue reading

E2 – collaborations and lessons learnt

E2. The advent of next generation sequencing allowed unimagined scope for large scale genetic studies. It quickly became clear that whilst new technologies could be used to solve single families, major advances would only occur by collaboration. This led to the formation of a number of Consortia – in the United States EPGP leading onto Epi4K and in Europe EuroEPINOMICS and EpiRES etc as well as a number of smaller consortia. Even with these multicentre collaborations it was clear that “bigger was better”, and attempts were made to try and synergize efforts across continents.  Continue reading

Understanding the SCN2A mystery – therapeutic responses in a heterogeneous disease

Heterogeneity. The diversity of clinical presentations and responses to anti-epileptic drugs (AEDs) has posed a major obstacle in developing strategies to treat patients with SCN2A-related epilepsies. While the literature provides multiple examples of single case reports with favorable responses to various AEDs, the broad range of disease presentations and known or presumed effects on channel function has made it extremely difficult to extrapolate findings from one patient to another. In a recent publication in Brain, we reviewed the largest cohort of patients with SCN2A-related neurodevelopmental disorders so far, including a subset of patients with detailed phenotypic data over time. With this data, we were able to find support for the hypothesis that age of seizure onset correlates with the functional effect of the mutations and the response to common anti-epileptic medications, taking a first step towards understanding the SCN2A mystery. Continue reading

Ultra-rare genetic variants in familial epilepsies

The final frontier. The last five years have seen enormous progress in understanding the genetic basis of sporadic severe, treatment-resistant epilepsies due to de novo mutations. However, there has been much less progress in understanding the basis of familial epilepsy, which has historically been the major focus of epilepsy genetics. Particularly small families with mild epilepsies are challenging to solve, with the exception of rare families with pathogenic variants in known epilepsy genes. Exome-first approaches in familial epilepsy are particularly challenging given the sheer amount of variants segregating in small families by chance. In a recent publication by the Epi4K Consortium, a novel approach is presented to identify the genetic basis of familial epilepsies, overcoming the limited power of small families by analyzing rare variants in probands in a case/control study design. Here are some fascinating insights from this study. Continue reading

The Focal Epilepsy Conference 2017 – an invitation to the Faroe Islands

Retreat. Part of the Kingdom of Denmark, the Faroe Islands are an archipelago between the Norwegian Sea and the North Atlantic halfway between Norway and Iceland. From May 24 to 26, 2017, the international epilepsy community will retreat to the Faroe Islands for a conference on the mechanisms of focal epilepsies. With this post, I am inviting clinicians and scientists who typically read our blog to this meeting. Take a quick glance at the program and you will understand why I think that this meeting is interesting. In 2017, a conference on the mechanisms of focal epilepsy has become a conference with a main focus on genetic mechanisms. Here is how our perception of the genetics of focal epilepsies changed over the last 18 years and why a trip to the middle of the North Atlantic may be worthwhile for you. Continue reading