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

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

ARX – a 2017 Update

Aristaless. When you look at the genes for neurodevelopmental disorders identified in modern-day exome studies, one gene is notably absent: ARX. The X-chromosomal aristaless related homeobox gene was one of the first genes for epilepsies and brain malformations to be discovered. Pathogenic variants in ARX can be identified in male patients with a variety of neurodevelopmental disorders including idiopathic West Syndrome – accordingly, ARX is on the differential list for patients with intractable infantile spasms without a known cause. One of the reasons why we hear so little about ARX is the fact that this gene is poorly covered in exomes. Furthermore, one of the major disease-causing variants is a repeat expansion that cannot be assessed through exome studies at all. Here is a brief summary of what we know about ARX in 2017. Continue reading

Scientific mistakes and the Book of Kells

Dublin. In September 2016, my way back from the ECE in Prague led through Dublin where I was able to spend two days, following an invitation by the Science Foundation Ireland. Given that there was a gap between the Prague congress and the day that I was supposed to be on-site, I arrived in Ireland early and spent 24h in Dublin. When I took a stroll into the city, I ended up in Trinity College and the exhibition about the Book of Kells, a 1200 year-old manuscript containing the Four Gospels of the New Testament. One part of the exhibition raised my interest, as it discussed the way that eighth century Irish scribes dealt with mistakes – I thought that this historical view would be an interesting introduction to review how we deal with scientific mistakes today. Continue reading

Pushing the boundary – 27 novel epilepsy genes in the 2017 DDD study

DDD. On January 25, the most recent publication of the Deciphering Developmental Disorders (DDD) study appeared online in Nature. This unprecedented study analyzed the data of 4,293 patient-parent trios with existing data from 3,287 published trios to identify de novo mutations in neurodevelopmental disorders. A study of this size has many aspects that are difficult to fully cover within the limited space of a journal article. Browsing through the data is interesting and will be the foundation for many studies utilizing this data in the near future. Within this first comprehensive blog post of 2017, I try to answer the question what this study means for the field of epilepsy genetics. For example, it provides us with more than 20 epilepsy genes that we did not know about so far. Continue reading

GABRB3 – from febrile seizures to epileptic encephalopathies

Beta-3. Even though the gene for the beta-3 subunit of the GABA-A receptor (GABRB3) has not been mentioned frequently in the context of epilepsy genes, it is a gene that is frequently involved in genetic changed that give rise to epilepsy. Given that GABRB3 is one of the genes found within copy number changes on chromosome 15, it may predispose to human epilepsies through various genetic mechanisms including copy number variations and de novo mutations. In a recent publication in Neurology, we reviewed the phenotypes of patients with GABRB3 variants and found an unusual complexity of sporadic and familial cases. Here are three things that I have learned about GABRB3. Continue reading

The Cavatica experience – running epilepsy exomes in the cloud

End of the year. The final weeks of the year are always a time when my curiosity for bioinformatics takes over. Four years ago, I was trying to teach myself sufficient command line and bioinformatics to run Denovogear on my computer. Now the field has moved on, from command line language to solutions that aim at bringing data closer to researchers. I hijacked a platform that was initially built for cancer research, CHOP’s Cavatica platform that was developed with Seven Bridges Genomics. In the same way as a few years ago, I started out with a simple question: Can I take an exome completely apart and then re-analyze it to find the SCN1A mutation in DRA1? Continue reading