Finding the missing sodium channel – SCN3A in epileptic encephalopathy

Sodium channel. Voltage-gated channels for sodium ions are a crucial component of helping neurons depolarize and repolarize in a way that enables generation of action potentials. However, in order to function properly, voltage-gated ion channels co-exist in a fragile balance, and genetic alterations leading to functional changes in these channels are known causes of disease. SCN1A, SCN2A, and SCN8A have been implicated as causes for human epilepsy. However, SCN3A encoding the Nav1.3 channel, one of the most obvious candidates, could not be linked to disease so far. In a recent publication, we were able identify disease-causing mutations in this major neuronal ion channel. Interestingly, patients with an early onset and the most severe presentation had a prominent gain-of-function effect that responded to known antiepileptic medications. Continue reading

SLC6A1 – a generalized epilepsy phenotype emerging

GAT1. When we first identified SLC6A1 in 2015, we were surprised that a significant proportion of patients with disease-causing variants in this gene had a rare epilepsy phenotype referred to as Myoclonic Astatic Epilepsy (MAE). Typically, at the time of gene discovery, it is often unclear how far the phenotypic spectrum expands. In a recent publication in Epilepsia, we reviewed the phenotype of 34 patients with SCL6A1-related epilepsy. Surprisingly, in contrast to many other epilepsy genes that showed a broad and occasionally non-specific phenotypic range, the SLC6A1-related phenotype expands beyond MAE, but remains centered around generalized epilepsies with a predominance of absence seizures and atonic seizures. It is a gene that has started to write its own story. Continue reading

Epilepsy genetics in 2018 – Three things that will happen and three things that won’t

Bomb Cyclone. While the entire US East Cost was held hostage by a weather system that introduced us to new catchy meterological concepts such as bombogenesis, I hope that everybody is staying warm and safe. I wanted to wish all our readers a Happy 2018 and try to give an outlook of the New Year in epilepsy genetics.  Here are three things in epilepsy genetics that will happen in 2018 – and three things that won’t. Continue reading

AES 2017 – Making Sense of Genetic Data in Epilepsy

Controversies. While you are packing your bags for the 71st Annual Meeting of the American Epilepsy Society in Washington, D.C., we wanted to point out one agenda item that may be of interest for you. The AES agenda typically has many parallel sessions, so I wanted to make a plug for our Genetics Special Interest Group (SIG) on Friday, 12/1 at 1:30PM. The topic of our SIG is going to be “Making Sense of Genetic Data in Epilepsy – Consensus and Controversy in 2017”. In contrast to regular sessions and lectures, a SIG is meant to stimulate discussion between SIG members. Therefore, in parallel to previous years, we would like to invite the attendees to use the opportunity to discuss challenging cases within a dedicated AES Special Interest Group. Continue reading

Guardians of the epilepsy genes

Epilepsiome, meet ClinGen. For more than a year, I have meant to write about the extension of the Epilepsiome effort to our ClinGen epilepsy working group. The overall ClinGen framework is a NIH-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. Within this framework, the ClinGen Epilepsy Working group is a group of curators to apply the formal framework to epilepsy genes. Given the explosion of genetic data, curating epilepsy genes is important as a basis for precision medicine and long overdue. Within our epilepsy working group, we build upon the ClinGen framework to make it applicable to epilepsy genes. Here is what you need to know about epilepsy gene curation.

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Mysteries of the cytoskeleton – SPTAN1 in epileptic encephalopathies

Neuronal spectrinopathies. Spectrins are a major component of the neuronal cytoskeleton, the scaffold underneath the cell membrane that gives cells their characteristic shape and anchors transmembrane proteins such as voltage-gated ion channels. SPTAN1, the gene coding for the non-erythrocyte alpha-II spectrin, has been known as a rare cause of early-onset epileptic encephalopathies with hypomyelination and atrophy. However, the full phenotypic spectrum and the range of pathogenic variants was unknown. In a recent publication in Brain, 20 patients with pathogenic variants in SPTAN1 are reported, expanding the known range of phenotypes and suggesting a very unusual disease mechanism through in-frame deletions or duplications. Here is what links the neuronal cytoskeleton to epileptic encephalopathies. 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