Heat at the synapse revisited. STX1B encodes syntaxin 1B, one of three proteins – along with SNAP25 and synaptobrevin – that form the SNARE complex. The SNARE complex is part of the protein machinery responsible for Ca2+-dependent fusion of the presynaptic neuronal cell membrane with the synaptic vesicle to enable neurotransmitter exocytosis. STXBP1 also plays an important role in this process, as the syntaxin binding protein encoded by STXBP1 interacts with the SNARE complex via binding to syntaxin. While pathogenic variants in STXBP1 are a well-established cause of early-onset epilepsies and related neurodevelopmental disorders, after the initial description of STX1B-related epilepsies in 2014, very little more was heard regarding STX1B in the intervening four years. Now, we contributed patients to a publication in Neurology, which provides an update regarding the clinical and genetic landscape of STX1B-related epilepsies. Continue reading
Computational phenotypes. Clinical epilepsy research requires the capturing of complex information in a way that then can be subjected to statistical analysis. For the analysis on the phenotype level, new standards are emerging that are heavily informed by genetic studies. In fact, in addition to the known domain-specific classifications such as the ILAE classification for epilepsy, interdisciplinary action is often required to improve the classification of neurological syndromes for a larger analysis. During the upcoming EMBO Practical phenotyping course in Luxembourg, we will introduce trainees in the field to concepts like the Human Phenotype Ontology (HPO), a controlled vocabulary to characterize syndromes and one of pillars of research in complex syndromes such as epilepsy and how to address aspects not covered in HPO. The course will be held in Luxembourg from Oct 4 to Oct 10, 2018. There has already been a strong interest in this course, but we have a few spots left if you would like to register!
Somatic mosaicism in focal epilepsy. Recent findings highlighted the role of somatic parental mosaicism in epileptic encephalopathies. However, somatic mosaicism has also emerged over the last few years as a prominent mechanism in the pathogenesis of lesional focal epilepsies, including focal cortical dysplasia (FCD) type 2 and hemimegalencephaly. Previous studies have identified the role of mosaicism of genes such as MTOR, TSC1/TSC2, and genes encoding components of the PI3K/AKT pathway in patients with epilepsy secondary to brain malformations. A recent study in Annals of Neurology has identified a new unrelated genetic cause of refractory non-lesional focal epilepsy, which leads us to wonder what role mosaicism may be playing in focal epilepsies without obvious findings on MRI.
Epilepsy gene panel. Testing for genetic causes in human epilepsy is typically performed using gene panels. In contrast to our research-based exome studies in an academic setting, much of the gene panel testing is performed through commercial laboratories and much of the existing data is usually inaccessible to the scientific community. In a recent publication in Epilepsia, a large US-based diagnostic laboratory reports on some of their existing data on epilepsy gene panels by reporting the results of more than 8500 epilepsy gene panels – a cohort size that is more than five times larger than any prior exome or gene panel study in the epilepsy field. I was asked to write an editorial on this publication, and I also wanted summarize on our blog three key messages that you can take away from this study. Continue reading
Psychosocial implications of uncertainty. As navigators of genetic testing, genetic counselors have seen it all – smooth seas, choppy waters and even the rare tsunami. Genetic testing sounds, well, so promising. Huge gene panels for epilepsy, whole exome sequencing – guaranteed to find an answer, right? Wrong. And let’s not even talk about secondary (incidental) findings, variants of uncertain significance and (gulp) non-paternity. While our technology has changed, navigating the choppy waters of psychosocial issues in genetic testing has not. Previous EpiGC posts to this blog have highlighted the challenges inherent to interpreting variants of uncertain significance. Now let’s talk about the psychosocial implications of dealing with uncertainty.
Key components. There are many factors for patients to consider when deciding whether to undergo genetic testing for epilepsy. Perceptions regarding the benefits and drawbacks can vary from one patient to another, and only the patient can determine whether the benefits of testing outweigh the drawbacks in their specific situation. Testing that seems straightforward to a clinician may not be so for a patient. As such, the process of informed consent is crucial to avoid harm and disappointment. Continue reading
Rett. We have written very little about MECP2 on Beyond the Ion Channel. MECP2 is the gene for Rett Syndrome, a neurodegenerative disorder almost exclusively affecting females. Classical Rett Syndrome is characterized by developmental regression in the first two years of life and the development of distinctive hand movements, which historically led to Rett Syndrome being considered a recognizable entity. This blog post is the introduction to our MECP2 Epilepsiome page. However, in 2016, a time when many genes are re-defined by exome studies, I was wondering whether Rett Syndrome is still the classical syndrome that I initially learned about.
The Wild West. The diagnostic genetic testing landscape in 2016 is a paradox. In theory genetic testing has never been more widely available clinically, with over 20 diagnostic laboratories in the US alone offering a variety of genetic testing options for patients with epilepsy, ranging from single gene testing to NGS panels to whole exome sequencing. However, access to and reimbursement of genetic services varies widely, with no consensus on an approach to testing or professional guidelines to aide clinicians. Here is our brief guide to epilepsy genetic test selection for busy clinicians. Continue reading
Inhibition. GABA is the main inhibitory neurotransmitter in the the Central Nervous System. Given that epilepsy is typically associated with increased excitability, all mechanisms related to GABA signaling are of natural interest to the epilepsy community. Almost 15 years ago, mutations in GABRA1, coding for alpha-1 subunit of the GABA-A receptor, have been identified in familial Juvenile Myoclonic Epilepsy, but there has been relative silence around this gene since. Now, two publications highlight the other side of GABRA1 as a gene for epileptic encephalopathies, putting the GABA receptor into the spotlight again.
The story of SCN1A. Variants in SCN1A were first reported in association with epilepsy in 2000, when familial heterozygous SCN1A missense variants were identified in two large families with GEFS+. The phenotype was characterized by incomplete penetrance and significant variable expressivity between family members, making it clear from the beginning that the SCN1A story would not be simple. Within the next few years, we learned that SCN1A variants could cause a wide spectrum of epilepsy phenotypes, including GEFS+, Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures, and, less frequently, infantile spasms and simple febrile seizures. As it became clear that SCN1A variants played an important role in genetic epilepsies, focus turned towards understanding the mechanism underlying seizure genesis, as well as identifying management and therapy options. Even after 15 years of study, our understanding of SCN1A-related epilepsy is still evolving. Keep reading to learn more about the most recent discoveries related to SCN1A. Continue reading