Families. We tend to think that we understand familial epilepsy. The mental image is almost fixed: large pedigrees, clean inheritance, recognizable syndromes, and genes that segregate exactly as expected. But in a recent study from our epilepsy genetics program, we looked at something different. Not discovery cohorts and carefully selected multiplex families, but real-world genetic testing in 484 consecutive families. All families were evaluated in routine clinical care through ENGIN, our Epilepsy Neurogenetics Initiative, which has now evaluated more than 7,000 individuals with epilepsy and related disorders. The result was a picture of familial epilepsy that is both reassuring and unexpectedly complicated. Here is what we found. Continue reading
Category Archives: Updates
Decoding CACNA1A: How Function Shapes Phenotypes
Cav2.1. Among the various neurogenetic disorders that we follow in our clinic, CACNA1A-related disorders are somewhat unique. Even though these conditions have been known for several decades, our understanding has remained fragmented, and the functional effect of most missense variants is still not well understood. In a recent study, we contributed to a comprehensive functional assessment of 42 missense variants in CACNA1A, approaching the problem in a structured, top-down manner. Here are the main findings from our study.
Glymphatic System, Mirror Neurons, and Other Stories We Tell Ourselves
Glymphatic. I stumbled over the term glymphatic system last week and briefly had to pause. The concept is now widely used and feels intuitive, but it did not exist when I was in medical school. The term was only introduced in 2012 to describe a glia-dependent, perivascular clearance pathway in the brain. And yet, everything it refers to, including perivascular spaces, astrocyte endfeet, cerebrospinal fluid flow, interstitial clearance, was already in the textbooks. All the parts were familiar to me, but the label was new. That moment of confusion stayed with me: neuroscience moves forward not just through data, but also through names.
RBFOX3 and the hunt for epilepsy genes in 100,000 genomes
Large scale. Novel epilepsy genes are typically discovered through collaborative studies that combine information across various centers and research groups. However, there are also large-scale sequencing initiatives on a national level that include individuals with epilepsy. In a recent study published in Nature, a wide range of clinical phenotypes were assessed in an initial cohort of 34,000 individuals in the UK 100,000 Genomes Project. Let me dive into the associations related to epilepsy in this publication.
Out of sync – HCN2, epilepsy, and the h-current current
Funny current. Neuronal firing patterns rely on the coordinated interplay of ion channels, mediating different aspects of how neurons fire and repolarize. In the early 70s, a strange phenomenon was observed: an ion current that became active when it shouldn’t. Subsequently named the h-current or funny current, it activates when neurons are at their resting potential, pulling them away from their resting membrane potential and helping with pace-making. HCN channels are the molecular equivalents of the h-current. In a recent publication, Houdayer and collaborators explore the phenotypic consequences of mutations in HCN2, one of the key components mediating the neuronal h-current. Here is a brief summary of the unusual clinical spectrum associated with variants in HCN2.
Understanding the SCN8A fingerprint through real-world data
Nav1.6. It has been several years since I last wrote a blog post about SCN8A. A wide range of clinical presentations have been described since, and significant progress has been made towards understanding the disease mechanism. However, SCN8A-related disorders have not become less puzzling. In a recent publication, we tried to understand whether SCN8A-related disorders have a unique clinical profile by harmonizing the electronic medical record data of 82 individuals across more than 600 patient years. Here is what we found.
Takeaways from the 2024 Dravet Syndrome Foundation Biennial Family and Professional Conference
DSF. This June, our team attended the Biennial Family and Professional Conference held by the Dravet Syndrome Foundation (DSF). Over three days in Minneapolis, research findings and therapeutic advances were discussed, and families shared their stories. As a first-time attendee, it was a humbling experience to be invited into this tight-knit, motivated, and inspiring community. Here, I would like to share some of the lessons I learned while in attendance.
Genetics of the GABA-A Receptor in Epilepsy
GABA. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. The main function of GABA is to reduce the excitability of neurons, which is the opposite of the excitatory glutamate that we described more extensively on our blog when talking about GRIN– and GRIA-related disorders. Many variants in GABA receptors are linked to epilepsy. Here, we will dive specifically into the genetics of the GABAA receptor.
Epilepsy Genetics Spycraft, UGDH, and Mardi Gras
The gene on your hand. We should never apologize for telling people about genetic epilepsies, we should apologize for not telling people enough about it. At the 2024 Mardi Gras celebration of the Epilepsy Foundation of Eastern Pennsylvania, I had the honor of being given the Charley and Peggy Roach Founders’ & Eric Burton Osberg Award, also known as “Philadelphia Epilepsy Medical Professional of the Year”. I am quite sure that there must have been a data entry error or that the selection committee slipped in the line when they made this decision. Many of our epilepsy nurses, nurse practitioners, EEG techs, researchers, and physicians caring for people with epilepsy in Eastern PA would have been much more eligible for this honor than myself. However, given this unlikely opportunity, I used my moment on the stage to highlight our team and dedicate this award to Connor Maule, one of my patients who passed away from a rare genetic epilepsy in 2021. To honor Connor and epilepsy patients alike, I asked the audience to take a gene home with them – signing their hands with a gene name using a sharpie.
Disparity in Genomic Databases
Genomics. The use and importance of genomics in clinical research and practice has grown exponentially as the cost of acquiring human genomic sequences has continually decreased. Genetic variation can be inherited, acquired, or present at birth. Within the realm of inherited variants, the evolutionary history of humans can account for much of the genetic variation seen across different groups. Genomic research can help in identification of genomic loci or variants that are potentially associated with human diseases and, hence, also enable the development of precision medicine. However, accounting for the normal spectrum of human genetic variation is critical, and the currently available tools are significantly limited in their ability to do so for a diverse range of human populations.