The missing ion channel. A little more than two years ago, we wrote about our discovery of SCN3A as a novel disease gene in epileptic encephalopathies. At the time, SCN3A was the missing ion channel, the only brain-expressed voltage gated sodium channel that did not have a clear gene-disease relationship. However, since the initial discovery of SCN3A as a disease gene, both the phenotypic spectrum and variant landscape have expanded considerably. In a recent publication, we updated our knowledge based on information of 22 individuals with SCN3A-related disorders, which showed brain malformations in more than 75% of individuals and an unusual clustering of pathogenic variants in parts of the Nav1.3 channel. Continue reading
Tag Archives: SCN3A
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
Publications of the week: SCN8A, SYN1, ZDHHC9, and SCNM1
Power outage. This week’s publications of the week were conceptualized in complete darkness. A thunderstorm had hit the Philadelphia area on Tuesday, leading to widespread power outages in the region. I found myself in the strange position of being without power for a night, but with full strength cell phone reception and a completely charged laptop battery. Here is our post on the most relevant publications of the last few weeks, written in the calm of a dark night where the only sound around was the howling of our neighbor’s backup generator. Continue reading
How to get started in epilepsy genetics – The Channelopathist’s third birthday
Happy birthday. The Channelopathist turned three last week, i.e. exactly three years ago we started writing regular blog posts on epilepsy and genes, starting with a post on how SCN2A was rediscovered in neurodevelopmental disorders. Since we had many new subscribers last year, I thought that I could use this opportunity to write a brief post on how you can get started on Beyond The Ion Channel and how you can navigate our blog. Continue reading
SCN8A encephalopathy – and how it differs from Dravet Syndrome
Nav1.6. For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome. Continue reading
Five unexpected things I realized at AES this year
Seattle 2014. This year, the 68th Annual Meeting of the American Epilepsy Society was held in Seattle. While much of the scientific content of AES is still under publication embargo and will be the topic of our next post, here are five unexpected things I learned at AES this year. Continue reading
The 1003 possible autism genes – a matter of constraint
Overview. There have been numerous publications on de novo mutations in autism and intellectual disability over the last three years. Many of these studies struggle to distinguish signal from noise, and the plethora of findings leaves the reader wondering which genes are bona fide autism genes and in which cases the evidence is limited. A recent paper in Nature Genetics uses a new metric to assess expected versus observed de novo mutations in more than published 1000 autism patient-parent trios – and the answers appear to be straightforward. Continue reading
Dravet Syndrome and rare variants in SCN9A
How monogenic is monogenic? Dravet Syndrome is a severe epileptic encephalopathy starting in the first year of life. More than 80% of patients have mutations or deletions in SCN1A, which makes Dravet Syndrome a relatively homogeneous genetic epilepsy. In addition to SCN1A, other genetic risk factors for Dravet Syndrome have been suggested, and current, large-scale studies including EuroEPINOMICS-RES are studying the genetic basis of the minority of Dravet patients negative for SCN1A. A recent paper in Epilepsia now suggests that a significant fraction of patients with Dravet Syndrome also carry rare variants in SCN9A in addition to the mutations in SCN1A. Is a mutation in SCN1A not sufficient to result in Dravet Syndrome, but needs additional genetic modifiers? Continue reading
Genome meets Connectome: gene networks and brain microstructure
Genetic imaging. There are two major fields in epilepsy research – functional imaging and genetics. Both fields live parallel lives and hardly ever interact. When they do, the interaction is usually short-lived and full of disappointments, as nothing has really ever worked. However, a grant application due today has led me to a recent publication in the Journal of Neuroscience, which combines imaging and GWAS. And believe it or not, the ion channels are back. Continue reading
