Pushing the reset button. The history of epilepsy genetics can broadly be distinguished into two major eras: the time before September 4th, 2012 and everything after this. September 4th, 2012 was the date that the first large genome-wide association study in IGE/GGE was published online in Human Molecular Genetics. Each of the >100 association studies in IGE listed in PubMed is now dated and needs to measure up against the current study, which will likely be remembered as the “EPICURE study”. The results of the EPICURE study are surprising and upset our conventional wisdom of what causes one of the most common forms of epilepsy. Continue reading
Category Archives: 2012
Exome shock with acute in-house deficiency
Sleep disturbances, double vision, writer’s cramp. As some of you might recall, I was not fully conscious during our Young Investigator’s meeting two weeks ago, spending most of the time in a haze either hacking random commands into my laptop with sweaty palms or desperately trying to communicate with my neighbor in Unix, Perl or Loglan. Ever since then, people have remarked that I have lost weight and that I haven’t smiled since. What has gotten a hold of me? It all started out with a small, innocent hard drive that made its way from Antwerp to Kiel. Continue reading
A literature collection for epilepsy genetics
We have set up a library in Mendeley to collect relevant papers for EuroEPINOMICS. Keeping up to date feels like a menial task yet no simple solution delivers good results. You can’t read all the tables of contents by mail (or RSS) and publishers have the tendency to spam those e-mails, but most likely you’re subscribed to the essentials. The more anxious of us employ automated search services at the NCBI or use the good old PubCrawler to follow their field of research, a particular gene, or the output of their nemesi or mentors.
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A little clonazepam to rescue behavioral deficits in SCN1A-deficient mice
Dravet Syndrome, behavior and cognition. Dravet Syndrome, or Severe Myoclonic Epilepsy of Infancy (SMEI), is a severe childhood epilepsy due to disruptions of the SCN1A gene. Besides the actual seizures, Dravet Syndrome is characterized by a plateauing of cognitive development in the second year of life. In childhood, most patients with Dravet Syndrome have intellectual disability, and the frequency of other neurodevelopmental disorders including autism are increased. Neurodevelopmental features of Dravet Syndrome have recently come into the focus of research, as de novo mutations in SCN1A were discovered in patients with autism. Now a recent study in Nature sheds some light on the underlying pathophysiology and discovers a surprising treatment effect. Continue reading
The RES-experiments: what results can be expected
Now the experiments to find de novo variants for epileptic encephalopathies within the Euroepinomics RES-project are well underway and first data are coming out, it is a good moment to pause and think about what results we can expect, and how these should be interpreted. For this it is very nice that recent large experiments in autism have provided so much useful data. In this post, I will explore what we can expect in experiments in which we perform whole exome sequencing in a group of patients and their parents to identify de novo variants that could be the cause of the disorder.
The years of our fathers: paternal age and the rate of de novo mutations
Aging fathers. An increase in risk of aneuploidies, i.e. chromosomal aberrations such as Trisomy 21, is well established with maternal age. Whether the paternal age also increases the risk for disorders in the offspring had long been disputed. However, a connection between paternal age and autism has been found in recent years. Now a recent study in Nature finds a surprisingly strong correlation on the genetic level… Continue reading
21st century digital boy: The Kiel Young Investigators’ Meeting
The children of the genomic revolution. There aren’t many possibilities for young researchers in epilepsy research to get together independently. Accordingly, we were in the fortunate position to host the first meeting for young researchers in pediatric epileptology in Kiel last week. I was asked by some participants to write a post on this. There were, however, two very specific instructions. First, I was asked to write about “Generations X and Y” and the resulting conflicts in science. Secondly, I was told not to write an ordinary meeting report, but something different… Continue reading
The exome fallacy
Are you fully covered? My experience with a phenomenon I shall call exome fallacy began in 2011. While browsing the exomes of a few patients with epileptic encephalopathies, we wanted to have a quick look at whether we could exclude mutations in the epilepsy gene SCN1A in our patients through exome data. As some of you might already guess, the words “exome” and “exclude” don’t go well together and we learned the hard way that each individual exome covers certain parts of the gene quite well. However, if you expect your exome data to have sufficient quality to cover an entire gene in several individuals, you end up disappointed. But there is even more to the exome fallacy than you might think… Continue reading
Of angels and interneurons
Angelman Syndrome and UBE3A. Angelman Syndrome is a severe neurodevelopmental disorder characterized by intellectual disability, typical facial features and a usually happy demeanor. Patients with Angelman Syndrome usually do not acquire active speech and often show a characteristic, atactic gait. Also, patients with Angelman Syndrome have a characteristic EEG pattern and many children have seizures. Angelman Syndrome is a genetic disorder due to loss of function of UBE3A, a ubiquitin ligase expressed in the CNS. Ubiquitin ligases are the bin collectors of the cell. By attaching ubiquitin to proteins, proteins are labelled for cellular degradation. How a malfunction of a cellular garbage truck causes such a complex neurodevelopmental disorder is poorly understood. A recent study, however, points out an important role for interneurons…. Continue reading
Mutations don’t always cause disease, quite the opposite
A mutation in APP protecting against Alzheimer’s disease. Alzheimer’s disease is one of the leading causes of dementia in the Western world. In rare familial forms of Alzheimer’s disease, variants in the APP gene are well-known to be disease-causing. This led Jonnson and colleagues to search for additional rare variants in the APP gene that might be associated with further cases of Alzheimer’s disease. When they analysed their datasets, they stumbled across an associated APP variant. However, this variant does not increase the risk for Alzheimer’s, it reduces it… Continue reading