The not so static genome. We usually think that our genome is static and that differences between cell types usually arise through mechanisms that do not necessarily involve alterations of the DNA structure. This suggestion has been challenged by initial data suggesting that retrotransposons may be particulary active in neurones. Now, a recent study in Cell investigates the role of jumping genes using single-cell sequencing of neurons.
A surprising finding. The genetic basis of many epileptic encephalopathies and familial epilepsies remains unknown. Novel sequencing technologies such as Next Generation Sequencing now offer the possibility to identify the genetic basis of these conditions. However, it is a rare event that a single gene is implicated in two completely different epilepsy subtypes. Such a finding has now been reported in Nature Genetics. The KCNT1 gene is found to be mutated in Malignant Migrating Partial Seizures of Infancy (MMPSI) and a severe form of Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). I doublechecked at least three times whether both papers actually talk about the same gene. Continue reading
Taking the gloves off. Historically, epilepsy is called the falling sickness because of episodes when patients suddenly crash to the ground and lose their posture. These seizures are called atonic or astatic seizures and are often the most troubling events for patients. During these events, patients may seriously hurt themselves. From the epileptological point of view, there is a long debate regarding the nature of these events. Are they purely due to loss of posture or are they associated with a brief myoclonic seizure? Lennox quotes Pierce Clark who states bluntly that describing an astatic seizure without a preceding jerk is due to “faulty clinical observation”. This is when Lennox takes the gloves off.
Where is West Syndrome? Earlier this week while browsing through the contents of Lennox’s book, I wondered where his description of West Syndrome was hidden. Lennox is very careful in reviewing the historical data on epilepsy, but for some reason, he did not mention the report by William James West, who described a particular type of epilepsy in his own son that would later be named after him. Then, when I had almost forgotten that I was on the lookout for West Syndrome, I stumbled upon it in the chapter on myoclonic seizures. Continue reading
Lights on and lights out. Staring spells, petits mals, pyknolepsy and absence seizures. The brief spells that occur in patients with epilepsy have riddled neurologists for centuries. This became clear to me when Zaid Afawi and myself saw an epilepsy family in the West Bank on Sunday. When are staring spells epileptic and what kind of seizures are they? For me, this was a good opportunity to read Lennox’s thoughts on this. Eventually, after a long day under the Middle Eastern sun, I fell asleep over the chapter on absence status. Continue reading
On the road. For this week, the Channelopathist will be a travel blog. I am on my way to Israel where we will be busy recruiting and phenotyping epilepsy families for the EuroEPINOMICS project for the next seven days. This trip abroad gives me the opportunity to do something that I have been thinking about for quite some time: reading “Epilepsy and Related Disorders” by William G. Lennox, one of the pioneers of epilepsy genetics. I will try to put some thoughts on Lennox into words this week while spending my time down here in Israel. Continue reading
The story continues. This week, I am trying to catch up with a number of recent papers in the field of neurogenetics. A recent publication in Nature Genetics highlights the role of de novo mutations identified through exome sequencing in schizophrenia. The authors also look at control data and compare their findings with the growing body of data available for autism research. And while many aspects regarding de novo mutations become more clear with every study published, the real difference is sometimes difficult to grasp. Continue reading
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
Diagnostic exome sequencing. Severe intellectual disability (ID) is unexplained in the vast majority of patients and is thought to be genetic. The genetics of intellectual disability has traditionally focused on the X chromosome, where more than 100 possibly causative genes for ID are located. But other, autosomal genes are also found in large number of cases. A recent study in the New England Journal of Medicine now reports on trio exome sequencing in patients with unexplained severe intellectual disability. The authors identify causative de novo events in a large proportion of patients. Interestingly, more than half of their patients had epilepsy. Continue reading
A new beast. Rare genetic variants probably account for a significant fraction of the genetic liability to many common and rare disorders. Rare variants occupy the liability space between monogenic variants and common genetic variants. Their existence has often been postulated, and genetic investigations looking at copy number variants have elucidated some examples of rare variants. These rare variants appear to carry particular properties that are quite unexpected including the way that these variants run in families. Now, in a recent paper in the European Journal of Human Genetics, we have developed a model of the way rare variants behave in families. And there is a lot of misbehaving. Continue reading