Intergalactic, planetary. At the end of last year, I gave a presentation on epilepsy genetics for epilepsy surgeons. Having worked in presurgical epilepsy monitoring myself for some time, I could not help realizing that the fields of epilepsy surgery and epilepsy genetics are quite distinct. Both fields use different terminologies and different concepts and virtually represent parallel worlds. In the vast majority of cases, this does not really matter as there is little overlap between the patients undergoing epilepsy monitoring for later surgery and patients where a genetic etiology is assumed. In a recent paper in Epilepsia, the case of a patient with an STXBP1 mutation is presented who successfully underwent epilepsy surgery. So who is right when both fields collide while treating a single patient?
STXBP1, a spectrum unfolding. In 2008, deletions in the gene coding for the syntaxin binding protein 1 (STXBP1) were identified in patients with Ohtahara Syndrome, a severe, early-onset epileptic encephalopathy. Ohtahara Syndrome starts in the first weeks of life with various seizure types. The EEG shows a suppression-burst pattern, which is the correlate of a severe cerebral dysfunction. Ohtahara Syndrome usually evolves into other epilepsy syndromes including West Syndrome. Almost all children with Ohtahara Syndrome have severe cognitive and physical disabilities. After the initial discovery, STXBP1 mutations were also discovered in other epilepsy phenotypes and –intriguingly- some patients with intellectual disability without seizures. The vast majority of patients with STXBP1-related epilepsy have epileptic spasms. However, many patients have some focal features that appear to be more prominent than in other genetic epilepsies. Weckhuysen and collaborators now report on a patient with an STXBP1 mutation who underwent epilepsy surgery prior to genetic diagnosis. The seizure frequency dropped dramatically.
Genetic or not? In the patient reported by the authors, histology on the resected brain tissue showed a focal cortical dysplasia (FCD). This lesion is known to cause focal epilepsy that is treatable by epilepsy surgery, but the connection between the FCD and the presumably causative genetic STXBP1 variant is less clear. There are reports of patients with Temporal Lobe Epilepsy with hippocampal sclerosis and SCN1B mutations, who became seizure-free after epilepsy surgery. However, in contrast to FCD, hippocampal sclerosis can be interpreted as secondary to a primary genetic epilepsy and is not considered developmental. Histology of brain tissue obtained in patients with other genetic epilepsies such as 16p13.11 microdeletions do not show any abnormalities. Therefore, the connection between the STXBP1 mutation and the FCD remains unclear. The take-home-message is that it is worthwhile to live in both parallel worlds, epilepsy genetics and presurgical work-up, when trying to understand and treat intractable epilepsy.
STXBP1 and the bubble bath. In order to understand the function of STXBP1, just imagine a bubble bath (on Sunday evenings, our little daughter usually has a bath, therefore, this example was obvious to me). Imagine two medium-sized bubbles floating on the water. What does it take to turn these two bubbles into one big bubble? Yes, it is quite difficult. The more you try to push them together, the more you risk generating many small bubbles rather than a single big one. For soap bubbles, this task is a bit easier, but also here you will end up with a burst bubble rather than a single big bubble in many cases. In terms of (bio)physics, the joining of bubbles is a matter of overcoming the repulsive forces when joining two lipid bilayers, i.e. it’s not natural for bubbles to join, you have to give them a push. To cut a long story short, why is this relevant for the human brain? Our synapses have the same problem thousands of times each millisecond. In order to enable synaptic transmission, we need to fuse synaptic vesicles. Each of these vesicles needs a little push to fuse with the presynaptic membrane. And STXBP1 is one of proteins providing this push.
The minimal fusion machinery. In 1998, Weber and colleagues proposed the concept of SNAREpins. According to this hypothesis, vesicle fusion occurs through the interaction of SNARE proteins, which are located on the vesicle and the plasma membrane. Once these proteins are in contact with each other, they actively twist around each other, pulling the vesicle closer to the membrane, which leads to membrane fusion. STXBP1, also called MUNC18-1 is one of the proteins that interacts with syntaxin, one of the membrane-bound proteins involved in this twist. More recent studies even suggest that STXBP1 might be one of the critical components of this machinery. This puts STXBP1 at the center of vesicle fusion. But why does a lack of STXBP1 result in epilepsy?
The lacking model for STXBP1 dysfunction. The situation appears contradictory at first glance. STXBP1 is critical for synaptic transmission, but mutations that abolish STXBP1 function lead to epilepsy. Experimental data in knock-out mice suggest that the CNS and the synaptic ultrastructure can develop normally even though there is absolutely no neurotransmission if MUNC18-1/STXBP1 is lacking. It can be hypothesized that the partial lack of STXBP1 affected the inhibitory neurotransmission disproportionately compared to the excitatory transmission, leading to overexcitation and seizures. Either way, there is a large translational gap between the basic research findings regarding vesicle fusion and the human phenotype resulting from STXBP1 haploinsufficiency.