Febrile seizures are among the most dreaded complications of infectious diseases in small children. An international research team composed of experts from the Universities of Tübingen, Leuven and Luxembourg has now made a breakthrough by demonstrating the existence of a previously unknown cause for this most frequent form of epileptic attacks in small children. As a study just published in the journal "Nature Genetics" shows, mutations in the STX1B gene are responsible for the children's pathological reactions to fever. The scientists now hope to develop new forms of therapy on the basis of their discoveries.
The gene mutations lead to an impaired regulation in the release of certain nerve cell messenger substances. The consequence of this is an increase of involuntary electrical discharges in the brain, accompanied by epileptic febrile seizures. In the long run, the newly discovered gene alterations can also be the source of serious epilepsy and mental disability.
Febrile seizures are the most frequent form of childhood epileptic attacks and affect roughly two to four per cent of all children worldwide. They often occur between the ages of three months and five years and can even appear upon mild hyperthermia. What is apparently even more decisive than the fever level, however, is the speed with which the fever rises.
"This explains why children can experience a febrile seizure even before the parents have noticed that the child is ill," says Professor Holger Lerche, M.D., Director of the Hertie Institute for Clinical Brain Research (HIH) and Medical Director of the Department of Neurology and Epileptology at the University of Tübingen. Parents naturally become worried when a small child shows a tendency to fever attacks.
However, the prospects in most cases are good: the attacks subside by the time of school age, and damaging aftereffects remain present only in rare and exceptional cases. The factors which contribute to the development of epilepsy from simple febrile seizures are still largely unknown.
"Genetic predisposition plays an important role. But up to now there has been an inadequate understanding of which genomic mutations are involved in detail," says the study's co-initiator, Professor Yvonne Weber, M.D., Assistant Medical Director of the Department of Neurology and Epileptology at the University of Tübingen.
The team of researchers came upon the track of these genetic mutations via exome sequencing, a special technique for examining a partial section of the genetic material. Even though the exome makes up only about one per cent of the human genotype, it also contains most of the pathogenic genetic alterations (mutations) which have been found to date. Analysis of genetic material first revealed STX1B mutations in two large families whose members are prone to both febrile seizures and epileptic attacks.
The analysis was then widened to include further patients, which led to the discovery of four further mutations. Here too, the affected persons suffered from febrile seizures and serious epileptic attacks, which had resulted over and above this in mental disabilities. "In other words, the STX1B mutations gave us an important clue: they do more than trigger epileptic febrile seizures, which of themselves often subside in these small patients by the time of the first school year; the mutations may also be the cause of serious cases of epilepsy, with consequent impairment of intellectual development", as Lerche explains. The researchers now hope to turn these insights to practical advantage in the form of better methods of treatment and even, in the ideal case, to successfully prevent the development of epilepsy.
Together with experts in the field of zebrafish research from the University of Leuven, Belgium and the University of Luxembourg's Centre for Systems Biomedicine (LCSB), the neuroscientists were able to confirm the impact of the newly discovered STX1B mutations with the aid of a model system. Zebrafish provide an excellent model for the study of epilepsy.
In the zebrafish, the development of organs such as the brain takes place at the level of molecular mechanisms in much the same way as in humans. "We were able to show not only that similar patterns of epileptiform attacks also occur in zebrafish with genetically altered STX1B genes, but also that brainwave changes appeared which were clearly aggravated by hyperthermia - as in the case of fever," says Dr. Camila Esguerra, the principal investigator who led this part of the study at the University of Leuven and is now in the process of forming a new research team at the University of Oslo, Norway.
Zebrafish are also especially well-suited for the development of new avenues of treatment. Together with Dr. Alexander Crawford (Luxembourg), Dr. Esguerra has already found a substance which can prevent the most violent form of attacks in zebrafish. "We hope that from this we will be able to develop a new drug in a few years which will prevent the development of certain forms of serious epilepsy in childhood," says Crawford. In addition, a search for new substances will also be carried out in STX1B mutations.
The project also included clinical and genetic experts of the EuroEPINOMICS Consortium, a European Science Foundation network initiated and directed by scientists in Tübingen, Kiel and Antwerp and funded in Germany with 2.5 million Euros from the German Research Foundation. This has brought clinicians together with scientists in the field of basic research to study both the genetic mechanisms of epilepsy and avenues for new methods of therapy.
Still another network, "IonNeurONet" is part of this project and is carrying on a search for the causes of rare forms of epilepsy and other nervous disorders (e.g. rare forms of migraine as well as retinal and muscular diseases). With the help of the German Federal Ministry for Education and Research (BMBF), which has provided support for the network, patients with the corresponding impairments have been gained as test subjects for the study.
Such large-scale networks, with the corresponding numbers of patients, are essential for the discovery and confirmation of new genetic defects. They are also a prerequisite for later clinical trials to confirm research results in patients. The work described here has brought the scientists and physicians of the present study a step closer to a discovery of new therapeutic options.
Original title of the publication:
Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes;
Nature Genetics, doi:10.1038/ng.3130
Silke Jakobi | idw - Informationsdienst Wissenschaft
Penn vet research identifies new target for taming Ebola
12.01.2017 | University of Pennsylvania
The strange double life of Dab2
10.01.2017 | University of Miami Miller School of Medicine
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering