Structure. Despite tremendous advances in understanding its genetic underpinnings in the last few years, electrical status epilepticus during slow-wave sleep (ESES) is a poorly understood neurodevelopmental disorder and to a certain extent the prototype of an epileptic encephalopathy. Slow-wave sleep in affected children is entirely replaced by epileptiform activity, leading to significant neurocognitive impairment with an emphasis on speech impairment. In a recent publication in Annals of Neurology, alterations in CNKSR2 are identified in families with a more severe course of ESES, highlighting the postsynapse as a possible player in ESES pathogenesis. Continue reading
Top 10. 2014 has been a very productive year in epilepsy gene discovery and with our final blog post this year, we wanted to provide a brief overview of what has been pertinent this year. From the multitude of novel genes identified this year, here are the 10 most relevant findings – including some genes that you probably didn’t expect. Continue reading
The 16p11.2 story. Among the various microdeletion and microduplication syndromes located on human chromosome 16, the 16p11.2 microdeletion has unique position. Historically, this microdeletion was the first of the “neurodels” to be identified through association studies in autism, where it can be identified in 0.5% of patients. However, there is more to the phenotypes of the 16p11.2 microdeletion, which is now addressed in a recent paper assessing the full phenotypes in 72 microdeletion carriers. 16p11.2 therefore represents one of the best-investigated microdeletions to date. Continue reading
Microdeletions in seizure disorders. In a recent paper in Nature, Golzio and colleagues identified KCTD13 as the main driver for the neurodevelopmental phenotype of the 16p11.2 microdeletion. Small losses of chromosomal material as found in microdeletions usually affect several neighbouring genes. Many deletions are due to the particular duplication architecture of the human genome and are canonical, i.e. they always have the same size and include the same genes. The same duplication architecture also makes these variants relatively common, and the full impact of microdeletion-associated genetic morbidity has startled the neurogenetics. The recent five years have led to the identification of several epilepsy-related microdeletions including variants at 15q13.3, 16p13.11 and 15q11.2. There are further microdeletions that are usually found in patients with autism or intellectual disability and to a lesser extent in patients with epilepsy. The 16p11.2 microdeletion, the first microdeletion to be identified through a large-scale association study, is one of these variants.
From deletion to causative genes. For many microdeletions, the statistical evidence for the association with a particular phenotype is often beyond reasonable doubt given that several thousands samples can be included nowadays. The identification of the underlying causative gene, however, is extremely difficult. It is technically challenging and time-consuming to investigate all included genes functionally through conventional model systems. The function of many genes included in microdeletions are not related to ion channels, the best known pathological substrate in epilepsies, and hampers testing effects through established electrophysiological techniques. Finally, microdeletions only lead to hemizygosity, i.e. the second copy of a gene should still be expressed at lower level, requiring model system looking for a quantitative rather than qualitative change. The bottom line is that epilepsy researchers are stuck without suitable model systems, which would allow for a medium-size throughput screening for genes in these deletions. This is where Danio rerio comes into play.
The zebrafish as a model for neurodevelopmental disorders. The zebrafish (Danio rerio) is a good model system for genetic and developmental research. The technologies for genetic manipulation are highly advanced. In addition, embryos are transparent and develop externally. Furthermore, a zebrafish develops quickly and produces a large number of offspring. For her studies on developmental genetics using the zebrafish as a model system, Christiane Nüsslein-Volhard received the Nobel Prize for Medicine in 1995.
Screening of the candidate genes of the 16p11.2 microdeletion. Golzio and coworkers focussed on a peculiar aspect of the 16p11.2 microdeletion as an outcome parameter for their genetic screening – macrocephaly, i.e. an enlarged head circumference. In contrast, patients with the corresponding 16p11.2 microduplication often show microcephaly, i.e. a reduced head circumference. Golzio and colleagues deviced a system to measure head circumference in zebrafish embryos and then overexpressed the 29 genes contained in the 16p11.2 microdeletion in the developing embryo. Strikingly, only KCTD13 resulted in microcephaly. Macrocephaly was seen when KCTD13 was knocked-out with a morpholino. This demonstrated that up- or downregulation of KCTD13 affects head size. The authors went on to show that these differences in head size are driven by differences in neuronal proliferation. KCTD13 is highly expressed in the human forebrain and recent studies have suggested a role for excessive neurons in the frontal lobe in autism.
Application to epilepsy research. The authors combine a clever screening strategy with a convincing follow-up study, highlighting the potential of zebrafish studies in neurogenetics. However, head circumference is not identical with autism and only represents a surrogate parameter. Therefore, even though the authors emphasize the role of head circumference as an essential part of the 16p11.2 phenotypes, it only represents a minor aspect of it. Nevertheless, the authors demonstrate that Danio rerio is a good model system for medium-throughput screening strategies, and epilepsy models in zebrafish do exist, suggesting that this study design might help decipher the plethora of candidate genes arising from the genetic studies in EuroEPINOMICS.