Cause or coincidence – recessive SCN1A variants in Dravet Syndrome

Recessive epilepsies. Dravet Syndrome is one of the most prominent genetic epilepsies and presents in the first year of life with prolonged fever-associated seizures. Haploinsufficiency of SCN1A, either through mutations or deletions, is the major cause of Dravet Syndrome. In a recent publication in the European Journal of Pediatric Neurology, two families with recessive Dravet Syndrome and biallelic SCN1A variants are reported. Let’s have a look at how to interpret these findings. Continue reading

Beyond SCN1A – Copy Number Variations in fever-associated epilepsies

Fever and epilepsy. When it comes to epilepsy and fever, either Febrile Seizures or Dravet Syndrome are usually the most prominent topics on our blog. However, in addition to these syndromes, there various other epilepsies that have fever-related seizures as a prominent feature. In a recent publication in Epilepsia, we investigated the role of microdeletions in a group of patients with prominent fever-associated epilepsies. Our findings suggest that fever-associated epilepsy syndromes may be a presentation of known microdeletion syndromes. Continue reading

Publications of the week – SRP9, Nebulin, and Kuf’s disease

Issue 2/2015. For the second issue of our publications of the week in 2015, we have selected recent publications on the genetics of Febrile Seizures, the complexities of interpreting variants in large genes and functional studies on progressive myoclonus epilepsies due to mutations in SCARB2 and CTSF. Continue reading

Heat at the synapse – STX1B mutations in fever-associated epilepsies

Febrile Seizures. The discovery of the genes for fever-associated epilepsies was one of the most relevant milestones in epilepsy genetics. Discovery of the underlying genes including SCN1A, SCN1B and GABRG2 was tightly linked to the development of the Genetic/Generalized Epilepsy with Febrile Seizures Plus (GEFS+) concept, describing the spectrum of epilepsy phenotypes seen in families with these mutations. Gene discovery in GEFS+, however, has slowed down in recent years, and no further causative genes had been identified for more than a decade. Now, in a recent paper in Nature Genetics, mutations in STX1B are found as a novel cause for fever-associated epilepsies. Continue reading

Have we given up on the genetics of febrile seizures?

Fever, genes, and seizures. Undoubtedly, febrile seizures are the most common epilepsy syndrome in humans. Up to 5% of children have febrile seizures. In most children, these febrile seizures are self-limiting, and there is no recurrence. Usually, no long-term treatment is required. We know from family studies and twin studies that febrile seizures have a significant genetic component. Now here are two surprising facts: first, the genetic contribution to febrile seizures is entirely unknown. Secondly, to my knowledge, the genetic contribution to the most common epilepsy syndrome in man has not been addressed in any of the current large-scale studies. Let’s review why this is the case and why we should change this. Continue reading

Switching inhibition on – SLC12A5/KCC2 variants in human epilepsy

Inhibition. We usually like to think of GABA as an inhibitory neurotransmitter, which counteracts the excitatory and potentially epileptogenic effects of glutamate. However, this is not always true during brain development. Initially, GABA is a powerful excitatory neurotransmitter. The excitatory effect of GABA has been shown to be important for brain development and the formation of dendritic spines – and the switch from excitation to inhibition is due to a single ion channel: KCC2, encoded by SLC12A5. Two recent publications in EMBO Reports now implicate genetic variation in SLC12A5 in human epilepsy. Continue reading

Modifier genes in Dravet Syndrome: where to look and how to find them

Converging thoughts. During late 2013, I had several unrelated discussions about the possible role of genetic modifiers of SCN1A in Dravet Syndrome. To some extent, SCN1A is a paradox. One the one hand, the connection between Dravet Syndrome and SCN1A is one of the clearest connections between gene and disease that we see in genetic epilepsies. On the other hand, we see a remarkable phenotypic heterogeneity in families, and some presumably pathogenic SCN1A variants can also be identified in unaffected control individuals. This leaves us with the question whether there are genetic modifiers in Dravet Syndrome that might help provide some insight into additional mechanisms of disease. This post is a collection of 10 individual thoughts that emerged during the discussions last year. Continue reading

From unaffected to Dravet Syndrome – extreme SCN1A phenotypes in a large GEFS+ family

The two faces of SCN1A. Even though the range of phenotypes associated with mutations in SCN1A can be conceptualized as a continuum, there are usually two distinct entities in clinical practice: the severe, epileptic encephalopathy of Dravet Syndrome due to de novo mutations and the usually mild fever-related epilepsies in autosomal dominant GEFS+ families. While Dravet Syndrome can also be seen in some families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), this is a rare phenomenon; there is usually little overlap between Dravet Syndrome and GEFS+. Within the Israel Epilepsy Family Project, we came across such a family with overlapping phenotypes. This recently published large GEFS+ family probably has the widest phenotypic range reported to date. Continue reading

CHD2 encephalopathy as a novel Dravet-like epilepsy syndrome

Negative for SCN1A. Today the first major paper by the EuroEPINOMICS-RES consortium was published in the American Journal of Human Genetics online. As you might recall from some of our previous posts, RES has worked on gene identification in patients with Dravet Syndrome negative for SCN1A using trio exome sequencing. A significant fraction of patients turned out to be positive for SCN1A with mutations initially missed using conventional sequencing techniques. However, there was also a second gene that we discovered in an initial cohort of patients with SCN1A-negative Dravet Syndrome. This gene was CHD2.  While working on the functional studies in zebrafish, CHD2 was also discovered as a novel gene for epileptic encephalopathies by both Carvill and collaborators and the Epi4K consortium. These parallel discoveries clearly highlight the relevance of this gene in human epilepsy and suggest that CHD2 mutations might be more common than mutations in many of the other candidate genes discovered in the last 12 months. In addition, when looking closer, the phenotype of the patients was not exactly Dravet Syndrome, but might represent a novel fever-related epileptic encephalopathy. Continue reading