800 years. The discovery of SCN1B as a causative gene for Genetic Epilepsy with Febrile Seizures Plus (GEFS+) was one of the most pivotal moments in epilepsy genetics. This discovery not only shaped our understanding of the channelopathy concept, but also highlighted the importance of careful phenotyping. Therefore, it may be surprising that SCN1B took almost a quarter of a century to accrue sufficient evidence to be considered as a definite epilepsy gene. However, this is not the only aspect where SCN1B operates on its own time scale. In a recent publication, one of the most common disease variants in SCN1B could be traced back more than 800 years to a single founder event. Here is a 2023 update on the journey of one of the most well-known but also most mysterious epilepsy genes whose origins are lost in the depth of time. Continue reading
Tag Archives: GEFS+
How SCN1A comes to its own rescue
Modifier genes. When I compiled the most important updates on SCN1A genetics a few weeks ago, I forgot one of the most unusual studies that makes you pause and think. To provide some background: ever since the initial discovery of familial epilepsy syndromes such as Genetic Epilepsy with Febrile Seizures Plus (GEFS+), the intrafamilial range of presentations has been a big mystery. Within single families, we typically observe a very broad spectrum of phenotypes. Furthermore, in some families, the range of phenotypes is extreme – the same SCN1A variant may cause Dravet Syndrome in one individual, while other individuals are unaffected. In a recent study, we stumbled upon an unusual cause for this variability: a second SCN1A variant that neutralizes the pathogenic effect of the familial variant. Here is a summary of this unusual story. Continue reading
ANO3, SCN1A, IL10 – the new genetics of febrile seizures
GWAS. Febrile seizures affect up to 5% of all children between six months and six years and are by far the most common seizure type. While seizures in the setting of fever may be a manifestation of an underlying epilepsy, in the majority of cases, children only have one or two febrile seizures in their lifetimes. We know from twin studies that there is a strong genetic component to febrile seizures, and you might think that we would know more about the most common seizure type. However, this has not been the case until recently. The genetics of febrile seizures have been largely understudied, and we know much more about the genetics of rare epilepsies than about the genetics of febrile seizures. A recent genome-wide association study has been a game changer, highlighting a combination of fever response genes and neuronal genes in the etiology of febrile seizures. Continue reading
Heat at the synapse revisited: an STX1B update
Heat at the synapse revisited. STX1B encodes syntaxin 1B, one of three proteins – along with SNAP25 and synaptobrevin – that form the SNARE complex. The SNARE complex is part of the protein machinery responsible for Ca2+-dependent fusion of the presynaptic neuronal cell membrane with the synaptic vesicle to enable neurotransmitter exocytosis. STXBP1 also plays an important role in this process, as the syntaxin binding protein encoded by STXBP1 interacts with the SNARE complex via binding to syntaxin. While pathogenic variants in STXBP1 are a well-established cause of early-onset epilepsies and related neurodevelopmental disorders, after the initial description of STX1B-related epilepsies in 2014, very little more was heard regarding STX1B in the intervening four years. Now, we contributed patients to a publication in Neurology, which provides an update regarding the clinical and genetic landscape of STX1B-related epilepsies. Continue reading
HCN1 enters the GEFS+ sphere
HCN1 update. Hyperpolarization-activated cation channels (HCN) are involved in neuronal pacemaker activity and regulate neuronal excitability through hyperpolarization-activated Ih current. In 2014 de novo missense variants in HCN1 were identified in five unrelated individuals with a Dravet Syndrome-like developmental and epileptic encephalopathy (DEE). However, in the intervening four years relatively little additional evidence has emerged regarding the role of HCN1 in epilepsy. Now, a recent publication in Brain identifies additional individuals with HCN1-related epilepsies and significantly expands the clinical spectrum beyond Dravet-like DEE. Continue reading
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
