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

TLR3 and the genetic predisposition to herpes encephalitis

Seizures with fever. Most times when we discussed seizures in the setting of fever on our blog, we either referred to simple Febrile Seizures or genetic syndromes such as Dravet Syndrome, which characteristically present with fever-associated seizures. However, if a child or an adult presents with a first seizure in the setting of a febrile illness and shows recurrent seizures or does not get back to baseline quickly, we are usually concerned about infections of the brain. Herpes simplex virus (HSV) encephalitis is one of the more common infections, which may result in significant impairment if not treated rapidly. A recent publication in Neurology reminds us of the genetic susceptibility of HSV encephalitis and suggests that predisposing genetic alterations can be found in an appreciable number of patients. 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

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

The top three publications in epilepsy genetics 25 years ago

Looking back. In this week’s ILAE Genetics Commission post, we would like to look 25 years back and examine the most important publication in the field in 1989, the year the Berlin wall fell. What concepts did we have back then and how did our understanding of epilepsy and genes change? Here are the top three publications of 1989. 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

The return of the h-current: HCN1 mutations in atypical Dravet Syndrome

Hyperpolarization. More than a quarter of a century ago, physiologists identified an electrical current in neurons and cardiac myocytes that behaved so strangely that it was called the “queer” or “funny” current: it paradoxically caused depolarization upon hyperpolarization. This current was finally named h-current and is mediated by HCN channels. The h-current has been associated with epilepsy through functional studies, but a genetic link has been elusive so far. In a recent publication in Nature Genetics, de novo mutations in HCN1 are identified in patients with early-onset epileptic encephalopathies resembling Dravet Syndrome. Continue reading

Epigenetic signatures – profiling the epilepsies beyond genetics

What is epigenetics? In a single idea: the molecular memory of a cell. The system stores information of previously external (e.g. environmental) or internal (e.g. developmental) stimuli, learns from this experience and responds. A collection of specific tags tells genes whether to be ON or OFF. Hardcore epigeneticists claim that an epigenetic tag should be meiotically and/or mitotically heritable, self-perpetuating, and reversible. DNA methylation is the mechanism coming closest to this ideal. A more liberal definition not focusing on heritability refers to any structural adaptation of the chromatin template that regulates gene expression. This would also include posttranslational histone tail modifications, incorporation of histone variants, chromatin remodeling processes, and action of non-coding RNAs. The large variety, flexibility, interdependence and potential synergistic effects of epigenetic mechanisms could provide the molecular basis for any phenotypic variation in physiological and pathological conditions. In epilepsy research this is especially interesting with regard to the stimulus-driven activity and connectivity of post-mitotic neurons in the adult brain. We set out to study methylation for the most common form of epilepsy in adults. Continue reading

Malaria, seizures and genes

Our old genome. When talking about seizures and genes, “malaria” is usually not the first thing that comes to mind. However, malaria-associated seizures are a major cause of neurological disability in Sub-Saharan Africa. Given the frequency of malaria infections on a worldwide scale, Plasmodium falciparum, the parasite causing malaria, is probably one of the most frequent causes of acute seizures. Our genome has adapted to dealing with parasites over evolutionary time and several disease-causing mutations are thought to be relatively frequent, as they also confer resistance to malaria. For malaria-associated seizures, family studies show an increase in epilepsy in relatives, suggesting that these parasite-induced epileptic seizures may also have a genetic predisposition. A recent study in Epilepsia now investigates malaria candidate polymorphisms as genetic risk factors for malaria-associated seizures. Continue reading

FS and FS+ are two distinct diseases, as suggested by twins

GEFS+ reloaded. The genetics of Febrile Seizures (FS) is one big mystery. Even though large families have been reported and multiple linkage studies have been performed, no single susceptibility gene for Febrile Seizures is known. This is somehow surprising, given that FS is by far the most common epilepsy syndrome. In contrast to common FS, genetic research has been very successful in families with Genetic Epilepsy with Febrile Seizures Plus (GEFS+), where Febrile Seizures Plus (FS+) are the most striking feature in families.  Ever since the definition of the GEFS+ spectrum was established, the distinction from common FS has been a matter of debate. Now a twin study in Epilepsy Research suggests FS and FS+ might actually be two very distinct diseases with little genetic overlap. Continue reading