From zero to one hundred in the genetics of Febrile Seizures

Finally. Only a few months ago, we wondered what happened to the genetics of Febrile Seizures, given that there was a paucity of publications in this field. Now, a recent publication in Nature Genetics presents the first well-powered genome-wide association study in Febrile Seizures in almost 2,000 patients, including a large subgroup of patients with Febrile Seizures after MMR vaccinations. The authors provide compelling evidence for common variants in known epilepsy genes. However, the strongest genetic risk for Febrile Seizures is in a known disease gene that nobody expected. Continue reading

The common variants in our genome that predispose to epilepsy – the ILAE GWAS

ILAE GWAS. This is one of the rare occasions when I can write on behalf of the ILAE Genetics Commission and discuss a recent publication. Earlier this week, the ILAE Consortium on complex epilepsies came online in Lancet Neurology. This study is a large meta-analysis of almost 9,000 patients and 26,000 controls looking at common genetic variants predisposing to common epilepsies, including the Idiopathic/Genetic Generalized Epilepsies and focal epilepsies. In a nutshell, when looking for common variants predisposing to the epilepsies, the answer is surprisingly simple. Continue reading

Critical brain-expressed exons and de novo mutations in autism

Selection. De novo mutations in neurodevelopmental disorders including autism, schizophrenia, and intellectual disability raise an important question: are the mutations identified in patients pathogenic or are they simply genomic noise? A recent study in Nature Genetics tries to answer this question by looking at expression of particular exons in the brain and the overall mutational burden in these exons. They come up with critical exons, which seem to be particularly vulnerable in Autism Spectrum Disorder. 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 OMIM epileptic encephalopathy genes – a 2014 review

EIEE1-19. Online Mendelian Inheritance in Man (OMIM) is one of the most frequently accessed online databases for information on genetic disorders. Genes for epileptic encephalopathies are organized within a phenotypic series entitled Early Infantile Epileptic Encephalopathy (EIEE). The EIEE phenotypic series currently lists 19 genes (EIEE1-19). Let’s review the evidence for these genes as of 2014. Continue reading

GABRA1 and STXBP1 as novel genes for Dravet Syndrome

Beyond SCN1A. Dravet Syndrome is a severe fever-associated epileptic encephalopathy. While the large majority of patients with Dravet Syndrome carry mutations in the SCN1A gene, the genetic basis is unknown in up to 20% of patients. Some female patients with Dravet-like epilepsies have mutations in PCDH19, but other than this, no additional major gene for typical Dravet Syndrome is known. In a recent paper in Neurology, de novo mutations in GABRA1 and STXBP1 are identified as novel causes for Dravet Syndrome. In addition, several SCN1A-negative patients were shown to have mutations in SCN1A that were initially missed. Continue reading

The endozepine mystery

Compound unknown. GABA is the main inhibitory neurotransmitter in the Central Nervous System and its effect is mediated through GABA receptors. Benzodiazepines are compounds that reinforce the action of GABA in the brain, which gives them antiepileptic properties. Consequently, benzodiazepines are one of the most common groups of antiepileptic drugs used to interrupt acute epileptic seizures. Interestingly, benzodiazepines have their own binding site on the GABA receptor, suggesting that they might actually mimic the effect of another, yet unknown substance that is present in the brain. The identity of this mysterious substance, the endogenous benzodiazepine or endozepine, has been one the romantic mysteries of neuroscience. Now, a recent paper in Neuron provides strong evidence that products of the DBI gene are the long-sought endozepine. Continue reading

Epileptic encephalopathies: de novo mutations take center stage

The de novo paradigm. De novo mutations play a significant role in many neurodevelopmental disorders including autism, intellectual disability and schizophrenia. In addition, several smaller studies have indicated a role for de novo mutations in severe epilepsies. However, unless known genes for human epilepsies are involved, findings from large-scale genetic studies are difficult to interpret. De novo mutations are also seen in unaffected individuals and only very few genes are observed more than once. Now, a publication in Nature by the Epi4K and EPGP collaborators uses a novel framework to tell pathogenic mutations from genomic noise. Their study provides very strong evidence for a predominant role of de novo mutations in Infantile Spasms and Lennox-Gastaut Syndrome. Continue reading