AP4S1 in fever-associated epilepsies and spastic paraplegia

Peds vs. adult. Sometimes it makes a fundamental difference in diagnosis whether a patient is seen in a pediatric setting or by an adult specialist later in life. Here is the most recent example from our consortium, which was just published in Human Molecular Genetics: what initially looked like recessive inheritance with intellectual disability and a peculiar fever-associated epilepsy syndrome eventually turned out to be the second reported family of the novel spastic paraplegia gene AP4S1. This raises the question of how much we are missing if we are looking at the wrong point in time. Let’s have a look at how genetics can help us see an overlap of diseases where we usually don’t have a chance to. Continue reading

Beyond recessive – KCNC1 mutations in progressive myoclonus epilepsy

PME. The progressive myoclonus epilepsies (PME) are a particular subtype of seizure disorders characterized by progressive myoclonus, generalized seizures and cognitive deterioration. Known causes of PME include recessive mutations in several well-known genes, but the genetic cause is unknown in a significant proportion of patients. Now, in a recent paper in Nature Genetics, de novo mutations in KCNC1 are identified as a novel cause of progressive myoclonus epilepsies. In addition to elucidating the genetic basis in a significant subset of patients with PME, the authors demonstrate that de novo mutations play an important role in a group of diseases usually thought to be recessive. 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

The three challenges of epilepsy precision medicine

Half Moon Bay. I am on my way back from the Precision Medicine Workshop at Half Moon Bay, realizing again that blog posts from scientific meetings are often boring and difficult to write. However, let me try to put together a few thoughts about this meeting. Basically, there are three challenges for epilepsy genetics in the era of precision medicine. Continue reading

Dynamin 1, the synapse, and why epilepsy gene discovery is now officially over

E2 consortium. Infantile Spasms and Lennox-Gastaut Syndrome are two epilepsy syndromes with a strong genetic component. De novo mutations play an important role in genetic epilepsies. However, given the overall mutational noise in the human genome, telling causative genes from innocent bystanders is difficult. In the largest and most comprehensive analysis so far, our E2 consortium just published a joint analysis of 356 patient-parent trios, which were analyzed by exome sequencing. In addition to implicating DNM1, GABBR2, FASN, and RYR3, this publication sends a clear message: the age of gene discovery in epilepsy is over – from now on, genes will find themselves. Let me tell you what I mean by this. Continue reading

How to find recessive disease genes for epileptic encephalopathies

The E2 story continues. There has been major progress in identifying the role of de novo mutations in infantile spasms and other epileptic encephalopathies. Over the last two years, more than 20 new genes for epileptic encephalopathies were discovered and we have good evidence suggesting that de novo mutations play a major role in these disorders. Moreover, we have gotten a good sense on how complicated it can be to call a de novo mutation pathogenic given the flood of rare genetic variants in the human genome. However, de novo mutations are not what we think about clinically when assessing a patient with new-onset epileptic encephalopathy. In a clinical setting, we are often concerned about underlying metabolic disorders, many of which are recessive. Accordingly, we felt that the next task of the E2 consortium was to assess the role of inherited variants in epileptic encephalopathies. Just to tell you in advance, it is not as easy as it sounds.

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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

Living in a post-linkage world, craving knowledge

Genomics meets linkage. This blog post is about family studies in epilepsy genetics. One of my tasks for the next two months is to write the “Trilateral Grant” – we were invited to submit a full proposal for a German-Israeli-Palestinian grant by the German Research Foundation (DFG) on the genetics of familial epilepsies. As keeping up our blogging schedule will be my other big task for the coming months, I thought that I could combine both and explore some topics regarding family studies on this blog. Let’s start with a sobering fact – small dominant families remain difficult to solve, not because of too little but rather too much genetic data. 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

The final EuroEPINOMICS General Assembly – Impressions from Helsinki

Time flies by. Last week, we have had the final General Assembly of the EuroEPINOMICS project in Tuusula, Finland. All four projects of the EuroEPINOMICS consortium presented the current, ongoing projects and it’s good to hear that there are multiple publications in various stages coming up. Over the three years of the consortium, the diverse groups grew closer together. During this meeting many unpublished results were shown, including extension of studies on genes such as HCN1, CHD2GRIN2A, GRIN2B or RBFOX1 as well as more data on epigenetics in acquired epilepsy.

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