Should we stop talking about heritability in 2014?

Genetic epidemiology. Long before the first epilepsy gene was discovered, clinicians and researchers were wondering about a genetic contribution to epilepsy. Some epilepsy syndrome were found to run in families in an autosomal dominant or recessive pattern. In other epilepsies, there was an obvious excess of affected family members in the immediate or extended family. And this is how we got stuck with the concept of heritability. Let’s review the perils and pitfalls of heritability and ask the question whether we should retire this concept in the current era of genomic medicine. Continue reading

Twisting DNA and seizures: TDP2 mutations in neurodegeneration with epilepsy

Torsional stress. The DNA double helix has one major problem that we know from telephone cords: it is difficult to untangle. However, our DNA is constantly twisted and untangled for gene transcription. This constant twisting and untwisting produces torsional stress that is relieved by topoisomerases. A recent publication in Nature Genetics now identified a human neurological phenotype that is caused by faulty activity of this mechanism: neurodegeneration with epileptic encephalopathy. However, there are some features of the phenotype that are not easily explained by erroneous DNA twisting. Continue reading

Three things about 16p11.2 duplications in Rolandic Epilepsy that surprised us

In depth. Last week, we briefly mentioned the publication by Reinthalter and collaborators on 16p11.2 duplications in Benign Rolandic Epilepsy. At first glance, you might think that Eva’s publication may just be another description of a microdeletion in another type of epilepsy. However, nothing could be further from the truth. It’s a game changer. Here are three reasons why. Continue reading

When will we have the $1000 epilepsy genome?

Falling prices. The initial Human Genome Project took 10 years and cost more than $3 billion US Dollars. The $1000 genome catch phrase was first used in 2001 and indicated that prices would need to fall significantly to allow for genome sequencing to be used for routine diagnostics. Currently, in 2014, the $1000 genome seems on the horizon. However, will we ever have a $1000 epilepsy genome? Continue reading

Magnesium, epilepsy, and CNNM2 mutations

Electrolytes. Sodium, calcium, and magnesium – I usually tell my students that imbalances in these serum electrolytes may result in seizures, when levels fall under a critical threshold. Amongst these imbalances, hypomagnesemia, a reduction of the serum magnesium level below 0.7 mmol/L, is a very rare cause of seizures, particularly in a pediatric population. However, there are genetic conditions that result in reduced magnesium levels and lead to neurological complications. In a recent paper in PLOS Genetics, the phenotype of CNNM2 mutation carriers is investigated – and magnesium is only the beginning of the story. 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

Precision medicine in genetic epilepsies – three criteria to consider

Three criteria. You hear the phrase precision medicine quite frequently these days and might wonder what this is all about. In a nutshell, in the context of genetic epilepsies, the basic idea behind precision medicine is to use genetic patient information for treatment decisions. The broader vision behind this aims at improving the lives of individuals with epilepsy by making smarter and faster treatment decisions, which lead to better treatment response and fewer side effects. But how should we assess information on reports of precision medicine in the literature? Here are the three important criteria to assess. Continue reading