Misusing the concept of epileptic encephalopathy – on purpose

EEs. The concept of epileptic encephalopathy refers to a process where epileptic activity impairs overall brain function, including cognitive function, language, and behavior. In a recent commentary in Epilepsia, our current use and misuse of the concept of epileptic encephalopathy is reviewed critically. In summary, the authors criticize that epileptic encephalopathy is used as a diagnostic category rather than a description of the actual epileptic process, suggesting that another term may be necessary for the group of patients with intellectual disability and epilepsy where we often find a genetic etiology. In this blog post, I would like to plead guilty on behalf of the epilepsy genetics community for having misused the concept of epileptic encephalopathies for almost a decade. And we have done this for at least three different reasons. Continue reading

SCN1A and Dravet Syndrome – your questions for the Channelopathist

Comments. After posting our 2015 update on what you should know about SCN1A, we received a number of comments on our blog and by email. We usually have the policy to respond to every comment individually. However, after we had realized that we had fallen behind with a few replies for several weeks, we felt that it might be worthwhile rephrasing some of the questions as general topics to write about, especially since many of your questions raised interesting points. Here are the questions that you asked regarding SCN1A and Dravet Syndrome. Continue reading

USP9X, Ubiquitin, and the PRICKLE interactome

PRICKLE. There are some genes implicated in human epilepsies that we have a hard time making sense of. PRICKLE1, implicated in a recessive progressive myoclonus epilepsy, is one of these genes. In a recent publication in PLoS Genetics, the interactome of the enigmatic PRICKLE proteins is explored. The authors rediscover an almost forgotten gene implicated in intellectual disability. Continue reading

Sequencing for developmental disorders on a national level – the DDD(UK) study

DDD. It’s probably the most impressive of all exome sequencing studies of 2014 and I almost missed it. Late December last year, the Deciphering Developmental Disorders study was published in Nature, reporting the genetic findings in more than 1,000 patient-parent trios, which were collected in a systematic nation-wide approach in the United Kingdom and Ireland. The analysis of more than 1,600 de novo mutations in this cohort provides another fascinating view into the genetics of neurodevelopmental disorders, independently confirming the role of DNM1 and pointing out several genes that act through either activating or dominant-negative mutations. Let me guide you through a study that comes to the sobering conclusion that even entire nations are too small to understand the genetics of neurodevelopmental disease. Continue reading

SCN8A encephalopathy – and how it differs from Dravet Syndrome

Nav1.6. For some reason, SCN8A always met some resistance. In contrast to other epilepsy genes, it took a while for the community to embrace this gene as a genuine cause of epileptic encephalopathies. A recent publication in Neurology now investigates the phenotypic spectrum of SCN8A encephalopathy – and points out important features that distinguish this condition from Dravet Syndrome. Continue reading

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

PURA mutations and when diverse phenotypes become a single syndrome

Reverse. With the increasing amount of genetic information available in patients with various neurodevelopmental syndromes, some genes will be observed more than once in patients. In a recent study in the Journal of Medical Genetics, the authors trace back the phenotypes of individuals carrying de novo mutations in PURA. However, there seems to be a wide range of clinical features with a seemingly inverse genotype-phenotype correlation. 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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