SCN1A – This is what you need to know in 2014

Update. As information on the epilepsies caused by SCN1A mutations are amongst our most frequently read posts, we thought that a quick update on the state-of-the art regarding SCN1A would be timely. These are the ten things about SCN1A that you should known in 2014.

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.

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.

Treatable causes of intellectual disability and epilepsy that you don’t want to miss

Think metabolic. We have discussed de novo mutations as a cause of epileptic encephalopathies repeatedly on our blog. While there is emerging evidence that de novo mutations in established genes such as SCN1A or CDKL5 or novel genes including GNAO1 or CHD2 are a major cause of genetic morbidity in patients with epileptic encephalopathies, investigations for de novo mutations are not the immediate knee-jerk reaction in clinical practice. In fact, if a child presents with an epileptic encephalopathy, excluding inborn errors of metabolism (IEM) takes priority. While metabolic causes of epileptic encephalopathies are rare, they need to be excluded as some of these conditions are treatable. In a recent review in Molecular Genetics and Metabolism, van Karnebeek and colleagues review the 89 causes of intellectual disability that are potentially treatable. Many of these conditions also present with epilepsy. They present an updated diagnostic algorithm and provide an online resource for these conditions – in a nutshell, there is an app for that. 

New epilepsy genes involved in epigenetics – a survey

A growing number of genes have been identified to be causative for genetic forms of epilepsy, which are neither ion channels, receptors nor other classical epilepsy genes but epigenetic players. The epigenetic enzymes and effector proteins described to be mutated in inherited genetic epilepsies as well as epileptic encephalopathies, intellectual disability syndromes and autism spectrum disorders with associated severe or occasional seizure phenotype are of various function. Since this function never seems to be sufficiently discussed in the respective publications and little is to be found on how these genes may be linked to the phenotype, here comes a little overview summarizing how epigenetics is contributing not only to symptomatic focal epilepsy but may also help to explain the phenotypic heterogeneity of genetic epilepsies.

Infantile Spasms/Lennox-Gastaut genetics goes transatlantic

Joining forces. The EuroEPINOMICS-RES consortium and Epi4K/EPGP are currently joining forces for genetic studies on epileptic encephalopathies. A first collaborative study focuses on de novo mutations in Infantile Spasms and Lennox-Gastaut-Syndrome. In the last two years, after decades of disappointment, we have finally managed to accomplish a breakthrough in understanding the genetic basis of epileptic encephalopathies. The method of trio-based exome sequencing works amazingly well to identify the genetic cause, and the field currently has the crucial momentum to reach the next level of research. Let’s briefly review why we need international collaborations to disentangle the genetic architecture of the epileptic encephalopathies.

Three things you didn’t know about epilepsy and genes

Fall colors. Just a brief summary of how this post originated. Eckernförde is a small city north of Kiel and the weekly Sunday destination of my daughter and me because of the wave pool.  This past Sunday, daylight saving and the fact that she didn’t like her dinner had confused the little girl, and we had been awake since 4AM. As a consequence, she fell asleep on the way, and I kept driving to let her sleep. We made it as far as Haddeby, and I used this time to mentally put a post together that I had been planning for some time. These are the three things that are often misunderstood with regards to epilepsy and genes.

CHD2 encephalopathy as a novel Dravet-like epilepsy syndrome

Negative for SCN1A. Today the first major paper by the EuroEPINOMICS-RES consortium was published in the American Journal of Human Genetics online. As you might recall from some of our previous posts, RES has worked on gene identification in patients with Dravet Syndrome negative for SCN1A using trio exome sequencing. A significant fraction of patients turned out to be positive for SCN1A with mutations initially missed using conventional sequencing techniques. However, there was also a second gene that we discovered in an initial cohort of patients with SCN1A-negative Dravet Syndrome. This gene was CHD2.  While working on the functional studies in zebrafish, CHD2 was also discovered as a novel gene for epileptic encephalopathies by both Carvill and collaborators and the Epi4K consortium. These parallel discoveries clearly highlight the relevance of this gene in human epilepsy and suggest that CHD2 mutations might be more common than mutations in many of the other candidate genes discovered in the last 12 months. In addition, when looking closer, the phenotype of the patients was not exactly Dravet Syndrome, but might represent a novel fever-related epileptic encephalopathy.

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.