Do you want to build a snowman? During this weekend, winter storm Jonas descended upon the Eastern United States. Delaware County became covered under about two feet of snow, basically shutting down public life in the Philadelphia and the surrounding suburbs. Being trapped in the house with the kids exhausted from playing outside gave me the opportunity to catch up on my blogging duties and to engage in creative writing. Besides a reference to the 1994 Weezer alternative rock anthem, here is what snow storm Jonas told me about science. Continue reading
This is what you need to know about PRRT2 in 2016
PRRT2. Finally, in 2016, I have managed to put a blog post together on the most common gene for benign epilepsies in the first year of life. Even though the PRRT2 gene was only discovered in 2011, it has become the most common cause of self-limiting infantile epilepsies. Despite its prominent role in human disease, the function of the PRRT2 protein remains unclear and it is assumed that it plays an important role in the presynapse. Here is what we know about PRRT2 in 2016. Continue reading
Areas of uncertainty – an unusual introduction to 2016
Happy 2016. Talking about things we don’t know or are not sure about may be a strange introduction to a new year that is full of promises for the field of epilepsy genetics. However, there were two questions during the holidays that carried over from 2015 into the new year that I didn’t know the answer to and that we repeatedly discussed in our group. Two relatively simple questions: Can we give lamotrigine to a patient with GEFS+ -not Dravet Syndrome– and a mutation in SCN1A? Should we withhold valproic acid from a patient with a single POLG mutation identified through diagnostic gene panel? You feel that you know the answer to these questions, but what is actual data and what is only inference? Follow me through a brief discussion on why we need to be careful when it comes to claiming knowledge that we don’t really have yet. Continue reading
The top 10 blog posts of 2015
2015 in review. This year has been a very busy year on Beyond the Ion Channel and this is my time to thank our contributors and readers. This blog and the Epilepsiome project have become an essential part of what I am doing. I am very thankful for all the feedback and advice that I have received this year. We have also finally launched the Epilepsiome project this year, the gene curation project of our epilepsy genetics community. As a summary of 2015, we have put together a summary of the most popular posts of 2015. Continue reading
My three holiday reads – reflections on science and life
The holiday season. On Dec 25th, I was forced to disable the long-range communication device of the Stellosphere – and all I had was a simple screwdriver. It was a tough choice, but when you’re out there by yourself, you have to make bold choices. If you now believe that I have a MacGyver-like engineer skillset, I hate to disappoint you. All I did was take out the batteries of one of the toys that our kids got for Christmas so it would stop making noise every time you touch it. Here are the three books that I am trying to read over the holiday season. I probably won’t get through them completely as I want to spend as much time with my family as possible, but here is what they have told me about epilepsy genetics so far. Continue reading
An unexpected twist in the SCN8A story – benign infantile seizures and dyskinesia
Completing the SCN8A spectrum. SCN1A was initially discovered in GEFS+, an autosomal dominant familial epilepsy syndrome. SCN2A was first identified in Benign Familial Neonatal-Infantile Seizures (BFNIS), also representing an autosomal dominant familial epilepsy syndrome. SCN8A, the third epilepsy-related sodium channel gene, has only been associated with severe, sporadic cases so far, not with more benign familial epilepsies. In a recent publication in Annals of Neurology, a novel recurrent mutation in SCN8A is identified, which causes benign infantile seizures and paroxysmal dyskinesia. While this finding adds the missing familial epilepsy syndrome to SCN8A, it also provides an intriguing link to the phenotypes caused by PRRT2. Continue reading
DEPDC5 – this is what you need to know in 2015
DEPDC5. We have selected DEPDC5 to be our gene of the week. DEPDC5 is currently the most common known gene for focal epilepsies. DEPDC5 mutations cause familial focal epilepsy with variable foci, an epilepsy syndrome with autosomal dominant inheritance where the affected family members can have different types of focal epilepsies, most frequently frontal lobe epilepsy. Despite seizure semiology that varies among family members, it is constant for each individual. Continue reading
Genome meets phenome to find novel recessive diseases
N=1. Even though many recessive disorders have been identified through next-generation sequencing, there is a major conceptual problem when it comes to interpreting the results of these studies. Recessive disorders are very rare and it is sometimes difficult to assess whether a given variant is truly disease-causing or simply an innocent bystander. A recent study in Nature Genetics has developed a novel concept to identify recessive disorders that rise above the overall genomic noise, finding four novel recessive disorders. In addition, the authors have enhanced their analysis by a statistical analysis of disease phenotypes.
WDR45 – this is what you need to know in 2015
BPAN. We have selected WDR45 to be our Epilepsiome gene of the week. WDR45 was initially identified as the causative gene for a rare phenotype referred to as static encephalopathy with neurodegeneration in adulthood (SENDA), which belongs to a group of neurodegenerative disorders that have accumulation of iron in the CNS as the common feature. In contrast to the narrow and very specific phenotype in most other disorders in this group, the phenotypic spectrum of WDR45 has expanded significantly since the initial discovery in 2013. Mutation in WDR45 can be identified in patients with a broad range of neurodevelopmental phenotypes including epileptic encephalopathies. Continue reading
Glut1 deficiency and Myoclonic Astatic Epilepsy – reassessed
Ketogenic. Several patients with Myoclonic Astatic Epilepsy (MAE) have a surprisingly positive response to the ketogenic diet, even after failing several antiepileptic medications. Given this observation, it is obvious to assume that SCL2A1 mutations play a significant role in MAE, and some earlier studies seemed to suggest that up to 5% of MAE patients carry SLC2A1 mutations. However, in a recent study, we failed to demonstrate a connection between SLC2A1 mutations and Myoclonic Astatic Epilepsy (MAE) in a large cohort of patients. Read more on why the genetics of MAE is an ongoing mystery and why we need a new approach to “keto-genetics”. Continue reading