The many faces of KCNA2: a 2017 update

KCNA2. We have previously discussed KCNA2 and that pathogenic variants in this gene can lead to a spectrum of neurological phenotypes. Pathogenic KCNA2 variants were first recognized in individuals with early-onset developmental and epileptic encephalopathies and have subsequently been found also in individuals and families with hereditary spastic paraplegia, episodic ataxia, and milder epilepsies. KCNA2 encodes the Kv1.2 potassium channel, a delayed rectifier class of potassium channel that enables neuronal repolarization after an action potential. A new study by Masnada and colleagues provides clinical and functional data from 23 patients, representing the largest KCNA2 cohort reported to date. Within the KCNA2-related encephalopathy spectrum, it now seems that there may be three distinct phenotypes. Continue reading

The rising role of synaptic transmission: the calcineurin link

Synaptic transmission. Over the last several years, pathogenic variants in multiple genes involved in synaptic transmission have been identified in early-onset epilepsies. STXBP1 and STX1B both encode components of the SNARE complex, a complicated protein complex that mediates the fusion of the plasma membrane of the presynapse and the synaptic vesicle to allow for neurotransmitter release. DNM1, encoding the dynamin-1 protein, plays an essential role in recycling synaptic vesicles back into the presynapse after neurotransmitter release. A new study by Myers and collaborators has identified several patients with de novo variants in PPP3CA, which encodes another protein involved in synaptic vesicle recycling, further highlighting the importance of synaptic transmission in the etiology of severe neurodevelopmental disorders. In the interest of full disclosure, I am also a co-author on this study. Continue reading

KCNB1 encephalopathy – widening the phenotypic spectrum

KCNB1 encephalopathy. Pathogenic variants in KCNB1 were first reported three years ago in three unrelated patients with an early-onset epileptic encephalopathy. Since the initial report, individual patients have been reported with de novo KCNB1 variants, but a comprehensive overview of the KCNB1 encephalopathy clinical picture has been lacking. A recent publication by de Kovel and colleagues provides a comprehensive overview of the clinical features and genetic variants in 26 individuals with KCNB1 encephalopathy, including 16 previously unreported patients, providing novel insights into the phenotype. In this post we will unpack this publication, including what new information about KCNB1 it tells us. Continue reading

Genetic testing in early-onset epilepsies: approaching a new consensus?

Early-onset epilepsies. In recent years, we have discovered several causative genes for severe epilepsies beginning in the first year of life, including KCNQ2, SCN2A, and STXBP1. Several studies have reported a high yield of diagnostic genetic testing, including NGS panel approaches and whole exome sequencing, particularly in patients with seizure onset in the neonatal period where detection rates are often reported to be above 50%. Two recent studies add to the growing pile of evidence that genetic testing, and in particular NGS-based testing methods, are valuable in the diagnostic workup of children presenting with seizures early in life. Will these two studies help push us towards a new consensus regarding genetic testing in epilepsy?

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SCN1A-related epileptic encephalopathy: Beyond Dravet syndrome

SCN1A phenotypes. Readers of Beyond the Ion Channel will know that we often post about SCN1A, one of the first discovered and most common genetic causes of epileptic encephalopathy. We more or less assume that we understand the phenotypes associated with pathogenic variants in SCN1A: most commonly Dravet syndrome, which is associated with de novo variants, and less commonly genetic epilepsy with febrile seizures plus (GEFS+), associated with inherited missense variants. However, a recent publication by Sadleir and colleagues suggests that the phenotypic spectrum of SCN1A-related disorders may be broader than we have previously appreciated. Are there SCN1A-related epileptic encephalopathies in addition to Dravet syndrome? Continue reading

Five things I learned at the FamilieSCN2a Annual Family and Professional Conference

FamilieSCN2A. On July 14th and 15th, Ingo and I had the pleasure of speaking at the FamilieSCN2a Annual Family and Professional Conference, which was hosted at the DuPont Children’s Hospital in Wilmington, Delaware. This meeting brings together families of children and young adults with SCN2A-related disorders and medical professionals and scientists working in the field, with the purpose of sharing information, learning from one another, and moving the field forward. This post won’t be a comprehensive recap of all that was discussed, since we heard from a broad range of professionals including therapists, electrophysiologists, epidemiologists, neurologists, and geneticists and it would be nearly impossible to sufficiently summarize everything. But I did want to share some of my impressions and thoughts. Here my five things I learned at the FamilieSCN2a Conference. Continue reading

A clinician’s guide to genetic test selection: navigating the Wild West

The Wild West. The diagnostic genetic testing landscape in 2016 is a paradox. In theory genetic testing has never been more widely available clinically, with over 20 diagnostic laboratories in the US alone offering a variety of genetic testing options for patients with epilepsy, ranging from single gene testing to NGS panels to whole exome sequencing. However, access to and reimbursement of genetic services varies widely, with no consensus on an approach to testing or professional guidelines to aide clinicians. Here is our brief guide to epilepsy genetic test selection for busy clinicians. Continue reading

Three Things I’ve Learned from Living with the Channelopathist

Today is a big day here at Beyond the Ion Channel – it’s Ingo’s birthday. I clearly remember celebrating Ingo’s birthday a decade ago, while we were living and working together in Melbourne. Back then, life was a little simpler. We were just beginning our careers together at the Epilepsy Research Centre and were a little more fresh faced and greener behind the ears. The GGEs were still the IGEs. Mutation screening was done via dHPLC. Family studies were still the way to go. Genetics was largely confined to the research realm and not a possibility for most patients in clinical practice. A lot has changed in epilepsy genetics in 10 years, and I have been fortunate to have my career run alongside Ingo’s during that time, sometimes running parallel to his and sometimes intertwining. We’ve learned a lot from each other. So what do you give someone like Ingo for his birthday? A blog post, of course. But don’t worry, it won’t be overly sentimental. As Ingo mentioned before, that’s not our style. Here are three things I’ve learned about epilepsy genetics from Ingo over the last ten years. Continue reading

Charting a bioethical gray zone: genotype-driven research recruitment

The need for re-contact. Genotype-driven research recruitment refers to the inclusion of research participants in future genetic studies based on the findings from previous studies.  For example, deep sequencing efforts within the EuroEPINOMICS Consortium may generate potentially interesting novel variants that warrant further investigation.  In some cases, it might be necessary to obtain more phenotypic information, in other cases, segregation in the family might be of interest.  Since many variants are rare in the general population, genotype-driven approaches are particularly attractive, i.e. research participants are selected based on genetic findings.  This so-called “bottom up” approach allows for targeted studies without the time-consuming and expensive step of re-screening large patient cohorts.  In the future, genotype-driven research efforts will likely become increasingly common, since it is unlikely that large-scale genomic studies alone will be able to sufficiently characterize rare genetic variants.  However, approaching patients based on genetic research data raises important questions. Continue reading

Next Generation Ethics: Struggling with petabyte consent forms

Everyone involved in research with human subjects knows about the importance of informed consent.  The purpose of informed consent is to promote educated decision-making and voluntary participation in research.  Whether or not you’re aware of the fundamental ethical principles underlying the process (patient autonomy and protection from harm, for those keeping score at home), you at least know that you have to get the study participant to sign the form. Continue reading