The two faces of GABRA1 – from familial epilepsy to epileptic encephalopathy

Inhibition. GABA is the main inhibitory neurotransmitter in the the Central Nervous System. Given that epilepsy is typically associated with increased excitability, all mechanisms related to GABA signaling are of natural interest to the epilepsy community. Almost 15 years ago, mutations in GABRA1, coding for alpha-1 subunit of the GABA-A receptor, have been identified in familial Juvenile Myoclonic Epilepsy, but there has been relative silence around this gene since. Now, two publications highlight the other side of GABRA1 as a gene for epileptic encephalopathies, putting the GABA receptor into the spotlight again.

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Nothing’s for sure, that’s for sure: Evaluating variants of uncertain significance

VUS. In recent EpiGC posts, we discussed how laboratories evaluate sequence variants and the challenges of communicating variants of uncertain significance (VUS) to patients. While VUS results can be frustrating, by working together clinicians and laboratories may accumulate additional evidence that enables a more definitive variant classification. But how, you ask? Well, there are several ways . . .

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The GRIN spirit – entering a new era of collaborative pediatric genomics

Completed. Last week, we completed the recruitment for one of the more visionary projects at CHOP that we are involved in – the epilepsy pilot project of the Genomics Research and Innovation Network (GRIN), a collaboration between CHOP, Boston Children’s Hospital, and Cincinnati Children’s Hospital. Here is my personal take on GRIN and why I think that forming, building, and expanding GRIN is so important in our current research environment. Continue reading

Five things I learned about SCN2A in Chicago

SCN2A. Last Thursday, I hopped on a plane to Chicago to join the first FamilieSCN2a Foundation Conference. SCN2A, one of the most common genes in genetic epilepsies, has emerged as a gene with a broad range of phenotypes, which makes understanding this gene relatively complicated. I am very happy that the SCN2A community is currently coming together to provide a platform for patient initiatives and connections to clinicians and researchers. Here is my list of five things I learned about the genetic shape-shifter in Chicago. Continue reading

Zeroing in on FAME – the dilemma of familial epilepsies

FAME. Some familial epilepsy syndromes are notoriously resistant to gene discovery. Familial Adult Myoclonus Epilepsy (FAME), a rare but distinct familial epilepsy, has been one of the familial epilepsy syndromes that has been around for more than a decade. Despite the power of modern massive parallel sequencing technologies, this syndrome has been hard to tackle.  In a recent publication, we take a small step in narrowing down the region for the FAME gene. Let’s use this opportunity for a reality check of the somewhat disappointing state of gene discovery in familial epilepsies in 2016 and what we can do about this. Continue reading

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

Where the genes have no names – KIAA2022 in epileptic encephalopathy

No name. The speed of gene discovery in human epilepsies is sometimes so fast that genetics beats biology. Some genes are implicated in disease faster than our ability to name them. In a recent publication, we describe the epilepsy phenotype of an X-linked gene that is only known by an identifier that indicates how little we know about it: KIAA2022. In contrast to a phenotype in males that is mainly characterized by intellectual disability, de novo mutations in KIAA2022 in females results in intractable myoclonic epilepsy. Continue reading

RORB in generalized epilepsy with absences – going retinoic

Retinoic receptor. A few years ago, when exome sequencing was still in its infancy, our group in Kiel identified a small de novo in frame deletion in a gene that we didn’t know how to interpret. In frame deletions that do not disturb the reading frame, but simply take one or several amino acids out, are usually less suspicious and are sometimes even filtered out by the algorithms that we and others typically use. We dismissed this finding for several years. However, a year ago, the plot thickened when other groups mentioned that they had found the same gene in their patients, including a family with six affected individuals. In a recent publication, we describe the improbable story of RORB, the latest gene for generalized epilepsies with prominent photosensitivity and absence seizures. Continue reading

SCN1A – what’s new in 2016?

The story of SCN1A. Variants in SCN1A were first reported in association with epilepsy in 2000, when familial heterozygous SCN1A missense variants were identified in two large families with GEFS+. The phenotype was characterized by incomplete penetrance and significant variable expressivity between family members, making it clear from the beginning that the SCN1A story would not be simple. Within the next few years, we learned that SCN1A variants could cause a wide spectrum of epilepsy phenotypes, including GEFS+, Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures, and, less frequently, infantile spasms and simple febrile seizures. As it became clear that SCN1A variants played an important role in genetic epilepsies, focus turned towards understanding the mechanism underlying seizure genesis, as well as identifying management and therapy options. Even after 15 years of study, our understanding of SCN1A-related epilepsy is still evolving. Keep reading to learn more about the most recent discoveries related to SCN1A. Continue reading

Explaining variants of uncertain significance – a guide for clinicians

VUSThe dreaded variant of uncertain significance. With the advent of next generation sequencing panels and exome sequencing, what used to be an occasional laboratory finding in epilepsy has now become a daily occurrence. Lab reports detailing multiple VUS findings for an individual patient have become a routine part of clinical practice. How do you, as a healthcare provider, explain the meaning and implications of VUS findings to patients and families in a way that is understandable to them?  Continue reading