Epilepsy genetics is more than just sending gene panels

Genetic testing. I smiled into my camera during our virtual Wednesday teaching session — pausing for effect. One of our junior team members has just made the statement that one of our patients qualified for a sponsored genetic testing program. I politely corrected them: “I think what you wanted to say was that this program qualifies for doing genetic testing on our patient”. The focus of epilepsy genetics is changing, shifting away from genetic testing to what genetic tests mean and how we can use them for better treatment. However, getting to a diagnosis requires the ability to perform genetic testing in the first place. And the framework for how this can be accomplished is vastly different within the US and internationally. In this second blog post on our review on epilepsy precision medicine, I would like to revisit the current state of genetic testing in the epilepsies. And yes, genetic testing should be standard of care and affordable for people with epilepsy. It’s that simple. Period. Continue reading

The new genetics of Dravet Syndrome

Sundance. I was asked to give a talk on the genetics of Dravet Syndrome at the Dravet Syndrome Foundation meeting in Fort Worth, Texas. I started my presentation asking the question whether there is actually anything novel to talk about given that it is well established that Dravet Syndrome is due to loss-of-function variants in SCN1A, and the challenges are in finding better treatments, not in refining SCN1A genetics. However, this is not quite true. There are several new aspects regarding the genetics of Dravet Syndrome that are worth highlighting. Continue reading

The Accelerando of epilepsy precision medicine

Half Moon Bay. Earlier this week, our precision medicine paper came online in Epilepsia, summarizing the state of the art in epilepsy precision medicine in 2022. This paper was initially inspired by the 2019 Precision Medicine Workshop in Washington, D.C., which was the sequel to our initial Half Moon Bay Conference in 2014. Yes, this was a publication that was almost three years in the making and I would like to give a shout-out to Juliet Knowles for pushing this herculean effort across the finish line. In this post, I would like to revisit what precision medicine actually is, sharing some of our initial thoughts that did not make it into the final version of our manuscript. But let’s first clarify what the Accelerando is. Continue reading

Why we need to understand what happened to child neurology back in March 2020

Looking back. The beginnings of the COVID-19 pandemic seem so long ago. Looking back at the early days of the pandemic from May 2022 may not seem to provide much information. Now that we are more than two years into the pandemic, our understanding, management, and treatment of COVID-19 has significantly evolved. So why would it be important to look back at what happened in the very early stages, especially when we consider pediatric neurological disorders? In brief, examining the early stages of the pandemic can provide insights into the robustness of child neurology care amid a crisis. In a recent publication, we did just this. Using data from more than 27,000 patients in seven pediatric tertiary care centers, we looked back at what happened to hospital-based child neurology care in the first six weeks of the Shelter-in-Place orders aka the “shutdown”. The results were disturbing. Even for child neurology emergencies, we found more than a 50% reduction of hospital admissions. In this blog post, we would like to review how the initial shutdown shook the foundations of child neurology. Continue reading

KCNC2 – a novel epilepsy gene harbors an unusual phenotypic spectrum

Shaw. It has been a while since we have written about novel gene discoveries in the epilepsies, so I wanted to start this blog post with a general introduction to the genes that are still undiscovered, waiting to be identified. Currently, we assume that there are several hundred genetic etiologies for human epilepsies “out there” that we have not characterized yet. One of the most recent members to join the group of epilepsy genes is KCNC2 that we described in a recent publication. KCNC2, coding for a member of the Shaw-related voltage-gated potassium channels, presents with a phenotypic spectrum that is different from many other epilepsy genes. Continue reading

Disease burden in genetic epilepsies – five things to know

Disease burden. One aspect of neurodevelopmental disorders that we cover insufficiently on our blog is how epilepsy affects families. Not just the symptoms of seizures and developmental delay, but how the overall burden of developmental and epileptic encephalopathies (DEEs) affects the quality of life of patients. In a recent study, we took a first step towards measuring quality of life and assessing to what degree seizure control and quality of life in DEEs are related. To our surprise, we found that objective seizure control and quality of life are unrelated. In contrast, quality of life is related to a more nuanced measure, the number of days that were minimally disrupted by seizures.

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ANO3, SCN1A, IL10 – the new genetics of febrile seizures

GWAS. Febrile seizures affect up to 5% of all children between six months and six years and are by far the most common seizure type. While seizures in the setting of fever may be a manifestation of an underlying epilepsy, in the majority of cases, children only have one or two febrile seizures in their lifetimes. We know from twin studies that there is a strong genetic component to febrile seizures, and you might think that we would know more about the most common seizure type. However, this has not been the case until recently. The genetics of febrile seizures have been largely understudied, and we know much more about the genetics of rare epilepsies than about the genetics of febrile seizures. A recent genome-wide association study has been a game changer, highlighting a combination of fever response genes and neuronal genes in the etiology of febrile seizures. Continue reading

The zebra finch people – the genetics of stuttering in 2022

Area X. Zebra finches are a small bird species that originate from Australia and can be found all around the world. They are highly social birds and even though some zebra finches may sometimes get aggressive when defending their territory, they are generally polite if unprovoked. Seven percent of all zebra finches have interruptions and repetitions in their bird songs which is a naturally occurring variation on how zebra finches communicate. When the same phenomenon occurs in humans, it is referred to this as dysfluency or stuttering. Even though there are many myths around the causes of stuttering, developmental stuttering, the most common form of dysfluency, is a neurodevelopmental disorder with a strong genetic component as shown by twin and family studies. Dysfluency is also a phenomenon that I know extremely well given that I am a person who stutters myself. In 2013, I wrote my first blog post on the genetics of stuttering, telling the story of how my differently wired brain tripped up an epilepsy neuroimaging study. Here is a 2022 update on one of the fascinating conditions that contributes to human neurodiversity. Continue reading

A large-scale analysis of KCNQ2 variants – overcoming the functional bottleneck

KCNQ2. I have to admit we have not written about KCNQ2 for a while, which does not do justice to the role of KCNQ2 in human epilepsies. KCNQ2-related epilepsies represent some of the most common genetic epilepsies and almost exclusively present with neonatal seizures. Historically, KCNQ2 was identified in families with self-limiting neonatal seizures. Subsequently, disease-causing variants were also identified in neonatal developmental and epileptic encephalopathies (DEEs). While self-limiting epilepsies were attributed to protein-truncating variants, KCNQ2-related DEEs are attributed to dominant-negative variants. However, as in many other DEEs, this conceptual black-and-white distinction is somewhat oversimplified, and the genotype-phenotype correlation in KCNQ2-related disorders is more complex. In a recent study, we assessed a total of 81 KCNQ2 variants’ functional effects in parallel, leading to some unexpected results about the function of disease-related KCNQ2 variants. Here is what this first large-scale electrophysiological analysis of an epilepsy-related ion channel told us. Continue reading