Modifier genes. When I compiled the most important updates on SCN1A genetics a few weeks ago, I forgot one of the most unusual studies that makes you pause and think. To provide some background: ever since the initial discovery of familial epilepsy syndromes such as Genetic Epilepsy with Febrile Seizures Plus (GEFS+), the intrafamilial range of presentations has been a big mystery. Within single families, we typically observe a very broad spectrum of phenotypes. Furthermore, in some families, the range of phenotypes is extreme – the same SCN1A variant may cause Dravet Syndrome in one individual, while other individuals are unaffected. In a recent study, we stumbled upon an unusual cause for this variability: a second SCN1A variant that neutralizes the pathogenic effect of the familial variant. Here is a summary of this unusual story. Continue reading
Category Archives: 2022
Understanding development and seizures in STXBP1 disorders
STX. I have to admit that the main gene that our team is working on has received relatively little attention on our blog, even as several manuscripts on STXBP1 have recently been published that add to our understanding of STXBP1-related disorders. I described STXBP1 at the Simons Foundation’s INSYNC-AS meeting as one of the genes with the “fastest growing knowledge,” now following close behind recognized neurodevelopmental disorders including Rett and Angelman Syndrome. In this post, I would like to feature one of our recent publications in Neurology Genetics that assessed the developmental trajectory of 48 individuals with STXBP1-related disorders. In particular, I would like to zero in on the most important result of this study, which expands on one of the controversies in the STX field. Continue reading
CACNA1A, hemiplegia, and the genetic of migraine
FHM. Each time I mention CACNA1A and its association with migraine to clinicians and scientists outside the field of pediatric neurology or neurointensive care, I need to take one step back. Yes, CACNA1A is one of the monogenic causes of hemiplegic migraine, but the clinical condition that we are typically concerned with has relatively little to do with common migraines. In contrast, we are talking about a neurodevelopmental disorder often associated with developmental concerns, ataxia, epilepsy and episodes of hemiplegia that may results in brain swelling and can be life-threatening. This condition, typically referred to as familial hemiplegic migraine type 1 (FHM1), neither runs in families nor does it typically result in migraine features. The historical naming conventions complicate awareness of one of the most enigmatic events in neurology, which we refer to as hemiplegic migraine episodes for a lack of a better word. However, I wanted to approach CACNA1A from a different perspective, given the recent publication of a large migraine genetic study in Nature Genetics. Continue reading
When telemedicine in child neurology does not work as expected
Telemedicine. Admittedly, this is a strange title for a blog post. This is a blog on epilepsy genetics, so why do we concern ourselves with telemedicine again? To make a long story short, telemedicine was the main avenue for outpatient child neurology care during the early phases of the pandemic. In the later phases of the pandemic, many centers have used a hybrid care model of in-person and telemedicine care. Evaluations for epilepsy genetics are more frequently performed via telemedicine than other child neurology indications, at least at some centers. Accordingly, for an epilepsy genetics team, understanding how well telemedicine works is highly relevant. Typically, scientific publications emphasize the successes of telemedicine. However, in a recent publication, we asked the opposite question: what happens when telemedicine does not work? Continue reading
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.