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

This was epilepsy genetics in 2021 – five things to remember

Looking back. Admittedly, I have not written an end-of-the-year review for a quite some time. However, there were a few notable moments in epilepsy genetics in 2021 that I think were worth remembering. The second year of the COVID-19 pandemic started out as a year of recovery and readjustment, only to run into unanticipated supply chain issues and novel COVID variants hanging over our transition into 2022. The scientific community was affected by these developments in different ways that made progress of science somewhat unpredictable and uneven. 2021 was the year when the phrase “unprecedented times” became stale and overused. Here are five things to remember from 2021, which will be remembered as part of a transitional phase in epilepsy genetics. Continue reading

This was AES 2021 – five takeaways from Chicago

Pandemic. This year’s Annual Meeting of the American Epilepsy Society (AES) was the 75th meeting, but it was a meeting like no other. #AES2021 was the first in-person meeting for the international epilepsy community with many international participants unable to join due to local restrictions and the US-based audience split between participating in-person and joining remotely. However, despite the unusual format, this year’s meeting was bustling and full of excellent science. Here are my five takeaways from AES 2021. Continue reading

STXBP1-related disorders: deciphering the phenotypic code

STX. Neurodevelopmental disorders due to disease-causing variants in STXBP1 are amongst the most common genetic epilepsies with an estimated incidence of 1:30,000. However, despite representing a well-known cause of developmental and epileptic encephalopathies in the first year of life, relatively little has been known about the overall genetic landscape and no genotype-phenotype correlations have been established. In our recent publication including almost 20,000 phenotypic annotations in 534 individuals with STXBP1-related disorders, we dive deep into the clinical spectrum, examine longitudinal phenotypes, and make first attempts at assessing medication efficacy based on objective information deposited in the Electronic Medical Records (EMR), including information from the almost 100 “STXers” seen at our center in the last four years. Continue reading

Introducing the revised Human Phenotype Ontology (HPO) – a new language for Big Data in the epilepsies

Classification. Our classification of the epilepsies periodically undergoes revision to align the way we think about the epilepsies with scientific progress in the field. While it is intuitive that relatively novel frameworks such as the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types capture the current spirit of the field more accurately than prior classifications, one relatively simple question is not easily answered: how much more accurate? How we get to such an answer requires us to take a step back and think about how the value of clinical information can be measured and compared. In our recent publication, we describe the revision of the Human Phenotype Ontology (HPO) according to the most recent ILAE classifications and other respected definitions in current use. This gives the answer to the prior question: 40% (which is a lot). Continue reading