Five things to know about PURA

PURA. The title of this blog, Beyond the Ion Channel, is intended to reflect the wide variety of genes that can cause epilepsy and related neurodevelopmental conditions. Our last post on CACNA1A brought us back to channelopathies, so this blog post will again shift our focus. This post will introduce the new gene page for PURA, a gene that we did not feature as prominently as we should have. Here are five things to know about PURA, which is relatively recent to be described as a condition, and is likely more common than originally thought. 

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Unlocking STXBP1 through Electronic Medical Records

Understanding the EMR. Several weeks ago, I gave a presentation at the STXBP1 Summit conference, the third annual meeting since the first in 2019 – a time when I had just entered the field of neurogenetics. It has been fascinating to follow one of the neurodevelopmental genes with the “fastest growing knowledge,” with the expanded scope of clinical studies and emergence of novel avenues for targeted gene therapies on the horizon. However, one of the many projects our STXBP1 team is currently working on takes a somewhat atypical approach – we aimed to map the natural disease history of STXBP1-related disorders based entirely on reconstructed Electronic Medical Records (EMR). Here are some of the challenges we have had to confront and what we learned searching for meaning in the depth of the EMR. Continue reading

CACNA1A – five things to know in 2022

Epilepsy genes. It has admittedly been quiet around the gene pages on our blog and many pages require an update. When we initially launched the Epilepsiome pages, we wanted to create a small resource for gene-based information according to the “what you need to know” principle, a condensed digest regarding epilepsy genes written by clinicians and researchers with deep expertise in the field. We chose CACNA1A as the first gene to get an update. The reason for this is the following: Laina has taken on the role of modernizing this blog and CACNA1A is the main condition that she is working on. Here are five things to know in 2022 about CACNA1A. Continue reading

Epilepsy genetics meets epilepsy surgery – an unexpected link

Presurgical work-up. In 2012, I gave a presentation entitled “Epilepsy genetics for epilepsy surgeons” to a group of epileptologists who mainly work in a presurgical setting. Back then, I was not sure whether anybody in the audience took anything away from this presentation. Traditionally, the thinking surrounding intractable epilepsies is divided, and epilepsies are often considered either genetic or surgical as if both categories were mutually exclusive. In fact, there are many overlaps. A recent review highlights the links between epilepsy surgery and 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

Copy Number Variations in the epilepsies – a 2020 update

CNV. There are different forms of genetic variation and historically, our ability to query the entire exome or genome is a relatively recent development. However, the first type of genetic variation that could be assessed in the epilepsies in large cohorts were copy number variations (CNV), small gains or losses of chromosomal materials. In a recent study, the entire Epi25 cohort was analyzed for CNVs, giving a long-needed update on the role of the structural genomic variations in various forms of epilepsies and highlighting that the overall landscape of CNVs in the epilepsies is well understood and delineated. With up to 3% of individuals with epilepsies carrying some of the recurrent CNVs, this type of genomic variation remains a rare, but important source of genetic morbidity in the epilepsies. Continue reading

Understanding the genetics of FIRES

FIRES. Without a clear trigger, some children suddenly develop super-refractory status epilepticus, ongoing seizure activity that is difficult to control despite maximal therapy in the intensive care unit. In cases when the onset of seizures is preceded by a febrile illness, these rare conditions are referred to as FIRES (Febrile Infection-Related Epilepsy Syndrome). Understanding why children develop FIRES has been an ongoing quest, and the underlying mechanisms are poorly understood. FIRES shares many features with some of the known genetic developmental and epileptic encephalopathies. In a recent study, we tried to understand the genetic basis of FIRES using exome sequencing and HLA sequencing. We were unable to identify genetic causes for FIRES, but we found interesting candidate genes and demonstrated that the genetic architecture of FIRES is substantially different from what we see in other genetic epilepsies. Continue reading

The genetics of Doose Syndrome or Myoclonic Astatic Epilepsy

MAE. There are many distinct childhood epilepsy syndromes that we have become critically aware of in the genomic era as they are linked to prominent genetic causes, including Dravet Syndrome (SCN1A) and Epilepsy of Infancy with Migrating Focal Seizures (KCNT1). However, there are many other epilepsy syndromes where a genetic cause has long been suspected, but has remained elusive. One of the epilepsy syndromes that has largely remained unexplored is Doose Syndrome, also referred to as Myoclonic Astatic Epilepsy (MAE) or Epilepsy with Myoclonic-Atonic Seizures. In a recent study in Epilepsia, we explored the genetic architecture of Doose Syndrome and identified monogenic causes in 14% of individuals, including SYNGAP1, NEXMIF (KIAA2022), and SLC6A1. Our study suggests that Doose Syndrome is genetically heterogeneous, possibly with a distinct genetic landscape. Continue reading