Neonatal seizures. Neonatal seizures can lead to serious consequences for newborns, including long-term morbidity and mortality. In high-resource neonatal intensive care units, screening for seizures with CEEG has become commonplace and is considered standard of care. Accurate seizure prediction can help optimize the allocation of CEEG resources and improve care for critically ill neonates. In our recent study, we aimed to develop seizure prediction models using data extracted from standardized EEG reports. Here is a brief overview of our findings using real-world data to predict seizures in neonates.
KCNA6 – a novel potassium gene in childhood epilepsy
Potassium. The channelopathies are the largest group of genetic epilepsies, and disease-causing variants in genes for neuronal sodium channels, calcium channels, and potassium channels are among the most common causes of genetic epilepsies. However, amongst the various ion channel families, potassium channels stand out due to sheer number. There are more than 70 potassium channel genes encoded in the human genome, and the combination of various subtypes and auxiliary units generates an enormous combinatorial potential. In a recent publication, de novo variants in KCNA6, the gene for the voltage-gated potassium channel Kv1.6, were identified in childhood-onset neurodevelopmental disorders. Here is the somewhat unusual story of the most recent potassium channel gene implicated in human epilepsy. Continue reading
CLDN5, the blood brain barrier, and alternating hemiplegia of childhood
AHC. Amongst the various episodic neurological disorders of childhood, alternating hemiplegia of childhood (AHC) is one of the most mysterious conditions. AHC is characterized by transient hemiplegic attacks and a wide range of other neurological features including dystonic attacks, seizures, neurodevelopmental features, and autonomic symptoms. Recurrent de novo variants in ATP1A3 represent the most common cause of AHC, even though a small subset of individuals have disease-causing variants in other genes. In a recent paper, de novo variants in CLDN5 were identified. In contrast to known causes of AHC, CLDN5 implicates an entirely new disease mechanism – disruptions of the blood-brain barrier. Continue reading
The science of data visualization in epilepsy genetics
Language. In the recent years, there has been an emerging focus on the phenotypic characterization of genetic epilepsies and neurodevelopmental disorders. With a rise in large-scale studies leveraging massive and complex genetic and phenotypic datasets, understanding how we make sense of big data becomes critical. However, determining what are clinically meaningful findings and communicating the conclusions we make from these datasets remain a challenge. While we typically think about data in the scope of ‘n’s, probabilities, and p-values, there is understated value in the visualization of information. Here is a different way of how we think about scientific communication and how we can “make data speak in childhood epilepsies.”
EuroEPINOMICS and the golden age of epilepsy gene discovery
Exome era. When a consortium disappears, where does it go and what does it leave behind? I realized last week that exactly 10 years ago, the EuroEPINOMICS Rare Epilepsy Syndrome (RES) consortium pushed the button for the second round of trio exome sequencing, a pivotal event in the history of epilepsy genetics that led to the discovery of more than a dozen genes for developmental and epileptic encephalopathies. The fact that this critical juncture in the history of epilepsy gene discovery went largely unnoticed lies within the nature of research consortia – they form, they work, and they disperse. However, as EuroEPINOMICS was formative for me as a junior researcher, I wanted to dedicate this blog post to the research consortia of the early 2010s and the golden era of epilepsy gene discovery, when I was a EuroEPINOMICS kid.
The future of biomarker development in rare disease
CNS Biomarkers. In the last two days, our team attended the Workshop for Multimodal Biomarkers in CNS Disorders held at the National Academies of Sciences, Engineering, and Medicine in Washington, DC. This conference provided a needed review of the current state of multimodal biomarker discovery and development. While most of the speakers focused on more common CNS disorders such as Alzheimer’s disease and neuropsychiatric disorders, there stands to be important lessons that can be translated into the rare disease field. Here is what we learned about the clinical utility of biomarkers and their potential as we move towards precision medicine in rare disease.
Artificial intelligence in epilepsy – the rare disease perspective
Breckenridge. This week, our team attended the first conference for Artificial Intelligence in Epilepsy in Breckenridge, Colorado. I was honored to be one of the two speakers representing the epilepsy genetics field, trying to build the bridge between the impressive amount of research in machine learning and EEG analysis with our current progress and research efforts in the genetic epilepsies. In this blog post, I would like to summarize some of my impressions from this meeting and discuss two aspects where rare disease research and machine learning already intersect, namely seizure forecasting and virtual clinical trials.
IRF2BPL in progressive myoclonus epilepsy – an unexpected phenotypic discovery
PME. The progressive myoclonus epilepsies (PME) are an important and distinct subgroup of genetic epilepsies. In contrast to many genetic epilepsies with a neurodevelopmental trajectory, the PMEs often follow a neurodegenerative course, which is characterized by a worsening myoclonus over time and frequently associated with cognitive decline. In a recent publication, protein-truncating variants in the intronless gene IRF2BPL were identified in two individuals with PME. However, in contrast to the relatively distinct nature of most other PME, the clinical presentation in IRF2BPL-related disorders is part of a phenotypic spectrum and emerges as one of the most usual phenotypic discoveries in the genetic epilepsies to date.
Phenotypes are like water – Rare Disease Day 2023
Phases. Today is Rare Disease Day. I would like to use this opportunity to explain some of the phenotype science that is critical for rare diseases. In contrast to common disorders, rare diseases face an unusual challenge. Once identified, the overall rareness of these condition poses the question of where phenotypes begin and where they end. For rare genetic disorders, is the phenotype of the first individual identified with a rare disease characteristic, or is there a larger spectrum that we should be aware of? Enter the various approaches to phenotype science that aim to decipher the full depth of clinical features associated with rare diseases. In order to understand the various approaches to rare diseases phenotypes, I would like to suggest a somewhat unusual analogy: phenotypes are like water.
The genetics of FIRES and status epilepticus in 2023
FIRES. As a rare and severe epilepsy syndrome, febrile-infection related epilepsy syndrome (FIRES) is characterized by refractory status epilepticus (RSE) preceded by a febrile illness and often leads to prolonged hospitalizations, cognitive impairment, and intractable epilepsy. There are currently no clear causative etiologies identified in FIRES, and the underlying genetic architecture remains elusive. Here is a brief summary of our recent manuscript on the genetics of FIRES and refractory status epilepticus. This is what we learned about one of the most enigmatic conditions in child neurology.
