Genome sequencing. Despite continual progress in understanding the genetic etiology of human disease, more than half of rare disorders remain unsolved. Resolving the remaining etiologies in rare disease are a major focus of ongoing efforts in the field, including a shift towards standardized analysis of large-scale genome sequencing data from large patient cohorts. In a recent study, Greene and collaborators aimed to identify associations between genes and rare disease subgroups, leveraging genomes of 77,539 people including 29,741 probands. Here is a brief review on their publication in the context of etiological resolution in rare disease.
Category Archives: Papers
Seizure prediction using real world data – a learning health system realized
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.
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.
The landscape of epilepsy genetics in 2023
Clinical neurogenetics. Characterization of the genetic landscape of the epilepsies continues at a rapid pace, and the effects of this vast gain of knowledge are beginning to show within routine clinical care of people with epilepsy. In our most recent review, we discuss an overview of epilepsy genetics in 2023, spanning topics of novel methods of gene identification, polygenic mechanisms, new presentations of established genes, and multifaceted efforts of phenotypic characterization. In addition, we discuss the increasingly critical roles of advocacy organizations. Here is a summary of our recent review.
TRPM3 – a heat sensor involved in epileptic encephalopathies
A long-awaited answer. Gene discovery in the epilepsies is continuing, and some novel genetic etiologies are quite surprising given that the particular genes had previously been described in a completely different context. One of these examples is TRPM3. In our recent publication, we further define TRPM3 as a gene causative of a variety of neurodevelopmental disorders. Also notably, we find that the anti-seizure medication primidone can be a helpful treatment in individuals with TRPM3. Beyond outlining the TRPM3 spectrum, our publication helped us find a long-awaited diagnosis for one of our research participants, one that took four years to prove. Here is the TRPM3 story. Continue reading
DNM1 encephalopathy – interneurons, endocytosis, and study group
Dynamin 1. De novo mutations in DNM1 coding for Dynamin 1 are increasingly recognized as a cause for epileptic encephalopathies. However, given the role of Dynamin 1 in endocytosis in a large number of cells, the precise mechanisms how mutations may result in seizures are poorly understood. Now two recent publications in PLOS Genetics and Neurology Genetics explore the functional effects of epilepsy-related DNM1 mutations. The publication of both manuscripts is also a timely reminder to announce our international DNM1 study group that has the aim to better understand the phenotype of this disease. Continue reading
This is what you should know about KCNT1 – a 2015 update
Dual phenotypes. When KCNT1 was first described as a gene for Migrating Partial Seizures of Infancy in 2012, it wasn’t just a novel gene for epileptic encephalopathies. In parallel, the same gene was found to underlie a novel subtype of autosomal dominant nocturnal frontal lobe epilepsies (ADNFLE). At the time, this left us scratching our heads how a gene could cause such distinct, but entirely separate phenotypes. In a recent publication in Epilepsia, Møller and collaborators revisit the phenotypic spectrum of KCNT1. They find that both phenotypes can occur within a single family and that KCNT1 mutations can result in other phenotypes, adding to the mystery of KCNT1. Continue reading
Cause or coincidence – recessive SCN1A variants in Dravet Syndrome
Recessive epilepsies. Dravet Syndrome is one of the most prominent genetic epilepsies and presents in the first year of life with prolonged fever-associated seizures. Haploinsufficiency of SCN1A, either through mutations or deletions, is the major cause of Dravet Syndrome. In a recent publication in the European Journal of Pediatric Neurology, two families with recessive Dravet Syndrome and biallelic SCN1A variants are reported. Let’s have a look at how to interpret these findings. Continue reading
Beyond SCN1A – Copy Number Variations in fever-associated epilepsies
Fever and epilepsy. When it comes to epilepsy and fever, either Febrile Seizures or Dravet Syndrome are usually the most prominent topics on our blog. However, in addition to these syndromes, there various other epilepsies that have fever-related seizures as a prominent feature. In a recent publication in Epilepsia, we investigated the role of microdeletions in a group of patients with prominent fever-associated epilepsies. Our findings suggest that fever-associated epilepsy syndromes may be a presentation of known microdeletion syndromes. Continue reading
CHD2 myoclonic encephalopathy – delineating a novel disease
CHD2. In 2013, mutations in CHD2 were reported in various publications including two major studies on epileptic encephalopathies, reinforcing the notion that de novo mutations in this gene are a recurrent cause of epileptic encephalopathies. However, large-scale studies often cannot fully appreciate the complete phenotype of the patient behind the gene finding. Therefore, it is difficult to appreciate similarities between patients and assess whether phenotypes constitute a recognizable entity. In a recent publication in Neurology, the phenotype of CHD2 encephalopathy is explored in detail – it represents a distinct, recognizable disease entity. Continue reading