EEs. The concept of epileptic encephalopathy refers to a process where epileptic activity impairs overall brain function, including cognitive function, language, and behavior. In a recent commentary in Epilepsia, our current use and misuse of the concept of epileptic encephalopathy is reviewed critically. In summary, the authors criticize that epileptic encephalopathy is used as a diagnostic category rather than a description of the actual epileptic process, suggesting that another term may be necessary for the group of patients with intellectual disability and epilepsy where we often find a genetic etiology. In this blog post, I would like to plead guilty on behalf of the epilepsy genetics community for having misused the concept of epileptic encephalopathies for almost a decade. And we have done this for at least three different reasons. Continue reading
Where the genes have no names – KIAA2022 in epileptic encephalopathy
No name. The speed of gene discovery in human epilepsies is sometimes so fast that genetics beats biology. Some genes are implicated in disease faster than our ability to name them. In a recent publication, we describe the epilepsy phenotype of an X-linked gene that is only known by an identifier that indicates how little we know about it: KIAA2022. In contrast to a phenotype in males that is mainly characterized by intellectual disability, de novo mutations in KIAA2022 in females results in intractable myoclonic epilepsy. Continue reading
RORB in generalized epilepsy with absences – going retinoic
Retinoic receptor. A few years ago, when exome sequencing was still in its infancy, our group in Kiel identified a small de novo in frame deletion in a gene that we didn’t know how to interpret. In frame deletions that do not disturb the reading frame, but simply take one or several amino acids out, are usually less suspicious and are sometimes even filtered out by the algorithms that we and others typically use. We dismissed this finding for several years. However, a year ago, the plot thickened when other groups mentioned that they had found the same gene in their patients, including a family with six affected individuals. In a recent publication, we describe the improbable story of RORB, the latest gene for generalized epilepsies with prominent photosensitivity and absence seizures. Continue reading
SCN1A – what’s new in 2016?
The story of SCN1A. Variants in SCN1A were first reported in association with epilepsy in 2000, when familial heterozygous SCN1A missense variants were identified in two large families with GEFS+. The phenotype was characterized by incomplete penetrance and significant variable expressivity between family members, making it clear from the beginning that the SCN1A story would not be simple. Within the next few years, we learned that SCN1A variants could cause a wide spectrum of epilepsy phenotypes, including GEFS+, Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures, and, less frequently, infantile spasms and simple febrile seizures. As it became clear that SCN1A variants played an important role in genetic epilepsies, focus turned towards understanding the mechanism underlying seizure genesis, as well as identifying management and therapy options. Even after 15 years of study, our understanding of SCN1A-related epilepsy is still evolving. Keep reading to learn more about the most recent discoveries related to SCN1A. Continue reading
Explaining variants of uncertain significance – a guide for clinicians
VUS – The dreaded variant of uncertain significance. With the advent of next generation sequencing panels and exome sequencing, what used to be an occasional laboratory finding in epilepsy has now become a daily occurrence. Lab reports detailing multiple VUS findings for an individual patient have become a routine part of clinical practice. How do you, as a healthcare provider, explain the meaning and implications of VUS findings to patients and families in a way that is understandable to them? Continue reading
TBC1D24 – what’s new in 2016?
The story of TBC1D24. As with many epilepsy genes, the TBC1D24 story increases in complexity over time. Initially described to be associated with autosomal recessive familial infantile myoclonic epilepsy by Falace and colleagues and with autosomal recessive focal epilepsy by Corbett and colleagues in 2010, pathogenic variants in TBC1D24 have since been identified as a major cause of DOORS syndrome and have also been identified in individuals with familial malignant migrating partial seizures of infancy, progressive myoclonus epilepsy, early-onset epileptic encephalopathy, and autosomal dominant and autosomal recessive non-syndromic hearing loss. However, little is known about a potential genotype-phenotype correlation of TBC1D24-related disorders, as well as the underlying mechanism. Keep reading to learn more about recent discoveries related to TBC1D24. Continue reading
The genetic sibling of NMDA receptor encephalitis
GRIN1 encephalopathy. In the early 2000s Dalmau and collaborators observed a condition in women with ovarian teratoma who presented with psychosis or memory problems and rapidly progressing neurological deficits that required prolonged intensive care support. Auto-antibodies against the NR1 subunit of the NMDA receptor were found to be the causative agent. The clinical spectrum of anti-NMDA-receptor encephalitis has since expanded significantly and this initial discovery fueled the discovery of an entirely disease mechanism, the concept of the autoimmune encephalitis. In a recent publication in Neurology, we describe a novel neurodevelopmental syndrome affecting the gene for the NR1 receptor, the genetic sibling of NMDAR encephalitis. This blog post is about the unexpected overlap of autoimmune disorders with the genetic epilepsies and the spectrum of GRIN1-related genetic encephalopathies. Continue reading
Closing the knowledge gap – this is SYNGAP1
Mind the Gap. Ever since its discovery in 2009, SYNGAP1 has been a prominent gene connected to autism and intellectual disability. However, even though probably more than half of all patients with pathogenic SYNGAP1 variants have seizures, it was never a gene that was particularly prominent in the epilepsy field. In a recent publication, we were able to delineate the epilepsy phenotype of patients with pathogenic SYNGAP1 variants, identifying a peculiar combination of generalized seizures types. Here is a blog post about a gene that I admittedly knew very little about before we started working on it. Continue reading
The story of the missed SCN1A mutations
Dravet Syndrome. In 2011, our EuroEPINOMICS-RES program was in full swing. We had recruited a cohort of 31 patients with Dravet Syndrome who had been previously tested negative for mutations in SCN1A with the aim to identify novel genes for this epileptic encephalopathy. Even though this cohort was crucial in our identification of CHD2, HCN1, and KCNA2 as novel genes for genetic epilepsies, the main finding in this cohort was something that we did not expect. Roughly one third of our 31 patients had mutations in SCN1A, even though they had previously been tested negative. In a recent publication in Molecular Genetics and Genomic Medicine, we tried to understand what had happened and joined forces with other groups who had made the same observation. Here is the story of the missed SCN1A mutations. Continue reading
Karl Marx, Hauts Forneaux, and the impact factor
Porta Nigra. This is part two of our travel diary. After a one hour drive through the rural Eifel mountains, you start a seemingly endless descent upon the Moselle Valley to get to Trier. A former Roman town with old ruins, a former summer residence of local royalty, a cathedral in redevelopment for 1500 years and Germany’s oldest city, Trier is rich with history. We didn’t know any of this as it was simply meant to be our stop on our way to Luxembourg, but it is hard to take a walk through the city without noticing. Yet Trier’s most famous son is a controversial historical figure who left to never return before starting any of his far-reaching work. Here is what we can learn from Karl Marx about the exchange value of scientific work in 2016. Continue reading