The story of PCDH19. The clinical features and unique inheritance pattern of PCDH19-related epilepsy were first described in 1971, and the clinical entity was coined Epilepsy in Females with Mental Retardation (EFMR), due to the presence of epilepsy and cognitive disability that seemed to be limited to females. Pathogenic PCDH19 variants were identified in females in 2008, and it soon became clear that PCDH19 is a major player in the genetic basis of epilepsy, with more than 100 patients with PCDH19 variants described to date. The inheritance pattern is one of the most striking features of this condition. Heterozygous females are affected, while hemizygous transmitting males are spared. At the cellular level, the disease mechanism seems to be loss of function. However, at the tissue level, the current hypothesis for the underlying mechanism is gain of function, resulting from the co-existence of two different PCDH19-expressing neuronal populations in females and mosaic males. Keep reading to learn more about recent discoveries related to PCDH19. Continue reading
Category Archives: Epilepsiome
What’s new with SCN8A – a 2016 update
An unexpected twist in the SCN8A story. SCN8A mutations were first implicated in epilepsy in 2012, when a de novo missense variant was identified in a patient with early infantile epileptic encephalopathy (EIEE) via genome sequencing. Since then, a number of patients with de novo heterozygous SCN8A variants and epilepsy have been reported, firmly establishing the role of SCN8A in EIEE, and we have learned a lot about the associated phenotype, mutation spectrum and disease mechanism within the last four years. Recently, a heterozygous familial SCN8A missense variant was identified in several families with a significantly milder epilepsy phenotype than reported in previous patients. Read further to learn more about the expanded SCN8A-associated epilepsy phenotype. Continue reading
The 2016 Epilepsiome series
Introduction. The Epilepsiome is our community-driven gene curation project. Ever since we last wrote about this project, many discussions have been going on in our community and we have decided to put together a 10-part post series this year to tell you where the journey is headed. Here is what we would like to put together in the first half of 2016. Continue reading
DEPDC5 – this is what you need to know in 2015
DEPDC5. We have selected DEPDC5 to be our gene of the week. DEPDC5 is currently the most common known gene for focal epilepsies. DEPDC5 mutations cause familial focal epilepsy with variable foci, an epilepsy syndrome with autosomal dominant inheritance where the affected family members can have different types of focal epilepsies, most frequently frontal lobe epilepsy. Despite seizure semiology that varies among family members, it is constant for each individual. Continue reading
WDR45 – this is what you need to know in 2015
BPAN. We have selected WDR45 to be our Epilepsiome gene of the week. WDR45 was initially identified as the causative gene for a rare phenotype referred to as static encephalopathy with neurodegeneration in adulthood (SENDA), which belongs to a group of neurodegenerative disorders that have accumulation of iron in the CNS as the common feature. In contrast to the narrow and very specific phenotype in most other disorders in this group, the phenotypic spectrum of WDR45 has expanded significantly since the initial discovery in 2013. Mutation in WDR45 can be identified in patients with a broad range of neurodevelopmental phenotypes including epileptic encephalopathies. Continue reading
CACNA1H – this is what you need to know in 2015
Evidence. This week, we will review the evidence that links CACNA1H to human epilepsies. While this gene was initially considered a promising candidate for absence epilepsies, more recent studies have produced little supportive evidence that CACNA1H is linked to human epilepsies. However, CACNA1H may play a role in a different group of diseases, namely early-onset hypertension due to primary aldosteronism. Let’s review what it takes to be candidate gene. Continue reading
GRIN2A – this is what you need to know in 2015
GRIN2A. Mutations in GRIN2A have initially been described in patients with neurodevelopmental disorders of diverse severity, including seizures, in 2010. In 2013, its prominent role in idiopathic focal epilepsies (IFE) was discovered simultaneously by three groups (Carvill 2013, Lemke 2013, Lesca 2013) and since that, mutations have repeatedly been associated with this spectrum of disorders. Continue reading
CHD2 – this is what you need to know in 2015
CHD2. Few genes have captured our attention over the last two years like CHD2 has. It is a gene that we almost missed, then sat on for more than a year since we didn’t believe it, only to realize in the end that it is a gene for a specific photosensitive epilepsy syndrome that many people had encountered, but that few people had a name for. Here is what you need to know about CHD2 in 2015. Continue reading
How the Epilepsiome works
Hitting the ground running. With the first 12 Epilepsiome gene reviews up, we want to provide you with a brief update and what we have learned from the experience in the last few months. A number of the new Epilepsiome members have asked us how exactly the gene review process will work and what we expect from them. Here are some of the questions you’ve posed and our answers. Continue reading
These are the 78 genes involved in human epilepsy – a survey
Questionnaire. This week we have a huge favor to ask from you. We need your input on our Epilepsiome project. Please help us prioritize the 60-80 genes that will be part of our ongoing gene review effort. Help us build the Epilepsiome. Your input is needed. Continue reading