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
Author Archives: Elizabeth Dechene
PCDH19 – what’s new in 2016?
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
SCN2A – a 2016 update
The story of SCN2A. Pathogenic SCN2A variants were first described in patients with autosomal dominant benign familial neonatal/infantile seizures (BFNIS) in the early 2000s. More recently, it has became clear that variants in SCN2A can cause a wider spectrum of epilepsy phenotypes, ranging from milder phenotypes, such as BFNIS, to severe phenotypes, such as infantile spasms and severe early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome. In addition, SCN2A variants have been identified in a small number of patients with autism, schizophrenia, and intellectual disability without seizures. Despite now having earned its title as a well-established epilepsy gene, we still have a lot to learn about SCN2A. Keep reading to learn more about the expansion of the SCN2A-associated epilepsy phenotype and other recent discoveries about SCN2A. Continue reading
What’s new with KCNT1 – a 2016 update
Continued expansion of the KCNT1 phenotype. In 2012, de novo heterozygous KCNT1 variants were first described in six individuals with migrating partial seizures of infancy (MPSI) (Barcia et al, 2012). In the same edition of Nature Genetics, Heron and colleagues (2012) described 3 families with frontal lobe epilepsy with prominent psychiatric features were also identified to have heterozygous disease-causing variants in KCNT1. Within the last 5 years, de novo and inherited heterozygous KCNT1 variants have been found in a number of patients with MPSI and ADNFLE. Yet, there have been no clear genotype-phenotype correlations established. Recently, several studies have identified KCNT1 variants in patients with other types of epilepsy. Keep reading to learn more about the expansion of the KCNT1-associated epilepsy phenotype. Continue reading
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
CHD2 – a 2016 update
Updates. Our “Beyond the Ion Channel” blog has been in existence for over 3 years, during which we have seen many advances in our knowledge of epilepsy genetics and done our best to share them with you. We hope that we have contributed to making epilepsy research more understandable. Recently, we have been pondering what we can do to make the emerging Epilepsiome knowledge base more useful for our readers, including clinicians, researchers, and families alike. Read further to see our first round of changes to our Epilepsiome Gene Pages that we have applied to our CHD2 Gene Page. Continue reading