Finding the missing sodium channel – SCN3A in epileptic encephalopathy

Sodium channel. Voltage-gated channels for sodium ions are a crucial component of helping neurons depolarize and repolarize in a way that enables generation of action potentials. However, in order to function properly, voltage-gated ion channels co-exist in a fragile balance, and genetic alterations leading to functional changes in these channels are known causes of disease. SCN1A, SCN2A, and SCN8A have been implicated as causes for human epilepsy. However, SCN3A encoding the Nav1.3 channel, one of the most obvious candidates, could not be linked to disease so far. In a recent publication, we were able identify disease-causing mutations in this major neuronal ion channel. Interestingly, patients with an early onset and the most severe presentation had a prominent gain-of-function effect that responded to known antiepileptic medications. Continue reading

NMDA receptors and brain malformations: GRIN1-associated polymicrogyria

Ion channels and brain malformations. When the “channelopathy” concept first emerged – the idea that dysfunction of neuronal ion channels leads to neurological disease including epilepsy – it seemed implausible that such dysfunction could lead to malformations of cortical development. However, recent research has suggested that ion channel dysfunction may indeed be linked with brain malformations. In 2017, we saw convincing evidence that germline de novo variants in GRIN2B can cause malformations of cortical development. Some suggestive, but less conclusive, evidence has also linked SCN1A and SCN2A to brain malformations. Now Fry and collaborators demonstrate that de novo pathogenic variants in GRIN1 can also cause significant polymicrogyria, expanding the phenotypic spectrum of GRIN1-related disorders. As a disclaimer, I am also a co-author on the publication by Fry and collaborators. Continue reading

PCDH19-related epilepsy: understanding cellular interference

Protocadherins. PCDH19-related epilepsy is the second most common genetic epilepsy, behind Dravet syndrome. PCDH19-related epilepsies display the unusual X-linked inheritance pattern in which heterozygous females are affected but hemizygous males are unaffected. Similarly, somatic mosaic males have also been reported. PCDH19 encodes protocadherin 19, a calcium-dependent cell-cell adhesion molecule that is highly expressed in the central nervous system. The long-hypothesized pathomechanism has been cellular interference, although experimental support has so far been lacking. Now, Pederick and collaborators provide evidence that supports the cellular interference mechanism in PCDH19-related epilepsies, bringing us closer to understanding the biology of this unusual genetic epilepsy. Continue reading

SLC6A1 – a generalized epilepsy phenotype emerging

GAT1. When we first identified SLC6A1 in 2015, we were surprised that a significant proportion of patients with disease-causing variants in this gene had a rare epilepsy phenotype referred to as Myoclonic Astatic Epilepsy (MAE). Typically, at the time of gene discovery, it is often unclear how far the phenotypic spectrum expands. In a recent publication in Epilepsia, we reviewed the phenotype of 34 patients with SCL6A1-related epilepsy. Surprisingly, in contrast to many other epilepsy genes that showed a broad and occasionally non-specific phenotypic range, the SLC6A1-related phenotype expands beyond MAE, but remains centered around generalized epilepsies with a predominance of absence seizures and atonic seizures. It is a gene that has started to write its own story. Continue reading

Epilepsy genetics in 2018 – Three things that will happen and three things that won’t

Bomb Cyclone. While the entire US East Cost was held hostage by a weather system that introduced us to new catchy meterological concepts such as bombogenesis, I hope that everybody is staying warm and safe. I wanted to wish all our readers a Happy 2018 and try to give an outlook of the New Year in epilepsy genetics.  Here are three things in epilepsy genetics that will happen in 2018 – and three things that won’t. Continue reading