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

AES 2017 – Making Sense of Genetic Data in Epilepsy

Controversies. While you are packing your bags for the 71st Annual Meeting of the American Epilepsy Society in Washington, D.C., we wanted to point out one agenda item that may be of interest for you. The AES agenda typically has many parallel sessions, so I wanted to make a plug for our Genetics Special Interest Group (SIG) on Friday, 12/1 at 1:30PM. The topic of our SIG is going to be “Making Sense of Genetic Data in Epilepsy – Consensus and Controversy in 2017”. In contrast to regular sessions and lectures, a SIG is meant to stimulate discussion between SIG members. Therefore, in parallel to previous years, we would like to invite the attendees to use the opportunity to discuss challenging cases within a dedicated AES Special Interest Group. Continue reading

The many faces of KCNA2: a 2017 update

KCNA2. We have previously discussed KCNA2 and that pathogenic variants in this gene can lead to a spectrum of neurological phenotypes. Pathogenic KCNA2 variants were first recognized in individuals with early-onset developmental and epileptic encephalopathies and have subsequently been found also in individuals and families with hereditary spastic paraplegia, episodic ataxia, and milder epilepsies. KCNA2 encodes the Kv1.2 potassium channel, a delayed rectifier class of potassium channel that enables neuronal repolarization after an action potential. A new study by Masnada and colleagues provides clinical and functional data from 23 patients, representing the largest KCNA2 cohort reported to date. Within the KCNA2-related encephalopathy spectrum, it now seems that there may be three distinct phenotypes. Continue reading

The rising role of synaptic transmission: the calcineurin link

Synaptic transmission. Over the last several years, pathogenic variants in multiple genes involved in synaptic transmission have been identified in early-onset epilepsies. STXBP1 and STX1B both encode components of the SNARE complex, a complicated protein complex that mediates the fusion of the plasma membrane of the presynapse and the synaptic vesicle to allow for neurotransmitter release. DNM1, encoding the dynamin-1 protein, plays an essential role in recycling synaptic vesicles back into the presynapse after neurotransmitter release. A new study by Myers and collaborators has identified several patients with de novo variants in PPP3CA, which encodes another protein involved in synaptic vesicle recycling, further highlighting the importance of synaptic transmission in the etiology of severe neurodevelopmental disorders. In the interest of full disclosure, I am also a co-author on this study. Continue reading

Guardians of the epilepsy genes

Epilepsiome, meet ClinGen. For more than a year, I have meant to write about the extension of the Epilepsiome effort to our ClinGen epilepsy working group. The overall ClinGen framework is a NIH-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. Within this framework, the ClinGen Epilepsy Working group is a group of curators to apply the formal framework to epilepsy genes. Given the explosion of genetic data, curating epilepsy genes is important as a basis for precision medicine and long overdue. Within our epilepsy working group, we build upon the ClinGen framework to make it applicable to epilepsy genes. Here is what you need to know about epilepsy gene curation.

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Mysteries of the cytoskeleton – SPTAN1 in epileptic encephalopathies

Neuronal spectrinopathies. Spectrins are a major component of the neuronal cytoskeleton, the scaffold underneath the cell membrane that gives cells their characteristic shape and anchors transmembrane proteins such as voltage-gated ion channels. SPTAN1, the gene coding for the non-erythrocyte alpha-II spectrin, has been known as a rare cause of early-onset epileptic encephalopathies with hypomyelination and atrophy. However, the full phenotypic spectrum and the range of pathogenic variants was unknown. In a recent publication in Brain, 20 patients with pathogenic variants in SPTAN1 are reported, expanding the known range of phenotypes and suggesting a very unusual disease mechanism through in-frame deletions or duplications. Here is what links the neuronal cytoskeleton to epileptic encephalopathies. Continue reading

KCNB1 encephalopathy – widening the phenotypic spectrum

KCNB1 encephalopathy. Pathogenic variants in KCNB1 were first reported three years ago in three unrelated patients with an early-onset epileptic encephalopathy. Since the initial report, individual patients have been reported with de novo KCNB1 variants, but a comprehensive overview of the KCNB1 encephalopathy clinical picture has been lacking. A recent publication by de Kovel and colleagues provides a comprehensive overview of the clinical features and genetic variants in 26 individuals with KCNB1 encephalopathy, including 16 previously unreported patients, providing novel insights into the phenotype. In this post we will unpack this publication, including what new information about KCNB1 it tells us. Continue reading