Heritable. Many epilepsy syndromes have signature EEG traits, and these traits are thought to have a strong genetic component. The endophenotype concept suggests that using these epilepsy-related traits in genetic studies will facilitate gene discovery, a concept that has failed us so far in epilepsy research, unfortunately. Now, in a recent publication in Brain, we were able to demonstrate that variants in CHD2 predispose to photosensitivity, an abnormal cortical response to flickering light. Finally, after several decades of persisting difficulties, there is some progress in the field of EEG genetics. Continue reading
Category Archives: Familial epilepsies
Publications of the week – GABRG2, CACNA1A, and ALG13
Issue 5/2015. Each of these three genes may ring a bell, but the context in which they were described this week is new. Here is our overview of some of the most relevant publications this week. Continue reading
Galanin mutations in Temporal Lobe Epilepsy
Transmitted. When we think about epilepsy-related neurotransmitters, we often limit ourselves to the most prominent transmitters in the Central Nervous System, namely glutamate, GABA and to some extent acetylcholine. However, besides these classical transmitters, there are more than 100 small peptides released in the mammalian brain, which are referred to neuropeptides. Here is the story of galanin, the first neuropeptide in epilepsy genetics. Continue reading
Speech dyspraxia and dysarthria – the other side of GRIN2A
GRIN2A. Mutations in several genes coding for NMDA receptor subunits have recently been found in various neurodevelopmental disorders. Amongst the different genes, GRIN2A is one of the most prominent ones and mutations in this gene are found in patients with epilepsy-aphasia syndromes. So far, we have mainly looked at GRIN2A from the epilepsy side. In a recent publication in Neurology, Turner and collaborators now examine the speech phenotype in GRIN2A families. They examine two families where speech issues are a prominent phenotypic feature. It turns out that GRIN2A mutations may predispose to a distinct speech phenotype. Continue reading
A genetic counselor’s wish list for epilepsy genetics in 2015
Mt. Rainier. After our recent posts about the 2014 AES in Seattle, we received an email from Beth in Boston, highlighting some of the issues that genetic counselor face in epilepsy genetics when dealing with next gen sequencing data. Beth drew up a wish list for 2015 and asked us for comments. Here is a brief discussion between Beth and me on how high throughput epilepsy genetics sometimes comes to grinding halt in clinical practice. Continue reading
Publications of the week – CNTNAP2, DEPDC5, and autism whole-genome sequencing
Issue 4/2015. Trying to keep up with the publications of the week in the field, we have selected three manuscripts this week, which challenge some of our well-established beliefs. It’s about an autism gene losing its statistical support, a familial epilepsy gene rediscovered in focal cortical dysplasia, and the surprises of whole-genome sequencing in familial autism. Continue reading
Publications of the week – SRP9, Nebulin, and Kuf’s disease
Issue 2/2015. For the second issue of our publications of the week in 2015, we have selected recent publications on the genetics of Febrile Seizures, the complexities of interpreting variants in large genes and functional studies on progressive myoclonus epilepsies due to mutations in SCARB2 and CTSF. Continue reading
AP4S1 in fever-associated epilepsies and spastic paraplegia
Peds vs. adult. Sometimes it makes a fundamental difference in diagnosis whether a patient is seen in a pediatric setting or by an adult specialist later in life. Here is the most recent example from our consortium, which was just published in Human Molecular Genetics: what initially looked like recessive inheritance with intellectual disability and a peculiar fever-associated epilepsy syndrome eventually turned out to be the second reported family of the novel spastic paraplegia gene AP4S1. This raises the question of how much we are missing if we are looking at the wrong point in time. Let’s have a look at how genetics can help us see an overlap of diseases where we usually don’t have a chance to. Continue reading
TADA – a joint analysis of de novo and inherited risk factors in autism
Beyond de novo. One of the most robust ways to interpret exome data is the analysis of de novo mutations. However, in addition to the 1-2 de novo events that we can identify in every individual, there is a plethora of inherited variants that often look suspicious. Unfortunately, other than looking at monogenic recessive disorders, we are often incapable of understanding the importance of these inherited variants and tend to ignore them. A recent publication in Nature now overcomes this difficulty by applying a joint analysis of inherited and de novo variants in autism. Continue reading
A question of conformation – chemical correction of LGI1 dysfunction
ADTLE. Autosomal Lateral Temporal Lobe Epilepsy is a rare monogenic epilepsy that has epileptic seizures with auditory auras as the most impressive feature. This condition is caused in LGI1. In contrast to most other autosomal dominant epilepsies, LGI1 is not an ion channel, but a secreted protein that binds to synaptic cell adhesion proteins. Therefore, the function of LGI1 has always remained slightly mysterious. In a recent publication in Nature Medicine, the functional properties of two LGI1 mutations are modelled in mice. Allowing neurons to secrete altered LGI1 protein otherwise targeted for degradation helped recover some of LGI1’s function. Continue reading
