Summary. The 68th Annual Meeting of the American Epilepsy Society is now over and I would like to use this opportunity to look at five epilepsy genetics posters that caught our attention. The genetics posters at AES this year were a mixture of expansion of known phenotypes and some novel genes that might be worth looking at. Continue reading
Tag Archives: CACNA1A
Beyond recessive – KCNC1 mutations in progressive myoclonus epilepsy
PME. The progressive myoclonus epilepsies (PME) are a particular subtype of seizure disorders characterized by progressive myoclonus, generalized seizures and cognitive deterioration. Known causes of PME include recessive mutations in several well-known genes, but the genetic cause is unknown in a significant proportion of patients. Now, in a recent paper in Nature Genetics, de novo mutations in KCNC1 are identified as a novel cause of progressive myoclonus epilepsies. In addition to elucidating the genetic basis in a significant subset of patients with PME, the authors demonstrate that de novo mutations play an important role in a group of diseases usually thought to be recessive. Continue reading
CACNA2D2, the ducky mouse, and what it takes to be an epilepsy gene
Subunit. Spontaneous mouse mutants help to identify candidate genes for disease mechanisms and have hinted at an important role for ion channels in epilepsy long before the first human channelopathies were identified. The ducky mouse has absence seizures and suffers from ataxia. A truncation mutation in CACNA2D2 could be identified in this phenotype, encoding for an auxiliary calcium channel subunit. This finding emphasizes the role of calcium channels in absence seizures and begs the question whether genetic variation in CACNA2D2 is also involved in human epilepsy. A recent publication in PLOS One now identifies the second recessive CACNA2D2 mutation in a patient with epileptic encephalopathy. But are two independent cases sufficient anymore to claim causality? Continue reading
Modifier genes in Dravet Syndrome: where to look and how to find them
Converging thoughts. During late 2013, I had several unrelated discussions about the possible role of genetic modifiers of SCN1A in Dravet Syndrome. To some extent, SCN1A is a paradox. One the one hand, the connection between Dravet Syndrome and SCN1A is one of the clearest connections between gene and disease that we see in genetic epilepsies. On the other hand, we see a remarkable phenotypic heterogeneity in families, and some presumably pathogenic SCN1A variants can also be identified in unaffected control individuals. This leaves us with the question whether there are genetic modifiers in Dravet Syndrome that might help provide some insight into additional mechanisms of disease. This post is a collection of 10 individual thoughts that emerged during the discussions last year. Continue reading
Why I am still struggling with SCN9A in Dravet Syndrome
Susceptibility. Two weeks ago, we published a post on rare variants in SCN9A as potential susceptibility genes for Dravet Syndrome with mutations in SCN1A. Ever since reading the article by Mulley and collaborators, I had tried to come up with an idea of what the genetic architecture might look like if both de novo variants and inherited variants contribute. I wanted to follow up on my earlier post with this brief back-of-the-envelope calculation. Continue reading
CACNA1A variants as genetic modifiers in Dravet Syndrome
Genetic modifiers. Dravet Syndrome, formerly Severe Myoclonic Epilepsy of Infancy (SMEI) is a severe epileptic encephalopathy starting in the first year of life. More than 80% of cases of Dravet Syndrome are caused by loss-of-functions mutations in SCN1A, a voltage-gated sodium channel predominantly expressed on GABAergic interneurons. Now, a recent paper in Neurobiological Disorders investigates the role of CACNA1A variants as possible genetic modifiers in Dravet Syndrome. Continue reading