GPHN deletions in IGE and mutation-dependent recessive inheritance

Bild1Living in Cologne is a little tough at the moment. Currently, we are in the middle of the Cologne Carnival, the world’s oldest carnival, which started in 1829. Until the upcoming Wednesday the entire city is one big festival. In addition to the 1 million Cologne citizens probably another million tourists will join. Due to this (positive) distraction I will write less than usual. However, I still consider this week’s publications noteworthy. Continue reading

Papers of the week – 15q11 duplications, Olig1 & Automated decision-making


A productive week in epilepsy genetics.  Scientists and editors were certainly busy this week reporting novel variants and deletions as well the experimental and statistical advances for their interpretation.

A de novo GRIN2A missensmutation in early-onset epileptic encephalopathy. We and others have associated variants affecting the GRIN2A gene with a range of childhood focal epilepsy syndromes. Continue reading

Papers of the week – Encephalitis-antibodies, FAN1, Art and Parent-of-Origin Effects

Dennis' paper of the week

Biggest surprise this week: Imprinted genes interact with non-imprinted genes frequently. But first sequencing reports, statistical frameworks for rare variants analyzes and an impressive translational result.

A novel encephalitis with seizures and the analysis of the effects of antibodies. In their study published in LANCET NEUROLOGY Petit-Pedrol and coworkers characterized serum and CSF samples for antigens in 140 patients with encephalitis, seizures or status epilepticus as well as antibodies to unknown neurophil antigens. High titres of serum and CSF GABAA receptor antibodies are reported to be associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both, which could be exploited for immunotherapy with 15 patients.

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Copy number variations and the forgotten epilepsy phenotypes

Complexity. Structural genomic variants or copy number variations (CNV) are known genetic risk factors for various epilepsy syndromes. In fact, CNVs might represent the single most studied type of genetic alterations across a very broad range of epilepsy syndromes. There is, however, a group of patients that is usually not investigated in genetic studies: patients with presumable lesional epilepsies or questionable findings on Magnetic Resonance Imaging (MRI). Many of these epilepsies are usually thought to be secondary to the identified lesion, and genetic risk factors are not considered.  In a recent study in the European Journal of Human Genetics last week, we investigated the role of CNVs in a cohort of patients with complex epilepsy phenotypes that were not easily classified into existing categories. Many of patients included had definite or questionable findings on MRI.  The results of our study made us wonder whether the boundary between lesional and genetic epilepsies needs to redrawn. Continue reading

The mosaic brain – single neuron copy number variations in humans

Variability. It has been rumored for quite some time, but only now is solid evidence present to show this phenomenon: the high degree of genomic diversity of human neurons. In a recent paper in Science, the genomic diversity among frontal brain neurons is explored on a cell-by-cell basis. The results are breathtaking: up to 40% of frontal cortex neurons have altered genomic material affected by large deletions or duplications. This study provides the linchpin for a plethora of new investigations aiming to understand the impact of this phenomenon in health and disease. Continue reading

Temperature rising: 17q12 microduplications and GEFS+

GEFS+, meet CNV. Microduplications at 17q12 have been identified in various neurodevelopmental disorders and in some unaffected individuals, a pattern familiar from other structural genomic variants such as microdeletions at 16p13.11 and 15q11.2. In contrast to the corresponding microdeletion, most 17q12 microduplications are inherited. This suggests that the microduplication is a risk factor, but does not fully explain the phenotype. In a recent paper in Neurology, Hardies and collaborators look at the families of 17q12 microduplication carriers with epilepsy. And this is when they noticed something strange. Continue reading

Dysregulation of a microRNA in the 22q11.2 microdeletion

Genotype to phenotype. Recurrent microdeletions at various sites in the human genome are known risk factors for a broad range of neurodevelopmental disorders including epilepsy, autism, intellectual disability and schizophrenia. Despite the fact that the pathogenic role is well established, the mechanisms linking the microdeletion to the neurodevelopmental phenotype remain obscure. In contrast to monogenic disorders, various genes are included and functional studies are difficult. Now, a recent paper in Cell examines the role of a specific microRNA that is dysregulated in the 22q11.2 microdeletion. The results are surprising. Continue reading

CASK aberrations in Ohtahara syndrome

Suppression-burst. Ohtahara Syndrome is a rare epileptic encephalopathy with onset in the first weeks of life. The typical EEG feature of Ohtahara Syndrome is suppression-burst activity, suggesting a profound disruption of cerebral function. Ohtahara Syndrome can be caused by severe brain malformations and neurometabolic disorders. In addition, mutations in ARX and STXBP1 are known causes of Ohtahara Syndrome. In a recent publication in Epilepsia, genetic alterations in CASK were identified in patients with Ohtahara Syndrome and cerebellar hypoplasia. Given that CASK mutations are the known cause for a complex X-chromosomal disorder, this report provides us with an interesting example of what happens when genes underlying distinct clinical dysmorphology syndromes cross over to the epilepsies. Continue reading

Copy numbers, seizures and speech

Why does this child with speech delay get an EEG? My first encounter with Landau-Kleffner-Syndrome and continuous spikes and waves during slow sleep (CSWS) was in medical school when my pediatric neurology attending faced me with this very question. I looked at him and basically had no idea. This is when I learned about the spectrum of rolandic epilepsies and how epilepsy interacts with speech. This concept is best explained by going back to the most common epilepsy in children, Benign Rolandic Epilepsy (BRE). And the genetics of BRE and the rolandic spectrum has been anything else but straightforward. Continue reading