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 – 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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Epigenetic signatures – profiling the epilepsies beyond genetics

What is epigenetics? In a single idea: the molecular memory of a cell. The system stores information of previously external (e.g. environmental) or internal (e.g. developmental) stimuli, learns from this experience and responds. A collection of specific tags tells genes whether to be ON or OFF. Hardcore epigeneticists claim that an epigenetic tag should be meiotically and/or mitotically heritable, self-perpetuating, and reversible. DNA methylation is the mechanism coming closest to this ideal. A more liberal definition not focusing on heritability refers to any structural adaptation of the chromatin template that regulates gene expression. This would also include posttranslational histone tail modifications, incorporation of histone variants, chromatin remodeling processes, and action of non-coding RNAs. The large variety, flexibility, interdependence and potential synergistic effects of epigenetic mechanisms could provide the molecular basis for any phenotypic variation in physiological and pathological conditions. In epilepsy research this is especially interesting with regard to the stimulus-driven activity and connectivity of post-mitotic neurons in the adult brain. We set out to study methylation for the most common form of epilepsy in adults. Continue reading

Dravet Syndrome, zebrafish and clemizole

Modeling disease. Animal models for genetic disease might help in discovering new treatment options, especially when a large number of drugs or compounds can be tested in this model. In a recent paper in Nature Communications, a zebrafish model for Dravet Syndrome is used for medium-throughput screening of compounds approved by the Foods and Drugs Administration (FDA). The authors identify a single compound that is capable of abolishing behavioral and electrographic seizures in SCN1A-deficient zebrafish. Continue reading

G proteins, GNAO1 mutations and Ohtahara Syndrome

G proteins. Intracellular signaling in neurons can occur through various mechanisms including so-called second messengers. G proteins constitute an important part of the signaling cascade that translates the signal from membrane-bound receptors. On neurons, GABA-B receptors or alpha-2 adrenergic receptors use signal transduction through the so-called G alpha-o proteins, which are particularly abundant in the CNS and encoded by the GNAO1 gene. Now a recent paper in the American Journal of Human Genetics describes de novo mutations in Ohtahara Syndrome and movement disorders. Continue reading

Methusalem proteins in the brain

You are what you eat. During medical school, I spent a year in Lexington, Kentuck,y as an exchange student. When I went out for lunch with some of my classmates one day, the discussion came up what percentage of my total body protein would be European versus American after one year. It turns out that most proteins have a high turnover rate and are constantly rebuilt and removed. This makes sense as proteins do not have dedicated repair mechanisms as does DNA. However, some proteins seem to linger. A recent study in Cell now identifies long-lived proteins in the brain.  And it appears that the gatekeepers of the neuronal nucleus are pretty much built to last forever, and dysfunction of these proteins may contribute to neurological diseases. Continue reading

The endozepine mystery

Compound unknown. GABA is the main inhibitory neurotransmitter in the Central Nervous System and its effect is mediated through GABA receptors. Benzodiazepines are compounds that reinforce the action of GABA in the brain, which gives them antiepileptic properties. Consequently, benzodiazepines are one of the most common groups of antiepileptic drugs used to interrupt acute epileptic seizures. Interestingly, benzodiazepines have their own binding site on the GABA receptor, suggesting that they might actually mimic the effect of another, yet unknown substance that is present in the brain. The identity of this mysterious substance, the endogenous benzodiazepine or endozepine, has been one the romantic mysteries of neuroscience. Now, a recent paper in Neuron provides strong evidence that products of the DBI gene are the long-sought endozepine. Continue reading

STRADA mutations, mTOR activation and personalized medicine using rapamycin

Rapamycin. The mTOR pathway, known through its role in Tuberous Sclerosis Complex (TSC), becomes increasingly important in epilepsy. A wide range of epilepsies caused by brain malformations are due to mutations in genes involved in this pathway, and several neurodevelopmental disorders associated with macrocephaly, intellectual disability and epilepsy are known, where components of this pathway are altered due to germline mutations. For one of these disorders named PMSE (polyhydramnios, megalencephaly and symptomatic epilepsy), a recent paper in Science Translational Medicine reports the effects of treatment with rapamycin, an mTOR inhibitor. The results demonstrate that personalized medicine might in part be promising, asexisting drugs can be used in rare genetic diseases. Continue reading

The Hippocampus Conspiracy

Slightly misleading. The green and blue histological staining that has become the EuroEPINOMICS logo features a human hippocampus, a part of the human brain that is particularly important in human epilepsy. Temporal Lobe Epilepsy (TLE) is the most common epilepsy in adults and involves the hippocampal region. Ironically, TLE is the human epilepsy that has always been at odds with genetic research. Let’s review what we know about the genetics of TLE and “hippocampal genetics”. Continue reading

A little clonazepam to rescue behavioral deficits in SCN1A-deficient mice

Dravet Syndrome, behavior and cognition. Dravet Syndrome, or Severe Myoclonic Epilepsy of Infancy (SMEI), is a severe childhood epilepsy due to disruptions of the SCN1A gene. Besides the actual seizures, Dravet Syndrome is characterized by a plateauing of cognitive development in the second year of life. In childhood, most patients with Dravet Syndrome have intellectual disability, and the frequency of other neurodevelopmental disorders including autism are increased. Neurodevelopmental features of Dravet Syndrome have recently come into the focus of research, as de novo mutations in SCN1A were discovered in patients with autism. Now a recent study in Nature sheds some light on the underlying pathophysiology and discovers a surprising treatment effect. Continue reading