Expanding the Types of Genetic Mutations Involved in Shared Mechanisms of Epilepsy and Sudden Death


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Thursday, October 30, 2014

In some humans and animal models, sudden unexpected death in epilepsy (SUDEP) may be due to a shared genetic predisposition to both seizures and lethal cardiac arrhythmias. Co-existing epilepsy and cardiac dysfunction may be due to defects that affect the excitability of cells in the brain, autonomic nerves and the heart. Most of the known mutations that lead to a shared seizure/arrhythmia predisposition are in genes that encode ion channels such as potassium and sodium channels (see review by Glasscock 2013). However, many other proteins influence the electrical activity of cells by modulating ion channel function through both transient and permanent modifications.

A Mouse Study Explores Heart and Brain Dysfunction

A recent study by Qi and colleagues demonstrates one example of how disruption of a modifier protein can lead to heart/brain dysfunction. The authors created a genetically engineered mouse with a deficiency in the protein Sentrin/SUMO-specific protease 2 (SENP2), an enzyme that modifies the structure of proteins by reducing the amount of post-translational modification by small ubiquitin-like modifiers (SUMO). Addition of SUMO (termed SUMOylation) to ion channels can alter the function.

In a series of elegant experiments, the authors demonstrate that the excessive SUMOylation in mice with low SENP2 activity leads to spontaneous seizures, SUDEP-like premature death, and spontaneous and seizure-related bradycardia and cardiac conduction abnormalities. Moreover, both the seizures and cardiac abnormalities were related to excessive SUMOylation of the Kv7.2 and Kv7.3 potassium channels, which mediate the M-current in central and peripheral neurons.

The reduction in M-current lead to excessive neuronal hyperexcitability in both the hippocampus, leading to seizures, and the parasympathetic nervous system, leading to bradyarrythmia. In the SENP2 mice, treatment with ezogabine (retigabine), an FDA-approved antiepileptic drug that acts on Kv7 channels to enhance M-current, blocked seizures.

Looking for Answers to Seizure and SUDEP Risk

The contribution of SENP2 mutations to human epilepsy and SUDEP is unknown. However, the regulation of cellular excitability depends on a complex network of proteins with multiple critical nodes.

These findings add to the growing body of evidence that the spectrum of genes that contribute to seizure and SUDEP risk likely extend beyond those that directly encode for ion channels.

Authored by: Daniel Friedman MD on 10/2014

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