Research ArticleNeurology

Arrhythmia in Heart and Brain: KCNQ1 Mutations Link Epilepsy and Sudden Unexplained Death

Science Translational Medicine  14 Oct 2009:
Vol. 1, Issue 2, pp. 2ra6
DOI: 10.1126/scitranslmed.3000289

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Editor's Summary

Patients with epilepsy face an extra frightening burden. Occasionally, otherwise healthy individuals with this disease die unexpectedly for no apparent cause. The incidence of sudden death is ~10% for epilepsy patients—a risk far greater than that faced by a non-epileptic person. Sudden unexplained death in epilepsy (SUDEP) frequently follows a seizure, and patients who experience many seizures have a greater risk of SUDEP. But the causes of SUDEP remain a mystery. Now, Goldman et al. shed new light on how defective potassium channels contribute to this syndrome.

Various causes of SUDEP have been proposed—some that produce irreversible cardiac dysfunction and some that produce respiratory distress. One suggested cause invokes the common dependence of the heart and brain on electrical activity for proper functioning. When ion channels—the membrane proteins that control electrical activity—go awry (by gene mutation or a drug), the brain becomes uncontrollably excited, producing a seizure, during which the regular beating of the heart is disrupted and can cease altogether. Both people and a mouse model display mutations in the KCNQ1 gene—which encodes a potassium channel in the heart—that give rise to heartbeat abnormalities and a higher risk for sometimes fatal arrhythmias.

Goldman et al. studied KCNQ1-mutant mice and found that this same potassium channel that causes problems in the heart is also present in neurons in the brain and is in particularly high abundance in regions that are susceptible to epilepsy. A closer look at the brains of these mice disclosed that their electrical discharges display abnormalities characteristic of epilepsy and that these aberrations often occur at the same time as abnormal heartbeats. Continuous video surveillance of these mice revealed that many also experienced overt seizures. In one instance, a mouse with the mutant ion channel suffered increasingly frequent seizures accompanied by irregular abnormal cardiac activity and ultimately went into cardiac arrest, a mouse version of SUDEP.

Taken together, these results reinforce hints in the literature that SUDEP may result from common excitability defects in the brain and heart. Cardiac abnormalities that resemble those in the mutant mice can be caused in humans by mutations in ~10 genes. The ability to screen epilepsy patients for these mutations would allow those who are at risk for cardiac-induced sudden death to take preventive measures.

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