New findings from a lab of an SMU biology professor have provided valuable clues in unraveling the mystery of sudden unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related mortality.

The underlying mechanisms behind SUDEP historically have been shrouded in mystery but work in Edward Glasscock’s lab is helping to pull back the curtain, SMU said.

SMU said that roughly 3 million people in the U.S. have epilepsy, making it the country’s fourth most common neurological disease; SUDEP claims more lives in the United States every year than the more widely publicized sudden infant death syndrome (SIDS).

The university said that in new research published in the journal Brain Communications, Kelsey Paulhus, a post-doctoral researcher in the Glasscock lab and lead author of the study, shows that excitatory neurons within the brain’s corticolimbic circuits have a prominent role to play in epilepsy and SUDEP.

A missing key protein

The researchers’ findings are the first to show that circuits lacking a specific protein, Kv1.1, in this subset of neurons promote seizures that can lead to lethal cardiorespiratory failure.

“For a long time, SUDEP has been suspected to involve a fatal breakdown in communication between the brain, heart, and lungs.” Paulhus said. “In this study, we actually observed this breakdown in real time using simultaneous recordings of brain, heart, and lung activity in mice without Kv1.1 in select brain circuits.”

The lab’s work is moving researchers closer to improved treatments.

“Identifying specific proteins and brain circuits involved in SUDEP moves us closer to developing interventions that may prevent this tragic epilepsy-related outcome,” said Vicky Whittemore, program director at the NIH’s National Institute of Neurological Disorders and Stroke, which funded the study.

“Given the unpredictable nature of SUDEP, observing the physiological mechanisms associated with lethal seizures is challenging and has only been accomplished experimentally a handful of times worldwide,” Glasscock said in a statement. “Therefore, this work provides a rare glimpse into the potential sequence of events that lead to sudden death in epilepsy.”

The Kv1.1 protein investigated in the study is encoded by the Kcna1 gene and belongs to a family of voltage-gated potassium channels known for their role in controlling signals in and between brain and heart cells. Mutations in Kcna1 are a common genetic cause of epilepsy in people. More severe mutations can lead to epileptic encephalopathy, an especially severe form of epilepsy associated with an increased risk of SUDEP.

SMU said that that the corticolimbic circuit, which is part of the forebrain, holds significant regulatory power over the heart and lung functions, even though the brainstem often is thought of as the place where the body regulates their functions. In addition to being a frequent seizure onset zone, this circuit, which includes the cortex, hippocampus, and amygdala, also is important for learning and memory function, the university said.

In people with epilepsy, seizures or direct simulation of the amygdala and/or hippocampus can pause breathing and impair heart function suddenly and without warning, possibly increasing the chances of sudden death when seizures invade these brain structures.

Tagging ‘a significant genetic risk’

SMU said that in another recent paper from the Glasscock lab in the Journal of General Physiology, post-doctoral fellow Man Si and colleagues investigated the role of Kv1.1 in cardiac pacemaker cells in the heart’s sinoatrial node, a patch of cells located along the upper wall of the right atrium.

Researchers said those cells generate electrical impulses that start every heartbeat.

Using mice, Si discovered that when Kv1.1 is missing or blocked, pacemaker cells have difficulty in maintaining normal electrical activity resulting in abnormal heart rhythms.

“Given the importance of Kv1.1 in maintaining proper brain and heart function, mutations affecting this protein could represent a significant genetic risk factor for SUDEP,” Glasscock said.

Ultimately, SMU said that study and the one published in Brain Communications, suggests Kv1.1 is a significant research target to uncover the complex multi-organ causes of SUDEP.

The university said that these studies are part of Glasscock’s ongoing research funded by the National Institutes of Health. Glasscock is the Prothro Distinguished Chair of Biological Sciences in SMU’s Dedman College of Humanities and Sciences.

Paulhus’ research also was supported by a predoctoral fellowship from the American Epilepsy Society. She also was a part of the Journal of General Physiology study, as were SMU’s Man Si and Praveen Kumar; Northwestern State’s Ahmad Darvish; and Louisiana State University Health Sciences Center’s Kathryn Hamilton.

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