June 21, 2019

Sudden Death in Epilepsy and Breathing Troubles Linked to Gene Mutation

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A mouse brain, showing how mutations in sodium channel gene 1a may cause both seizures in the cortex and respiratory dysfunction in the brainstem, and so contribute to death. (Figure by Dan Mulkey & Virge Kask)

In Sudden Unexpected Death in Epilepsy (SUDEP), people stop breathing for no apparent reason. Now, a group of UConn neuroscientists have a lead as to why, they report in the journal eLife.

“People with epilepsy have a high mortality rate, but it’s mysterious,” says Dan Mulkey, a neuroscientist in UConn’s physiology and neurobiology department.

Mulkey and his colleagues, graduate students Fu-Shan Kuo and Colin Clearly, wondered if there was a genetic basis for SUDEP. Perhaps the same genetic mutation that causes the seizures also disrupts the cells in the brainstem that control breathing.

To understand how this [genetic mutation] might lead to SUDEP, Kuo wanted to test two things: first, whether the mice with the Dravet syndrome mutation show breathing problems and die prematurely of SUDEP, and second, whether the cells in the part of the mice’s brainstem that controls breathing were normal or were somehow perturbed by the mutation.

The first question was answered quickly: the mice with Dravet syndrome had bad seizures that became more severe when the mice got hot, exactly like humans with Dravet syndrome. They tended to die very young, in a manner similar to SUDEP; none lived much past three weeks.

The second question took longer to answer, but there were early clues that Kuo and Mulkey were on to something. The mice with Dravet Syndrome had disordered breathing. They tended to hypoventilate (breathe too little) for no apparent reason sometimes. Other times they would have long apneas, or pauses between breaths. And these mice didn’t breathe more in response to high carbon dioxide levels in the air, the way humans and normal mice do.

When Kuo zoomed in on the part of the brainstem that controls breathing, she saw that the inhibitory cells – the stadium bouncers of the brainstem – were definitely less active than they should have been. This led the excitatory neurons to run wild, and constantly tell the part of the brain that generates the breathing rhythm to push faster. But shouldn’t this lead to increased breathing, not stopping?

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