Mice with a genetic mutation that’s been observed in patients with epileptic encephalopathy, a severe form of congenital epilepsy, exhibit not only the seizure, developmental and behavioral symptoms of the disorder, but also neural degeneration and inflammation in the brain, researchers found in a new study. The findings highlight the mutation as an important part of the disease’s pathology and a potential target for treatment.

Patients with epileptic encephalopathy begin having seizures when they are born, and display progressive developmental delay, intellectual disability and autism like behavior, said the study leader.

“The dogma regarding epileptic encephalopathy has been that the epileptic seizures are driving the pathogenesis of intellectual disability and developmental delay. But we wanted to answer the question, is it really just the seizures driving the intellectual disability and developmental delay?” the author said. “This study is the first to show that expressing this human epileptic encephalopathy mutation in mice can cause not only spontaneous seizure and intellectual disability, but also neural degeneration.”

Previous work from the group found that epileptic encephalopathy is correlated with a mutation in a gene that codes for a potassium channel essential to regulating neuron activity. The mutation prevented the potassium channel from properly embedding in the cell membranes of neurons, causing it to build up inside the neuronal cells instead. Yet, whether and how the mutation played a role in the pathology of epileptic encephalopathy remained unknown.

In the new study, published in the Proceedings of the National Academy of Sciences, the group bred a population of mice with the gene mutation. The researchers studied the mice from birth to observe whether they developed symptoms and how the mutation affected the expression of the potassium channels as well as their brains.

The mice developed spontaneous seizures analogous to human patients, who begin having seizures as infants. The mice also had an increase in mortality – half of mice with the mutation died as juveniles. The surviving mice showed significant deficits in learning and memory, as well as repetitive behaviors associated with human autistic behavior.

“It was very interesting to us that, from a young age, the mice displayed not only seizure activity consistent with human patients, but also the intellectual, developmental and behavior symptoms displayed by human patients,” the author said.

In the brain, researchers saw widespread neural degeneration and inflammation  that started as early as the weaning age and grew progressively worse as the mice aged.

The findings open up two potential therapeutic targets: the defective potassium channel and the inflammation and neural degeneration, the researchers said.

“A lot of epileptic encephalopathy patients are not responsive to anti-epileptic drugs. So if we cannot block the seizures, what is the next thing to do?” the author said. “We know that the neural degeneration is happening in mice at least as early as weaning age. Can we block that that early on before things get worse? That is a very important therapeutic intervention that we should think about.”

Next, the researchers want to study what causes the neurons to die, and whether other mutations to the potassium channel cause the same symptoms. They also hope to use the mouse line with the mutation to study potential treatments. 

https://news.illinois.edu/view/6367/1884974120

https://www.pnas.org/content/118/51/e2021265118