Febrile Seizures: New therapy target for children

Fever-induced childhood seizures, known as febrile seizures, can be terrifying for parents to witness. The full-body convulsions, which mostly affect children six months to five years old, can last from mere seconds up to more than 40 minutes.

Currently, children are not treated with daily anticonvulsant medication to prevent these seizures even when they recur repeatedly because toxic side effects of existing treatments outweigh potential benefits.

While scientists know these seizures typically occur when a fever is above 100.4 degrees Fahrenheit (38 degrees Celsius), the exact mechanism at work has been unclear.

Now, in a new study appearing in the June 12, 2013 issue of The Journal of Neuroscience, a team of Northwestern Medicine researchers has identified a new key factor in the generation of febrile seizures, leading to a new therapeutic target for humans.

The team further found that nimodipine (Nimotop), a commonly available L-type calcium-channel blocker, dramatically reduced the incidence and duration of febrile seizures in animals.

Marco Martina

"Until now, most scientists believed L-type calcium channels, pores in the membrane that allow calcium into cells, were not engaged in the initiation of the brain electrical activity," said the study's lead author Marco Martina, MD, associate professor in physiology at Northwestern University Feinberg School of Medicine.

"We show that the activation of these channels, which are temperature sensitive, actually drives the electrical activity, not just follows it. As such, these channels may play a key role in seizure associated with high body temperature. Consequently, we can develop better treatments for toddlers and reduce the risk of negative outcomes."

Febrile seizures affect about five percent of children in the United States and are mostly benign, but do carry a risk of negative long-term consequences on brain development.

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Down syndrome: Researchers target a particular aspect

The protrusion of a neuron without Dscam protein (green) and that of a neuron with an abnormally high level of Dscam protein (red). 

The protrusions are overlaid on the fruitfly's equivalent of the human spinal cord (blue). Credit: Xin Wang 

University of Michigan researchers have determined how a gene that is known to be defective in Down syndrome is regulated and how its dysregulation may lead to neurological defects, providing insights into potential therapeutic approaches to an aspect of the syndrome.

Normally, nerve cells called neurons undergo an intense period of extending and branching of neuronal protrusions around the time of birth.

During this period, the neurons produce the proteins of the gene called Down syndrome cell-adhesion molecule, or Dscam, at high levels.

After this phase, the growth and the levels of protein taper off. However, in the brains of patients with Down syndrome, epilepsy and several other neurological disorders, the amount of Dscam remains high.

The impact of the elevated Dscam amount on how neurons develop is unknown. Bing Ye, a faculty member at U-M's Life Sciences Institute, found that in the fruit fly Drosophila, the amount of Dscam proteins in a neuron determines the size to which a neuron extends its protrusions before it forms connections with other nerve cells.

An overproduction of Dscam proteins leads to abnormally large neuronal protrusions.

Ye also identified two molecular pathways that converge to regulate the abundance of Dscam. One, dual leucine zipper kinase (DLK), which is involved in nerve regeneration, promotes the synthesis of Dscam proteins.

Another, fragile X mental retardation protein (FMRP), which causes fragile X syndrome when defective, represses Dscam protein synthesis.

Because humans share these genes with Drosophila, the DLK-FMRP-Dscam relationship presents a possible target for therapeutic intervention, Ye said.

Many genes are involved in neurological disorders like Down syndrome, and how molecular defects cause the disease is complex.

"But because of the important roles of Dscam in the development of neurons, its related defect is very likely to be an aspect of Down syndrome and it may be an aspect of the syndrome that can be treated," said Ye, an assistant professor in the Department of Cell and Developmental Biology at the U-M Medical School.

Ye's next step is to test the effects of over-expression of Dscam in mice to see how it changes the development of the nervous system and the behavior of the animal.

Down syndrome occurs in about one in 830 newborns; an estimated 250,000 people in the U.S. have the condition, according to the National Library of Medicine's Genetics Home Reference.

Ye's study is scheduled to be published online June 5 in Neuron.