Tiny worms, with help from Brown University researchers, may hold key to treating rare childhood disease

PROVIDENCE, R.I. [Brown University] - A new worm model developed by Brown University researchers could play a key role in treating a rare genetic disease that causes paralysis in children and worsens with age.

Developed in the lab of neuroscientist Anne Hart, a genetically engineered C. elegans nematode model provides a fast, inexpensive way to evaluate potential drug treatments for alternating hemiplegia of childhood, or AHC, a disorder that currently has no cure or effective treatments.

"Humans and C. elegans nematodes share many of the same genes, including those affected by AHC," said Hart, a professor of neuroscience at Brown affiliated with the University's Carney Institute for Brain Science. "Because these animals are so tiny and easy to grow, they are perfect for rapidly screening drugs to find ones that have the greatest impact on AHC symptoms."

The research, led by Brown Ph.D. student Diana Wall, was published in Disease Models and Mechanisms.

Symptoms of AHC vary widely, the study notes. Some children experience daily episodes of paralysis that last minutes; others may experience monthly episodes that last for days. Patients experience profound neurological symptoms, from full-body paralysis and painful muscle spasms to seizures and autonomic dysfunction, with episodes that can last from minutes to days.

AHC is caused by mutations of the ATP1A3 gene, which produces an enzyme important for nerve and muscle function. Analysis of the team's worm model revealed that gene mutations connected to the disease actively interfere with this enzyme and showed why AHC can have such different symptom expressions in children.

"Each of the worm AHC models shows different defects in neuron and muscle behavior, as well as slightly different sleep/arousal problems," Wall said. "This is similar to how each patient mutation causes different problems in children who have AHC. Each mutation has a slightly different effect on how this important protein works."

Existing test models of AHC, including those based on rodents and human cells, lack the most common patient variants as well as the ease and scalability of nematodes. The team is developing methods for use in screening potential drug treatments for the disease, a game-changing possibility for patients and their families.

"We're going from having very few treatment options to being able to screen thousands of compounds on not just one variant of AHC, but three variants that make up about 50% of all AHC cases," said Nina Frost, who founded the nonprofit RARE Hope, which helped fund the study.

Frost's daughter Annabel lives with the disease. "To somebody like me, with a 10-year-old whose symptoms are increasing over time, that's a really exciting development," Frost said.

Wall, who has met families affected by the disease at the annual AHC symposium, said that she was drawn to working on an understudied condition given the potential to make a difference.

"Being in the same room with children with AHC and knowing that these are the people whose disease I am trying to help cure - that has been really rewarding," Wall said.

Funding for the research was provided by the National Institutes of Health (F31NS143238), the RARE Hope Foundation, the Hope4Livi Foundation, the Alternating Hemiplegia of Childhood Foundation and Cure AHC.