Worms help researchers tackle rare childhood genetic disease

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.

Genetically engineered, developed in the laboratory of neuroscientist Anne Hart C. elegans The nematode model provides a fast, inexpensive way to evaluate potential drug treatments for childhood alternating hemiplegia, or AHC, a disorder for which there is currently no cure or effective treatment.

humans and C. elegans Nematodes have many genes in common, including genes affected by AHC. Because these animals are so small and easy to raise, they are perfect for rapid drug testing to find drugs that have the greatest impact on AHC symptoms.

Anne Hart, Professor, Neuroscience, Brown University

Brown Ph.D. Research led by. Student Diana Wall, published in Disease models and mechanisms.

The study notes that symptoms of AHC vary widely. Some children experience daily episodes of paralysis that last for minutes; Others may experience monthly episodes that last for several days. Patients experience profound neurological symptoms, ranging from full-body paralysis and painful muscle spasms to seizures and autonomic dysfunction, which 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. The team’s analysis of worm models revealed that disease-associated gene mutations actively interfere with this enzyme and showed why AHC can have so many different symptoms in children.

“Each worm AHC model 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’s mutation causes different problems in children with AHC. Each mutation has a slightly different effect on the way this important protein works.”

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

“We’re being able to screen thousands of compounds ranging from very few treatment options to not just one type of ACH, but three types, which make up about 50% of all ACH cases,” said Nina Frost, who founded the nonprofit Rare Hope.

Frost’s daughter Annabel suffers from this disease. “For someone like me, a 10-year-old whose symptoms have been increasing over time, this is a really exciting development,” Frost said.

Wall, who has met families affected by the disease at the annual AHC symposium, said she was drawn to the study because of its potential to make a difference.

“Being in the same room with kids with ACH and knowing that these are the same people whose disease I’m trying to help cure — it’s been really rewarding,” Wall said.