Science and Medicine: Why are neurodevelopmental problems common in Duchenne muscular dystrophy?

Duchenne muscular dystrophy (DMD) is a devastating genetic disease that is usually diagnosed when children are around two or three years old when they normally start crawling or walking. These important steps are difficult and can be delayed in children with DMD. Most will need a wheelchair between the ages of twelve and fourteen and many will die in their twenties.

DMD is inherited on the X chromosome, so it is more likely to affect people with only one X chromosome, usually boys. Girls often have a second X chromosome that can compensate for the first mutation. About 20,000 people live with this condition in the United States.

The genetic variation in DMD causes a deficiency or absence of a protein that protects muscles from degeneration, called dystrophin, which leads to progressive muscle wasting. Dystrophin also protects the heart muscle and diaphragm, and its deficiency leads to heart failure or respiratory failure.

However, last year, the Food and Drug Administration approved a gene therapy for DMD that uses a virus to produce a type of dystrophin in muscles. This can slow the deterioration and give hope for a longer life for people with DMD.

Now, families are looking for ways to improve that quality of life, according to Jason Pugh, Ph.D. He is a neurologist and associate professor in the Department of Cellular and Integrative Physiology at UT Health San Antonio. “As we get closer to treating the muscular symptoms of this disease, parents are really looking for information and research about what’s going on in the brain,” Pugh said.

That has been the focus of Pugh’s work for nearly a decade. At the time, he was studying the Purkinje cell, a type of neuron in the cerebellum that plays an important role in motor coordination. He wondered if they might be involved in muscle wasting. In fact, Purkinje cells have the highest expression of dystrophin in the brain.

What does that mean for the brains of children with Duchenne muscular dystrophy? Pugh says children with DMD often have cognitive dysfunction as well as muscle wasting.

“These often include deficits in working memory and verbal memory,” Pugh said. “Many of these patients are also diagnosed with neurodevelopmental problems. Autism spectrum disorder, ADHD, and OCD are very common among boys with muscular dystrophy.”

Pugh is trying to determine if dystrophin deficiency has a role to play in this, too. In his lab, they use a mouse model to try to answer a series of questions about the protein.

“What is the function of dystrophin in neurons? How does the loss of dystrophin change neuronal function? Pugh asked. “Can we find ways to restore neuronal function in the absence of dystrophin?”

If you could reactivate the Purkinje cells to produce dystrophin in the brain, would that restore synaptic activity and reduce cognitive dysfunction? Or does dystrophin need to be present during earlier, critical periods of development?

Very little research has been done on the effect of muscle damage on the brain. Pugh is truly a pioneer in the field, and for a long time, it was difficult to find support for his work, he said. After all, the people he wanted to help didn’t live that long.

“One of the first grants I sent on this, the analysts came back and said, ‘Why should we care about what’s going on in the brain when these kids are dying of muscle symptoms?'” But I think we’re at a point where we’ve made a lot of progress in treating muscle symptoms, it’s time to understand what’s going on in the brain.

Parents often approach him, Pugh added, wanting to know what he has learned and what he hopes to learn.

He said: “I think that is the future of research on muscle breakdown, understanding what happens in the brain and other organ systems.

Answering these questions could also help scientists better understand the patterns of neurodevelopmental disorders like autism and ADHD in the general population, which could lead to more effective treatments for both those with and without DMD.

Science & Medicine is a collaboration between TPR and The University of Texas Health Science Center at San Antonio that examines how scientific discovery in San Antonio advances the way medicine is used everywhere.