Study to analyze brains of kids with rare disorder

Researchers at Washington University School of Medicine in St. Louis have received a five-year, $2.7 million grant to detect and analyze differences in the brains of children with a rare illness, Wolfram syndrome.

The disorder, which is caused by mutations in a single gene, includes a severe form of diabetes, hearing and vision loss and kidney problems. Eventually, patients lose muscle control and coordination due to degeneration in the brain. More than half of the patients die before they turn 40, often due to atrophy in the brainstem that contributes to respiratory failure. The illness affects an estimated one in 770,000 children.

As part of the new study, researchers will conduct MRI scans to measure and quantify changes in the brain during the course of the disorder.

“In preliminary studies, we have been able to detect differences in the size and volume of several brain structures in kids who have Wolfram syndrome,” says principal investigator Tamara Hershey, PhD, professor of psychiatry, of neurology and of radiology. “Our goal in the new study is to look for patterns of changes in the brain that might help us identify problems earlier, with the eventual hope of being able to intervene.”

Hershey says work in animal models of Wolfram syndrome is progressing rapidly toward possible interventions and treatments, so it is important to better understand how the disorder develops and progresses. She says using MRI scans and conducting behavioral testing to measure changes in the brain provide an opportunity to do that.

“The neurological features of the disease may be the most feasible thing to target and monitor in clinical trials,” she explains. “That’s because by the time a child gets a diagnosis of Wolfram syndrome, the insulin-producing cells in the pancreas already are damaged or destroyed, and the child has developed insulin-dependent diabetes. By identifying time points at which it’s possible to intervene, we may be able to prevent some of the severe problems that occur later in the course of Wolfram syndrome.”


Hershey’s group already has identified some key differences in the brainstem and the cerebellum. They have learned that in children with Wolfram syndrome, those structures tend to be smaller than those of other children their age, and there are differences in the thickness of the brain’s cortex, especially in an area related to vision.

By tracking patients with Wolfram syndrome over time with regular MRI scans and other neurological tools, Hershey says it may be possible to distinguish between changes that occur as the brain develops during childhood and those that occur due to degeneration related to the disorder.

Wolfram syndrome is caused by mutations in the WSF-1 gene, which was first identified in 1998 by the late M. Alan Permutt, MD, a former professor of medicine and of cell biology and physiology at the School of Medicine. He later developed an animal model of the disorder and set up an international patient registry.

In 2010, Washington University organized the world’s first, multidisciplinary clinic for patients with Wolfram syndrome, funded in part by the Snow Foundation, a family organization dedicated to raising funds for Wolfram syndrome research. Children worldwide came to St. Louis for testing and evaluation. Those clinics now are an annual event at St. Louis Children’s Hospital.

The Internet address for the Wolfram Syndrome International Registry’s website is

The Internet address for the Snow Foundation website is

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.