Years of research brought together in one weekend

Kristen Klenk is a 13-year-old girl with a bright smile and sweet personality. She was diagnosed with profound hearing loss at 20 months, and at age 3, developed type 1 diabetes requiring insulin injections. Her vision has gotten progressively worse since first receiving glasses at age 6, and she now is legally blind. But it took physicians more than 12 years to put the pieces of the puzzle together – Kristen has a rare genetic disease called Wolfram syndrome.

Kristen and her mother, Jennifer, came to Washington University School of Medicine in St. Louis from Massachusetts in August to take part in the first multidisciplinary clinic in the world for patients with Wolfram syndrome. M. Alan Permutt, MD, professor of medicine and of cell biology and physiology, has studied the syndrome in the lab for two decades, but because it is so rare, the clinic participants were the first patients with Wolfram syndrome he had ever seen.

Permutt and his staff brought 10 patients, ranging in age from 7-23, and their families to Washington University Medical Center for two days of intensive testing. Nearly a dozen School of Medicine faculty tested blood, vision, balance and hearing, performed MRI scans, neurological and psychological testing and provided genetic counseling. The clinic followed more than a year of organization and communication with families through an online registry, set up by Jonathon Wasson, who manages Permutt’s research lab. Wasson says 36 patients are enrolled in the registry, housed within the Department of Medicine.

Wolfram syndrome involves several primary symptoms, including type 1 diabetes, hearing loss, optic atrophy and renal and neurological problems. While its exact prevalence is not known, Permutt estimates it affects fewer than one in a million people. Sixty percent of patients die before their 30th birthday as a result of progressive neurodegeneration.

“Washington University is a major medical center with renowned diabetes specialists, but none had ever seen a patient with Wolfram syndrome,” Permutt says. “So how can a typical pediatrician know about it?”

During his introduction to patients and their families at the clinic, Permutt was moved by how it all came together.

“For years I’ve been getting letters and e-mails from patients asking for help, and I’ve never been able to,” Permutt says. “And there I was at the clinic with 10 Wolfram patients at St. Louis Children’s Hospital. It was very rewarding to finally be in a position to help.”

The first evidence of Wolfram syndrome is typically type 1 diabetes. Children may also have diabetes insipidus, a hypothalamic-pituitary disorder characterized by the inability to concentrate urine. Optic atrophy leads to the loss of nerve fibers in the optic nerve, causing vision loss. Patients may also develop depression, chronic fatigue, seizures, anemia and other disorders.

Wasson was on the team with Permutt in 1998 when they discovered mutations in the WFS1 gene, which researchers say causes Wolfram syndrome. Since then, more than 100 mutations of the gene have been found. Children with a mutation in WFS1 have a complete loss of the Wolfram protein, which leads to abnormal quality control of protein synthesis. Over time, this leads to the death of cells, including pancreatic cells, and neurons in the optic nerve and in the auditory centers of the brain.

Permutt says the goal of the clinic and research is to identify targets for therapeutic intervention and to provide patients with information about clinical trials when they are introduced.

Kristen Klenk was diagnosed with Wolfram syndrome in January 2010, though she has been seeing geneticists and other specialists since she was a baby. Kristen’s diabetes physician learned of the registry and encouraged the family to participate. That’s how they learned of the clinic.

“It was important for us to come to meet other families and to get support because there is not much information out there,” Jennifer Klenk says.

Permutt says the School of Medicine’s Institute of Clinical and Translational Sciences will help organize the data collected at the weekend clinic. He plans to use it to provide a baseline for these patients and to follow them over time to see how the disorder progresses. In addition, he said he hopes to design clinical trials to help find better treatments for these patients. Treatments discovered may be applicable to more common forms of diabetes or neurodegeneration.

Faculty and staff donating their time and services to the clinic were Bess Marshall, MD, associate professor of pediatrics; Abby Hollander, MD, associate professor of pediatrics; Neil White, MD, professor of pediatrics; Josh Shimony, MD, PhD, assistant professor of radiology; Alex Paciorkowski, MD, instructor in neurology; Timothy Hullar, MD, assistant professor of otolaryngology; Tamara Hershey, PhD, associate professor of psychiatry; James Hoekel, O.D., staff optometrist; Linda Manwaring, a genetic counselor in pediatrics; and Wasson. Julio Leey, MD, a former endocrine fellow in Permutt’s lab, also helped organize the weekend clinic.

Permutt received several grants from within the School of Medicine to help pay for the clinic and the testing, and medical students volunteered as family guides.

Although Permutt has been studying Wolfram for many years, he said he learned much from the weekend clinic.

“My lab discovered the gene 12 years ago and developed an animal model, and we never thought we’d be able to take it from a laboratory exercise to a mouse model to having patients with this problem and trying to develop drugs to treat them,” he says. “This has really been a bench-to-bedside exercise, and it’s very gratifying that it’s come to this place.”