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Volunteers Help Babies With A
Rare Genetic Disease

Emergency phone calls are rare for most research molecular biologist-biochemists. When the phone rings at 3 a.m. for Charlotte Phillips, she answers it immediately.

Phillips is part of a volunteer team at the University of Missouri whose members for the last decade have worked to save babies born with a devastating genetic disease. Without a special dietary formula, these infants have just three days before they suffer brain damage. Untreated they will likely die within two weeks.

The disease, Maple Syrup Urine Disease (MSUD) is a rare condition, affecting an estimated one in 225,000 infants worldwide. But it occurs more frequently in the Old Order Mennonite populations, in which the incidence is about one in 150 newborns.

Complicating the situation is the isolated farm life that the Mennonites choose. With a lifestyle more akin to the 19th century, many do not drive or own telephones. As Mennonite women often give birth at home or in rural clinics, it can be several hours, if not days, before a newborn can be tested for the disease.

This is where the informal team of MU physicians, dieticians, sociologists and geneticists come in. They identify families at risk and provide counseling, set up elaborate relay teams to get samples from newborns to specialized testing facilities in Columbia, and then rush the information back if the baby needs a prescription special formula.

MSUD is an inherited disorder in which the body is unable to process certain amino acids from protein into energy. The urine of affected infants has a distinctive sweet odor, like burned caramel, which gives the condition its name.

MSUD develops when mutations occur in one of the four genes that direct certain proteins to break down specific amino acids present in foods such as milk, meat and eggs. As a result, excess of certain amino acids and byproducts build up in the body. High levels of these substances are toxic to the brain.

Damage begins within 72 hours after birth when brains of affected babies swell. The babies lapse into a coma and die from neurological complications.

There is no cure. Treatment must begin soon after birth. Babies must eat a special and expensive prescription formula that contains only enough essential amino acids to allow them to develop normally. Afflicted adults use this formula as their primary protein source, too.

MSUD disproportionally affects the Mennonite community where members tend to marry within a relatively small population. The MU team maintains close ties with the Mennonites near Versailles and Memphis, two Missouri cities with the largest Mennonite communities.
While babies born in hospitals can be immediately tested for MSUD, the Mennonite practice of giving birth at home slows identification of the disease. Because many Mennonites live far from major medical centers, it can be several hours or days before testing can be initiated.

Not helping the situation is that the most common test for MSUD is a blood test to measure amino acids levels. Here, blood is sampled at 12, 24, 48 and 72 hours after birth to note accumulation of offending amino acids and confirm the diagnosis. Under the best of circumstances, this test takes too long. Additional delay, such as communicating via horse-drawn carriage, exacerbates an already tight timeline.

A faster diagnostic test had to be devised.

The ad-hoc MU team formed in 1995 after a 1993 incident when two babies almost died. The team began when Richard Hillman, MD and medical geneticist, sought out Phillips to help develop a DNA-based MSUD test. Phillips, an associate professor of biochemistry and clinical molecular geneticist in the Department of Biochemistry, College of Agriculture, Food and Natural Resources at the University of Missouri, specializes in research of inherited and acquired diseases of the bone and kidney. Joel Hartman, a rural sociologist, and dieticians and medical students, rounded out the initial group.

Jonathan Dyer, an MU biochemistry alumnus who later graduated from the MU School of Medicine, also helped develop that initial test. Later, Phillips worked with genetics graduate student Latisha Love-Gregory to better track the MSUD gene in the Versailles Mennonite population. They were able to go back 10 generations and find common ancestors and provide important scientific clues.

The DNA assay developed was significantly faster — delivering confirmation in 12 hours. Recently, an even faster test provides results in as little as five hours.

Unfortunately, the new assay that Phillips and her post-doctoral fellow, Stephanie Carleton, developed requires an expensive piece of equipment. That’s when molecular geneticist Elizabeth Bryda became involved in the project.

When Bryda came to work at the MU College of Veterinary Medicine’s Research Animal Diagnostic Laboratory (RADIL) in September 2003, Phillips was one of the first people she met. Bryda joined the faculty from the Marshall University School of Medicine where she had conducted grant-funded research on mouse models of polycystic kidney disease and mouse models of hereditary deafness as well as participated in several cardiovascular-related collaborations. She also taught and was course director for the human genetics course for second-year medical students. She came to MU because she said she was attracted to the scientific opportunities and collaborations that were possible working with other RADIL faculty, the chance to bring genetics expertise to the mouse and rat resource centers, as well as the potential to develop new genetic-based services through the RADIL fee-for-service lab.

With the blessings of Marshall’s administration, she brought with her a piece of equipment that she had been able to purchase with a grant ― the $50,000 ABI Prism 7000 Sequence Detection System that Phillips needed to run the DNA assay. While Bryda typically uses her DNA testing device to conduct quantitative real time polymerase chain reaction tests, she turns the equipment over to Phillips and her team when an at-risk baby needs testing.

The test, like the program itself, has been “creatively” funded during the last 14 years, Phillips said. A $100,000 grant from the National Institutes of Health helped, as did donations from the Children’s Miracle Network, the Leda J. Sears Trust Foundation, MU Healthcare, and most recently Heartland Genetics and Newborn Screening Collaborative. “We operate on a shoestring. We can’t not do the testing, it is too important.” Phillips said.

Helping the scientists and healthcare personnel are other volunteers who work with the Mennonite community and watch over at-risk pregnant women. When a baby is delivered, these people rush a baby’s DNA sample to Columbia. When the sample is assayed, the news to either give or not give the special formula goes back to the parent via the volunteers.

“One of the first families that we worked with lived in northwest Missouri, five hours from the nearest major medical center,” Phillips said. “We knew both parents were carriers, which meant their offspring had a 25 percent chance of developing the disease. As the family did not have a telephone or car, we had to pre-arrange, like a kind of water bucket brigade, a series of team couriers to bring the baby’s DNA sample to Columbia where we could conduct the test.”

Twenty four hours after the baby was born, the team had the baby’s sample. The baby had MSUD. “We telephoned the results to a pre-positioned volunteer positioned near the Mennonite community who delivered the news to put the baby on sugar water and bring him to University Hospital,” Phillips said. “At 41 hours old the baby was placed on diet and he did beautifully and had no neurological impact. But this baby was the driving force for us to develop the even faster five-hour assay that we are currently testing.”

Though operating on a patched-together budget, the team is looking to expand its service to other Mennonite communities. Phillips and Dawn Peck, an MU genetic counselor, are co-principal investigators in a community outreach project to eight states with Mennonite communities. Working with them is Julie Grasela, a clinical nutritionist.

Though funded on a shoestring, using borrowed scientific equipment and maintaining an informal network of volunteers, the program has been successful. Since its start, the team has not lost a baby to MSUD, even when the call for help comes in at odd hours.

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Last Update: February 29, 2012