Clinicians, researchers identify gene mutation as cause of boy’s rare disorder

From the Summer 2016 edition of Vanderbilt Medicine Magazine

Maribel Giron, center, holds  her son, Denny Majano, with members of the Monroe Carell Jr. Children’s Hospital team who cared for him. From left are, Hernan Correa, M.D., Kelly Thomsen, M.D., MSCI, Sari Acra, M.D., MPH, and James Goldenring, M.D., Ph.D. Photo by Joe Howell.
Maribel Giron, center, holds her son, Denny Majano, with members of the Monroe Carell Jr. Children’s Hospital team who cared for him. From left are, Hernan Correa, M.D., Kelly Thomsen, M.D., MSCI, Sari Acra, M.D., MPH, and James Goldenring, M.D., Ph.D. Photo by Joe Howell.

Test after test failed to reveal why Denny Majano wasn’t gaining weight or why he suffered from severe, chronic diarrhea. At 5 weeks old Denny had lost a pound since birth.

He was admitted to Monroe Carell Jr. Children’s Hospital at Vanderbilt in 2011, where he would spend almost two and a half years in the hospital, often struggling to survive. But perseverance and collaboration, along with the discovery of a rare genetic mutation, would eventually allow Denny to spend his first Christmas at home in December 2015 with his mother, father and sister. His case exemplifies what happens when basic science meets clinical care.

“He was really bad. He wasn’t able to eat; he couldn’t hold anything in his stomach. Everything he ate, he would throw up,” said Denny’s mother, Maribel Giron. “The doctors did one test after another and they came out OK.”

One early test early suggested Denny had autoimmune enteropathy, a rare disorder that affects the immune system and is characterized by diarrhea. But the treatments deemed effective for that disorder, including potent immunosuppressant medications, weren’t working for Denny. His physicians concluded the test was likely a false positive.

“He was ill enough that he wasn’t able to meet his nutritional or fluid needs with eating and drinking by mouth, so for a long period of time he required nutrition and hydration through an IV,” said Denny’s pediatric specialist, Kelly Thomsen, M.D., MSCI, assistant professor of Pediatrics in the D. Brent Polk Division of Gastroenterology, Hepatology and Nutrition.

His care team took a step back to explore the bigger picture, bringing together Vanderbilt clinicians and basic research scientists to look at his genetic makeup with whole exome sequencing.

“What’s available here at Vanderbilt is this collaboration between clinical teams and basic scientists to solve real problems and to take care of children in a way that other places may not be able to,” said Sari Acra, M.D., MPH, medical director of the Division of Gastroenterology, Hepatology and Nutrition.

In conferring with Hernan Correa, M.D., chief of Pathology at Children’s Hospital, Correa and Acra noticed subtle changes in the epithelial lining of the intestine that suggested abnormalities in epithelial development. For further help, they enlisted James Goldenring, M.D., Ph.D., an internationally recognized authority on intestinal epithelial biology.

Goldenring determined that some key nutrient transporters were not making it to the intestinal cell lining. Recognizing the similarities to another rare form of congenital diarrhea he had characterized, Goldenring felt it was imperative that gene sequencing be performed on Denny. Goldenring, Paul W. Sanger Professor of Experimental Surgery and co-director of the Epithelial Biology Center, used his own unrestricted research funds to make that happen.

Acra, Goldenring and Correa then conceived of a research study that was supported by the NIH-funded Digestive Disease Research Center (DDRC) at Vanderbilt. Ultimately, in collaboration with the HudsonAlpha Institute, they identified a gene mutation in Denny known as DGAT1 (Diacylglycerol O-Acyltransferase 1), an enzyme that catalyzes the formation of triglycerides in the intestine. The team has also helped diagnose genetic mutations in two other children with rare diarrheal diseases.

The abnormal enzyme function in Denny can lead to profound diarrhea, and the team is now investigating how that causes abnormalities in the delivery of nutrient transporters to the intestinal lining.

In infants, severe, chronic diarrhea can cause dehydration and failure to thrive and has potentially life-threatening consequences. The team theorizes that genetic abnormalities in infants who have symptoms similar to Denny’s are the cause of many cases of undiagnosed neonatal diarrhea. With Denny’s specific mutation, they found that there were only two other published cases, and three suspected cases, in the world.

“Gaining that information was really important because we were able to communicate with the physicians who had cared for those children,” said Thomsen. “One of these children had gotten better with dietary changes. So we started making the dietary changes for Denny, and he did wonderfully with them.”

Following the discovery of the mutation in May 2015, Denny, age 3, was placed on an extremely low-fat diet.

“We had tried so many formulas,” Giron said. “Then, practically from one day to the next (after starting the new formula) he got better. He is almost entirely another child.”

Acra and Goldenring said Denny’s case laid important groundwork at Vanderbilt for a new approach to diagnose and study undiagnosed neonatal diarrhea. It highlighted the importance of the judicious use of genetic analysis to identify specific in-born causes of these devastating diarrheal diseases.