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Researchers discover new disorder that causes chronic diarrhea in children

20.07.2006
Discovery may help further stem cell research for type I diabetes and intestinal disorders

UCLA researchers have unraveled a mysterious condition that causes congenital diarrhea and intestinal failure in children. The new disorder, named enteric anendocrinosis, is caused by a mutation in the gene Neurogenin-3 (NEUROG3).

The findings represent the first description of a disease-causing mutation of NEUROG3 in humans and the first new discovery within the past 15 years of a disorder that causes intestinal failure.

Patients with this condition have an abnormally low number of endocrine cells in their intestine and also eventually develop type I diabetes.

"Rare diseases help us understand how the body works," said principal investigator, Dr. Martín G. Martín, professor of pediatrics in the division of gastroenterology and nutrition at Mattel Children's Hospital at UCLA. "We now know that the hormone-producing endocrine cells of the intestine have an essential role in facilitating nutrient absorption. These findings have already led to the detection of subset forms of enteric anendocrinosis."

Martín and his colleagues describe their research in the July 20 issue of the peer-reviewed New England Journal of Medicine.

The study focuses on three children who each showed symptoms of vomiting, diarrhea and dehydration during the first few weeks of life, following consumption of formula.

Researchers used genomic DNA from the patients to screen for mutations of NEUROG3. They then tested the ability of the mutations to alter NEUROG3's function.

Martín anticipates that this discovery will provide the framework to further understand type I diabetes, as well as other diarrheal disorders, including inflammatory bowel disease and diarrhea-predominant irritable bowel syndrome.

"Since patients with enteric anendocrinosis develop type I diabetes, we hope stem cell researchers can apply the knowledge from this discovery to the role of NEUROG3 in the development of insulin-producing islet cells in the pancreas," Martín said.

"In mice, Neurogenin-3 initiates the development of the endocrine cells in the pancreas, including the insulin-producing cells," said Dr. Michael German, professor of medicine at the University of California, San Francisco, Hormone Research Institute. "In the absence of Neurogenin-3, no insulin-producing cells are generated in the pancreas, and the animals develop diabetes at birth. Therefore, Neurogenin-3 has been termed a 'pro-endocrine' gene, since it drives progenitor cells to mature into endocrine cells."

"The cure for enteric anendocrinosis and diabetes--two diseases that involve failure of a specific type of cell--may eventually be derived from stem cells that are able to replace the dysfunctional cells and produce the right kind of hormones," said Dr. Doron Kahana, a pediatric gastroenterology research fellow in Martín's lab.

There are about 30 known causes of chronic diarrhea. It affects approximately 5 percent of the population and only rarely occurs during the first several weeks of life.

Unlike acute diarrhea--which is normally caused by a virus, bacteria or parasite and generally improves within a few days or weeks--chronic diarrhea persists and can lead to severe malnutrition and growth failure in children.

For newborns with enteric anendocrinosis, their condition is worsened by eating. Treatment usually involves specialized formulas and intravenous nutrition to minimize the diarrheal symptoms and promote growth. Currently, there is no cure for the illness.

Amy Waddell Albin | EurekAlert!
Further information:
http://www.mednet.ucla.edu

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