Researchers Discover New Inflammatory Disease––Otulipenia

Genetic malfunction leads to inflamed joints in children

Scientists at the National Institutes of Health (NIH) have discovered a rare and sometimes lethal inflammatory disease––otulipenia––that primarily affects young children. They have also identified anti-inflammatory treatments that ease some of the patients' symptoms, which include fever, skin rashes, diarrhea, joint pain, and a failure to grow or thrive.

Otulipenia is caused by the malfunction of OTULIN, a single gene on chromosome 5. When functioning properly, OTULIN regulates the development of new blood vessels and the mobilization of cells and proteins to fight infection. The researchers published their findings in the Proceedings of the National Academy of Sciences.

An international network of scientists studying inflammatory diseases identified four children from Pakistani and Turkish families with unexplained skin rashes and inflamed joints. NIH scientists then searched for disease-causing genes using next-generation DNA sequencing.

Once they found that the OTULIN gene was abnormal in the sick children, they studied the immune pathway to understand the mechanisms of the disease and to improve the treatment of these patients. They discovered a problem in the processing of a small protein, ubiquitin, which is critical to the regulation of many other proteins in the body, including immune molecules. In the affected children, the inability to remove ubiquitin proteins from various molecules resulted in the increased production of inflammatory cytokines.

The researchers determined that the children with otulipenia might respond to drugs that turned off tumor necrosis factor (TNF), a chemical messenger involved in systemic inflammation. Inflammation subsided in the children who had been treated with TNF inhibitors. These drugs are commonly used to treat chronic inflammatory diseases, such as rheumatoid arthritis.

“The malfunction in this protein has not been previously linked to clinical disorders of the human immune system,” said coauthor Ivona Aksentijevich, MD. “This discovery suggests a direction that can be explored for development of new therapies for patients with a wide range of inflammatory diseases.”

Source: NIH; August 22, 2016.