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Medical Mysteries

The NIH Undiagnosed Diseases Program

Female researcher holding vials of blood

“This demonstrates that genomic tools are a powerful ally in our search to discover and understand rare diseases,” says Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI).

The National Institutes of Health (NIH) has been bringing sick people to its Bethesda, Md., campus for decades, usually to participate in clinical studies that have a defined focus, such as a particular cancer. Not only may they get helped, they also contribute to the overall understanding of disease.

But the Undiagnosed Diseases Program (UDP) is different. Instead of a single disease, UDP tackles the hardest-to-diagnose disorders, relying on NIH specialists in endocrinology, immunology, oncology, dermatology, dentistry, cardiology, genetics, and other areas to come up with insights about each case. A unified diagnosis is the optimal but often elusive endpoint.

Begun in 2008, the program is a clinical research initiative of the National Human Genome Research Institute (NHGRI), the NIH Clinical Center, and the NIH Office of Rare Diseases Research (ORDR). The UDP has responded to approximately 4,600 inquiries, received nearly 1,700 sets of medical records, and accepted roughly 380 cases from all over the country. Patients must be referred by a physician and provide all medical records and diagnostic test results requested by NIH. Those meeting program criteria then undergo an additional weeklong evaluation at the NIH Clinical Center.

Researcher’s hand holding a vial

NIH Genetic Sleuths Diagnose Mysterious Inherited Disorder

Researchers for the National Institutes of Health’s Undiagnosed Diseases Program (UDP) have pinpointed a genetic mutation as the cause of a rare and debilitating blood vessel disorder that had defied medical science for more than 100 years.
“This is the first novel disease discovered through the program’s collaborative, interdisciplinary approach,” says NIH Director Francis S. Collins, M.D., Ph.D. “The disorder had long-evaded conventional diagnosis.”

Called ACDC, the condition is characterized by painful and debilitating calcium buildup in arteries below the waist and in the hands and feet, yet spares the coronary arteries. It blocks blood flow, making movement painful and difficult. UDP scientists examined members of two families with ACDC and identified a third case outside the country.

Suspecting a recessive gene was at fault in the five affected siblings of one family, researchers analyzed the DNA of the entire family (see “Thankful…,” page 12). Each sibling had two copies of a particular mutation in a gene called NT5E, while each parent had only a single copy. When siblings inherit two such mutations, one from each parent, disease symptoms appear.

Similar mutations were detected in all the other affected patients studied. The NT5E gene normally makes the CD73 protein, which produces a small molecule, adenosine, which protects the arteries from calcifying. Calcification blocks blood flow, hampering normal, pain-free movement.

“This demonstrates that genomic tools are a powerful ally in our search to discover and understand rare diseases,” says Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI).

Manfred Boehm, M.D., lead investigator for the National Heart, Lung, and Blood Institute (NHLBI),  says, “In addition to providing insight for this unique patient group and their physicians, it adds to our knowledge of vascular biology.”

Concerning the patients, William A. Gahl, M.D., Ph.D., NHGRI clinical director, and director of the NIH Undiagnosed Diseases Program, adds, “We hope that an understanding of this faulty mechanism will guide us in providing helpful treatments for them.”

Entering its third year, the UDP takes cases referred from around the country that challenge the diagnostic know-how and resources of the medical community at large. Participating patients undergo extensive diagnostic testing and evaluation at the NIH Clinical Center.


Spring 2011 Issue: Volume 6 Number 1 Page 10-11