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Undiagnosed Diseases Program unravels mystery of rare illness

Undiagnosed Diseases Program unravels mystery of rare illness

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Medical mystery solved! What causes painful joints and calcium buildup in the arteries of legs? A genetic mutation called ACDC.

The national Undiagnosed Diseases Program has discovered its first novel disease! They've identified the genetic cause of a rare artery-hardening disorder never before explained in medical literature.

This vascular condition sets in during adulthood and causes increasingly painful calcium buildup in arteries below the waist (pictured) and in the joints of hands and feet. It isn’t rheumatoid arthritis, and arteries of the heart are unaffected.

The researchers are calling it ACDC, and its hitherto unexplained cause is a genetic mutation.

This National Institutes of Health (NIH) program was launched in 2008 with two goals: (1) to provide answers to patients with mysterious conditions that have long eluded diagnosis and (2) to advance medical knowledge about rare and common diseases.

“Patients who have rare diseases are often abandoned by the medical community,” says coauthor William Gahl, director of UDP. They have since scheduled 330 patients.

This is the first novel disease discovery identified by the 3-year-old UDP. "This disorder previously baffled the medical field and evaded diagnosis when conventional methods were used,” says NIH Director Francis Collins.

Nature reports:

For Louise Benge the mystery began over twenty years ago, when her legs began to hurt. Now it is part of her daily life. It hurts when she stands. It hurts when she walks. X-rays revealed that arteries in her legs were hardening, but doctors couldn't explain why.

What was clear, however, was that Benge was not alone: her four siblings had the same problem. The pain was so severe that not one of them could walk for more short distances. "It has slowed me down quite a bit," says Benge. Her sister, Paula Allen, says that her own pain sometimes keeps her up at night…

In 2009, a referral arrived [at the NIH campus] from a physician in Mount Vernon, Kentucky. Her patient, Benge, had leg, buttock, and foot pain, but it was her misshapen, hardened arteries that caught the team's attention.

There are only 9 people known to have this condition, and they come from 3 unrelated families in Kentucky, San Francisco, and Italy.

The researchers suspected a recessive inheritance – where each child receives two copies of a gene mutation, one from each parent. So they analyzed DNA from the entire family and made comparisons with 200 unaffected people.

Everyone with the disorder had the same mutated NT5E gene – which normally makes the CD73 protein that produces a molecule, adenosine, that protect the arteries from calcifying.

Hence ACDC, for ‘arterial calcification due to CD73 deficiency.’

"Vascular calcification often results from poor diet and lack of exercise," says Gahl. "The calcium buildup in arteries of our patients, however, arises because the systems to inhibit it are not working in their cells."

Researchers are already preparing a clinical trial to treat the faulty mechanism. The team's awaiting approval from ethics committees to test bone loss drug bisphosphonate on the ACDC patients.

"Even if they can't help us, maybe someday they can help someone else with these problems," Benge says.

And understanding rare diseases can give insights into more common ones, Gahl adds. The results could help develop treatments for osteoporosis, where bone is lost, or atherosclerosis, when arteries become hardened and clogged, leading to heart attacks and strokes.

UDP receives $3.5 million per year through 2012. They published the discovery in the New England Journal of Medicine last week.

Image: knee x-ray of ACDC patient reveals calcification in the main artery supplying blood to the lower leg / NIH

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Janet Fang

Contributing Editor

Janet Fang has written for Nature, Discover and the Point Reyes Light. She is currently a lab technician at Lamont-Doherty Earth Observatory. She holds degrees from the University of California, Berkeley and Columbia University. She is based in New York. Follow her on Twitter. Disclosure