Researchers find gene at root of rare hardening of arteries

National Institutes of Health researchers have discovered a gene that causes a rare but extremely painful buildup of calcium in the arteries of legs and hands, the first mystery that has been solved in the NIH’s Undiagnosed Disease Program. Although researchers have so far identified only nine patients with the ailment, they suspect that identifying the cause of the problem will provide insight into much more common disorders.

The NIH launched the program in 2008 in an effort to help patients for whom all other attempts at diagnosis have failed. The program brings together NIH scientists and outside specialists who use the most advanced tools available to try to explain the previously inexplicable. “People who have rare diseases are often abandoned by the medical community,” said Dr. William A. Gahl, director of the program. “We don’t know how to treat if we don’t have a diagnosis. This is a program that speaks to how society treats the poorest among us.” So far, the program has received 1,700 referrals and accepted 330 patients, who come in for a week of specialized testing.

In the spring of 2009, Dr. Karen Saylor of Mt. Vernon, Ky., referred sisters Louise Benge, 56, and Paula Allen, 51, to the program. Benge developed symptoms in her 20s and can now barely walk. Calcium deposits have accumulated in the blood vessels in her legs and hands to the point where almost no blood can flow through. Her calves are rock hard. Saylor tried administering sodium thiosulfate to flush out some of the calcium, but it only made Benge sick. Allen’s symptoms were only slightly less severe. Two younger sisters and two younger brothers had earlier stages of the disease. When the NIH researchers took X-rays, “the radiological images astounded us,” Gahl said. The arteries had so much calcium, they looked almost like bones.

Surprisingly, however, arteries in the chest and the rest of the women’s bodies were normal, so they were in no immediate danger of dying from atherosclerosis.

Because all six children had the disorder, but neither parent -- who are cousins -- the researchers suspected a recessive genetic disease. That is, they suspected that each parent carried one copy of a defective gene and, through extreme bad luck, each child had received the bad gene from both parents. Analyzing DNA from the parents and the children, they quickly focused on a sequence of 92 genes that carried what they suspected to be the defective gene, said Dr. Manfred Boehm of the National Heart, Lung and Blood Institute.

Further study quickly narrowed the search to a single gene, called NT5E, the team reported Thursday in the New England Journal of Medicine. This gene normally makes a protein, called CD73, which is important in the production of adenosine. Adenosine, in turn, protects arteries from calcifying. The team has since identified the same defect in two other families, for a total of nine patients. “We hope the publication of this paper will lead to other patients coming in,” Boehm said.

The team is now trying to devise a treatment program for the patients. One possibility is to use bisphosphonates, which are used to prevent osteoporosis. The team is now attempting to get a treatment protocol approved by their ethics board. There are also experimental drugs that might alter adenosine metabolism, Gahl said, but developing a protocol for them will be more difficult than for the bisphosphonates, which are already approved by the Food and Drug Administration.

Louise Benge said she and her sister are “very excited that they found out what is causing this. ... Maybe someday they will be able to help someone with this problem.”