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NIH Discovers New Vascular Disease, ACDC

Knee X-Ray

Clinical researchers from the National Institute of Health (NIH) have used DNA analysis to discover a rare and debilitating vascular disorder not previously explained in the medical literature. The researchers refer to the condition as ACDC, or arterial calcification due to CD73 deficiency.

The NIH researchers are part of the Undiagnosed Disease Program (UDP). Their report of the new disease finding has been published in the February 3rd issue of the New England Journal of Medicine.

ACDC is an adult-onset condition associated with progressive and painful calcification of arteries of the legs. Arteries of the heart remain unaffected. There is also calcium buildup in the joints of the patient’s hands and feet.

“This is the first novel disease discovery identified through the collaborative and interdisciplinary approach employed by clinical researchers in the NIH Undiagnosed Diseases Program," said NIH Director Francis S. Collins, M.D., Ph.D. "This disorder previously baffled the medical field and evaded diagnosis when conventional methods were used."

ACDC has been observed in nine individuals from three unrelated families. The NIH clinical researchers examined members of two families with the arterial calcification disorder as part of the UDP, and identified a third case outside the country. Seven medical cases like those described in this study have been reported in medical journals over the past century, but these previous studies did not include any insights about the molecular basis of the disorder.

Medical evaluations had ruled out rheumatoid arthritis or other joint-related problems. The NIH researchers were able to do a genetic analyses and pinpointed the cause of the condition as mutations, or variants, in the NT5E gene.

Members of two of the three families reported in this study were enrolled and examined as part of the UDP. The patients experienced pain and cramping in the calves, thighs, buttocks and feet due to poor circulation. MRIs and x-rays of the patients' vasculature indicated calcium deposits in artery walls. Peripheral blood vessels compensate to some extent for diminished blood flow in affected arteries, but not always and may result in the need for amputations.

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In one of the families with five affected siblings, clinical researchers suspected a recessive inheritance, in which offspring receive two copies of a gene variant - one from each parent - that produces disease symptoms only when combined. The researchers analyzed DNA from all members of the family to compare the parents' DNA to that of their affected children. This allowed researchers to detect genomic regions where the siblings' DNA contained two copies of a particular DNA segment compared to their parents' DNA, which contained just a single copy.

The comparison revealed one such region, which the researchers subsequently analyzed for sequence variants not present in a population of 200 unaffected people. The siblings all had the same variant in a gene called NT5E. This gene normally makes the CD73 protein, which produces a small molecule, adenosine, which protects the arteries from calcifying. The researchers also detected variants in NT5E in all the other affected patients in the study.

The researchers were able to characterize the molecular basis of the arterial calcification disorder and to validate various molecular activities in cells with NT5E variants, tying the elevation in TNAP activity with increases in arterial calcification. They also suggest that the location of calcification may correspond to the distribution of specific adenosine receptors in the body.

Lead author Cynthia St. Hilaire, Ph.D., a postdoctoral fellow at the National Heart, Lung, and Blood Institute (NHLBI) explains "We were able to illustrate that elevated activity of a key enzyme in tissue calcification, called TNAP, was due to the lack of extracellular adenosine. In turn, TNAP degrades an inhibitor of calcification, called pyrophosphate.”

"Vascular calcification often results from poor diet and lack of exercise," said co-author William A. Gahl, M.D., Ph.D., NHGRI clinical director and director of the NIH Undiagnosed Diseases Program. "The calcium buildup in arteries of our patients, however, arises because the systems to inhibit it are not working in their cells. We hope that an understanding of this faulty mechanism will guide us in providing helpful treatments for these patients."

At this time no treatment has been found, but the researchers hope that, having pinpointed the genetic roots of the disease, they will be able to discover improved treatment for these patients.

More photos and video are available at: www.genome.gov/27543153.

U.S. National Institutes of Health, news release, Feb. 2, 2011
NT5E Mutations and Arterial Calcifications; Cynthia St. Hilaire, Ph.D., William A. Gahl, M.D., Ph.D., and Manfred Boehm, M.D., et al; N Engl J Med 2011; 364:432-442February 3, 2011
Image source: Genome.gov