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BETHESDA, Md.—The NIH Undiagnosed Diseases Program (UDP) has identified the genetic cause of a rare and debilitating vascular disorder not previously explained in the medical literature. The adult-onset condition is associated with progressive and painful arterial calcification affecting the lower extremities; the coronary arteries are spared. The new disease finding was published in the New England Journal of Medicine.
The UDP was launched in May 2008 and in its almost three year history has fielded 4,600 inquires, accepted 380 cases, and sees patients at the rate of about 150 to 200 per year. Thirty-five patients have received some sort of diagnosis and about 25 others are pending. The range in time to reach a diagnosis has varied from one week to two years.
The researchers refer to the rare arterial condition as ACDC, or arterial calcification due to CD73 deficiency. It has been seen in nine individuals from three unrelated families. Although symptoms of the disorder include leg and joint discomfort, medical evaluations of the patients ruled out rheumatoid arthritis or other joint-related problems. Genetic analyses performed by the National Institutes of Health (NIH) researchers suggested a novel disorder and pinpointed the cause of the condition as mutations, or variants, in the NT5E gene.
Although funded at the relatively modest level of $3.5 million per year through 2012, the program might be seen as fairly expensive on a per-patient basis. But Dr. William Gahl, an M.D. and Ph.D. who's a pediatrician and clinical and biochemical geneticist as well as being the clinical director at the National Human Genome Research Institute (NHGRI) and director of UDP, is optimistic about the program's broader impact. "The significance of a finding like this is really not determined immediately," he observes. "In other words, we won't really know how significant this is until perhaps a year from now, five years, ten years from now. Because this has the potential to have applications to all sorts of calcification processes in our body, including the normal calcification processes of bone, and possibly abnormal calcification processes in other places including calcification in the vessels, it has the potential to be enormously important."
"This study shows that genomic tools are a powerful ally in our search to discover and understand rare diseases," says Dr. Eric D. Green, director of the NHGRI.
Members of two of the three families reported in the study underwent extensive testing at the NIH Clinical Center in Bethesda, Md. 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. For one of the patients, the condition was advanced and had been treated with surgeries to reroute blood flow through alternate vessels, as well as a joint amputation in the foot.
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 the NT5E gene, which normally makes the CD73 protein. This protein 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 performed laboratory tests to characterize the molecular basis of the arterial calcification disorder and to validate various molecular activities in cells with NT5E variants. "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," said lead author Dr. Cynthia St. Hilaire, a postdoctoral fellow at the National Heart, Lung, and Blood Institute (NHLBI). In turn, TNAP degrades an inhibitor of calcification, called pyrophosphate. The researchers therefore tied 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.
"We're able to bring patients in here over the course of the week to get enough clinical studies done that would've taken perhaps a year or two years on an outpatient basis because insurance is required for those individuals where as it isn't required for us" Gahl states. "In addition, we have the capacity to do state of the art genetic screening and genetic studies to try to determine the molecular basis for some of these disorders," he adds.
In addition to NHGRI and NHLBI, the study included researchers from the NIH Office of Rare Disease Research; the NIH Clinical Center; St. John the Baptist Hospital, Turin, Italy; University of California, San Francisco; and Great Ormond Street Hospital-University College, London.