NIH Researchers Identify Genetic Cause of Rare Vascular Disorder

Clinical researchers at the National Institutes of Health’s
Undiagnosed Diseases Program (UDP) have 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, yet spares
patients’ coronary arteries. The new disease finding was published in the
New England Journal of Medicine.

The rare arterial condition caused by calcium buildup in arteries below
the waist and in the joints of patient’s hands and feet has been observed
in nine individuals from three unrelated families, who are the only people
known to have the disorder. The researchers refer to the condition as ACDC, or
arterial calcification due to CD73 deficiency. 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 NIH researchers suggested a novel disorder and
pinpointed the cause of the condition as mutations, or variants, in the NT5E

“This is the first novel disease discovery identified through the
collaborative and interdisciplinary approach employed by clinical researchers
in the NIH Undiagnosed Diseases Program,” Francis S. Collins, MD, PhD, NIH
director, stated in a press release. “This disorder previously baffled the
medical field and evaded diagnosis when conventional methods were used.”

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

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. For one of the patients, advancement of the condition had been
treated with surgeries to reroute blood flow through alternate vessels, as well
as a joint amputation in the foot. Peripheral blood vessels compensate to some
extent for diminished blood flow in affected arteries.

“In terms of their ambulation, they are pretty impaired,” Catherine Groden, a nurse practitioner at the UDP, told O&P Business News. “The average distance [they can walk] before they have to stop and rest is probably about a block, which is not very far.”
Walking in general is not an easy option for these patients, Groden said. The only treatment for this disorder consists of maximizing exercise and pushing through pain to maintain the current level of functionality.
“They all have a significant amount of pain,” she said.

“The diagnosis of this faulty gene is the first molecular
description of this disorder,” Manfred Boehm, MD, lead senior author and
NHLBI investigator, stated. “In addition to providing insight for this
unique patient group and their physicians, the study has placed this condition
among disorders it resembles, adding to our knowledge of vascular

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