New genetic vascular calcification disease may have some similarity to pseudoxanthoma elasticum (PXE)


MARCH 17, 2011
By Christine Vocke, Director of Education and Information, PXE International


St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, Carlson-Donohoe H, Lederman RJ, Chen MY, Yang D, Siegenthaler MP, Arduino C, Mancini C, Freudenthal B, Stanescu HC, Zdebik AA, Chaganti RK, Nussbaum RL, Kleta R, Gahl WA, Boehm M. NT5E mutations and arterial calcifications. N Engl J Med. 2011 Feb 3;364(5):432-42. Free article in PubMed.

Markello TC, Pak LK, St Hilaire C, Dorward H, Ziegler SG, Chen MY, Chaganti K, Nussbaum RL, Boehm M, Gahl WA. Vascular pathology of medial arterial calcifications in NT5E deficiency: Implications for the role of adenosine in pseudoxanthoma elasticum. Mol Genet Metab. 2011 May;103(1):44-50. Free article in PubMed.


Clinical researchers at the National Institutes of Health's Undiagnosed Diseases Program (UDP) have identified the genetic cause of an extremely 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 is called arterial calcification due to CD73 deficiency, or ACDC. The paper, titled NT5E mutations and arterial calcifications, was published February 3, 2011 in the New England Journal of Medicine.

Read the abstract

"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 [ACDC] 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."

ACDC results from mutations in the NT5E gene. This gene normally makes a protein called CD73. CD73 produces a small molecule, adenosine, which circulates in the bloodstream and protects the arteries from calcifying. Lead author and postdoctoral fellow at the National Heart, Lung and Blood Institute (NHLBI) Cynthia St. Hilaire says, "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."

A related paper published in the Molecular Genetics and Metabolism Journal in February 2011 compares this finding to the calcification process in pseudoxanthoma elasticum (PXE). In Vascular pathology of medial arterial calcifications in NT5E deficiency: Implications for the role of adenosine in pseudoxanthoma elasticum (read the abstract), the authors propose that the arterial calcification of ACDC may be similar to that of PXE. They suggest that the mutation in the ABCC6 gene might prevent adenosine from being transported in the blood to peripheral tissues where it would prevent mineralization.

Researchers in the PXE International Research Consortium are already looking at adenosine and devising experiments to test this new hypothesis. At present, there is no evidence that adenosine is involved in the mineralization of pseudoxanthoma elasticum.

Read more about the discovery of ACDC

Read more about NIH's Undiagnosed Diseases Program (UDP)