Arterial calcification due to deficiency of CD73 (ACDC) is a rare

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

that causes

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

buildup in the

arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...

and joints of the hands and feet, and other areas below the waist. Although patients exhibiting these symptoms have been identified as early as 1914, this disorder had not been studied extensively until recently. The identification of the specific ACDC gene and mutations occurred in 2011. ACDC is caused by a mutation in the

NT5E 5′-nucleotidase (5′-NT), also known as ecto-5′-nucleotidase or CD73 (cluster of differentiation 73), is an enzyme that in humans is encoded by the ''NT5E'' gene. CD73 commonly serves to convert AMP to adenosine. Transcription factor bindin ...

gene, which prevents calcium-removing agents from functioning,. Patients with this mutation experience chronic pain, difficulty moving, and increased risk of cardiovascular problems. In experiments at the molecular level, treatment with

adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...

or a

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...

inhibitor reversed and prevented calcification, suggesting they could be used as possible treatment methods. There is currently no cure for ACDC, and patients have limited treatment options which focus primarily on removal of blood calcium and improving mobility.

Cause

In ACDC, the gene NT5E, which produces the enzyme CD73, is mutated. A mutation in NT5E causes CD73 to form incorrectly. A nonsense mutation, a single nucleotide insertion, and a missense mutation have all been found to produce essentially the same inactivation of CD73. Normally, CD73 binds to adenosine monophosphate, a nucleotide in DNA, and converts it to adenosine. In affected patients, little to no CD73 was functional. The

calcification Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue,Miller, J. D. Cardiovascular calcification: Orbicular origins. ''Nature Mat ...

of cells is caused in part by a lack of

pyrophosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...

, which is broken down throughout the body by tissue-nonspecific alkaline phosphatase (TNAP). Without pyrophosphate,

calcium phosphate The term calcium phosphate refers to a family of materials and minerals containing calcium ions (Ca2+) together with inorganic phosphate anions. Some so-called calcium phosphates contain oxide and hydroxide as well. Calcium phosphates are white ...

crystals cannot be broken down. Since the inactive CD73 is unable to produce adenosine, which inhibits TNAP, there is an increase in TNAP levels and a decrease in pyrophosphate levels.

Diagnosis

Treatment

The gene NT5E is related to the gene ENPP1, which when mutated is known to cause arterial calcification in infants. Treatments for the ENPP1 mutation, such as

bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...

s, which are non-hydrolysable pyrophosphate analogs, and adenosine reuptake inhibitors, provide possible routes of treatment for the NT5E mutation, as the mechanism of both disorders are very similar.

References

{{Reflist, refs= {{cite journal , author1=St Hilaire C. , author2=Ziegler S. G. , author3=Markello T. C. , author4=Brusco A. , author5=Groden C. , author6=Gill F. , author7=Boehm M. , year = 2011 , title = NT5E mutations and arterial calcifications , journal = New England Journal of Medicine , volume = 364 , issue = 5, pages = 432–442 , pmc=3049958 , pmid=21288095 , doi=10.1056/NEJMoa0912923 MacDougall, R. National Human Genome Research Institute, NIH Undiagnosed Diseases Program. (2011). NIH researchers identify genetic cause of new vascular disease. Retrieved from website: http://www.genome.gov/27543152 {{cite journal , author1=Markello T. C. , author2=Pak L. K. , author3=St Hilaire C. , author4=Dorward H. , author5=Ziegler S. G. , author6=Chen M. Y. , author7=Gahl W. A. , year = 2011 , title = Vascular pathology of medial arterial calcifications in NT5E deficiency: Implications for the role of adenosine in pseudoxanthoma elasticum , journal = Molecular Genetics and Metabolism , volume = 103 , issue = 1, pages = 44–50 , doi=10.1016/j.ymgme.2011.01.018, pmid=21371928 , pmc=3081917 {{cite journal , author1=Rutsch F. , author2=Nitschke Y. , author3=Terkeltaub R. , year = 2011 , title = Genetics in Arterial Calcification Pieces of a Puzzle and Cogs in a Wheel , journal = Circulation Research , volume = 109 , issue = 5, pages = 578–592 , doi=10.1161/circresaha.111.247965 , pmid=21852556 , pmc=3248761 {{cite journal , author1=Nitschke Y. , author2=Baujat G. , author3=Botschen U. , author4=Wittkampf T. , author5=du Moulin M. , author6=Stella J. , author7=Rutsch F. , year = 2012 , title = Generalized Arterial Calcification of Infancy and Pseudoxanthoma Elasticum Can Be Caused by Mutations in Either ENPP1 or ABCC6 , journal = The American Journal of Human Genetics , volume = 90 , issue = 1, pages = 25–39 , doi=10.1016/j.ajhg.2011.11.020, pmid=22209248 , pmc=3257960 ''This article incorporates public domain text from the National Institutes of Health. http://www.genome.gov/27543157'' Genetic diseases and disorders Circulatory system