In 2008, the NIH launched the Undiagnosed Diseases Program (UDP). The UDP is a collaborative effort that spans across multiple disciplines such as the National Human Genome Research Institute (NHGRI), the National Institutes of Health (NIH) Office of Rare Diseases Research (ORDR) and the NIH Clinical Center. The initiative was quite ambitious in both size and scope and was created with 2 simple goals in mind:
- To provide answers to patients with mysterious conditions that have long eluded diagnosis.
- To advance medical knowledge about rare and common diseases.
Recently, the UDP has identified a new rare disease aptly named ACDC.
Arterial Calcification Due to CD73 Deficiency (ACDC)
In 2009, Paula Allen and her sister Louise Benge were referred by their physician to the UDP after suffering through decades of pain due to unexplained arterial blockages in their legs. Neither Paula nor Louise had anything remarkable in their medical histories up until the ages of 18 and 20, respectfully. Paula described her childhood as typical. She had plenty of friends and would love to run and play games such as kick the can or ghost in the graveyard. At first, she began having pain in her hands and was initially diagnosed with arthritis. However, test results were negative. She was sent home with no answers. Over the years, the pain intensified and traveled to her lower extremities. In her 30s, the pain in her legs became so severe that she suffered many sleepless nights. Still without a diagnosis, doctors suggested that an arterial bypass may alleviate the pain, but the procedure would have to be repeated every 5 years. Paula declined.
Once accepted into the UDP study, Paula Allen and her family were 1 of 3 participating families. There were 9 people in total with this strange affliction. All participants (excluding parents) presented with varying degrees of pain manifesting from an insufficient blood supply to their lower extremities. Clinical, radiological, and genetic screenings were done. In general, every affected individual had some degree of calcification in their peripheral arteries. A contrast-enhanced angiography showed occlusions in the iliac, femoral popliteal, and tibial arteries in many of the subjects. Subsequent X-rays revealed arterial calcifications in their lower extremities and the enlargement of affected arteries (arteriomegaly). One patient from another family had previously undergone a femoral popliteal bypass because of the severity of the occlusion. In another patient, the joints in her hands were also affected.
Thankfully, the disease spares the major arteries above the diaphragm and primarily affects areas below the waist. The participants’ serum calcium, phosphate, vitamin D, creatinine, cholesterol, and other values were all in the normal range. Genetic screenings from the Allen family revealed a homozygous nonsense mutation on chromosome 6q14-q21 for the ecto-5′-nucleotidase gene (NT5E). The parents, who were third cousins, were heterogeneous carriers, and therefore it was concluded that the disease is inherited in a recessive manner.
Adenosine may be a contributing factor in other diseases unrelated to ACDC.
The NT5E gene encodes the CD73 enzyme. CD73 is essential in the creation of extracellular adenosine and in the extracellular metabolism of adenosine triphosphate (ATP). CD73 exerts an influence downstream of ENPP1 in the extracellular ATP-degradation pathway. ENPP1 is associated with another calcification disease, generalized arterial calcification of infancy (GACI). GACI is associated with mutations in ENPP1 and is typically fatal. Unlike GACI, ACDC presents later in life and is not fatal. Arterial calcifications in ACDC are associated with the enzyme TNAP (tissue-nonspecific alkaline phosphatase). TNAP appears to be expressed to a greater extent in the affected arteries and it is responsible for the degradation of pyrophosphate. Pyrophosphate is essential in inhibiting cellular calcification. It is known that increased levels of pyrophosphate lead to bone demineralization in patients with hypophosphatasia. In patients with ACDC, decreased CD73 activity leads to decreased extracellular adenosine and enhanced TNAP activity, thus degrading pyrophosphate at a greater rate and increasing calcification where TNAP is highly expressed. Simply speaking, under normal conditions, adenosine inhibits TNAP activity and allows for pyrophosphate to degrade calcium. In ACDC, the inhibitor (CD73 and by extension adenosine) is inhibited, resulting in calcium deposits in affected arteries.
ACDC is the first novel disease discovered by the UDP. Presently, 3 types of mutations have been identified: a single-nucleotide insertion frameshift, and both nonsense and missense mutations. The role adenosine plays in this disease is intriguing. Wiiliam Gahl, clinical director of the NHGRI, is optimistic about these findings and believes that further research into this disorder and the mechanism of action of adenosine may open doors for other disorders, such as atherosclerosis.
“For example, there’s calcification of the vessels of what we use to call hardening of the arteries, atherosclerosis. That is probably a different mechanism but the role of adenosine in even that should now be investigated. And then there are calcifications of organs and vessels when there is damage. And that calcification process may involve adenosine as well. We don’t know that yet but I think there is a real possibility that they’ll be broad applications.”
He goes on to explain that there is another patient with a different unexplained calcification disorder affecting vessels in the brain. Intriguingly, cultures taken from afflicted tissue showed increased amounts of adenosine monophosphate. Adenosine may be a contributing factor in other diseases unrelated to ACDC. Presently, the National Heart, Lung and Blood Institute is investigating etidronate, currently indicated for Paget’s disease and to treat heterotopic ossification, as a potential treatment for ACDC.
- Etidronate for arterial calcifications due to deficiency in CD73 (ACDC). Clinical Trials website. Updated November 27, 2013. http://clinicaltrials.gov/show/NCT01585402.
- Gahl W. Video sound bites. Genome website. http://www.genome.gov/27543181#al-2.
- Kentucky sisters now have clues to lifelong, painful disorder. NIH Medline Plus website. Spring 2011.
- New vascular disease ACDC identified by NIH, first in a decade. Medical News Today website. February 3, 2011.
- NIH researchers identify genetic cause of new vascular disease. NIH News website. February 2, 2011. http://www.nih.gov/news/health/feb2011/nhgri-02.htm.
- St. Hilaire C, Ziegler SG, Markello TC, et al. NT5E mutations and arterial calcifications. N Engl J Med. 2011;364:432-442.