Rare new disease identified – calcium accumulates in blood vessels

By Dr. Ananya Mandal, MDFeb 3 2011

Dr Ananya Mandal, MD

A new rare disease has been identified. Louise Benge’s started having difficulty in walking when she was 25. She developed hardening and pain over her calves and hands. She worsened over the next 20 years. Her family physician in Mount Vernon, Ky., was at a loss, as were a vascular specialist, a hand specialist and a kidney specialist. Her two sisters and two brothers had the problem too, but no doctor could understand why.

Her X-rays showed that the blood vessels in her legs, feet and hands were accumulating calcium deposits like the scales that can form inside water pipes. The deposits had grown so thick that blood could hardly pass through. But calcium was only in the blood vessels of her legs and hands; her heart’s vessels were spared, so it was not life threatening. She was given weekly infusions of a drug, sodium thiosulfate. This did not work.

Then at their wits’ ends the doctors treating her sent her medical history to the Undiagnosed Diseases Program at the National Institutes of Health. The program, set up in 2008, relies on teams of specialists who use the most advanced tools of medicine and genomics to try to figure out the causes of diseases that have baffled doctors. The idea was that understanding rare diseases can give insights into more common ones, said Dr. William A. Gahl, director of the program.

Dr. Gahl said, “Patients who have rare diseases are often abandoned by the medical community…We don’t know how to treat if we don’t have a diagnosis. The way our society treats abandoned individuals is a measure of our society. It speaks to how our society treats the poorest among us.” Ms Benge and her siblings were diagnosed with the new disease and their case is reported in the latest issue of The New England Journal of Medicine. It is caused by a mutation in a gene that prevents calcium from depositing in blood vessels.

The UDP took up the case on May 11, 2009, when Ms. Benge was 56, and her sister Paula Allen was 51. Nine people are suffering from the disease that is called “arterial calcification due to CD73 deficiency”. Researchers analyzed the DNA of five affected siblings and found that they all had mutations of the NT5E gene, which codes for the CD73 enzyme that produces adenosine - a molecule that helps prevent arteries from calcifying.

The researchers found that cells use the gene to make extracellular adenosine, a common compound that in this case was needed to suppress calcification. No one had known about this metabolic pathway, said Dr. Manfred Boehm, a vascular biologist at the National Heart, Lung and Blood Institute. Dr. Dwight Towler, a bone endocrinologist at Washington University in St. Louis who was not part of the study also commended the study.

The investigators are putting together plans to test bisphosphonates (drugs used against osteoporosis) and submitting them to ethics boards for approval. “We hope to know in three or four months whether we can go forward,” Dr. Gahl said.

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