What we know about DADA2

The short version is that no one yet knows very much. So far, only a few dozen cases have been recorded in the medical literature. 

What causes DADA2?

DADA2 is a recessive genetic condition, which means that in affected people neither of their two copies of the relevant gene works properly. (A person with one dysfunctional and one functioning gene is a carrier of the disease.) In DADA2, mutations in the CECR1 gene prevent it from correctly encoding the enzyme Adenosine Deaminase 2 or ADA2. Some patients are homozygous, meaning they have the same mutation in each gene. Others are compound heterozygous and have two different mutations. In some cases genetic testing has identified only one mutation. Patients have virtually no ADA2 in their systems. Carriers have some, but significantly less than the rest of the population.

What does ADA2 do?

The ADA2 that circulates in the blood seems to play a role in stabilizing the lining of blood vessels — this is why people without the enzyme can have serious problems in their vascular systems. In the immune system, researchers have found that ADA2 is involved in the process by which monocytes (a type of white blood cell) differentiate into macrophages (another type of white blood cell which can either provoke or block inflammation). A lack of ADA2 may result in more pro-inflammatory macrophages, which release cytokines like IL-1, IL-6, and TNF alpha. These cause inflammatory symptoms and can eventually lead to organ damage. 

What are the symptoms of DADA2?

The known patient population is very small, so we still have a lot to learn about the symptoms of the disease. We do know that the symptoms vary in both kind and severity among patients with DADA2, sometimes even in the same families. Most patients have a lacy, mottled rash called livedo reticularis or livedo racemosa, and some have a red bumpy rash as well. Many have symptoms of systemic inflammation like fevers, anemia, joint pain, and fatigue. Some have recurrent strokes or cerebral hemorrhages that begin in childhood. Some have immune deficiencies. Other symptoms may include hypertension, enlarged liver and spleen, gastrointestinal problems, enlarged lymph nodes, and kidney dysfunction.

How is it treated?

Many patients find that many of their symptoms can be controlled by TNF inhibitors like Enbrel and Humira. As far as we know, no patients have had further strokes while being treated with TNF inhibitors, but there is very little data to tell us how well these work over the long term. A few patients have been successfully treated with hematopoietic stem cell transplantation (a type of bone marrow transplant), but the vascular problems associated with DADA2 may increase the likelihood of certain serious side effects of transplantation. There is no enzyme replacement therapy available for ADA2 deficiency. We need more and better treatment options and, ultimately, a cure!