Project Description

ADA2 deficiency


ADA2 deficiency is a disease that doctors have only recently become aware of. In 2014, the first patients with the disease were described. Several dozen patients have been documented in the medical literature. The following is a summary of what we know so far.

What causes the symptoms of the disease ADA2 deficiency?

The enzyme ADA2, which circulates in the blood, seems to play a role in stabilising the wall of the blood vessels. This is why people without the enzyme can have serious problems with their blood vessels. Researchers have found that in the immune system, the enzyme ADA2 is involved in the process by which monocytes (a type of white blood cell) develop into macrophages (another type of white blood cell, which can cause inflammation). A lack of ADA2 can lead to more pro-inflammatory macrophages (defence cells that cause inflammation), which release cytokines such as IL-1, IL-6 and TNF-alpha (these substances in turn lead to additional inflammation). This causes inflammation and can eventually lead to organ damage.

What do we know about the genetic background of the disease?

ADA2 deficiency is a recessive genetic disease, which means that in patients neither of the two copies of the relevant gene works properly. (A person with 1 non-functioning gene is called a carrier of the disease.) With ADA2 deficiency, mutations in the CECR1 gene cause the enzyme Adenosine Deaminase 2 (ADA2) to not be produced properly. Some patients are homozygous for the disorder, which means that they have the same mutation in each of their 2 copies of the gene. Others are compound heterozygous and have two different mutations. In some cases, genetic testing has identified only one mutation, while these patients have virtually no ADA2 in their blood. Carriers do have enzyme activity, but significantly less than the rest of the population.

What are the symptoms of ADA2 deficiency?

The known patient population worldwide is very small (about 140 in total), 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 ADA2 deficiency, 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 and painful rash as well. Many have symptoms of systemic inflammation, such as a fever, anaemia, joint pain, and fatigue. Some have recurrent strokes (cerebral infarctions) or cerebral haemorrhages (bleeding in the brain) that may begin in childhood. Some have immune deficiencies, or severe anaemia. Other symptoms include hypertension (high blood pressure), enlarged liver and spleen, gastrointestinal problems (abdominal pain), enlarged lymph nodes, and kidney dysfunction.

How is ADA2 deficiency treated?

Many patients find that many of their symptoms can be controlled by TNF alpha inhibitors like Enbrel and Humira. Doctors also observe that inflammation in the blood decreases. This mainly concerns symptoms of inflammation, such as fever, inflammation of the skin, and inflammation of the vessels. As far as we know, no patients have had further strokes while being treated with TNF alpha inhibitors. But there is very little data to tell us how well these medicines work over the long term. A few patients have been successfully treated with hematopoietic stem cell transplantation (or: bone marrow transplant). Currently, this option is mainly considered for patients whose symptoms are not well controlled with medication. There is no enzyme replacement therapy available for ADA2 deficiency. We need more and better treatment options and, ultimately, a cure.

What is the prognosis of the disease?

Because only very few patients are known yet, we don’t yet have a very good idea about the long-term prognosis. We do know that most patients respond very well to the TNF alpha blocking treatment. At least, in terms of their symptoms of inflammation. As mentioned, so far we have not seen any more strokes in patients who were on this medication. However, if the production of blood cells is impaired, this disease often does not respond well to this treatment. If the symptoms are severe and do not respond well to medication, stem cell transplantation is an option.