What is DADA2?
Deficiency of adenosine deaminase 2 (DADA2) is a rare, genetic autoinflammatory condition that involves systemic (body-wide) inflammation. Key symptoms of DADA2 include fevers, skin rash and vasculitis. Vasculitis is inflammation of the vasculature (blood vessels such as veins, arteries and capillaries). Adenosine plays an important role in regulating the vasculature, and the deficiency of adenosine’s regulatory enzyme, adenosine deaminase 2 (ADA2), means that inflammation in DADA2 is particularly focussed in the vasculature. People with DADA2 have a high risk of stroke and the development of blood disorders.
The gene that carries the instructions for the adenosine deaminase enzyme is called ADA2. A copy of the ADA2 gene is inherited from each parent, and usually both copies need to have a disease-causing variant (also known as a pathogenic mutation) for a person to have DADA2. This type of inheritance is known as recessive. high risk of stroke and the development of blood disorders.
It is not clear how many cases of DADA2 there are. The estimated number of patients with DADA2 in Australia is not explicitly stated, but globally, according to the US-based DADA2 Foundation, there are approximately 600+ DADA2 patients reported today, with a potential global population of 35,000 affected individuals. The disease is considered rare, with a prevalence of 1 in 220,000 individuals worldwide.
Genetic prediction technology has estimated prevalence to be as high as 4 in 100,000. As with all rare autoinflammatory diseases, DADA2 is undoubtedly underdiagnosed or misdiagnosed in the population. Carrier frequency is predicted to be as high as 1 in 236 people.
Who can have DADA2?
DADA2 is usually inherited, and symptoms usually appear in early childhood. Inheritance is autosomal recessive, which means two copies of the disease-causing gene variant are needed to have DADA2, and it can skip generations. People with one copy of the disease-causing gene variant are known as carriers of DADA2. When both parents are DADA2 carriers, each of their children has a 25% chance of inheriting two disease-causing variant genes and thus being born with DADA2.
Asymptomatic family members of a person with DADA2 may undergo genetic screening to ascertain their carrier status, particularly in context of family planning.
The ADA2 gene is physically located on chromosome 22. Because it is not a sex chromosome, inheritance is said to be autosomal. So DADA2 inheritance is autosomal recessive. Autosomal means there is no gender bias with DADA2.
There are cases where DADA2 is not inherited from a parent. Disease-causing variants in the ADA2 gene can be spontaneous, also known as de novo mutations. There’s no known predisposing factor or any particular ethnic background associated with DADA2, although two ‘founder’ populations have been identified, one from the Middle East and one from northern Europe. That means the identified cases in those populations have been found to share a common ancestry.
What are the symptoms of DADA2?
Symptoms of DADA2 include fevers, skin rashes (usually a type called livedo racemosa that has a mottling type of appearance) and vasculitis. Symptoms can occur in any part of the body and usually begin in childhood, along with early-onset recurrent strokes, which are due to inflammation of the vasculature.
People with DADA2 can show low white blood cell counts, particularly deficiencies in B cells and antibody production, bone marrow failure, anaemia and hepatosplenomegaly (enlarged liver and spleen). Despite the increased activity in innate immunity (inflammation), the dampening effects on the adaptive immune system (B cells and antibodies) can increase the risk of infection in people with DADA2 and put them at an increased risk of developing secondary blood disorders.
People with DADA2 can experience periods of remission and flares. Sometimes there is a suspected trigger, such as an infection or particularly stressful event. Sometimes there is no obvious reason. It's frustrating and frightening and it's nobody's fault.
DADA2 occurs when there is a disease-causing variant (also known as a pathogenic variant or a mutation) in a gene called ADA2.
Genes provide instructions for the body to make proteins. The ADA2 gene provides instructions for the body to make the ADA2 protein (adenosine deaminase). When there is a change in the gene sequence that causes the ADA2 protein to be made differently, this can affect its function so much that it can’t do its job. We inherit two copies of the ADA2 gene (one from each parent) and, in most cases, having one good copy will be able to compensate for the bad one. This is the case in recessive inheritance.
DADA2 is a recessively inherited diseases, and usually both copies of ADA2 will need to contain a disease-causing variant for a person to have DADA2. There are exceptions to this, because biology doesn’t care about the rules we give it. Research is active in this area and there is still a lot to figure out.
Adenosine deaminase (ADA2) is an enzyme in the human body that is responsible for removing amines from adenosine. The details really don’t matter unless you have a biochemistry test tomorrow, but adenosine deaminase has an important job because it keeps adenosine in check.
You have heaps of adenosine. It is a component of your DNA. It is involved in sleep regulation, and it also helps regulate your heart rate and vasculature, not to mention being a key component of cellular energy (if you’ve ever heard of ATP as the ‘powerhouse of the cell’, the A part of ATP stands for adenosine).
Adenosine is important and it does heaps of stuff. When adenosine deaminase can’t keep adenosine in check, the result is DADA2.
How is DADA2 diagnosed?
The first presentation of DADA2 is often due to vascular symptoms, particularly early onset stroke. Doctors will usually need to rule out other conditions, such as polyarteritis nodosa, which involves a vasculitis similar to DADA2. There are many other diseases that can present similarly to DADA2 (known as ‘differential diagnoses’) and hence establishing the diagnosis can be a drawn out process. Delays in diagnosis are commonly reported in DADA2 and delays in treating DADA2 can have devastating effects, such as organ failure.
Blood tests may reveal elevated inflammatory markers (CRP and ESR), low lymphocytes (particularly B cells) and low IgG and IgM antibodies, which can help doctors make a diagnosis of DADA2.
Genetic testing (blood test) can reveal disease-causing variants in the ADA2 gene for a positive confirmation of DADA2. Where disease-causing variants are not found, or only one known variant is found, ADA2 enzyme activity testing is also possible.
What is the treatment for DADA2?
Treatment may begin with corticosteroids or disease-modifying antirheumatic drugs, which may help reduce symptoms initially, but these are not good long-term treatment choices for DADA2 and are less likely to prevent strokes.
Biologics that target TNFα (eg adalimumab, golimumab and infliximab) are the most effective treatments for the inflammatory symptoms of DADA2, including vasculitis and preventing strokes. These are sometimes given with drugs like methotrexate to prevent the development of immune resistance (antibodies) to the biologics, although clinical evidence is divided on whether this is actually effective.
DADA2 is a complex condition and the biologics that target TNFα do not address blood abnormalities. Patients with persistently low levels of total IgG antibodies or IgG antibodies to specific infective organisms such as pneumococcus or salmonella typhi.
Patients will need IV antibodies (intravenous immunoglobulin) and in cases of bone marrow failure, patients will need to undergo a bone marrow transplant.
What's the reality of life with DADA2?
Due to the serious complications of the disease including vasculitis, stroke, haematological malignancies and bone marrow failure, DADA2 can be life-threatening.
Individuals with DADA2 are also at high risk of acquiring infective illnesses such as influenza, COVID-19 or the common cold. This can make socialising inherently risky.
Constitutional symptoms of fatigue and general malaise are often misunderstood and can cause people with DADA2 to withdraw socially.
Life before and after diagnosis can be both frustrating and frightening for the person with the condition and their family. Early intervention is important because early treatment with the correct drug can change the course of the person’s development, particularly considering the high risk of stroke in children under 10 years of age that can be prevented by treatment with biologic drugs that target TNFα.
People with DADA2 often have to see many different specialists to deal with the various parts of their bodies affected by the condition. It is common for someone with DADA2 to be under the care of a paediatrician, haematologist, neurologist, gastroenterologist and more, in addition to their GP who is responsible for coordinating their care.
So, is DADA2 autoinflammatory or autoimmune?
Autoimmune diseases involve the adaptive (specific) immune system, which can recognise ‘self’ and ‘non-self’ with exquisite specificity. Autoinflammatory diseases involve the innate (non-specific) immune system, the first-response system that throws up a very general inflammatory response to an infection or injury (eg pain, redness, swelling).
DADA2 is not caused by a problem with self-recognition, but it does affect B cells, bone marrow and other components that are defined as part of the adaptive immune system. For this reason, it may be considered an autoimmune disease. However, DADA2 also fits the profile of an autoinflammatory disease, because symptoms are driven by non-specific and uncontrolled inflammation.
Helpful info:
- The DADA2 Foundation, based in the US is a great patient resource https://dada2.org.
- The ultimate resource for any clinician treating DADA2 https://www.ncbi.nlm.nih.gov/books/NBK544951/.
Recommended reading
- Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement published in 2023 by the Journal of American Medical Association Network Open https://doi.org/10.1001/jamanetworkopen.2023.15894.
- This 2024 case study was published by a Melbourne group of paediatric rheumatologists https://doi.org/10.1111/jpc.16572. This 4 year old boy presented with fever, joint and muscle pain and abnormal sensations in his limbs. He did not have a rash or any family history of DADA2 but clinicians found enough clues to prompt a test for DADA2. This case highlights the diagnostic challenge of DADA2 and is unfortunately behind a subscription paywall but there’s a good amount of information on the preview.
- This links to the heartbreaking story of an Australian boy who had DADA2 and a secondary blood condition (Evans Syndrome) who tragically passed away in July 2025 https://www.gofundme.com/f/Help-Ruben-our-little-fighter#
IMPORTANT NOTE:
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