DADA2 (deficiency of ADA2)

Overview

Deficiency of Adenosine Deaminase 2 (DADA2) is a rare genetic condition characterised by chronic inflammation, damage to blood vessels (vasculopathy), and problems with the immune system [PMID:24660333]. These issues arise because the body cannot produce enough functional adenosine deaminase 2 (ADA2) enzyme. ADA2 plays a crucial role in regulating inflammation and maintaining the health of blood vessels, so its deficiency can lead to a range of symptoms. The condition was first identified in 2014 and is increasingly recognised as a cause of unexplained inflammatory and vascular problems, particularly in children and young adults [PMID:24660333].

Symptoms & clinical features

The symptoms of DADA2 can vary widely among affected individuals, even within the same family. Common features include recurrent fevers, usually without an obvious cause, and often accompanied by skin rashes, livedo reticularis (a lace-like pattern on the skin), or painful skin nodules [PMID:24660333]. Joint pain and swelling are also frequently reported. One of the most serious manifestations is vasculopathy, which refers to inflammation and damage to blood vessels. This can lead to strokes, particularly in children and young adults, and may also affect blood flow to other organs. The immune system dysfunction in DADA2 can manifest as low blood cell counts, enlarged liver or spleen, and an increased susceptibility to certain infections.

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Affected organs

DADA2 can affect multiple organ systems due to its widespread impact on inflammation and blood vessels. The skin is often affected, showing various rashes, nodules, or livedo reticularis. Joints can become painful and swollen. The brain and nervous system are particularly vulnerable due to vasculopathy, which can lead to transient ischaemic attacks (TIAs) or strokes. Blood vessels throughout the body, including those supplying the gut, kidneys, and eyes, may also be inflamed and damaged. The immune system is affected, potentially leading to cytopenias (low counts of certain blood cells) and issues with infection control. The liver and spleen may also become enlarged.

Immune cells

Immune system dysfunction

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of DADA2 is highly variable, ranging from mild symptoms that appear intermittently to severe, life-threatening complications. The condition often presents during childhood or early adulthood, though onset can be later in some cases. Individuals with DADA2 have an increased risk of strokes, particularly in childhood, which can lead to long-term neurological problems. Chronic inflammation can also contribute to organ damage over time. The exact prevalence of DADA2 is not well established, but it is considered a rare disease. Early diagnosis and management are important to help prevent serious complications and improve quality of life.

Genetic causes

DADA2 is caused by genetic changes (variants) in the ADA2 gene. This gene provides instructions for making an enzyme called adenosine deaminase 2. ADA2 is primarily found outside cells and plays a critical role in controlling inflammation and promoting the healthy development and function of blood vessels. When there are pathogenic variants in ADA2, the body cannot produce enough functional enzyme, disrupting the normal regulation of inflammation. This leads to an overactive inflammatory response and damage to blood vessels, contributing to the diverse range of symptoms seen in DADA2 [PMID:26760074].

• ADA2
  adenosine deaminase 2
  The ADA2 gene provides instructions for producing the adenosine deaminase 2 enzyme, which is involved in immune system regulation and inflammation processes.

Inheritance pattern

DADA2 is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic ADA2 variant - one from each parent - to develop the condition. People who inherit only one pathogenic variant are called carriers; they typically do not show symptoms of DADA2 themselves but can pass the variant on to their children. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two pathogenic variants and be affected by DADA2, a 50% chance the child will be a carrier, and a 25% chance the child will inherit two unaffected copies of the gene.

Diagnosis & testing

Diagnosing DADA2 often involves a combination of clinical assessment and specialised laboratory tests. Clinical suspicion may arise in individuals, particularly children, who present with recurrent unexplained fevers, strokes, vasculopathy, or immune system abnormalities. Blood tests might show elevated markers of inflammation. A key diagnostic step involves measuring the activity of the ADA2 enzyme in the blood, which is typically very low or undetectable in affected individuals [PMID:24660333]. Confirmation of the diagnosis is made through genetic testing of the ADA2 gene, identifying two pathogenic variants. In the UK, genetic testing for DADA2 may be accessed through the NHS Genomic Medicine Service, often following referral to a clinical genetics service or specialist immunology/rheumatology team. Relevant NHS R-codes would be used for ordering specific genomic tests.

Management & lifestyle

Management of DADA2 primarily focuses on controlling inflammation, preventing strokes, and addressing specific symptoms. Treatment often involves medications that suppress the immune system and reduce inflammation. Tumour necrosis factor (TNF) inhibitors, such as adalimumab or etanercept, have shown significant effectiveness in many individuals, helping to control fevers, rashes, and vasculopathy [PMID:26760074]. In some severe cases, or for those who do not respond to other treatments, allogeneic haematopoietic stem cell transplantation may be considered. Regular follow-up with specialist physicians, such as immunologists, rheumatologists, and neurologists, is crucial to monitor disease activity and adjust treatment as needed. Genetic counsellors can provide valuable support for affected individuals and their families, discussing the genetic aspects of the condition and family planning options.

UK care pathway

In the UK, individuals suspected of having DADA2 would typically be referred by their GP or another specialist to a clinical genetics service or a specialised immunology/rheumatology clinic. These services are part of the NHS Genomic Medicine Service (GMS) pathways. Genetic testing, guided by GMS R-codes, would be arranged to confirm the diagnosis. A genetic counsellor will also be available to provide information and support to individuals and families regarding the genetic aspects of DADA2, inheritance patterns, and implications for relatives.

Related conditions

DADA2 shares some clinical features with other inflammatory conditions and vasculitides, which can sometimes make diagnosis challenging. These include polyarteritis nodosa, Kawasaki disease, and other autoinflammatory syndromes. While there can be symptom overlap, the distinct genetic cause and specific enzyme deficiency in DADA2 differentiate it from these conditions. Understanding these differences is important for accurate diagnosis and appropriate management.

Frequently asked questions