Adenosine Deaminase 2 (ADA2) deficiency, or DADA2 and Polyarteritis Nodosa (PAN)

By SWA

Adenosine Deaminase 2 (ADA2) deficiency, or DADA2, is a rare genetic condition that can manifest similarly to polyarteritis nodosa (PAN), involving systemic inflammation and vasculitis, which is the inflammation of blood vessels. This resemblance to PAN sometimes classifies ADA2 deficiency within the same spectrum of disorders, although not all experts agree on this classification.

Cause of DADA2 Disease

DADA2 is a monogenic disorder, meaning it is caused by mutations in a single gene—specifically, the ADA2 gene located on chromosome 22q11.3. The disease results from biallelic pathogenic variants in this gene. Patients with DADA2 typically exhibit a range of symptoms, including systemic vasculitis, early-onset strokes, bone marrow failure, and immunodeficiency.

Function of ADA in the Immune System

The ADA gene encodes the enzyme adenosine deaminase, which is crucial for the proper functioning of the immune system, particularly in lymphocytes. These immune cells are vital for defending the body against pathogens like viruses and bacteria. The highest levels of this enzyme are found within these cells, highlighting its importance in immune response regulation.

ADA2 as an Autoimmune Disease

As an autoinflammatory condition, DADA2 involves abnormal inflammation that can lead to multiple organ systems being affected without the typical triggers of autoantibodies or antigens commonly seen in autoimmune diseases. The inflammatory process in DADA2 primarily involves blood vessels, leading to significant clinical complications such as strokes and blood cell deficiencies.

Testing for ADA2 Deficiency

Diagnostic testing for ADA2 deficiency typically involves next-generation sequencing (NGS) to detect sequence variants and/or copy number variations in the ADA2 gene. This test is highly sensitive and is suitable for individuals displaying symptoms indicative of the disorder, or those with a family history suggesting its possibility.

Symptoms of ADA2 Deficiency

Symptoms of ADA2 deficiency are diverse and can include periodic fevers, unique skin discolorations resembling tendrils, enlargement of liver and spleen, recurrent strokes, and various immune abnormalities.

Treatment Options for ADA2 Deficiency

While no standardized treatment protocol exists for ADA2 deficiency, some therapeutic approaches have included exogenous ADA2 enzyme replacement and the use of immunomodulatory drugs like TNF inhibitors, which help manage inflammation.

Differences Between ADA and ADA2

While ADA1 and ADA2 are both forms of adenosine deaminase, they differ significantly in their functions and genetic origins. ADA1, encoded by the ADA gene, is crucial for preventing severe combined immunodeficiency and operates intracellularly. Conversely, ADA2, encoded by the CECR1 gene, functions extracellularly in the plasma and is involved in inflammatory processes rather than immune deficiency.

Normal Range for ADA

The normal range for ADA enzyme levels in both males and females is typically around 40 units/L. Deviations from this range can indicate various health conditions, emphasizing the enzyme's role in health and disease monitoring.

Broader Implications of ADA Activity

There is growing evidence linking ADA activity with autoimmune diseases. Changes in ADA activity have been observed in patients with various autoimmune disorders, suggesting that it could serve as a biomarker for diagnosis in clinical settings.

This summary provides a comprehensive overview of ADA2 deficiency, encompassing its causes, symptoms, testing, and treatment options, along with insights into the general function of ADA in health and disease. For those interested in a more detailed study of ADA's role in genetics and autoimmunity, refer to the systematic approach provided in the literature on genetic variants and their clinical significance here.

Reference:

  1. PubMed: An excellent resource for peer-reviewed articles on genetics and medical conditions. You can search using terms like "ADA2 deficiency," "DADA2," or "adenosine deaminase 2 function." Visit PubMed

  2. Google Scholar: Useful for a broader search, including both articles and citations in various fields of study. Similar search terms can be used here. Visit Google Scholar

  3. ClinicalTrials.gov: For ongoing or completed clinical trials related to ADA2, which can provide information on recent research and treatments. Search for "ADA2 deficiency" or specific treatments being studied. Visit ClinicalTrials.gov

  4. OMIM (Online Mendelian Inheritance in Man): This database provides detailed information on known genetic disorders, including gene location, clinical synopsis, and research links for ADA2 deficiency. Search for "ADA2" or the gene "CECR1." Visit OMIM

Using these resources, you can access the most current and comprehensive scientific literature and data related to ADA2 deficiency, its symptoms, treatment options, and ongoing research.

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