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

By SWA

Overview
Adenosine Deaminase 2 (ADA2) deficiency—also known as Deficiency of ADA2 or DADA2—is a rare, inherited autoinflammatory condition that can mimic polyarteritis nodosa (PAN), a type of systemic vasculitis. Due to overlapping clinical features, DADA2 is sometimes considered part of the PAN disease spectrum, though not all researchers agree on this classification.

Cause of DADA2

DADA2 is a monogenic disorder caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the CECR1 gene (also known as ADA2), located on chromosome 22q11.3. The disease leads to a wide range of clinical manifestations, including systemic vasculitis, early-onset strokes, bone marrow failure, and immunodeficiency.

Role of ADA2 in the Immune System

ADA2 is an enzyme encoded by the CECR1 gene and is primarily active in the extracellular space. It plays a regulatory role in the immune system, particularly in modulating inflammation and the function of monocytes and macrophages. Unlike ADA1, which acts intracellularly and is crucial for purine metabolism in lymphocytes, ADA2 is involved in vascular integrity and immune homeostasis.

ADA2 Deficiency as an Autoinflammatory Disease

DADA2 is classified as an autoinflammatory disorder because it involves unprovoked, persistent inflammation without the typical markers of autoimmunity (e.g., autoantibodies). The disease most notably affects blood vessels, leading to potentially severe complications like strokes, cytopenias, and organ damage.

Diagnostic Testing

The preferred method for diagnosing ADA2 deficiency is next-generation sequencing (NGS), which can identify both sequence variants and copy number alterations in the ADA2 gene. Testing is recommended for individuals presenting with unexplained vasculitis, early strokes, bone marrow failure, or family history suggestive of DADA2.

Symptoms of DADA2

Clinical presentations of DADA2 vary widely and may include:

  • Recurrent fever

  • Livedo racemosa (a net-like skin discoloration)

  • Hepatosplenomegaly (enlarged liver and spleen)

  • Recurrent ischemic or hemorrhagic strokes

  • Immunodeficiency and cytopenias

Treatment Approaches

Currently, there is no standardized treatment protocol for DADA2. However, various therapies have been used with some success:

  • TNF inhibitors (e.g., etanercept, adalimumab): Commonly used to manage vasculitis and systemic inflammation

  • Exogenous ADA2 enzyme therapy: Experimental and still under investigation

  • Hematopoietic stem cell transplantation (HSCT): Considered in severe cases with bone marrow failure

ADA1 vs. ADA2: Key Differences

  • ADA1 is encoded by the ADA gene and is vital for purine metabolism in lymphocytes. Deficiency in ADA1 leads to Severe Combined Immunodeficiency (SCID).

  • ADA2, encoded by the CECR1 gene, functions mainly in plasma and plays a role in immune modulation and inflammation, not purine metabolism.

ADA Enzyme Levels

The normal reference range for ADA enzyme activity in serum is approximately 40 units/L in both males and females. Deviations may suggest underlying inflammatory, immunologic, or genetic disorders.

ADA Activity in Autoimmune Disorders

Emerging evidence points to altered ADA activity in various autoimmune diseases, reinforcing its potential as a diagnostic biomarker and therapeutic target.

Severe Combined Immunodeficiency (SCID): A Related Immunologic Condition

SCID is a group of rare genetic disorders marked by severe impairment in T lymphocyte development, often affecting B and NK cell function as well. Without intervention, infants with SCID rarely survive past infancy due to recurrent, life-threatening infections.

Key Genes Associated with SCID

  • IL2RG: Most common cause of X-linked SCID; encodes a shared subunit for multiple interleukin receptors.

  • JAK3: Functions in the IL-2 receptor signaling pathway.

  • ADA (ADA1): Deficiency causes accumulation of toxic metabolites, impeding lymphocyte survival.

  • RAG1 and RAG2: Critical for V(D)J recombination in T and B cell receptor development.

  • Artemis: Involved in DNA repair and antigen receptor gene rearrangement.

  • IL7R: Essential for T cell development via IL-7 signaling.

T-Cell Development in SCID

T lymphocytes mature in the thymus and are essential to adaptive immunity. In SCID:

  • T cell numbers are drastically reduced or absent.

  • T cell function is often severely impaired, even when cells are present.

Clinical Features of SCID

  • Extreme susceptibility to bacterial, viral, and fungal infections

  • Failure to thrive in infancy

  • Absence of lymphoid tissue (e.g., tonsils)

Diagnosis and Treatment of SCID

  • Newborn Screening: Detection via T-cell receptor excision circles (TRECs)

  • Genetic Testing: Identification of causative mutations

  • Treatment Options:

    • Hematopoietic stem cell transplantation (HSCT)

    • Enzyme replacement therapy (for ADA deficiency)

    • Gene therapy (available for select SCID subtypes)

Conclusion

ADA2 deficiency (DADA2) represents a significant but under-recognized contributor to systemic vasculitis and immunologic dysfunction. Its overlap with PAN and distinction from ADA1-related SCID highlight the complexity of adenosine deaminase functions in immune health. As genetic testing becomes more accessible, early diagnosis and personalized interventions will play a growing role in managing these rare yet serious conditions.

References: 

Mutations in genes required for T-cell development:IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review
https://www.nature.com/articles/gim20042

Severe combined immunodeficiency
https://www.ncbi.nlm.nih.gov/books/NBK22254/

T Cell Immunity
https://link.springer.com/chapter/10.1007/978-3-319-77674-3_2#:~:text=T%20cells%20are%20major%20effector%20and%20regulatory,undergo%20an%20intricate%20maturation%20and%20selection%20process.

Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non-Hodgkin lymphoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC3031482/#:~:text=The%20IL7R%20encodes%20a%20receptor%20for%20IL%2D7.,role%20in%20V(D)J%20recombination%20during%20lymphocyte%20development.

 

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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