ADA2 – Vasculitis due to ADA2 Deficiency

Adenosine deaminase 2 (ADA2), encoded by HGNC:1839, is a secreted enzyme critical for endothelial integrity and immune homeostasis. Biallelic loss-of-function mutations in ADA2 cause an autosomal recessive vasculitic syndrome, commonly referred to as deficiency of ADA2 (DADA2; MONDO_0014306). The disorder manifests with systemic inflammation, small- and medium-vessel vasculopathy, early-onset ischemic and hemorrhagic strokes, and immunodeficiency.

Genetic studies have identified over 206 unrelated patients from more than 43 families carrying compound heterozygous or homozygous ADA2 variants ([PMID:31599797]) with clear segregation in multiple pedigrees, including consanguineous kindreds. Segregation analysis across siblings and extended relatives supports recessive inheritance and pathogenicity of ADA2 alleles.

The variant spectrum spans missense, frameshift, and splice-site mutations, with recurrent founder alleles such as c.139G>C (p.Gly47Arg) ([PMID:24737293]). Loss-of-function lesions predominate, leading to absent or severely reduced enzymatic activity. One representative pathogenic change is c.139G>C (p.Gly47Arg), which disrupts homodimer formation and ADA2 secretion.

Functional assays demonstrate that patient-derived macrophages and endothelial models exhibit heightened inflammatory cytokine production and impaired vascular support. Structural modeling of mutations like p.Leu351Gln and p.Ala357Thr reveals active site perturbation ([PMID:25106422]). Gene therapy approaches using a lentiviral ADA2 vector in hematopoietic stem/progenitor cells restore enzymatic function and normalize macrophage cytokine profiles ([PMID:34424322]).

Clinically, DADA2 patients present in infancy to adolescence with livedo reticularis, recurrent fever, early ischemic stroke (HP:0001297), immunodeficiency (HP:0002721), and cytopenias (HP:0001903). Anti-TNF therapy effectively prevents stroke recurrence and controls systemic vasculitis, whereas hematopoietic stem cell transplantation may be curative in refractory hematological phenotypes.

Assessments

• Clinical validity: Definitive; >206 unrelated probands, multi-family segregation, concordant functional data.
• Genetic evidence: Strong; numerous biallelic loss-of-function variants across >200 patients reach the ClinGen genetic cap.
• Functional evidence: Moderate; in vitro and in vivo assays confirm loss of ADA2 activity and pathogenic inflammatory phenotype, with gene rescue studies.

Key take-home: ADA2 deficiency is a clinically actionable monogenic vasculitis for which early genetic testing and targeted anti-TNF or cell-based therapies markedly improve outcomes.

References

• Current opinion in rheumatology • 2020 • A monogenic autoinflammatory disease with fatal vasculitis: deficiency of adenosine deaminase 2 PMID:31599797
• European journal of pediatrics • 2014 • Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy PMID:24737293
• Molecular & cellular proteomics: MCP • 2014 • The bromodomain of Gcn5 regulates site specificity of lysine acetylation on histone H3 PMID:25106422
• Blood advances • 2021 • Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency PMID:34424322
• Neurology®️ Neuroimmunology & Neuroinflammation • 2023 • TNF-Blockade for Primary Stroke Prevention in Adenosine Deaminase 2 Deficiency: A Case Series PMID:36941081

Evidence Based Scoring (AI generated)