ADA2 – Deficiency of Adenosine Deaminase 2

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory vasculopathy caused by biallelic loss-of-function variants in the ADA2 gene. Initially described as a childhood-onset polyarteritis nodosa-like syndrome with livedo racemosa and strokes, DADA2 presentations now encompass systemic inflammation, immunodeficiency, cytopenias, and hematologic failure (PMID:31599797).

Genetic evidence for ADA2–DADA2 association is robust. Over 206 affected individuals from >100 unrelated families harbor biallelic ADA2 pathogenic variants, including missense, splice-site, frameshift, and exon-duplication alleles, with concordant low enzyme activity and familial segregation (PMID:31599797; PMID:32638197).

Inheritance is autosomal recessive. Segregation studies in multiple consanguineous and non-consanguineous pedigrees document 15 additional affected relatives with early-onset vasculitis or cytopenias segregating compound heterozygous or homozygous ADA2 variants.

The ADA2 variant spectrum includes >95 distinct alleles: missense substitutions (e.g., p.Gly47Arg, p.Arg169Gln), canonical splice-site changes (c.973-2A>G), frameshifts, and deep intronic events. A recurrent founder p.Gly47Arg allele is common in European cohorts; other variants show population specificity (PMID:31008556).

Mechanistically, ADA2 deficiency impairs extracellular adenosine catabolism, leading to endothelial dysfunction and skewed macrophage polarization toward proinflammatory M1 phenotypes. Loss of ADA2 enzymatic activity underlies vasculopathy and bone marrow compromise.

Functional studies demonstrate markedly reduced ADA2 activity in patient plasma, upregulated type II interferon signatures with STAT1 hyperactivation in monocytes and B cells, and rescue of inflammatory macrophage responses by TNF inhibition or lentiviral ADA2 expression in hematopoietic progenitors (PMID:33529688; PMID:34424322).

In conclusion, ADA2–DADA2 association meets Strong ClinGen criteria, supported by extensive case series, segregation, and functional concordance. Early genetic testing and enzymatic assays enable diagnosis and guide management with TNF blockers or hematopoietic stem cell transplantation. Clinical utility is high for differential diagnosis of vasculitis, stroke, and cytopenias.

References

• Arthritis & rheumatology (Hoboken, N.J.) • 2019 • Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis. PMID:31008556
• Journal of clinical immunology • 2020 • Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance. PMID:32638197
• Current opinion in rheumatology • 2020 • A Monogenic Autoinflammatory Disease with Fatal Vasculitis: Deficiency of Adenosine Deaminase 2. PMID:31599797
• The Journal of allergy and clinical immunology • 2021 • Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation. PMID:33529688
• Blood advances • 2021 • Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency. PMID:34424322

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