ADA2 – Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a necrotizing medium-vessel vasculitis that, in childhood-onset cases, is frequently caused by autosomal recessive loss-of-function mutations in ADA2 (PMID:24552285). ADA2 (CECR1) encodes a secreted adenosine deaminase, and its deficiency (DADA2) manifests with systemic inflammation, livedo reticularis, hypertension, peripheral neuropathy, early-onset strokes and variable immunodeficiency.

Genetic evidence for ADA2 in PAN includes biallelic pathogenic variants identified in at least 15 unrelated families with childhood vasculitis (PMID:28522451). The variant spectrum encompasses missense substitutions (e.g., c.139G>C (p.Gly47Arg)), splice-site alterations, frameshifts and deep intronic changes. Recurrent founder alleles such as p.Gly47Arg (Georgian Jewish population carrier frequency 0.10) and p.Gly47Val have been described, and compound heterozygosity is common.

Segregation analysis demonstrates autosomal recessive inheritance with confirmed segregation of biallelic ADA2 mutations in 15 affected probands and multiple affected siblings across families ([PMID:24552285]; [PMID:28522451]). No phenotype is observed in heterozygous carriers in most pedigrees, consistent with recessive transmission.

Functional assays reveal markedly reduced ADA2 enzymatic activity in patient sera and monocyte cultures ([PMID:24552285]; [PMID:28522451]). Lentiviral correction of ADA2 in patient-derived hematopoietic progenitors restores enzyme activity and normalizes macrophage cytokine profiles in vitro ([PMID:34424322]). These data support haploinsufficiency of ADA2 as the primary pathogenic mechanism.

No convincing conflicting evidence has been reported; monoallelic carriers rarely exhibit clinical symptoms despite reduced enzyme activity, and no alternative genetic etiologies mimic the full DADA2 spectrum in these cohorts.

In summary, ADA2 deficiency is a well-validated cause of early-onset PAN. Genetic screening for ADA2 mutations and enzyme assays should be incorporated into the diagnostic workup of hepatitis B–negative idiopathic PAN, guiding targeted anti-TNF therapy and consideration of hematopoietic stem cell or gene therapy.

Key Take-home: Identification of biallelic ADA2 mutations enables precise diagnosis of DADA2 and informs tailored anti-TNF and cell-based therapies that significantly reduce vasculitic complications.

References

• The New England journal of medicine • 2014 • Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy PMID:24552285
• Annals of the rheumatic diseases • 2017 • ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study PMID:28522451
• Blood advances • 2021 • Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency PMID:34424322

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