Getting to know adenosine deaminase 2 deficiency inside and out.

Ten years after the description of the first cohorts of patients with adenosine deaminase (ADA2) deficiency (DADA2), the pathomechanisms underlying the disease on a cellular level remain poorly understood. With the establishment of the lysosomal localization of the ADA2 protein and its involvement in nucleic acid sensing, the pathophysiologic focus has shifted to the inside of the cell. At the same time, extracellular (serum) ADA2 enzyme activity continues to be the diagnostic reference standard in patients with suspected DADA2. The diverse clinical phenotype and weak genotype-phenotype correlations further complicate the identification of shared cellular mechanisms that cause inflammation, immunodeficiency, and bone marrow failure in the absence of functional ADA2. This review inspects the characteristics of the ADA2 protein and its proposed function. The latter is discussed in the context of possible mechanisms driving the clinical phenotype in patients lacking functional ADA2. We discuss established processes and introduce unexplored pathways in the pathogenesis of DADA2.