The mechanism by which mutations in ADA2 lead to disease manifestations is not fully clear. ADA2 is a primarily extracellular protein highly expressed by myeloid immune cells such as monocytes, macrophages, and dendritic cells. ADA2 has been hypothesized to have multiple functions, including as an enzyme, a growth factor, and an intracellular DNA sensor. Deficiencies in each of these functions could lead to the chronic inflammatory phenotype associated with DADA2. Less is known about the role of ADA2 dysfunction in the immunologic and hematologic aspects of the disease. ADA2 catalyzes the reaction of adenosine to inosine and<unk> ’deoxyadenosine in the blood. All DADA2 patients display less than 5% of the normal activity of ADA2 in blood samples, implicating the potential importance of this enzymatic role. Adenosine levels are higher in patients than healthy individuals. Adenosine binds to cell surface receptors on neutrophils, causing the formation of neutrophil extracellular traps (NETs). NETs have been identified at increased levels in both affected tissue and in circulation of DADA2 patients. NETs go on to cause inflammatory responses from macrophages, including excess release the pro-inflammatory cytokine TNFa. TNFa likely plays a major role in the vasculitic phenotype of DADA2 due the efficacy of TNFa targeting drugs in treating symptoms. However, the enzymatic activity of ADA2 is 100 fold lesser than that of the intracellular adenosine<unk>  ADA1, and at physiological concentrations of adenosine the enzymatic activity of ADA2 is near zero. This indicates that loss of ADA2 may cause disease by other mechanisms. Endothelial cell activation and damage is a further source of inflammation and vascular symptoms caused by DADA2. Endothelial cells from patients are extensively damaged and secrete pro-inflammatory cytokines. However, endothelial cells themselves don't express the ADA2 protein, so this phenotype is likely mediated by the effects of mutant ADA2 on other cell types feeding back onto endothelial cells. For example, ADA2 mutant monocytes display abnormal differentiation into macrophages, and endothelial cells grown in the presence of ADA2 deficient monocytes are similarly extensively damaged. The molecular underpinnings of the immunologic disease are unclear, but the upregulation of type I interferon-stimulated genes, poor B cell differentiation, reduced antibody production, and lymphoproliferation have been noted. The cause of severe hematologic manifestations such as pure red cell aplasia and bone marrow failure are also unknown. However, the ADA2 protein is similar in structure to the adenosine<unk>  growth factors found in other species. Deficiencies of these proteins in frogs and fruit flies have been shown to cause developmental abnormalities, such as small size and early death respectively. In humans, extracellular ADA2 interacts with many immune cell types, including neutrophils, monocytes, NK cells, and specific B and T cell subtypes. This interaction can lead to functional changes, as ADA2 has been shown to bind to monocytes and CD4+ T cells to increase monocyte differentiation and T cell proliferation when present together. Thus, DADA2 might lead to poor immune cell development directly or through the generally high inflammation.
Adenosine deaminase 2 deficiency
Adenosine deaminase deficiency
Adenine phosphoribosyltransferase deficiency
Adenosine monophosphate deaminase deficiency type 1
Guanidinoacetate methyltransferase deficiency
Galactose-1-phosphate uridylyltransferase deficiency
Aminoacylase 1 deficiency
Methylenetetrahydrofolate reductase deficiency