Diagnostic workflow for Adenosine Deaminase-2 Deficiency (DADA2): a proposal

Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease caused by homozygous or compound heterozygous mutations in the ADA2 gene (formerly CECR1 Cat Eye Syndrome Chromosome Region 1). Clinical manifestations of DADA2 are highly variable and include systemic inflammation with fever, early stroke, vasculopathy, immune dysregulation (hypogammaglobulinemia, lymphoproliferation, increased rate of infections), and hematologic abnormalities (pure red cell aplasia, bone marrow failure, cytopenias). The most promising treatments are anti-TNF inhibitors, the only drugs that can prevent the serious consequences of the disease. Early diagnosis is therefore critical. DADA2 can be diagnosed by genetic analysis or functional tests (biochemical diagnosis) that allow the enzyme activity to be assayed. At the Giannina Gaslini Institute, a children's hospital in Italy, a method based on liquid chromatography coupled with tandem mass spectrometry has been developed to measure enzyme activity. A diagnostic workflow is adopted at the institute that involves the assay of ADA2 activity followed by genetic confirmation when the biochemical test is altered.