The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency
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VASCULITIS (L ESPINOZA, SECTION EDITOR)
The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency Jennifer Lee Kendall 1 & Jason Michael Springer 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review We aim to describe the pathophysiology, clinical findings, diagnosis, and treatment of deficiency of adenosine deaminase 2 (DADA2). Recent Findings DADA2 is a multi-organ disease of children and less often adults, which can present with wide-ranging manifestations including strokes, medium vessel vasculitis, hematologic disease, and immunodeficiency. Diagnosis is through detection of reduced activity level of the adenosine deaminase 2 (ADA2) enzyme and/or identification of bi-allelic mutations in the ADA2 gene. Outside of high-dose glucocorticoids, conventional immunosuppression has been largely ineffective in treating this relapsing and remitting disease. Vasculitic-predominant manifestations respond extremely well to tumor necrosis factor-α inhibition. Hematopoietic stem cell transplantation can lead to normalization of enzyme activity, as well as resolution of vasculitic, hematologic, and immunologic manifestations, although treatment-related adverse effects are not uncommon. Summary Early detection of this disease across multiple disciplines could prevent devastating clinical outcomes, especially in genetically pre-disposed populations. Keywords Adenosine . Adenosine deaminase 2 deficiency . Vasculitis . Polyarteritis nodosa . Monogenic disease
Introduction
Pathophysiology of DADA2
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder that affects multiple organ systems with highly variable clinical presentations. First described in 2014 by two separate groups as a mimic of polyarteritis nodosa (PAN), there have been over 260 cases of DADA2 identified to date [1••, 2••]. Abnormalities in adenosine breakdown play a key role in the pathogenesis.
Adenosine is formed by the breakdown of adenine nucleotides, with increased concentrations seen in the setting of cellular damage [3, 4]. The effect of adenosine is mediated by four G protein-coupled cell surface receptors (A1, A2A, A2B, and A3), present on many different cell types [5••]. Receptor activation triggers either a decrease (A1 and A3) or increase (A2A and A2B) in intracellular cyclic AMP, which then mediates a change in cellular activation [3]. The varying effect of adenosine on cellular activity and local inflammation seems to be determined by the interplay between the local adenosine concentration, degree of cellular receptor expression, receptor type, and the receptor affinity; most of which can be affected by environmental factors [5••]. Drugs that manipulate the adenosine pathway can be effective in inflammatory diseases [4]. The adenosine deaminases catalyze the deamination of adenosine to inosine, and deoxyadenosine to deoxyinosine, a key part of the purinergic pathway [6••] (Fig. 1). There are two primary isoforms of adenosine deaminase in huma
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