Abstract
Adenosine deaminase (ADA) deficiency is best known as a form of severe combined immunodeficiency (SCID) that results from mutations in the gene encoding ADA. Affected patients present with clinical and immunological manifestations typical of a SCID. Therapies are currently available that can target these immunological disturbances and treated patients show varying degrees of clinical improvement. However, there is now a growing body of evidence that deficiency of ADA has significant impact on non-immunological organ systems. This review will outline the impact of ADA deficiency on various organ systems, starting with the well-understood immunological abnormalities. We will discuss possible pathogenic mechanisms and also highlight ways in which current treatments could be improved. In doing so, we aim to present ADA deficiency as more than an immunodeficiency and suggest that it should be recognized as a systemic metabolic disorder that affects multiple organ systems. Only by fully understanding ADA deficiency and its manifestations in all organ systems can we aim to deliver therapies that will correct all the clinical consequences.
Highlights
What Is the Role of Adenosine Deaminase in the Purinergic Signaling Pathway?Adenosine deaminase (ADA) is a ubiquitously expressed metabolic enzyme that plays an integral role in numerous cellular processes
We aim to present ADA deficiency as more than an immunodeficiency – it should be recognized as a systemic metabolic disorder that results in multiple organ pathologies
If adenosine is implicated in the pathogenesis of other diseases, it is possible that alterations in adenosine metabolism occurring in ADA deficiency are affecting the functioning of the central nervous systems (CNS), resulting in the neurological abnormalities reported in many patients
Summary
Adenosine deaminase (ADA) is a ubiquitously expressed metabolic enzyme that plays an integral role in numerous cellular processes. It is expressed both intracellularly and, in certain cell types, is complexed with CD26 on the cell surface. Deficient and impaired ADA activity results in the accumulation of metabolic substrates of which adenosine, deoxyadenosine, and dATP are of particular importance due to their profound effects on cellular function (2). Lymphocyte maturation and function is affected and, deficiency of ADA leads to a severe combined immunodeficiency (SCID) (1). Mutations in ADA2 can lead to polyarteritis nodosa and other vasculopathies, and some patients with immunodeficiency have been identified (4–6). For the purpose of this review, we will discuss only ADA1 encoded for by the ADA gene, since this is the enzyme that is implicated in ADA-SCID, and we will refer to it throughout as ADA
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