Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency

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.

Keywords: SCID; adenosine deaminase; enzyme replacement therapy; gene therapy; hematopoietic stem cell transplantation; immunodeficiency; neurological abnormalities.

Figure 1

The purine salvage pathway is an integral metabolic pathway, responsible for the regulation and availability of purines. ADA catalyzes the deamination of adenosine and deoxyadenosine, forming inosine and deoxyinosine (respectively), which can then undergo further downstream processing. Alternatively, adenosine and deoxyadenosine may be released to activate downstream pathways.

Figure 2

Potential treatment options for ADA deficiency include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy (GT). There are varying benefits and potential problems for each available treatment and patients require individual assessment to decide on the appropriate course of action. This table has been created using information from (, –13).

Figure 3

This figure shows the cell membrane with the adenosine receptors embedded into the phospholipid bilayer. Adenosine receptors are G-protein-coupled receptors made up of seven transmembrane domains. There are four subtypes of adenosine receptor: A1, A2A, A2B, and A3. The A1 and A3 adenosine receptors are coupled to Gαi, which causes a decrease in cAMP downstream of receptor activation. Conversely, A2A and A2B are both coupled to Gαs, which causes an increase in cAMP.

Figure 4

ADA deficiency leads to an accumulation of adenosine (A) and deoxyadenosine (B) – different mechanisms are proposed for the increased concentration of each metabolic substrate. (A) An increase in extracellular adenosine concentration leads to an increase in intracellular cyclic AMP (cAMP) caused by increased A2A receptor activation. cAMP is proposed to mediate lymphotoxic effects by disrupting TCR signaling and inhibiting the immune response to a stimulus. (B) Extracellular accumulation of 2′deoxyadenosine increases the intracellular concentration of 2′deoxyadenosine via diffusion down its concentration gradient. 2′deoxyadenosine inhibits SAH hydrolase and plays a role in apoptosis, by activating the p53 pathway. Alternatively, 2′deoxyadenosine can undergo conversion to dATP. dATP inhibits ribonucleotide reductase and also plays a role in apoptosis.

Figure 5

There is peripheral expression of all four adenosine receptor subtypes in the brain, which are found pre, post, and non-synaptically (34). A1 receptors are ubiquitously expressed with high concentrations particularly found in the cortex, hippocampus, and cerebellum (34). Conversely, levels of A2A receptor are generally lower throughout the brain but are concentrated predominantly on medium spiny neurons of the striatum (34). Furthermore, the A1 receptor subtype is preferentially activated by released adenosine, and the A2A receptors are preferentially activated by adenosine formed from adenine nucleotides (35). Low levels of A2B and A3 receptors are found in the brain; these receptors are thought to be involved in pathological situations (35, 36).