Biochemical testing demonstrates absent or greatly reduced ADA activity (< 1% of normal) and marked elevation of the metabolite dATP or total dAdo nucleotides (the sum of dAMP, dADP and dATP) in erythrocytes. Diagnosisĭiagnosis of ADA-deficiency is established by biochemical and molecular genetic testing. Adenosine receptors belong to the family of G protein-coupled receptors, of which there are four subtypes (A 1, A 2A, A 2B and A 3), which play different roles in regulating normal cellular physiology in a wide variety of tissues including the brain, cardiovascular system and lungs. Adenosine is an important extracellular signalling molecule disruption of these signalling pathways is thought to interfere with normal immune responses. Increased intracellular uptake of 2’deoxyadenosine followed by phosphorylation by deoxycytidine kinase leads to accumulation of deoxyadenosine triphosphate (dATP) which inhibits ribonucleotide reductase, preventing normal DNA synthesis and repair. 2’deoxyadenosine irreversibly inhibits the enzyme S-adenosylhomocysteine (SAH) hydrolase causing accumulation of SAH, which subsequently prevents S-adenosylmethionine-mediated methylation processes required for normal thymocyte differentiation, likely contributing to the impairment of T-lymphocyte development evident in ADA-deficiency. Adenosine primarily derives from breakdown of adenosine triphosphate (ATP) and RNA, and 2’deoxyadenosine from breakdown of DNA. Absent or impaired function consequently results in both intracellular and extracellular accumulation of these substrates. With purine nucleoside phosphorylase, it forms an essential component of the purine salvage pathway, responsible for the irreversible deamination of adenosine and 2’deoxyadenosine into inosine and 2’deoxyinosine respectively. BiochemistryĪDA is a ubiquitously expressed metabolic enzyme, although level of enzyme activity varies, with highest levels observed in lymphoid tissues, particularly the thymus, the brain and gastrointestinal tract, and is expressed both intracellularly and on the cell surface complexed with CD26. Current treatment options include enzyme replacement therapy (ERT), allogeneic haematopoietic stem cell transplant (HSCT), and autologous gene therapy (GT). Early diagnosis of ADA-deficient SCID and initiation of treatment is essential in this otherwise fatal condition. The incidence of ADA-deficiency in Europe is estimated to be between 1:375,000 to 1:660,000 live births.

ADA-deficient SCID is characterized by severe lymphocytopaenia affecting T-and B-lymphocytes and NK cells, but, because of the ubiquitous nature of the enzyme, non-immunological manifestations are also observed, including neurodevelopmental deficits, sensorineural deafness and skeletal abnormalities. Absent or impaired ADA function leads to the accumulation of the toxic metabolites adenosine, 2’deoxyadenosine and deoxyadenosine triphosphate (dATP).

This article reviews the biology, clinical presentation, diagnosis and treatment of ADA-deficiency.Īdenosine deaminase (ADA) is a key enzyme of the purine salvage pathways and deficiency caused by mutations in the ADA gene results in one of the more common causes of autosomal recessive severe combined immunodeficiency (SCID), accounting for approximately 10–15% of cases in outbred populations.

More recently, the use of gene addition techniques to correct the genetic defect in autologous haematopoietic stem cells treatment has demonstrated immunological and clinical efficacy. Hematopoietic stem cell transplant has long been established as the treatment of choice, particularly where a matched sibling or well matched unrelated donor is available. Initial treatment with enzyme replacement therapy may alleviate acute symptoms and enable partial immunological reconstitution, but treatment is life-long, immune reconstitution is incomplete, and the reconstituted immune system may nullify the effects of the enzyme replacement. Three treatment options are currently available. Affected patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency. Whilst most notable affects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental affects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency.

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