Biology of ADA-SCID
ADA deficiency is an inherited disorder that damages the immune system and causes SCID. People with SCID lack virtually all immune protection from bacteria, viruses and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. These infections are often caused by opportunistic organisms that ordinarily do not cause illness in people with a normal immune system.
The main symptoms of ADA deficiency are pneumonia, chronic diarrhoea and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay.
Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life. Without treatment, these infants usually do not survive past the age of 2. In approximately 10–15% of cases, the onset of immune deficiency is delayed to between 6 and 24 months of age (delayed onset) or even until adulthood (late onset). Immune deficiency in these later-onset cases tends to be less severe, causing primarily recurrent upper respiratory and ear infections, but over time, affected individuals may develop chronic lung damage, malnutrition and other health problems.
ADA is an enzyme of the purine salvage pathway. It is ubiquitously expressed in all tissues of the body, with the greatest concentration found in the thymus. Mutation of the ADA gene results in SCID, presenting as the absence of cellular- and humoral-mediated immunity, including deficiency of T, B and NK (natural killer) cell development, recurrence of opportunistic infections, and failure to thrive. Given the ubiquitous expression of ADA, these patients also suffer from skeletal, lung, liver and neural abnormalities.
The ADA gene is located on chromosome 20. This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
ADA catalyses the deamination of the purine nucleoside adenosine (Ado) and the deoxydenosine (dAdo) into inosine and deoxyinosine , respectively. Deleterious mutations of the ADA gene render the ADA protein unable to catalyse these processes and, consequently, for Ado and dAdo to accumulate both intra- and extra-cellularly. Intracellular accumulation of dAdo is converted into dATP (deoxyadenosinetrisphosphate) by the enzyme deoxycytidine kinase (dCydK). High levels of intracellular dATP are considered to be the main cause of lymphotoxicity in the thymus. dATP induces apoptosis of developing thymocytes and interferes with terminal deoxynucleotidyl transferase (TdT) activity, thereby adversely affecting V(D)J recombination during T and B cell maturation and thus antigen receptor diversity.
Intracellular dAdo also inactivates the enzyme S-adenosylhomocysteine hydrolase (SAHH) and results in the accumulation of S-adenosyl homocysteine (AdoHcy), which, in turn inhibits the transmethylation reactions necessary for effective lymphocyte activation.
In addition, elevated levels of Ado, acting through cell surface G-protein-coupled receptors, may contribute to immune dysfunction and pulmonary inflammation associated with ADA deficiency.
Finally, accumulation of both Ado and dAdo also affects T-cell activation; dAdo is able to bind to the A2A receptor, thereby inhibiting T-cell receptor activation and reducing proliferation and cytokine secretion.
Written by Paul Taylor, Senior Medical Education Writer at Springer Healthcare IME, and reviewed and approved by all Editorial Board Members, Andrew Gennery, Bobby Gaspar and Robbert Bredius.
Adenosine Deaminase Deficiency.
Encyclopedia of Molecular Mechanisms of Disease pp36-37, 2009
Florian Lang (Ed.)
Genetics of SCID
Ital J Pediatr. 2010 Nov 15;36: 76
Combined T and B Cell Immunodeficiencies.
Bonilla FA, Barlan IB, Aydiner E, Al-Herz W, Eibl MM, Espanol T, Martín A, Maródi L, Pourhamdi S, Soler-Palacín P, Wolf HM, Aghamohammadi A
Clinical Cases in Primary Immunodeficiency Diseases pp77-112, 2012
Aghamohammadi A, Rezaei N (Eds)