A 5-month-old boy with chronic diarrhea and failure to thrive is found to have a low blood T-lymphocyte count and severely decreased serum immunoglobulin. After thorough evaluation, an experimental treatment is proposed to his parents. The therapy consists of infecting the patient's cells with a retroviral vector containing the gene for a protein that is deficient in this patient. Which of the following proteins is most likely coded by this gene?
This patient has manifestations characteristic of severe combined immunodeficiency (SCID). Adenosine deaminase (ADA) deficiency is the second most common cause of SCID, after X-linked SCID (eg, IL-2 receptor mutation). ADA is present throughout the human body and functions to eliminate excess adenosine from cells by deaminating adenosine to inosine. Adenosine accumulation is highly toxic to mitotically active cells such as developing lymphocytes; ADA insufficiency leads to widespread death of both T- and B-lymphocytes with resultant combined cellular and humoral immunodeficiency. Because both humoral and cell-mediated immunity are deficient in these patients, they are vulnerable to recurrent, severe infections by bacteria, viruses, and fungi.
Treatment is with hematopoietic (bone marrow) transplantation, but retroviral gene therapy is a promising treatment for patients without an HLA match. Retroviral vectors are used to infect patient hematopoietic stem cells with the genetic code for ADA, resulting in production of ADA by all daughter cells of that stem cell.
(Choice B) Myeloperoxidase is a neutrophil enzyme that helps kill phagocytosed organisms by catalyzing the production of hypochlorite (bleach) from hydrogen peroxide and chloride. A deficiency of this enzyme results in immunodeficiency characterized by recurrent Candida infections.
(Choice C) NADPH oxidase is the enzyme that is deficient in chronic granulomatous disease (CGD). Without NADPH oxidase, neutrophils are unable to form reactive oxygen species such as superoxide. CGD manifests clinically with recurrent infections by catalase-producing organisms (eg, staphylococci). Dihydrorhodamine or nitroblue tetrazolium testing can be used to diagnose CGD.
(Choice D) Reverse transcriptase is a retroviral enzyme that converts viral genomic RNA (in this case, ADA) to DNA. Although it plays a role in the effectiveness of the retrovirus as a vector for the treatment of SCID, reverse transcriptase is not deficient in patients with this condition.
(Choice E) Xanthine oxidase is the enzyme responsible for the formation of uric acid from hypoxanthine and xanthine and is essential as the final step of purine degradation. Xanthine oxidase deficiency leads to abnormally low levels of uric acid in the serum; it can also lead to renal calculi due to the relative insolubility of xanthine at urine's pH level.
Educational objective:
The second most common cause of severe combined immunodeficiency is autosomal recessive deficiency of adenosine deaminase, an enzyme necessary for the elimination of excess adenosine within cells. Toxic levels of adenosine accumulate within lymphocytes in this condition, leading to lymphocyte cell death and resultant cellular and humoral immunodeficiency. Patients with this condition can be treated with hematopoietic cell transplantation or gene therapy.