A six-month-old infant presents with chronic, persistent diarrhea, oral thrush, and a severe diaper rash. The infant was treated four weeks ago for an upper respiratory and ear infection. A family history is significant for a consanguineous relationship between the mother and father. Physical examination demonstrates the absence of palpable lymph nodes. Accumulation of which of the following would lead to this disease phenotype?
The presentation of chronic persistent diarrhea and several fungal and bacterial infections along with the absence of palpable lymph nodes is suggestive of an immunodeficiency disorder. The defect in this patient is the enzyme adenosine deaminase that results in the accumulation of deoxyadenosine.
Adenosine deaminase (ADA) deficiency is one of the most common causes of severe combined immunodeficiency due to a mutation in the adenosine deaminase gene. ADA plays a significant role in the purine salvage pathway that converts adenosine and deoxyadenosine to inosine. The accumulation of adenosine and deoxyadenosine result in the overproduction of deoxyadenosine triphosphate (dATP), which through feedback inhibition of ribonucleotide reductase, prevents the de novo synthesis of nucleotides. Thus, cells are unable to divide due to a halt in DNA synthesis. Cells most affected by this mutation are those of the immune system, B and T cells, and lead to a significant decrease in these cells as well as immunodeficiency.
Sauer et al. set out to review the symptoms, complications, and treatments regarding adenosine deaminase deficiency. Patients usually present with a deficient cellular and humorial immune response, lymphopenia, failure to thrive, and recurrent bacterial, fungal, and viral infections. Treatments for this disorder range from bone marrow transplantation, gene therapy, and enzyme replacement with bovine adenosine deaminase. Due to dysregulation of the immune system, mild sufferers of this disorder are usually affected by other immunne complications such as autoimmune hypothyroidism, type 1 diabetes, and immune thrombocytpenia.
Giblett et al. report on cases of people afflicted with adenosine deaminase deficiency. One case is of a 22-month-old female child from a consanguineous relationship, in which the ADA deficiency manifested as a T-lymphocyte deficiency. The child had recurrent respiratory infections, lymphopenia, and candidiasis. The deficiency was confirmed when they tested the adenosine deaminase levels in the child and found no detectable levels of adenosine deaminse in her RBCs, and both her parents had roughly a 50% decrease of activity in their RBCs as well.
Illustration A is a schematic of ADA deficiency resulting in the inhibition of de novo nucleotide synthesis.