Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis
- Arye Rubinstein, MD
Arye Rubinstein, MD
- Professor of Pediatrics Microbiology and Immunology
- Albert Einstein College of Medicine and Montefiore Hospital Medical Center
Adenosine deaminase (ADA) deficiency (MIM 102700) was the first immunodeficiency in which the specific molecular defect was described. This autosomal recessive genetic disorder typically leads to a severe combined immunodeficiency (SCID) with dysfunction of T, B, and natural killer (NK) cells (T-B-NK- SCID) that presents in the first few months of life (table 1). However, there are also a few patients with a later onset and relatively milder disease. The wide spectrum of the ADA deficiency phenotype is largely related to the variability in genetic mutations.
The pathogenesis, clinical manifestations, and diagnosis of ADA deficiency are presented in this topic review. The treatment of ADA deficiency is discussed separately, as is the related combined immunodeficiency disorder, purine nucleoside phosphorylase deficiency. (See "Adenosine deaminase deficiency: Treatment" and "Purine nucleoside phosphorylase deficiency".)
An overview of SCID and detailed discussions on other SCID syndromes and combined immunodeficiencies are also covered separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "Combined immunodeficiencies".)
ADA deficiency has an overall incidence of 1 in 200,000 livebirths. It accounts for approximately one-third of all cases of autosomal recessive severe combined immunodeficiency (SCID) and approximately 15 percent of all cases of SCID [1,2].
ADA deficiency is caused by mutations in the ADA1 gene at 20q13.11 (MIM 608958) [3-6]. ADA is an ubiquitous enzyme found in all cells, including red and white blood cells, and in the serum. It catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, which are converted to waste products and excreted. In the absence of functional ADA, there is an intracellular accumulation of adenosine and deoxyadenosine. The replicative activity of the cell dictates the level of sensitivity to these toxic metabolites.
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- CLINICAL MANIFESTATIONS
- Severe combined immunodeficiency (SCID) phenotype
- - Physical examination
- Other phenotypes
- Neurologic abnormalities
- Dermatofibrosarcoma protuberans
- Pulmonary alveolar proteinosis
- Revertant somatic mosaicism
- LABORATORY FINDINGS
- Metabolic abnormalities
- Immune laboratory values
- Prenatal diagnosis
- Newborn screening
- Differential diagnosis