Adenosine deaminase deficiency
A metabolic disorder causing severe combined immunodeficiency.
Adenosine deaminase deficiency, or ADA deficiency, is an inherited metabolic condition that severely weakens the immune system. It results from mutations in the ADA gene and is responsible for roughly 10 to 20 percent of all autosomal recessive cases of severe combined immunodeficiency (SCID), when cases linked to inbreeding are set aside. Worldwide, fewer than one in every 100,000 newborns is affected. The age at which symptoms appear and how severe they become depend on which of the 29 known genotypes a person carries; onset can occur in infancy, childhood, adolescence, or adulthood.
The main signs of ADA deficiency stem not from the missing enzyme itself but from the frequent, severe infections it allows. These include pneumonia, chronic diarrhea, widespread skin rashes, jaundice from liver infections, and candidiasis in the mouth and esophagus. Children grow much more slowly than normal—a condition called failure to thrive—which can lead to other developmental delays. Because their B-cells cannot produce significant amounts of IgG antibodies, they are especially prone to repeated infections from the same viruses, bacteria, and fungi. Most individuals are diagnosed with SCID within the first six months of life. A small minority, however, have a milder form and remain undiagnosed until later in childhood, adolescence, or adulthood. An association with polyarteritis nodosa has also been reported.
The ADA gene, which codes for the enzyme adenosine deaminase, sits on chromosome 20. The disorder follows an autosomal recessive inheritance pattern: a child must inherit two defective copies of the gene—one from each parent—to be born with it. Parents who each carry one copy typically show no symptoms. The enzyme deficiency leads to a buildup of deoxyadenosine, which causes dATP to accumulate in all cells. This dATP buildup inhibits ribonucleotide reductase, blocking DNA synthesis and preventing cell division. Because developing T-cells and B-cells are among the most actively dividing cells, they are especially vulnerable. Additionally, the buildup of S-adenosylhomocysteine—since adenosine deaminase plays a role in the purine salvage pathway—is toxic to immature lymphocytes, which then fail to mature. The result is a complete or near-complete absence of T-cells, B-cells, and NK cells. The thymus, where T-cells normally develop, is typically small and underdevelo
- discovered_by
- Eloise Giblett
- year_discovered
- 1972
- inheritance
- Autosomal recessive
- gene
- ADA gene on chromosome 20
- prevalence
- Fewer than 1 in 100,000 live births
- first_gene_therapy_patient
- Ashanti DeSilva
Lore & Background
ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the University of Washington. Giblett identified a lack of ADA enzyme activity in an immunocompromised patient being evaluated for a bone marrow transplant. After a second case was found, ADA deficiency was recognized as the first identified cause of severe combined immunodeficiency (SCID). However, the first recognized immunodeficiency disorder overall was Bruton's agammaglobulinemia, described in 1952.
The main symptoms include pneumonia, chronic diarrhea, widespread skin rashes, jaundice, and candidiasis of the mouth and esophagus. Affected children grow much more slowly than healthy children, referred to as 'failure to thrive.' These symptoms result from frequent severe infections due to a lack of B-cells and inability to produce IgG antibodies. Most individuals are diagnosed with SCID in the first 6
Reader's Guide
Adenosine deaminase deficiency is significant as the first recognized immunodeficiency disorder, discovered in 1972 by Eloise Giblett. It accounts for 10–20% of autosomal recessive SCID cases and results from mutations in the ADA gene, leading to accumulation of deoxyadenosine and dATP, which inhibit DNA synthesis and prevent lymphocyte maturation. This causes severe immune compromise, with most cases diagnosed in infancy. The disorder's age of onset and severity relate to 29 known genotypes. Definitive treatments include hematopoietic stem cell transplantation and gene therapy, the latter first performed in 1990. The development of Strimvelis, a stem cell gene therapy endorsed by the European Medicines Agency in 2016, offers an option for children without a matching bone marrow donor. ADA deficiency highlights the intersection of metabolic and immune disorders and has been a pioneering target for gene therapy.
Did You Know?
- ADA deficiency accounts for about 10–20% of all autosomal recessive SCID cases after excluding disorders related to inbreeding.
- The first gene therapy for ADA deficiency was performed in September 1990 on a four-year-old girl named Ashanti DeSilva.
- ADA deficiency was discovered in 1972 by Eloise Giblett and was recognized as the first immunodeficiency disorder.
- The disorder occurs in fewer than one in 100,000 live births worldwide.
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