Adenosine deaminase deficiency
Adenosine deaminase deficiency | |
---|---|
Other names | ADA deficiency, ADA-SCID, and Severe combined immunodeficiency due to ADA deficiency |
Adenosine deaminase deficiency has an autosomal recessive pattern of inheritance. | |
Specialty | Immunology |
Adenosine deaminase deficiency (ADA deficiency) is a
ADA deficiency can present in infancy, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known genotypes associated with the disorder.[3] It occurs in fewer than one in 100,000 live births worldwide.
Signs and symptoms
The main symptoms of ADA deficiency include pneumonia, chronic diarrhea, widespread skin rashes,
These symptoms are not due to the enzyme deficiency itself, but rather to the effects of frequent severe infections from viruses, bacteria, and certain fungi.[4] Children are particularly vulnerable to repeated infections from the same organisms, as their lack of B-cells means they cannot produce IgG antibodies in significant amounts, which protect most people from pathogens that have infected them before.[5] Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life.[6]
The large majority of cases of ADA deficiency are identified and diagnosed in children. However, a small minority have a less-severe form of the disease and remain undiagnosed until childhood, adolescence, or adulthood.[4][6]
An association with polyarteritis nodosa has been reported.[7]
Genetics
The enzyme adenosine deaminase is encoded by the ADA gene on
Age of onset and severity is related to some 29 known genotypes associated with the disorder.[3]
Pathophysiology
ADA deficiency is due to a lack of the enzyme adenosine deaminase. This deficiency results in an accumulation of deoxyadenosine,[2][9] which, in turn, leads to:
- A buildup of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis, so cells are unable to divide. Since developing T cells and B cells are some of the most mitotically active cells, they are highly susceptible to this condition.
- An increase in lymphocytes, which thus fail to mature.
- Complete or near-complete absence of T-cells, B-cells, and NK cells.[2]
Because T cells undergo proliferation and development in the thymus, affected individuals typically have a small, underdeveloped thymus.[10] As a result, the immune system is severely compromised or completely lacking.
Diagnosis
Diagnosis in developed nations is usually done through standardized
In the absence of newborn screening or to differentiate from other causes of SCID, some (but not all) children will display one or more of these features which are sometimes seen in ADA deficiency but not other forms of SCID:[4]
- Earlier onset of failure to thrive
- Respiratory distress in an infant that is not caused by an infection
- Abnormal rib cage development
- Neurologic disorders, especially hearing loss
When ADA deficiency is suspected, the diagnosis may be confirmed through several lab tests of the patient's red blood cells, or via genetic testing.[4]
Treatment
Treatment of ADA deficiency focuses on reducing the frequency and severity of infections.
In addition to antibiotics,
Enzyme replacement therapy is provided to newborns until a definitive therapy plan can be implemented.[11] There is some evidence that ERT also prevents tissue damage related to accumulated dATP and other molecules.[12]
Stem cell transplantation
Long-term definitive treatment of ADA deficiency is typically achieved by transplantation of hematopoietic stem cells from a matched family member donor, preferably a sibling. Before transplantation, testing must be done to ensure that human leukocyte antigen (HLA) properties of the donor and the transplant recipient align, to avoid transplant rejection.[11]
Gene therapy
The other definitive therapy available for ADA deficiency is gene therapy. These therapies use a viral vector to integrate a working copy of the gene into the patient's genome.[11]
In September 1990, the first gene therapy to combat this disease was performed by Dr. William French Anderson on a four-year-old girl, Ashanti DeSilva, at the National Institutes of Health, Bethesda, Maryland, U.S.A.[13] In April 2016 the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed and recommended for approval a stem cell gene therapy called Strimvelis, for children with ADA-SCID for whom no matching bone marrow donor is available.[14][15]
History
ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the University of Washington.[16] The ADA gene was used as a marker for bone marrow transplants. A lack of ADA activity was discovered by Giblett in an immunocompromised transplant candidate. After discovering a second case of ADA deficiency in an immunocompromised patient, ADA deficiency was recognized as the first immunodeficiency disorder.[16]
References
- ^ PMID 29690908.
- ^ ISBN 978-1264268504.
- ^ PMID 9758612.
- ^ a b c d e f g Grunebaum E, Kohn DB (September 2023). "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis". UpToDate. Wolters Kluwer. Retrieved 2023-12-20.
- PMID 27579027.
- ^ S2CID 43108821.
- PMID 31092714.
- PMID 17181544.
- ^ "Adenosine Deaminase (ADA) Deficiency". Genetic Science Learning Center. The University of Utah. Archived from the original on 2008-02-12. Retrieved 2008-02-28.
- ISBN 978-0-415-95590-4.
- ^ a b c d e Grunebaum E, Kohn DB (July 2023). "Adenosine deaminase deficiency: Treatment and prognosis". UpToDate. Wolters Kluwer. Retrieved 21 Dec 2023.
- PMID 30194989.
- ^ Naam R (2005-07-03). "'More Than Human' - New York Times". The New York Times. Retrieved 2008-02-28.
- ^ House DW (1 April 2016). "European Ad Comm backs Glaxo's stem cell therapy Strimvelis for rare autoimmune disorder". Seeking Alpha. Retrieved 13 April 2016.
- ^ "Summary of opinion1 (initial authorisation) Strimvelis" (PDF). European Medicines Agency. 1 April 2016. pp. 1–2. Retrieved 13 April 2016.
- ^ a b Motulsky A, Gartler S (2009). "Biographical Memoirs: Eloise R. Giblett" (PDF). National Academy of Sciences.