imported>IntentionallyDense: Undid revision 1322872592 by ~2025-34466-55 (talk) undo change that changed meaning. the disease is present from birth since it is genetic but it presents with symptoms at different ages

2025-11-18T22:06:31Z

Undid revision 1322872592 by ~2025-34466-55 (talk) undo change that changed meaning. the disease is present from birth since it is genetic but it presents with symptoms at different ages

New page

{{About| a metabolic disorder caused by ADA gene mutations | the vasculitis syndrome caused by ADA2 gene mutations |Adenosine deaminase 2 deficiency}}
{{Infobox medical condition (new)
| name = Adenosine deaminase deficiency
| image = Autosomal recessive - en.svg
| caption = Adenosine deaminase deficiency has an autosomal recessive pattern of [[inheritance]].
|
| synonyms = '''ADA deficiency''', '''ADA-SCID''', and '''Severe combined immunodeficiency due to ADA deficiency'''
| symptoms =
| complications =
| onset =
| duration =
| types =
| causes =
| risks =
| diagnosis =
| differential =
| prevention =
| treatment =
| medication =
| prognosis =
| frequency =
| deaths =
}}
'''Adenosine deaminase deficiency''' ('''ADA deficiency''') is a [[metabolic disorder]] that causes [[immunodeficiency]]. It is caused by mutations in the [[ADA (gene)|ADA gene]]. It accounts for about 10–20% of all cases of [[autosome|autosomal]] [[dominance (genetics)|recessive]] forms of [[severe combined immunodeficiency]] (SCID) after excluding disorders related to [[inbreeding]].<ref name="Flinn_2018">{{Cite journal |vauthors=Flinn AM, Gennery AR |date=April 2018 |title=Adenosine deaminase deficiency: a review |journal=Orphanet Journal of Rare Diseases |volume=13 |issue=1 |article-number=65 |doi=10.1186/s13023-018-0807-5 |pmc=5916829 |pmid=29690908 |doi-access=free}}</ref><ref name="Fischer_2022">{{Cite book |title=Harrison's Principles of Internal Medicine |vauthors=Fischer A |publisher=McGraw Hill |year=2022 |isbn=978-1264268504 |edition=21st |language=English |chapter=Chapter 351: Primary Immune Deficiency Diseases}}</ref>

ADA deficiency can present in [[infant|infancy]], childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known [[genotype]]s associated with the disorder.<ref name="Arredondo-Vega_1998">{{Cite journal |vauthors=Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS |date=October 1998 |title=Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles |journal=American Journal of Human Genetics |volume=63 |issue=4 |pages=1049–1059 |doi=10.1086/302054 |pmc=1377486 |pmid=9758612}}</ref> 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, [[jaundice]] (from hepatic infections), and [[candidiasis]] of the mouth and esophagus. Affected children also grow much more slowly than healthy children, commonly referred to as "[[failure to thrive]]," which may lead to other [[developmental delays]].<ref name="Grunebaum_2023">{{Cite web |date=September 2023 |title=Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis |url=https://www.uptodate.com/contents/adenosine-deaminase-deficiency-pathogenesis-clinical-manifestations-and-diagnosis |access-date=2023-12-20 |website=UpToDate |publisher=Wolters Kluwer |vauthors=Grunebaum E, Kohn DB}}</ref>

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.<ref name="Grunebaum_2023" /> Children are particularly vulnerable to repeated infections from the same organisms, as their lack of [[B cell|B-cells]] means they cannot produce [[Immunoglobulin G|IgG antibodies]] in significant amounts, which protect most people from pathogens that have infected them before.<ref>{{Cite journal |vauthors=Whitmore KV, Gaspar HB |date=2016-08-16 |title=Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency |journal=Frontiers in Immunology |volume=7 |pages=314 |doi=10.3389/fimmu.2016.00314 |pmc=4985714 |pmid=27579027 |doi-access=free}}</ref> Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life.<ref name="Shovlin_1994">{{Cite journal |display-authors=6 |vauthors=Shovlin CL, Simmonds HA, Fairbanks LD, Deacock SJ, Hughes JM, Lechler RI, Webster AD, Sun XM, Webb JC, Soutar AK |date=September 1994 |title=Adult onset immunodeficiency caused by inherited adenosine deaminase deficiency |journal=Journal of Immunology |volume=153 |issue=5 |pages=2331–2339 |doi=10.4049/jimmunol.153.5.2331 |pmid=8051429 |s2cid=43108821}}</ref>
[[File:Oral thrush Aphthae Candida albicans. PHIL 1217 lores.jpg|thumb|Oral candidiasis, an infection frequently seen in SCID]]
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.<ref name="Grunebaum_2023" /><ref name="Shovlin_1994" />

An association with polyarteritis nodosa has been reported.<ref name="Liebowitz_2019">{{Cite journal |vauthors=Liebowitz J, Hellmann DB, Schnappauf O |date=August 2019 |title=Thirty Years of Followup in 3 Patients with Familial Polyarteritis Nodosa due to Adenosine Deaminase 2 Deficiency |journal=The Journal of Rheumatology |volume=46 |issue=8 |pages=1059–1060 |doi=10.3899/jrheum.180820 |pmid=31092714 |doi-access=free}}</ref>

==Genetics==
The enzyme adenosine deaminase is encoded by the ADA gene on [[chromosome 20 (human)|chromosome 20]].<ref name="Flinn_2018" /> ADA deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an [[autosome]] (chromosome 20 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both [[genetic carrier|carry]] one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.<ref name="Grunebaum_2023" /><ref>{{Cite journal |vauthors=Sanchez JJ, Monaghan G, Børsting C, Norbury G, Morling N, Gaspar HB |date=May 2007 |title=Carrier frequency of a nonsense mutation in the adenosine deaminase (ADA) gene implies a high incidence of ADA-deficient severe combined immunodeficiency (SCID) in Somalia and a single, common haplotype indicates common ancestry |journal=Annals of Human Genetics |volume=71 |issue=Pt 3 |pages=336–347 |doi=10.1111/j.1469-1809.2006.00338.x |pmid=17181544}}</ref>

Age of onset and severity is related to some 29 known [[genotype]]s associated with the disorder.<ref name="Arredondo-Vega_1998" />

==Pathophysiology==
ADA deficiency is due to a lack of the [[enzyme]] [[adenosine deaminase]]. This deficiency results in an accumulation of [[deoxyadenosine]],<ref name="Fischer_2022" /><ref name="Univ_Utah">{{Cite web |title=Adenosine Deaminase (ADA) Deficiency |url=http://learn.genetics.utah.edu/units/disorders/whataregd/ada/ |url-status=dead |archive-url=https://web.archive.org/web/20080212052329/http://learn.genetics.utah.edu/units/disorders/whataregd/ada/ |archive-date=2008-02-12 |access-date=2008-02-28 |website=Genetic Science Learning Center |publisher=The University of Utah}}</ref> which, in turn, leads to:
* A buildup of [[Deoxyadenosine triphosphate|dATP]] in all cells, which inhibits [[ribonucleotide reductase]] and prevents [[DNA synthesis]], so cells are unable to divide. Since developing [[T cell]]s and [[B cell]]s are some of the most mitotically active cells, they are highly susceptible to this condition.
* An increase in [[S-adenosylhomocysteine]] since the enzyme adenosine deaminase is important in the [[purine salvage pathway]]; both substances are toxic to immature [[lymphocytes]], which thus fail to mature.
* Complete or near-complete absence of T-cells, B-cells, and [[Natural killer cell|NK cells]].<ref name="Fischer_2022" />
Because T cells undergo proliferation and development in the [[thymus]], affected individuals typically have a small, underdeveloped [[thymus]].<ref>{{Cite book |title=The Immune System |vauthors=Parham P |date=2009 |publisher=Garland Science |isbn=978-0-415-95590-4 |edition=3rd |location=London and New York |page=347}}</ref> As a result, the [[immune system]] is severely compromised or completely lacking.{{cn|date=October 2024}}

==Diagnosis==
Diagnosis in developed nations is usually done through standardized [[newborn screening]] tests for a range of [[congenital diseases]], including ADA deficiency. Most newborns with SCID, including those with ADA deficiency as an underlying cause, can be identified before the onset of major infections due to their decreased levels of [[T-cell receptor excision circles]] (TRECs). TRECs are a normal product of T-cell development, and a deficit of them indicates a problem with lymphocyte maturation.<ref name="Grunebaum_2023" />

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:<ref name="Grunebaum_2023" />
* Earlier onset of [[failure to thrive]]
* [[Shortness of breath|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]].<ref name="Grunebaum_2023" />

==Treatment==
Treatment of ADA deficiency focuses on reducing the frequency and severity of infections. [[Antibiotic]]s are typically prescribed as a [[prophylactic]] measure to make the body more difficult for pathogenic organisms to colonize. Due to the frequency it is encountered and its indifference to most antibiotics, clinicians must be careful to include a medication that can prevent [[Pneumocystis pneumonia|''Pneumocystis'' pneumonia]].<ref name="Grunebaum_2023_2">{{Cite web |date=July 2023 |title=Adenosine deaminase deficiency: Treatment and prognosis |url=https://www.uptodate.com/contents/adenosine-deaminase-deficiency-treatment-and-prognosis |access-date=21 Dec 2023 |website=UpToDate |publisher=Wolters Kluwer |vauthors=Grunebaum E, Kohn DB}}</ref>

In addition to antibiotics, [[Immunoglobulin therapy|intravenous immunoglobulin]] (IVIG) therapy is also provided when available. This treatment provides a layer of [[humoral immunity]] from healthy [[Plasma donation|plasma donors]].<ref name="Grunebaum_2023_2" />

[[Enzyme replacement therapy]] is provided to newborns until a definitive therapy plan can be implemented.<ref name="Grunebaum_2023_2" /> There is some evidence that ERT also prevents tissue damage related to accumulated dATP and other molecules.<ref>{{Cite journal |display-authors=6 |vauthors=Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E |date=March 2019 |title=Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency |journal=The Journal of Allergy and Clinical Immunology |volume=143 |issue=3 |pages=852–863 |doi=10.1016/j.jaci.2018.08.024 |pmc=6688493 |pmid=30194989}}</ref>

=== Stem cell transplantation ===
Long-term definitive treatment of ADA deficiency is typically achieved by [[Hematopoietic stem cell transplantation|transplantation]] of [[hematopoietic stem cell]]s 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]].<ref name="Grunebaum_2023_2" />

=== 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.<ref name="Grunebaum_2023_2" />

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.<ref name="titleMore Than Human - New York Times">{{Cite news |date=2005-07-03 |title='More Than Human' - New York Times |url=https://www.nytimes.com/2005/07/03/books/chapters/0703-1st-naam.html |access-date=2008-02-28 |work=The New York Times |vauthors=Naam R}}</ref>
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.<ref>{{Cite web |date=1 April 2016 |title=European Ad Comm backs Glaxo's stem cell therapy Strimvelis for rare autoimmune disorder |url=http://seekingalpha.com/news/3171007-european-ad-comm-backs-glaxos-stem-cell-therapy-strimvelis-rare-autoimmune-disorder |access-date=13 April 2016 |website=Seeking Alpha |vauthors=House DW}}</ref><ref name="EMA+Strimvelis">{{Cite web |date=1 April 2016 |title=Summary of opinion1 (initial authorisation) Strimvelis |url=http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003854/WC500203918.pdf |access-date=13 April 2016 |website=European Medicines Agency |pages=1–2 |ref=EMA/CHMP/160482/2016 |archive-date=28 January 2018 |archive-url=https://web.archive.org/web/20180128062329/http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003854/WC500203918.pdf |url-status=dead }}</ref>

==History==
ADA deficiency was discovered in 1972 by [[Eloise Giblett]], a professor at the [[University of Washington]].<ref name="Motulsky_2009">{{Cite web |date=2009 |title=Biographical Memoirs: Eloise R. Giblett |url=https://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/giblett-eloise.pdf |website=National Academy of Sciences |vauthors=Motulsky A, Gartler S}}</ref> The ADA gene was used as a marker for [[Hematopoietic stem cell transplantation|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.<ref name="Motulsky_2009" />

== References ==
{{Reflist}}

== Further reading ==
* [https://web.archive.org/web/20081212104607/http://ghr.nlm.nih.gov/condition=adenosinedeaminasedeficiency Adenosine deaminase deficiency - Genetics Home Reference]
== External links ==
{{Medical resources
| DiseasesDB = 260
| ICD10 = {{ICD10|D|81|3|d|80}}
| ICD9 = {{ICD9|279.2}}
| ICDO =
| OMIM = 102700
| MedlinePlus =
| eMedicineSubj =
| eMedicineTopic =
| MeshID =
| GeneReviewsNBK = NBK1483
| GeneReviewsName = Adenosine Deaminase Deficiency
}}
{{Immune disorders}}
{{Purine, pyrimidine, porphyrin, bilirubin metabolic pathology}}

{{DEFAULTSORT:Adenosine Deaminase Deficiency}}
[[Category:Autosomal recessive disorders]]
[[Category:Rare diseases]]
[[Category:Inborn errors of purine-pyrimidine metabolism]]
[[Category:Combined T and B–cell immunodeficiencies]]

Adenosine deaminase deficiency - Revision history

imported>IntentionallyDense: Undid revision 1322872592 by ~2025-34466-55 (talk) undo change that changed meaning. the disease is present from birth since it is genetic but it presents with symptoms at different ages