Adenosine deaminase 2 deficiency: Difference between revisions

Deficiency of Adenosine Deaminase 2
Deficiency of Adenosine Deaminase 2
Other names	DADA2
	Autosomal recessive pattern is the inheritance manner of this condition
Specialty	Medical genetics, Pediatrics, Rheumatology, Neurology, Dermatology, Immunology, Hematology
Usual onset	Variable, but commonly in early childhood
Duration	Lifelong
Causes	Mutations in the ADA2 gene
Diagnostic method	Genetic or Enzymatic Testing

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Revision as of 17:12, 17 October 2021

Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic disease associated with systemic inflammation and vasculopathy that affects a wide variety of organs in different patients. As a result, it is hard to characterize a patient with this disorder. Manifestations of the disease include but are not limited to recurrent fever, livedoid rash (reticularis or racemosa), various cytopenias, stroke, immunodeficiency, and bone marrow failure.^[1]^[2] Symptoms often onset during early childhood, but some cases have been discovered as late as 65 years old.^[3]

DADA2 is caused by mutations in the ADA2 gene, and is inherited in an autosomal recessive manner. The protein product of this gene, adenosine deaminase 2 (ADA2), is an extracellular enzyme that breaks down adenosine and may also serve as a growth factor. Pathogenic mutations decrease this enzymatic activity in patient blood, leading to disease manifestations. However, mutational status and residual enzyme activity levels do not explicitly correlate with the type of disease a patient displays.^[4]^[2]^[1]

The most common treatment for DADA2 is TNF inhibitors. This therapy tends to prevent vasculitis-related manifestations such as rash and stroke,^[5]^[6] but does not perform well in individuals presenting with severe hematologic and immunologic abnormalities such as bone marrow failure or severe recurrent infections.^[7] In these cases, hematopoietic stem cell transplantation has led to major improvements in the vascular, hematologic, and immunologic manifestations of disease.^[8]

Signs and symptoms

The signs and symptoms of disease are wide-ranging in severity, but can be grouped into vascular, immunologic, and hematologic manifestations. Individual patients typically present with disease of only one of these subtypes, but this is not always the case. Symptoms have also been known to abate and recur even without treatment.^[9] Twenty-four percent of patients have disease onset before 1 year of age, and 77% of patients have disease onset before 10 years of age.^[2]

Vasculopathy is the hallmark of DADA2, and was the most prominent feature of the disease upon its initial discovery.^[10]^[11] The vasculitis seen in DADA2 is similar to polyarteritis nodosa (PAN), often leading to misdiagnosis. However, DADA2 patients typically have earlier disease onset, and a greater prevalence of skin and neurologic manifestations.^[12] The systemic inflammation present in DADA2 leads to this vasculopathy, with symptoms involving but not limited to skin, brain, gastrointestinal tract, and kidneys. Livedo racemosa and livedo reticularis are the most common manifestations in skin, although other symptoms such as digital necrosis, subcutaneous nodules, and non-specific rash have been seen. The most common neurological manifestations of DADA2 are secondary to vasculitis. Fifty-one percent of patients present with neurologic disease, typically in the form of lacunar stroke.^[2] In some patients, stroke can be the first indication of disease.^[13]

Approximately 50% of patients have some form of immunologic or hematologic disease.^[2] While patients with vascular-predominant disease typically have only mild deficiencies in these areas,^[4] most DADA2 patients display deficiencies in IgG and IgM antibody production as well as overall poor B cell function.^[14] Bone marrow failure, pure red cell aplasia (PRCA), or immunodeficiency are the most serious manifestations in those who don't display the classic vascular disease. Those with the bone marrow failure phenotype commonly have hepatosplenomegaly, recurrent infection, and various cytopenias. Meanwhile, those with PRCA can display a similar disease to Diamond-Blackfan anemia.^[15] The onset of PRCA caused by DADA2 is commonly before one year of age, while children with bone marrow failure typically onset around two years of age.^[4] In patients with severe immunodeficiencies, upper and lower respiratory infections are most common. However, intestinal and urinary tract infections have been seen alongside various more rare infections such as viral encephalitis.^[14]

There are a variety of rare DADA2 symptoms that have only been reported in a handful of patients. For example, lymphoproliferation and large granular lymphocytic leukemia have been reported.^[16]^[17]^[18] Other symptoms are becoming more known over time – reports of hypertension associated with DADA2 have increased in recent years.^[19]^[20]^[21]

Pathophysiology

The mechanism by which mutations in ADA2 lead to disease manifestations is not fully clear. ADA2 is a primarily extracellular protein highly expressed by myeloid immune cells such as monocytes, macrophages, and dendritic cells.^[22]^[23] ADA2 has been hypothesized to have multiple functions, including as an enzyme, a growth factor, and an intracellular DNA sensor.^[24]^[2] Deficiencies in each of these functions could lead to the chronic inflammatory phenotype associated with DADA2. Less is known about the role of ADA2 dysfunction in the immunologic and hematologic aspects of the disease.^{[citation needed]}

ADA2 catalyzes the reaction of adenosine to inosine and 2’deoxyadenosine in the blood. All DADA2 patients display less than 5% of the normal activity of ADA2 in blood samples, implicating the potential importance of this enzymatic role.^[4] Adenosine levels are higher in patients than healthy individuals.^[25] Adenosine binds to cell surface receptors on neutrophils, causing the formation of neutrophil extracellular traps (NETs). NETs have been identified at increased levels in both affected tissue and in circulation of DADA2 patients.^[25] NETs go on to cause inflammatory responses from macrophages, including excess release the pro-inflammatory cytokine TNFa. TNFa likely plays a major role in the vasculitic phenotype of DADA2 due the efficacy of TNFa targeting drugs in treating symptoms. However, the enzymatic activity of ADA2 is 100 fold lesser than that of the intracellular adenosine deaminase ADA1, and at physiological concentrations of adenosine the enzymatic activity of ADA2 is near zero.^[2] This indicates that loss of ADA2 may cause disease by other mechanisms.^{[citation needed]}

Endothelial cell activation and damage is a further source of inflammation and vascular symptoms caused by DADA2. Endothelial cells from patients are extensively damaged and secrete pro-inflammatory cytokines. However, endothelial cells themselves don't express the ADA2 protein, so this phenotype is likely mediated by the effects of mutant ADA2 on other cell types feeding back onto endothelial cells. For example, ADA2 mutant monocytes display abnormal differentiation into macrophages, and endothelial cells grown in the presence of ADA2 deficient monocytes are similarly extensively damaged.^[11]

The molecular underpinnings of the immunologic disease are unclear, but the upregulation of type I interferon-stimulated genes, poor B cell differentiation, reduced antibody production, and lymphoproliferation have been noted.^[2] The cause of severe hematologic manifestations such as pure red cell aplasia and bone marrow failure are also unknown.^[2] However, the ADA2 protein is similar in structure to the adenosine deaminase growth factors found in other species. Deficiencies of these proteins in frogs and fruit flies have been shown to cause developmental abnormalities, such as small size and early death respectively.^[26]^[27]^[28] In humans, extracellular ADA2 interacts with many immune cell types, including neutrophils, monocytes, NK cells, and specific B and T cell subtypes.^[29] This interaction can lead to functional changes, as ADA2 has been shown to bind to monocytes and CD4+ T cells to increase monocyte differentiation and T cell proliferation when present together.^[22] Thus, DADA2 might lead to poor immune cell development directly or through the generally high inflammation.^{[citation needed]}

Genetics

DADA2 is caused by mutations in DNA encoding the gene ADA2, formerly known as CECR1. The ADA2 gene is located on chromosome 22q11.1.^[30] Many different kinds of mutations have been reported, including missense, nonsense, splice-site, frameshift, deletions, and duplications. As of 2021, there are 117 known mutations, although classification into disease-causing and benign is ongoing.^[31] This disease is inherited in an autosomal recessive fashion meaning that both versions of this gene, one inherited from each parent, must be defective in a patient. While those with only one known mutant allele have been found to have disease manifestations, it is thought that those individuals have a mutation not found upon initial genomic sequencing.^{[citation needed]}

While there is some relationship between the genetic mutations a patient displays and their experience with the disease, the relationship is not one to one. Patients with DADA2 that share the same mutation are more likely to experience similar disease, but even family members with the same mutations have had entirely different disease courses.^[4]^[32]^[33] While the reasons for this difference are not well defined in DADA2 this is common in other so-called monogenic diseases, where environment and modifier genetics have been shown to play a role.^[34]^[35]^[36]^[37] However, multiple groups have found some correlation between mutation and phenotype. There is some indication that mutations present in the dimerization domain of ADA2 predispose towards vasculitis-associated disease, whereas mutations in the catalytic domain lead to the Diamond Blackfan anemia-like phenotype.^[38] In another study, specific mutations segregated perfectly into groups based on the type of the disease the patient displayed. In this analysis, the common G47R mutation always found in individuals with vasculitic disease, and the G358R mutation always seen in those with severe hematologic disease. However, some mutations did not separate as well. For example, the R169Q mutation was found in both vasculitic- and hematologic-forward disease subtypes.^[4] An analysis of the enzymatic activity of mutated ADA2 enzyme in vitro found that mutations yielding greater enzyme activity favored vasculitis, whereas mutations with less residual activity favored hematologic manifestations.^[4]

Epidemiology

As of 2020, over 260 cases of DADA2 have been identified since the disease's discovery in 2014.^[39] Since this disease is inherited in an autosomal recessive manner, men and women are equally likely to be diagnosed with DADA2. Based on computational analyses, the prevalence of DADA2 could be as high as 4 in 100,000.^[40] Generally, populations with high degrees of consanguinity or with founder variants have a higher prevalence of DADA2. For example, the Georgian-Jewish and Turkish populations are estimated to have a 1:10 and 1:500 likelihood of carrying the G47R mutation respectively. The R169Q variant is also more common in northern Europe, with a carrier frequency of 1:500.^[40]

Diagnosis

Currently, screening for DADA2 is initiated upon a physician's judgement. Criteria to trigger screening have been proposed however, including at least one sign of inflammation and vasculitis.^[41] The specific diagnosis of DADA2 requires either confirmation of known pathogenic mutations in ADA2 or low ADA2 enzymatic activity in patient blood.^[39] Genetic testing for DADA2 has been performed as either a single-gene test through Sanger sequencing, or a multi-gene test through panel testing, whole exome sequencing, or whole genome sequencing.^[39] These techniques vary in cost, intensity, and detection, and mutations have been missed due to the technique initially used.^[42]^[43] As such, more extensive analysis is sometimes necessary if suspicion of DADA2 remains. Enzymatic activity analysis can confirm whether or not the ADA2 gene should be investigated further in these situations, and has been recommended by some as the premier diagnostic technique.^[44]

Management

The most common management of DADA2 after diagnosis is TNFa inhibition (TNFi). This treatment serves those with vasculitic forms of the disease best, improving most symptoms and significantly preventing strokes.^[5]^[6] TNFi is ineffective in those with severe bone marrow dysfunction or immunodeficiency.^[45] In these patients, hematopoietic stem cell transplant is considered and upon successful completion can be curative.^[45]^[8] However, the risks associated with this procedure preclude its use in most patients. ^{[citation needed]}

Ongoing pre-clinical studies are researching gene therapy.^[46]^[47] Both gene therapy and enzyme replacement therapy have been successful in the adenosine deaminase deficiency,^[48]^[49] indicating their potential future success in DADA2.

History

DADA2 was discovered in 2014 by two independent groups at the NIH and in Jerusalem, each reporting systemic inflammation and vasculitis syndromes caused by mutations in ADA2.^[10]^[11] The DADA2 Foundation was formed in 2016 to serve patients with DADA2 by providing information and spurring research progress. The Foundation has organized an international DADA2 Conference held every 2 years since 2016, being held in 2016, 2018, and 2020.^[50]

References

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^ Bourgeois G, Richard M, Danset M, Pérard L, Breton AL, Berthoux E (March 2021). "Deficiency of adenosine deaminase 2 diagnosed at 65 years of age". Lancet. 397 (10277): 913. doi:10.1016/S0140-6736(20)32660-X. PMID 33676630. S2CID 232116912.
^ ^a ^b ^c ^d ^e ^f ^g Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, et al. (June 2020). "Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)". The Journal of Allergy and Clinical Immunology. 145 (6): 1664–1672.e10. doi:10.1016/j.jaci.2019.12.908. PMC 7282972. PMID 31945408.
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[:0-1] Lee PY (2018). "Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2". Frontiers in Pediatrics. 6: 282. doi:10.3389/fped.2018.00282. PMC 6200955. PMID 30406060.

[:1-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Meyts I, Aksentijevich I (July 2018). "Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment". Journal of Clinical Immunology. 38 (5): 569–578. doi:10.1007/s10875-018-0525-8. PMC 6061100. PMID 29951947.

[3] Bourgeois G, Richard M, Danset M, Pérard L, Breton AL, Berthoux E (March 2021). "Deficiency of adenosine deaminase 2 diagnosed at 65 years of age". Lancet. 397 (10277): 913. doi:10.1016/S0140-6736(20)32660-X. PMID 33676630. S2CID 232116912.

[:2-4] ^ ^a ^b ^c ^d ^e ^f ^g Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, et al. (June 2020). "Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)". The Journal of Allergy and Clinical Immunology. 145 (6): 1664–1672.e10. doi:10.1016/j.jaci.2019.12.908. PMC 7282972. PMID 31945408.

[:3-5] Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, et al. (April 2019). "Treatment Strategies for Deficiency of Adenosine Deaminase 2". The New England Journal of Medicine. 380 (16): 1582–1584. doi:10.1056/NEJMc1801927. PMC 7372950. PMID 30995379.

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 }}
-'''Deficiency of Adenosine deaminase 2''' ('''DADA2''') is a [[Genetic disease|monogenic disease]] associated with [[systemic inflammation]] and [[vasculopathy]] that affects a wide variety of organs in different patients.  As a result, it is hard to characterize a patient with this disorder. Manifestations of the disease  include but are not limited to recurrent fever, livedoid rash ([[Livedo reticularis|reticularis]] or [[Livedo racemosa|racemosa]]), various [[cytopenia]]s, [[stroke]], [[immunodeficiency]], and [[bone marrow failure]].<ref name=":0">{{cite journal | vauthors = Lee PY | title = Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2 | journal = Frontiers in Pediatrics | volume = 6 | pages = 282 | date = 2018 | pmid = 30406060 | pmc = 6200955 | doi = 10.3389/fped.2018.00282 }}</ref><ref name=":1">{{cite journal | vauthors = Meyts I, Aksentijevich I | title = Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment | journal = Journal of Clinical Immunology | volume = 38 | issue = 5 | pages = 569–578 | date = July 2018 | pmid = 29951947 | pmc = 6061100 | doi = 10.1007/s10875-018-0525-8 }}</ref> Symptoms often onset during early childhood, but some cases have been discovered as late as 65 years old.<ref>{{cite journal | vauthors = Bourgeois G, Richard M, Danset M, Pérard L, Breton AL, Berthoux E | title = Deficiency of adenosine deaminase 2 diagnosed at 65 years of age | journal = Lancet | volume = 397 | issue = 10277 | pages = 913 | date = March 2021 | pmid = 33676630 | doi = 10.1016/S0140-6736(20)32660-X }}</ref>
+'''Deficiency of Adenosine deaminase 2''' ('''DADA2''') is a [[Genetic disease|monogenic disease]] associated with [[systemic inflammation]] and [[vasculopathy]] that affects a wide variety of organs in different patients.  As a result, it is hard to characterize a patient with this disorder. Manifestations of the disease  include but are not limited to recurrent fever, livedoid rash ([[Livedo reticularis|reticularis]] or [[Livedo racemosa|racemosa]]), various [[cytopenia]]s, [[stroke]], [[immunodeficiency]], and [[bone marrow failure]].<ref name=":0">{{cite journal | vauthors = Lee PY | title = Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2 | journal = Frontiers in Pediatrics | volume = 6 | pages = 282 | date = 2018 | pmid = 30406060 | pmc = 6200955 | doi = 10.3389/fped.2018.00282 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Meyts I, Aksentijevich I | title = Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment | journal = Journal of Clinical Immunology | volume = 38 | issue = 5 | pages = 569–578 | date = July 2018 | pmid = 29951947 | pmc = 6061100 | doi = 10.1007/s10875-018-0525-8 }}</ref> Symptoms often onset during early childhood, but some cases have been discovered as late as 65 years old.<ref>{{cite journal | vauthors = Bourgeois G, Richard M, Danset M, Pérard L, Breton AL, Berthoux E | title = Deficiency of adenosine deaminase 2 diagnosed at 65 years of age | journal = Lancet | volume = 397 | issue = 10277 | pages = 913 | date = March 2021 | pmid = 33676630 | doi = 10.1016/S0140-6736(20)32660-X | s2cid = 232116912 }}</ref>
 DADA2 is caused by [[mutation]]s in the [https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADA2 ''ADA2'' gene], and is inherited in an [[Autosomal Recessive|autosomal recessive]] manner.  The protein product of this [[gene]], [https://www.uniprot.org/uniprot/Q9NZK5 adenosine deaminase 2] (ADA2), is an extracellular [[enzyme]] that breaks down [[adenosine]] and may also serve as a [[growth factor]].  Pathogenic mutations decrease this [[enzymatic activity]] in patient blood, leading to disease manifestations. However, mutational status and residual enzyme activity levels do not explicitly correlate with the type of disease a patient displays.<ref name=":2">{{cite journal | vauthors = Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, Alosaimi MF, Stafstrom K, Platt CD, Stauber T, Raz S, Tirosh I, Weiss A, Jordan MB, Krupski C, Eleftheriou D, Brogan P, Sobh A, Baz Z, Lefranc G, Irani C, Kilic SS, El-Owaidy R, Lokeshwar MR, Pimpale P, Khubchandani R, Chambers EP, Chou J, Geha RS, Nigrovic PA, Zhou Q | display-authors = 6 | title = Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2) | language = English | journal = The Journal of Allergy and Clinical Immunology | volume = 145 | issue = 6 | pages = 1664–1672.e10 | date = June 2020 | pmid = 31945408 | pmc = 7282972 | doi = 10.1016/j.jaci.2019.12.908 }}</ref><ref name=":1" /><ref name=":0" />
-The most common treatment for DADA2 is [[TNF inhibitor]]s.  This therapy tends to prevent [[vasculitis]]-related manifestations such as rash and stroke,<ref name=":3">{{cite journal | vauthors = Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, Romeo T, Barham B, Pinto-Patarroyo G, Toro C, Soldatos A, Zhou Q, Deuitch N, Aksentijevich I, Sheldon SL, Kelly S, Man A, Barron K, Hershfield M, Flegel WA, Kastner DL | display-authors = 6 | title = Treatment Strategies for Deficiency of Adenosine Deaminase 2 | journal = The New England Journal of Medicine | volume = 380 | issue = 16 | pages = 1582–1584 | date = April 2019 | pmid = 30995379 | pmc = 7372950 | doi = 10.1056/NEJMc1801927 }}</ref><ref name=":4">{{cite journal | vauthors = Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, Bhatia P, Sharma V, Bhattad S, Chengappa KG, Gupta V, Misra DP, Chavan PP, Malaviya S, Dudam R, Sharma B, Kumar S, Bhojwani R, Gupta P, Agarwal V, Sharma K, Singhal M, Rathi M, Nada R, Minz RW, Chaturvedi V, Aggarwal A, Handa R, Grossi A, Gattorno M, Huang Z, Wang J, Jois R, Negi VS, Khubchandani R, Jain S, Arostegui JI, Chambers EP, Hershfield MS, Aksentijevich I, Zhou Q, Lee PY | display-authors = 6 | title = Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India | journal = Arthritis & Rheumatology | volume = 73 | issue = 2 | pages = 276–285 | date = February 2021 | pmid = 32892503 | pmc = 7902299 | doi = 10.1002/art.41500 }}</ref> but does not perform well in individuals presenting with severe [[Hematology|hematologic]] and [[Immunology|immunologic]] abnormalities such as bone marrow failure or severe recurrent infections.<ref>{{cite journal | vauthors = Conticini E, Sota J, Falsetti P, Lamberti A, Miracco C, Guarnieri A, Frediani B, Cantarini L | display-authors = 6 | title = Biologic drugs in the treatment of polyarteritis nodosa and deficit of adenosine deaminase 2: A narrative review | journal = Autoimmunity Reviews | volume = 20 | issue = 4 | pages = 102784 | date = April 2021 | pmid = 33609794 | doi = 10.1016/j.autrev.2021.102784 }}</ref> In these cases, [[hematopoietic stem cell transplantation]] has led to major improvements in the vascular, hematologic, and immunologic manifestations of disease.<ref name=":5">{{cite journal | vauthors = Hashem H, Kumar AR, Müller I, Babor F, Bredius R, Dalal J, Hsu AP, Holland SM, Hickstein DD, Jolles S, Krance R, Sasa G, Taskinen M, Koskenvuo M, Saarela J, van Montfrans J, Wilson K, Bosch B, Moens L, Hershfield M, Meyts I | display-authors = 6 | title = Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2 | journal = Blood | volume = 130 | issue = 24 | pages = 2682–2688 | date = December 2017 | pmid = 28974505 | pmc = 5731089 | doi = 10.1182/blood-2017-07-798660 }}</ref>
+The most common treatment for DADA2 is [[TNF inhibitor]]s.  This therapy tends to prevent [[vasculitis]]-related manifestations such as rash and stroke,<ref name=":3">{{cite journal | vauthors = Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, Romeo T, Barham B, Pinto-Patarroyo G, Toro C, Soldatos A, Zhou Q, Deuitch N, Aksentijevich I, Sheldon SL, Kelly S, Man A, Barron K, Hershfield M, Flegel WA, Kastner DL | display-authors = 6 | title = Treatment Strategies for Deficiency of Adenosine Deaminase 2 | journal = The New England Journal of Medicine | volume = 380 | issue = 16 | pages = 1582–1584 | date = April 2019 | pmid = 30995379 | pmc = 7372950 | doi = 10.1056/NEJMc1801927 }}</ref><ref name=":4">{{cite journal | vauthors = Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, Bhatia P, Sharma V, Bhattad S, Chengappa KG, Gupta V, Misra DP, Chavan PP, Malaviya S, Dudam R, Sharma B, Kumar S, Bhojwani R, Gupta P, Agarwal V, Sharma K, Singhal M, Rathi M, Nada R, Minz RW, Chaturvedi V, Aggarwal A, Handa R, Grossi A, Gattorno M, Huang Z, Wang J, Jois R, Negi VS, Khubchandani R, Jain S, Arostegui JI, Chambers EP, Hershfield MS, Aksentijevich I, Zhou Q, Lee PY | display-authors = 6 | title = Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India | journal = Arthritis & Rheumatology | volume = 73 | issue = 2 | pages = 276–285 | date = February 2021 | pmid = 32892503 | pmc = 7902299 | doi = 10.1002/art.41500 | pmc-embargo-date = February 1, 2022 }}</ref> but does not perform well in individuals presenting with severe [[Hematology|hematologic]] and [[Immunology|immunologic]] abnormalities such as bone marrow failure or severe recurrent infections.<ref>{{cite journal | vauthors = Conticini E, Sota J, Falsetti P, Lamberti A, Miracco C, Guarnieri A, Frediani B, Cantarini L | display-authors = 6 | title = Biologic drugs in the treatment of polyarteritis nodosa and deficit of adenosine deaminase 2: A narrative review | journal = Autoimmunity Reviews | volume = 20 | issue = 4 | pages = 102784 | date = April 2021 | pmid = 33609794 | doi = 10.1016/j.autrev.2021.102784 | s2cid = 231979636 }}</ref> In these cases, [[hematopoietic stem cell transplantation]] has led to major improvements in the vascular, hematologic, and immunologic manifestations of disease.<ref name=":5">{{cite journal | vauthors = Hashem H, Kumar AR, Müller I, Babor F, Bredius R, Dalal J, Hsu AP, Holland SM, Hickstein DD, Jolles S, Krance R, Sasa G, Taskinen M, Koskenvuo M, Saarela J, van Montfrans J, Wilson K, Bosch B, Moens L, Hershfield M, Meyts I | display-authors = 6 | title = Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2 | journal = Blood | volume = 130 | issue = 24 | pages = 2682–2688 | date = December 2017 | pmid = 28974505 | pmc = 5731089 | doi = 10.1182/blood-2017-07-798660 }}</ref>
 ==Signs and symptoms==
-The signs and symptoms of disease are wide-ranging in severity, but can be grouped into vascular, immunologic, and hematologic manifestations. Individual patients typically present with disease of only one of these subtypes, but this is not always the case.  Symptoms have also been known to abate and recur even without treatment.<ref>{{cite journal | vauthors = Betrains A, Staels F, Moens L, Delafontaine S, Hershfield MS, Blockmans D, Liston A, Humblet-Baron S, Meyts I, Schrijvers R, Vanderschueren S | display-authors = 6 | title = Diagnosis of deficiency of adenosine deaminase type 2 in adulthood | journal = Scandinavian Journal of Rheumatology | volume = 0 | issue = 0 | pages = 1–4 | date = February 2021 | pmid = 33627040 | doi = 10.1080/03009742.2021.1881156 | url = https://lirias.kuleuven.be/bitstream/123456789/671373/3/DADA2_060121.pdf }}</ref> Twenty-four percent of patients have disease onset before 1 year of age, and 77% of patients have disease onset before 10 years of age.<ref name=":1" />
+The signs and symptoms of disease are wide-ranging in severity, but can be grouped into vascular, immunologic, and hematologic manifestations. Individual patients typically present with disease of only one of these subtypes, but this is not always the case.  Symptoms have also been known to abate and recur even without treatment.<ref>{{cite journal | vauthors = Betrains A, Staels F, Moens L, Delafontaine S, Hershfield MS, Blockmans D, Liston A, Humblet-Baron S, Meyts I, Schrijvers R, Vanderschueren S | display-authors = 6 | title = Diagnosis of deficiency of adenosine deaminase type 2 in adulthood | journal = Scandinavian Journal of Rheumatology | volume = 0 | pages = 1–4 | date = February 2021 | pmid = 33627040 | doi = 10.1080/03009742.2021.1881156 | s2cid = 232048348 | url = https://lirias.kuleuven.be/bitstream/123456789/671373/3/DADA2_060121.pdf }}</ref> Twenty-four percent of patients have disease onset before 1 year of age, and 77% of patients have disease onset before 10 years of age.<ref name=":1" />
-Vasculopathy is the hallmark of DADA2, and was the most prominent feature of the disease upon its initial discovery.<ref name=":6">{{cite journal | vauthors = Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, Zlotogorski A, Berkun Y, Press JJ, Mukamel M, Voth I, Hashkes PJ, Harel L, Hoffer V, Ling E, Yalcinkaya F, Kasapcopur O, Lee MK, Klevit RE, Renbaum P, Weinberg-Shukron A, Sener EF, Schormair B, Zeligson S, Marek-Yagel D, Strom TM, Shohat M, Singer A, Rubinow A, Pras E, Winkelmann J, Tekin M, Anikster Y, King MC, Levy-Lahad E | display-authors = 6 | title = Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 921–31 | date = March 2014 | pmid = 24552285 | doi = 10.1056/NEJMoa1307362 }}</ref><ref name=":7">{{cite journal | vauthors = Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CC, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I | display-authors = 6 | title = Early-onset stroke and vasculopathy associated with mutations in ADA2 | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 911–20 | date = March 2014 | pmid = 24552284 | pmc = 4193683 | doi = 10.1056/NEJMoa1307361 }}</ref> The vasculitis seen in DADA2 is similar to [[polyarteritis nodosa]] (PAN), often leading to misdiagnosis. However, DADA2 patients typically have earlier disease onset, and a greater prevalence of skin and [[Neurology|neurologic]] manifestations.<ref>{{cite journal | vauthors = Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, Conti G, Marchetti F, Picco P, Tommasini A, Martino S, Malattia C, Gallizzi R, Podda RA, Salis A, Falcini F, Schena F, Garbarino F, Morreale A, Pardeo M, Ventrici C, Passarelli C, Zhou Q, Severino M, Gandolfo C, Damonte G, Martini A, Ravelli A, Aksentijevich I, Ceccherini I, Gattorno M | display-authors = 6 | title = ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study | journal = Annals of the Rheumatic Diseases | volume = 76 | issue = 10 | pages = 1648–1656 | date = October 2017 | pmid = 28522451 | doi = 10.1136/annrheumdis-2016-210802 }}</ref> The systemic inflammation present in DADA2 leads to this vasculopathy, with symptoms involving but not limited to skin, brain, gastrointestinal tract, and kidneys. Livedo racemosa and livedo reticularis are the most common manifestations in skin, although other symptoms such as [[digital necrosis]], [[subcutaneous nodules]], and non-specific rash have been seen.  The most common neurological manifestations of DADA2 are secondary to vasculitis.  Fifty-one percent of patients present with neurologic disease, typically in the form of [[lacunar stroke]].<ref name=":1" /> In some patients, stroke can be the first indication of disease.<ref>{{cite journal | vauthors = Elbracht M, Mull M, Wagner N, Kuhl C, Abicht A, Kurth I, Tenbrock K, Häusler M | display-authors = 6 | title = Stroke as Initial Manifestation of Adenosine Deaminase 2 Deficiency | journal = Neuropediatrics | volume = 48 | issue = 2 | pages = 111–114 | date = April 2017 | pmid = 28024309 | doi = 10.1055/s-0036-1597611 }}</ref>
+Vasculopathy is the hallmark of DADA2, and was the most prominent feature of the disease upon its initial discovery.<ref name=":6">{{cite journal | vauthors = Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, Zlotogorski A, Berkun Y, Press JJ, Mukamel M, Voth I, Hashkes PJ, Harel L, Hoffer V, Ling E, Yalcinkaya F, Kasapcopur O, Lee MK, Klevit RE, Renbaum P, Weinberg-Shukron A, Sener EF, Schormair B, Zeligson S, Marek-Yagel D, Strom TM, Shohat M, Singer A, Rubinow A, Pras E, Winkelmann J, Tekin M, Anikster Y, King MC, Levy-Lahad E | display-authors = 6 | title = Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 921–31 | date = March 2014 | pmid = 24552285 | doi = 10.1056/NEJMoa1307362 }}</ref><ref name=":7">{{cite journal | vauthors = Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CC, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I | display-authors = 6 | title = Early-onset stroke and vasculopathy associated with mutations in ADA2 | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 911–20 | date = March 2014 | pmid = 24552284 | pmc = 4193683 | doi = 10.1056/NEJMoa1307361 }}</ref> The vasculitis seen in DADA2 is similar to [[polyarteritis nodosa]] (PAN), often leading to misdiagnosis. However, DADA2 patients typically have earlier disease onset, and a greater prevalence of skin and [[Neurology|neurologic]] manifestations.<ref>{{cite journal | vauthors = Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, Conti G, Marchetti F, Picco P, Tommasini A, Martino S, Malattia C, Gallizzi R, Podda RA, Salis A, Falcini F, Schena F, Garbarino F, Morreale A, Pardeo M, Ventrici C, Passarelli C, Zhou Q, Severino M, Gandolfo C, Damonte G, Martini A, Ravelli A, Aksentijevich I, Ceccherini I, Gattorno M | display-authors = 6 | title = ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study | journal = Annals of the Rheumatic Diseases | volume = 76 | issue = 10 | pages = 1648–1656 | date = October 2017 | pmid = 28522451 | doi = 10.1136/annrheumdis-2016-210802 | s2cid = 39815969 }}</ref> The systemic inflammation present in DADA2 leads to this vasculopathy, with symptoms involving but not limited to skin, brain, gastrointestinal tract, and kidneys. Livedo racemosa and livedo reticularis are the most common manifestations in skin, although other symptoms such as [[digital necrosis]], [[subcutaneous nodules]], and non-specific rash have been seen.  The most common neurological manifestations of DADA2 are secondary to vasculitis.  Fifty-one percent of patients present with neurologic disease, typically in the form of [[lacunar stroke]].<ref name=":1" /> In some patients, stroke can be the first indication of disease.<ref>{{cite journal | vauthors = Elbracht M, Mull M, Wagner N, Kuhl C, Abicht A, Kurth I, Tenbrock K, Häusler M | display-authors = 6 | title = Stroke as Initial Manifestation of Adenosine Deaminase 2 Deficiency | journal = Neuropediatrics | volume = 48 | issue = 2 | pages = 111–114 | date = April 2017 | pmid = 28024309 | doi = 10.1055/s-0036-1597611 }}</ref>
-Approximately 50% of patients have some form of immunologic or hematologic disease.<ref name=":1" />  While patients with vascular-predominant disease typically have only mild deficiencies in these areas,<ref name=":2" /> most DADA2 patients display deficiencies in [[IgG]] and [[IgM]] antibody production as well as overall poor [[B cell]] function.<ref name=":8">{{cite journal | vauthors = Schepp J, Proietti M, Frede N, Buchta M, Hübscher K, Rojas Restrepo J, Goldacker S, Warnatz K, Pachlopnik Schmid J, Duppenthaler A, Lougaris V, Uriarte I, Kelly S, Hershfield M, Grimbacher B | display-authors = 6 | title = Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood | journal = Arthritis & Rheumatology | volume = 69 | issue = 8 | pages = 1689–1700 | date = August 2017 | pmid = 28493328 | doi = 10.1002/art.40147 }}</ref>  Bone marrow failure, [[pure red cell aplasia]] (PRCA), or immunodeficiency are the most serious manifestations in those who don't display the classic vascular disease.  Those with the bone marrow failure phenotype commonly have [[hepatosplenomegaly]], recurrent infection, and various cytopenias.  Meanwhile, those with PRCA can display a similar disease to [[Diamond-Blackfan anemia]].<ref>{{cite journal| vauthors = Sasa G |date=2015|title=Adenosine Deaminase 2 Deficiency As a Cause of Pure Red Cell Aplasia Mimicking Diamond Blackfan Anemia|url=https://ashpublications.org/blood/article/126/23/3615/92721/Adenosine-Deaminase-2-Deficiency-As-a-Cause-of?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Blood_TrendMD_0|journal=Blood|volume=126|pages=3615|via=ASH Publications}}</ref> The onset of PRCA caused by DADA2 is commonly before one year of age, while children with bone marrow failure typically onset around two years of age.<ref name=":2" />  In patients with severe immunodeficiencies, upper and lower [[Respiratory tract infection|respiratory infections]] are most common. However, [[Intestinal infection|intestinal]] and [[Urinary tract infection|urinary tract]] infections have been seen alongside various more rare infections such as [[viral encephalitis]].<ref name=":8" />
+Approximately 50% of patients have some form of immunologic or hematologic disease.<ref name=":1" />  While patients with vascular-predominant disease typically have only mild deficiencies in these areas,<ref name=":2" /> most DADA2 patients display deficiencies in [[IgG]] and [[IgM]] antibody production as well as overall poor [[B cell]] function.<ref name=":8">{{cite journal | vauthors = Schepp J, Proietti M, Frede N, Buchta M, Hübscher K, Rojas Restrepo J, Goldacker S, Warnatz K, Pachlopnik Schmid J, Duppenthaler A, Lougaris V, Uriarte I, Kelly S, Hershfield M, Grimbacher B | display-authors = 6 | title = Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood | journal = Arthritis & Rheumatology | volume = 69 | issue = 8 | pages = 1689–1700 | date = August 2017 | pmid = 28493328 | doi = 10.1002/art.40147 | s2cid = 205433642 }}</ref>  Bone marrow failure, [[pure red cell aplasia]] (PRCA), or immunodeficiency are the most serious manifestations in those who don't display the classic vascular disease.  Those with the bone marrow failure phenotype commonly have [[hepatosplenomegaly]], recurrent infection, and various cytopenias.  Meanwhile, those with PRCA can display a similar disease to [[Diamond-Blackfan anemia]].<ref>{{cite journal| vauthors = Sasa G |date=2015|title=Adenosine Deaminase 2 Deficiency As a Cause of Pure Red Cell Aplasia Mimicking Diamond Blackfan Anemia|url=https://ashpublications.org/blood/article/126/23/3615/92721/Adenosine-Deaminase-2-Deficiency-As-a-Cause-of?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Blood_TrendMD_0|journal=Blood|volume=126|issue=23|pages=3615|doi=10.1182/blood.V126.23.3615.3615|via=ASH Publications}}</ref> The onset of PRCA caused by DADA2 is commonly before one year of age, while children with bone marrow failure typically onset around two years of age.<ref name=":2" />  In patients with severe immunodeficiencies, upper and lower [[Respiratory tract infection|respiratory infections]] are most common. However, [[Intestinal infection|intestinal]] and [[Urinary tract infection|urinary tract]] infections have been seen alongside various more rare infections such as [[viral encephalitis]].<ref name=":8" />
-There are a variety of rare DADA2 symptoms that have only been reported in a handful of patients.  For example, [[Lymphoproliferative disorders|lymphoproliferation]] and [[large granular lymphocytic leukemia]] have been reported.<ref>{{cite journal | vauthors = Trotta L, Martelius T, Siitonen T, Hautala T, Hämäläinen S, Juntti H, Taskinen M, Ilander M, Andersson EI, Zavialov A, Kaustio M, Keski-Filppula R, Hershfield M, Mustjoki S, Tapiainen T, Seppänen M, Saarela J | display-authors = 6 | title = ADA2 deficiency: Clonal lymphoproliferation in a subset of patients | language = English | journal = The Journal of Allergy and Clinical Immunology | volume = 141 | issue = 4 | pages = 1534–1537.e8 | date = April 2018 | pmid = 29391253 | doi = 10.1016/j.jaci.2018.01.012 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M | title = Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis | journal = Pediatric Blood & Cancer | volume = 65 | issue = 4 | pages = e26912 | date = April 2018 | pmid = 29271561 | doi = 10.1002/pbc.26912 }}</ref><ref>{{cite journal | vauthors = Saettini F, Fazio G, Corti P, Quadri M, Bugarin C, Gaipa G, Penco F, Moratto D, Chiarini M, Baronio M, Gazzurelli L, Imberti L, Paghera S, Giliani S, Cazzaniga G, Plebani A, Badolato R, Lougaris V, Gattorno M, Biondi A | display-authors = 6 | title = Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations | journal = Clinical Immunology | volume = 218 | pages = 108525 | date = September 2020 | pmid = 32659374 | doi = 10.1016/j.clim.2020.108525 }}</ref> Other symptoms are becoming more known over time – reports of [[hypertension]] associated with DADA2 have increased in recent years.<ref>{{cite journal | vauthors = Springer JM, Gierer SA, Jiang H, Kleiner D, Deuitch N, Ombrello AK, Grayson PC, Aksentijevich I | display-authors = 6 | title = Deficiency of Adenosine Deaminase 2 in Adult Siblings: Many Years of a Misdiagnosed Disease With Severe Consequences | journal = Frontiers in Immunology | volume = 9 | pages = 1361 | date = 2018-06-14 | pmid = 29963054 | pmc = 6010516 | doi = 10.3389/fimmu.2018.01361 }}</ref><ref>{{cite journal| vauthors = Ouail DE, Tebbani M, Ahmed DS, Bouali F |date=July 2019|title=Youth Hypertension Associated With ada2 Deficiency. About Three Cases |journal=Journal of Hypertension | volume=37 |pages=e215 |doi=10.1097/01.hjh.0000572764.95461.72 |doi-access=free }}</ref><ref>{{cite journal | vauthors = Sahin S, Adrovic A, Barut K, Baran S, Tahir Turanli E, Canpolat N, Kizilkilic O, Ozkaya O, Kasapcopur O | display-authors = 6 | title = A 9.5-year-old boy with recurrent neurological manifestations and severe hypertension, treated initially for polyarteritis nodosa, was subsequently diagnosed with adenosine deaminase type 2 deficiency (DADA2) which responded to anti-TNF-α | journal = Paediatrics and International Child Health | volume = 40 | issue = 1 | pages = 65–68 | date = February 2020 | pmid = 30642227 | doi = 10.1080/20469047.2018.1559495 }}</ref>
+There are a variety of rare DADA2 symptoms that have only been reported in a handful of patients.  For example, [[Lymphoproliferative disorders|lymphoproliferation]] and [[large granular lymphocytic leukemia]] have been reported.<ref>{{cite journal | vauthors = Trotta L, Martelius T, Siitonen T, Hautala T, Hämäläinen S, Juntti H, Taskinen M, Ilander M, Andersson EI, Zavialov A, Kaustio M, Keski-Filppula R, Hershfield M, Mustjoki S, Tapiainen T, Seppänen M, Saarela J | display-authors = 6 | title = ADA2 deficiency: Clonal lymphoproliferation in a subset of patients | language = English | journal = The Journal of Allergy and Clinical Immunology | volume = 141 | issue = 4 | pages = 1534–1537.e8 | date = April 2018 | pmid = 29391253 | doi = 10.1016/j.jaci.2018.01.012 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M | title = Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis | journal = Pediatric Blood & Cancer | volume = 65 | issue = 4 | pages = e26912 | date = April 2018 | pmid = 29271561 | doi = 10.1002/pbc.26912 | s2cid = 3441818 }}</ref><ref>{{cite journal | vauthors = Saettini F, Fazio G, Corti P, Quadri M, Bugarin C, Gaipa G, Penco F, Moratto D, Chiarini M, Baronio M, Gazzurelli L, Imberti L, Paghera S, Giliani S, Cazzaniga G, Plebani A, Badolato R, Lougaris V, Gattorno M, Biondi A | display-authors = 6 | title = Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations | journal = Clinical Immunology | volume = 218 | pages = 108525 | date = September 2020 | pmid = 32659374 | doi = 10.1016/j.clim.2020.108525 | s2cid = 220521603 }}</ref> Other symptoms are becoming more known over time – reports of [[hypertension]] associated with DADA2 have increased in recent years.<ref>{{cite journal | vauthors = Springer JM, Gierer SA, Jiang H, Kleiner D, Deuitch N, Ombrello AK, Grayson PC, Aksentijevich I | display-authors = 6 | title = Deficiency of Adenosine Deaminase 2 in Adult Siblings: Many Years of a Misdiagnosed Disease With Severe Consequences | journal = Frontiers in Immunology | volume = 9 | pages = 1361 | date = 2018-06-14 | pmid = 29963054 | pmc = 6010516 | doi = 10.3389/fimmu.2018.01361 | doi-access = free }}</ref><ref>{{cite journal| vauthors = Ouail DE, Tebbani M, Ahmed DS, Bouali F |date=July 2019|title=Youth Hypertension Associated With ada2 Deficiency. About Three Cases |journal=Journal of Hypertension | volume=37 |pages=e215 |doi=10.1097/01.hjh.0000572764.95461.72 |doi-access=free }}</ref><ref>{{cite journal | vauthors = Sahin S, Adrovic A, Barut K, Baran S, Tahir Turanli E, Canpolat N, Kizilkilic O, Ozkaya O, Kasapcopur O | display-authors = 6 | title = A 9.5-year-old boy with recurrent neurological manifestations and severe hypertension, treated initially for polyarteritis nodosa, was subsequently diagnosed with adenosine deaminase type 2 deficiency (DADA2) which responded to anti-TNF-α | journal = Paediatrics and International Child Health | volume = 40 | issue = 1 | pages = 65–68 | date = February 2020 | pmid = 30642227 | doi = 10.1080/20469047.2018.1559495 | s2cid = 58576432 }}</ref>
 ==Pathophysiology==
-The mechanism by which mutations in ADA2 lead to disease manifestations is not fully clear.  ADA2 is a primarily [[extracellular]] protein highly expressed by [[Myeloid lineage|myeloid]] [[immune cells]] such as [[monocyte]]s, [[macrophage]]s, and [[dendritic cell]]s.<ref name=":9">{{cite journal | vauthors = Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G | title = Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages | journal = Journal of Leukocyte Biology | volume = 88 | issue = 2 | pages = 279–90 | date = August 2010 | pmid = 20453107 | doi = 10.1189/jlb.1109764 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Iwaki-Egawa S, Yamamoto T, Watanabe Y | title = Human plasma adenosine deaminase 2 is secreted by activated monocytes | journal = Biological Chemistry | volume = 387 | issue = 3 | pages = 319–21 | date = March 2006 | pmid = 16542154 | doi = 10.1515/BC.2006.042 }}</ref> ADA2 has been hypothesized to have multiple functions, including as an enzyme, a growth factor, and an [[intracellular]] [[DNA]] sensor.<ref>{{cite journal| vauthors = Greiner-Tollersrud OK, Krausz M, Bartok E, Boehler V, Ebersbach H, Baash S, Guerini D, Hartmann G, Huebscher K, Kochs G, Marchant M | display-authors = 6|date=2020-06-22|title=ADA2 is a lysosomal DNase regulating the type-I interferon response|url=https://www.biorxiv.org/content/10.1101/2020.06.21.162990v2|journal=bioRxiv|language=en|pages=2020.06.21.162990|doi=10.1101/2020.06.21.162990}}</ref><ref name=":1" />  Deficiencies in each of these functions could lead to the [[chronic inflammatory]] [[phenotype]] associated with DADA2.  Less is known about the role of ADA2 dysfunction in the immunologic and hematologic aspects of the disease.{{cn|date=September 2021}}
+The mechanism by which mutations in ADA2 lead to disease manifestations is not fully clear.  ADA2 is a primarily [[extracellular]] protein highly expressed by [[Myeloid lineage|myeloid]] [[immune cells]] such as [[monocyte]]s, [[macrophage]]s, and [[dendritic cell]]s.<ref name=":9">{{cite journal | vauthors = Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G | title = Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages | journal = Journal of Leukocyte Biology | volume = 88 | issue = 2 | pages = 279–90 | date = August 2010 | pmid = 20453107 | doi = 10.1189/jlb.1109764 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Iwaki-Egawa S, Yamamoto T, Watanabe Y | title = Human plasma adenosine deaminase 2 is secreted by activated monocytes | journal = Biological Chemistry | volume = 387 | issue = 3 | pages = 319–21 | date = March 2006 | pmid = 16542154 | doi = 10.1515/BC.2006.042 | s2cid = 34740291 }}</ref> ADA2 has been hypothesized to have multiple functions, including as an enzyme, a growth factor, and an [[intracellular]] [[DNA]] sensor.<ref>{{cite journal| vauthors = Greiner-Tollersrud OK, Krausz M, Bartok E, Boehler V, Ebersbach H, Baash S, Guerini D, Hartmann G, Huebscher K, Kochs G, Marchant M | display-authors = 6|date=2020-06-22|title=ADA2 is a lysosomal DNase regulating the type-I interferon response|url=https://www.biorxiv.org/content/10.1101/2020.06.21.162990v2|journal=bioRxiv|language=en|pages=2020.06.21.162990|doi=10.1101/2020.06.21.162990| s2cid = 220044343}}</ref><ref name=":1" />  Deficiencies in each of these functions could lead to the [[chronic inflammatory]] [[phenotype]] associated with DADA2.  Less is known about the role of ADA2 dysfunction in the immunologic and hematologic aspects of the disease.{{cn|date=September 2021}}
-ADA2 catalyzes the reaction of adenosine to inosine and [[2'-Deoxyadenosine|2’deoxyadenosine]] in the blood.  All DADA2 patients display less than 5% of the normal activity of ADA2 in blood samples, implicating the potential importance of this enzymatic role.<ref name=":2" />  Adenosine levels are higher in patients than healthy individuals.<ref name=":10">{{cite journal| vauthors = Carmona-Rivera C |date=2019 |title=Deficiency of adenosine deaminase triggers adenosine-mediated NETosis and TNF production in patients with DADA2 |journal=Blood |volume=134 |pages=395–406}}</ref> Adenosine binds to [[cell surface receptor]]s on [[neutrophil]]s, causing the formation of [[neutrophil extracellular traps]] (NETs).  NETs have been identified at increased levels in both affected tissue and in circulation of DADA2 patients.<ref name=":10" /> NETs go on to cause inflammatory responses from macrophages, including excess release the [[pro-inflammatory cytokine]] [[TNFA|TNFa]].  TNFa likely plays a major role in the vasculitic phenotype of DADA2 due the efficacy of TNFa targeting drugs in treating symptoms.  However, the enzymatic activity of ADA2 is 100 fold lesser than that of the intracellular [[Adenosine deaminase|adenosine deaminase ADA1]], and at physiological concentrations of adenosine the enzymatic activity of ADA2 is near zero.<ref name=":1" /> This indicates that loss of ADA2 may cause disease by other mechanisms.{{cn|date=September 2021}}
+ADA2 catalyzes the reaction of adenosine to inosine and [[2'-Deoxyadenosine|2’deoxyadenosine]] in the blood.  All DADA2 patients display less than 5% of the normal activity of ADA2 in blood samples, implicating the potential importance of this enzymatic role.<ref name=":2" />  Adenosine levels are higher in patients than healthy individuals.<ref name=":10">{{cite journal| vauthors = Carmona-Rivera C |date=2019 |title=Deficiency of adenosine deaminase triggers adenosine-mediated NETosis and TNF production in patients with DADA2 |journal=Blood |volume=134 |issue=4 |pages=395–406|doi=10.1182/blood.2018892752 |pmid=31015188 |pmc=6659253 }}</ref> Adenosine binds to [[cell surface receptor]]s on [[neutrophil]]s, causing the formation of [[neutrophil extracellular traps]] (NETs).  NETs have been identified at increased levels in both affected tissue and in circulation of DADA2 patients.<ref name=":10" /> NETs go on to cause inflammatory responses from macrophages, including excess release the [[pro-inflammatory cytokine]] [[TNFA|TNFa]].  TNFa likely plays a major role in the vasculitic phenotype of DADA2 due the efficacy of TNFa targeting drugs in treating symptoms.  However, the enzymatic activity of ADA2 is 100 fold lesser than that of the intracellular [[Adenosine deaminase|adenosine deaminase ADA1]], and at physiological concentrations of adenosine the enzymatic activity of ADA2 is near zero.<ref name=":1" /> This indicates that loss of ADA2 may cause disease by other mechanisms.{{cn|date=September 2021}}
 [[Endothelial cell]] [[Immunologic activation|activation]] and damage is a further source of inflammation and vascular symptoms caused by DADA2. Endothelial cells from patients are extensively damaged and secrete pro-inflammatory cytokines. However, endothelial cells themselves don't express the ADA2 protein, so this phenotype is likely mediated by the effects of mutant ADA2 on other cell types feeding back onto endothelial cells. For example, ADA2 mutant monocytes display abnormal [[Cellular differentiation|differentiation]] into macrophages, and endothelial cells grown in the presence of ADA2 deficient monocytes are similarly extensively damaged.<ref name=":7" />
-The molecular underpinnings of the immunologic disease are unclear, but the upregulation of [[Type I Interferon|type I interferon]]-stimulated genes, poor B cell differentiation, reduced antibody production, and lymphoproliferation have been noted.<ref name=":1" /> The cause of severe hematologic manifestations such as pure red cell aplasia and bone marrow failure are also unknown.<ref name=":1" /> However,  the ADA2 protein is similar in structure to the [[adenosine deaminase growth factors]] found in other species.  Deficiencies of these proteins in frogs and fruit flies have been shown to cause developmental abnormalities, such as small size and early death respectively.<ref>{{cite journal | vauthors = Iijima R, Kunieda T, Yamaguchi S, Kamigaki H, Fujii-Taira I, Sekimizu K, Kubo T, Natori S, Homma KJ | display-authors = 6 | title = The extracellular adenosine deaminase growth factor, ADGF/CECR1, plays a role in Xenopus embryogenesis via the adenosine/P1 receptor | language = English | journal = The Journal of Biological Chemistry | volume = 283 | issue = 4 | pages = 2255–64 | date = January 2008 | pmid = 18032387 | doi = 10.1074/jbc.M709279200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dolezal T, Dolezelova E, Zurovec M, Bryant PJ | title = A role for adenosine deaminase in Drosophila larval development | journal = PLoS Biology | volume = 3 | issue = 7 | pages = e201 | date = July 2005 | pmid = 15907156 | pmc = 1135298 | doi = 10.1371/journal.pbio.0030201 }}</ref><ref>{{cite journal | vauthors = Dolezelova E, Zurovec M, Dolezal T, Simek P, Bryant PJ | title = The emerging role of adenosine deaminases in insects | journal = Insect Biochemistry and Molecular Biology | volume = 35 | issue = 5 | pages = 381–9 | date = May 2005 | pmid = 15804573 | doi = 10.1016/j.ibmb.2004.12.009 }}</ref> In humans, extracellular ADA2 interacts with many [[White blood cell|immune cell]] types, including neutrophils, monocytes, [[NK cells]], and specific B and [[T cell]] subtypes.<ref>{{cite journal | vauthors = Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, Aksentijevich I, Zavialov AV | display-authors = 6 | title = Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells | journal = Cellular and Molecular Life Sciences | volume = 74 | issue = 3 | pages = 555–570 | date = February 2017 | pmid = 27663683 | doi = 10.1007/s00018-016-2357-0 }}</ref>  This interaction can lead to functional changes, as ADA2 has been shown to bind to monocytes and [[CD4+ T cell|CD4+ T]] cells to increase monocyte differentiation and T cell proliferation when present together.<ref name=":9" /> Thus, DADA2 might lead to poor immune cell development directly or through the generally high inflammation.{{cn|date=September 2021}}
+The molecular underpinnings of the immunologic disease are unclear, but the upregulation of [[Type I Interferon|type I interferon]]-stimulated genes, poor B cell differentiation, reduced antibody production, and lymphoproliferation have been noted.<ref name=":1" /> The cause of severe hematologic manifestations such as pure red cell aplasia and bone marrow failure are also unknown.<ref name=":1" /> However,  the ADA2 protein is similar in structure to the [[adenosine deaminase growth factors]] found in other species.  Deficiencies of these proteins in frogs and fruit flies have been shown to cause developmental abnormalities, such as small size and early death respectively.<ref>{{cite journal | vauthors = Iijima R, Kunieda T, Yamaguchi S, Kamigaki H, Fujii-Taira I, Sekimizu K, Kubo T, Natori S, Homma KJ | display-authors = 6 | title = The extracellular adenosine deaminase growth factor, ADGF/CECR1, plays a role in Xenopus embryogenesis via the adenosine/P1 receptor | language = English | journal = The Journal of Biological Chemistry | volume = 283 | issue = 4 | pages = 2255–64 | date = January 2008 | pmid = 18032387 | doi = 10.1074/jbc.M709279200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dolezal T, Dolezelova E, Zurovec M, Bryant PJ | title = A role for adenosine deaminase in Drosophila larval development | journal = PLOS Biology | volume = 3 | issue = 7 | pages = e201 | date = July 2005 | pmid = 15907156 | pmc = 1135298 | doi = 10.1371/journal.pbio.0030201 }}</ref><ref>{{cite journal | vauthors = Dolezelova E, Zurovec M, Dolezal T, Simek P, Bryant PJ | title = The emerging role of adenosine deaminases in insects | journal = Insect Biochemistry and Molecular Biology | volume = 35 | issue = 5 | pages = 381–9 | date = May 2005 | pmid = 15804573 | doi = 10.1016/j.ibmb.2004.12.009 }}</ref> In humans, extracellular ADA2 interacts with many [[White blood cell|immune cell]] types, including neutrophils, monocytes, [[NK cells]], and specific B and [[T cell]] subtypes.<ref>{{cite journal | vauthors = Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, Aksentijevich I, Zavialov AV | display-authors = 6 | title = Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells | journal = Cellular and Molecular Life Sciences | volume = 74 | issue = 3 | pages = 555–570 | date = February 2017 | pmid = 27663683 | doi = 10.1007/s00018-016-2357-0 | s2cid = 23033160 }}</ref>  This interaction can lead to functional changes, as ADA2 has been shown to bind to monocytes and [[CD4+ T cell|CD4+ T]] cells to increase monocyte differentiation and T cell proliferation when present together.<ref name=":9" /> Thus, DADA2 might lead to poor immune cell development directly or through the generally high inflammation.{{cn|date=September 2021}}
 ==Genetics==
 DADA2 is caused by mutations in [[DNA]] encoding the gene ''ADA2'', formerly known as ''CECR1''. The ADA2 gene is located on [[chromosome]] 22q11.1.<ref>{{cite web|title=ADA2 Gene - GeneCards {{!}} ADA2 Protein {{!}} ADA2 Antibody|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADA2|access-date=2021-04-12|website=www.genecards.org}}</ref>  Many different kinds of mutations have been reported, including [[Missense mutation|missense]], [[Nonsense mutation|nonsense]], [[Splice site mutation|splice-site]], [[Frameshift mutation|frameshift]], [[Deletion mutation|deletions]], and [[Copy number variation|duplications]]. As of 2021, there are 117 known mutations, although classification into disease-causing and benign is ongoing.<ref>{{cite web| vauthors = Aksentijevich I |title=ADA2 Sequence Variants|url=https://infevers.umai-montpellier.fr/web/search.php?n=20|url-status=live|access-date=2021-04-12|website=infevers.umai-montpellier.fr}}</ref> This disease is inherited in an autosomal recessive fashion meaning that both versions of this gene, one inherited from each parent, must be defective in a patient.  While those with only one known mutant allele have been found to have disease manifestations, it is thought that those individuals have a mutation not found upon initial [[DNA sequencing|genomic sequencing]].{{cn|date=September 2021}}
-While there is some relationship between the genetic mutations a patient displays and their experience with the disease, the relationship is not one to one. Patients with DADA2 that share the same mutation are more likely to experience similar disease, but even family members with the same mutations have had entirely different disease courses.<ref name=":2" /><ref>{{cite journal | vauthors = Schnappauf O, Zhou Q, Moura NS, Ombrello AK, Michael DG, Deuitch N, Barron K, Stone DL, Hoffmann P, Hershfield M, Applegate C, Bjornsson HT, Beck DB, Witmer PD, Sobreira N, Wohler E, Chiorini JA, Center TA, Dalgard CL, Center NI, Kastner DL, Aksentijevich I | display-authors = 6 | title = Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance | journal = Journal of Clinical Immunology | volume = 40 | issue = 6 | pages = 917–926 | date = August 2020 | pmid = 32638197 | pmc = 7416912 | doi = 10.1007/s10875-020-00817-3 }}</ref><ref>{{cite journal | vauthors = Neishabury M, Mehri M, Fattahi Z, Najmabadi H, Azarkeivan A | title = Novel variants in Iranian individuals suspected to have inherited red blood cell disorders, including bone marrow failure syndromes | journal = Haematologica | volume = 105 | issue = 1 | pages = e1-e4 | date = January 2020 | pmid = 31097629 | pmc = 6939539 | doi = 10.3324/haematol.2019.216069 }}</ref> While the reasons for this difference are not well defined in DADA2 this is common in other so-called monogenic diseases, where [[Biophysical environment|environment]] and [[modifier gene]]tics have been shown to play a role.<ref>{{cite journal | vauthors = Weatherall DJ | title = Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias | journal = Nature Reviews. Genetics | volume = 2 | issue = 4 | pages = 245–55 | date = April 2001 | pmid = 11283697 | doi = 10.1038/35066048 }}</ref><ref>{{cite journal| vauthors = Scriver CR, Waters PJ |date=July 1999|title=Monogenic traits are not simple: lessons from phenylketonuria |journal=Trends in Genetics|language=en|volume=15|issue=7|pages=267–272|doi=10.1016/S0168-9525(99)01761-8}}</ref><ref>{{cite journal | vauthors = Gallati S | title = Disease-modifying genes and monogenic disorders: experience in cystic fibrosis | journal = The Application of Clinical Genetics | volume = 7 | pages = 133–46 | date = July 2014 | pmid = 25053892 | doi = 10.2147/TACG.S18675 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Davidson BA, Hassan S, Garcia EJ, Tayebi N, Sidransky E | title = Exploring genetic modifiers of Gaucher disease: The next horizon | journal = Human Mutation | volume = 39 | issue = 12 | pages = 1739–1751 | date = December 2018 | pmid = 30098107 | pmc = 6240360 | doi = 10.1002/humu.23611 }}</ref> However, multiple groups have found some correlation between mutation and phenotype. There is some indication that mutations present in the [[Protein dimer|dimerization]] [[Protein domain|domain]] of ADA2 predispose towards vasculitis-associated disease, whereas mutations in the [[catalytic domain]] lead to the Diamond Blackfan anemia-like phenotype.<ref>{{cite journal | vauthors = Özen S, Batu ED, Taşkıran EZ, Özkara HA, Ünal Ş, Güleray N, Erden A, Karadağ Ö, Gümrük F, Çetin M, Sönmez HE, Bilginer Y, Ayvaz DÇ, Tezcan I | display-authors = 6 | title = A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2 | journal = The Journal of Rheumatology | volume = 47 | issue = 1 | pages = 117–125 | date = January 2020 | pmid = 31043544 | doi = 10.3899/jrheum.181384 }}</ref> In another study, specific mutations segregated perfectly into groups based on the type of the disease the patient displayed. In this analysis, the common G47R mutation always found in individuals with vasculitic disease, and the G358R mutation always seen in those with severe hematologic disease. However, some mutations did not separate as well. For example, the R169Q mutation was found in both vasculitic- and hematologic-forward disease subtypes.<ref name=":2" />  An analysis of the enzymatic activity of mutated ADA2 enzyme [[in vitro]] found that mutations yielding greater enzyme activity favored vasculitis, whereas mutations with less residual activity favored hematologic manifestations.<ref name=":2" />
+While there is some relationship between the genetic mutations a patient displays and their experience with the disease, the relationship is not one to one. Patients with DADA2 that share the same mutation are more likely to experience similar disease, but even family members with the same mutations have had entirely different disease courses.<ref name=":2" /><ref>{{cite journal | vauthors = Schnappauf O, Zhou Q, Moura NS, Ombrello AK, Michael DG, Deuitch N, Barron K, Stone DL, Hoffmann P, Hershfield M, Applegate C, Bjornsson HT, Beck DB, Witmer PD, Sobreira N, Wohler E, Chiorini JA, Center TA, Dalgard CL, Center NI, Kastner DL, Aksentijevich I | display-authors = 6 | title = Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance | journal = Journal of Clinical Immunology | volume = 40 | issue = 6 | pages = 917–926 | date = August 2020 | pmid = 32638197 | pmc = 7416912 | doi = 10.1007/s10875-020-00817-3 }}</ref><ref>{{cite journal | vauthors = Neishabury M, Mehri M, Fattahi Z, Najmabadi H, Azarkeivan A | title = Novel variants in Iranian individuals suspected to have inherited red blood cell disorders, including bone marrow failure syndromes | journal = Haematologica | volume = 105 | issue = 1 | pages = e1–e4 | date = January 2020 | pmid = 31097629 | pmc = 6939539 | doi = 10.3324/haematol.2019.216069 }}</ref> While the reasons for this difference are not well defined in DADA2 this is common in other so-called monogenic diseases, where [[Biophysical environment|environment]] and [[modifier gene]]tics have been shown to play a role.<ref>{{cite journal | vauthors = Weatherall DJ | title = Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias | journal = Nature Reviews. Genetics | volume = 2 | issue = 4 | pages = 245–55 | date = April 2001 | pmid = 11283697 | doi = 10.1038/35066048 | s2cid = 205014931 }}</ref><ref>{{cite journal| vauthors = Scriver CR, Waters PJ |date=July 1999|title=Monogenic traits are not simple: lessons from phenylketonuria |journal=Trends in Genetics|language=en|volume=15|issue=7|pages=267–272|doi=10.1016/S0168-9525(99)01761-8|pmid=10390625}}</ref><ref>{{cite journal | vauthors = Gallati S | title = Disease-modifying genes and monogenic disorders: experience in cystic fibrosis | journal = The Application of Clinical Genetics | volume = 7 | pages = 133–46 | date = July 2014 | pmid = 25053892 | doi = 10.2147/TACG.S18675 | pmc = 4104546 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Davidson BA, Hassan S, Garcia EJ, Tayebi N, Sidransky E | title = Exploring genetic modifiers of Gaucher disease: The next horizon | journal = Human Mutation | volume = 39 | issue = 12 | pages = 1739–1751 | date = December 2018 | pmid = 30098107 | pmc = 6240360 | doi = 10.1002/humu.23611 }}</ref> However, multiple groups have found some correlation between mutation and phenotype. There is some indication that mutations present in the [[Protein dimer|dimerization]] [[Protein domain|domain]] of ADA2 predispose towards vasculitis-associated disease, whereas mutations in the [[catalytic domain]] lead to the Diamond Blackfan anemia-like phenotype.<ref>{{cite journal | vauthors = Özen S, Batu ED, Taşkıran EZ, Özkara HA, Ünal Ş, Güleray N, Erden A, Karadağ Ö, Gümrük F, Çetin M, Sönmez HE, Bilginer Y, Ayvaz DÇ, Tezcan I | display-authors = 6 | title = A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2 | journal = The Journal of Rheumatology | volume = 47 | issue = 1 | pages = 117–125 | date = January 2020 | pmid = 31043544 | doi = 10.3899/jrheum.181384 | s2cid = 143423444 }}</ref> In another study, specific mutations segregated perfectly into groups based on the type of the disease the patient displayed. In this analysis, the common G47R mutation always found in individuals with vasculitic disease, and the G358R mutation always seen in those with severe hematologic disease. However, some mutations did not separate as well. For example, the R169Q mutation was found in both vasculitic- and hematologic-forward disease subtypes.<ref name=":2" />  An analysis of the enzymatic activity of mutated ADA2 enzyme [[in vitro]] found that mutations yielding greater enzyme activity favored vasculitis, whereas mutations with less residual activity favored hematologic manifestations.<ref name=":2" />
 ==Epidemiology==
-As of 2020, over 260 cases of DADA2 have been identified since the disease's discovery in 2014.<ref name=":11">{{cite journal | vauthors = Kendall JL, Springer JM | title = The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency | journal = Current Rheumatology Reports | volume = 22 | issue = 10 | pages = 64 | date = August 2020 | pmid = 32845415 | pmc = 7448703 | doi = 10.1007/s11926-020-00944-1 }}</ref> Since this disease is inherited in an autosomal recessive manner, men and women are equally likely to be diagnosed with DADA2. Based on computational analyses, the prevalence of DADA2 could be as high as 4 in 100,000.<ref name = "Aksentijevich_1993">{{cite book | vauthors = Aksentijevich I | chapter = Adenosine Deaminase 2 Deficiency |date=1993 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK544951/ | title = GeneReviews | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A }}</ref>  Generally, populations with high degrees of [[consanguinity]] or with [[Founder mutation|founder variants]] have a higher prevalence of DADA2. For example, the [[History of the Jews in Georgia|Georgian-Jewish]] and [[Turkey|Turkish]] populations are estimated to have a 1:10 and 1:500 likelihood of carrying the G47R mutation respectively.  The R169Q variant is also more common in northern Europe, with a carrier frequency of 1:500.<ref name = "Aksentijevich_1993" />
+As of 2020, over 260 cases of DADA2 have been identified since the disease's discovery in 2014.<ref name=":11">{{cite journal | vauthors = Kendall JL, Springer JM | title = The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency | journal = Current Rheumatology Reports | volume = 22 | issue = 10 | pages = 64 | date = August 2020 | pmid = 32845415 | pmc = 7448703 | doi = 10.1007/s11926-020-00944-1 }}</ref> Since this disease is inherited in an autosomal recessive manner, men and women are equally likely to be diagnosed with DADA2. Based on computational analyses, the prevalence of DADA2 could be as high as 4 in 100,000.<ref name = "Aksentijevich_1993">{{cite book | vauthors = Aksentijevich I | chapter = Adenosine Deaminase 2 Deficiency |date=1993 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK544951/ | title = GeneReviews | publisher = University of Washington, Seattle | pmid = 31393689 | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A }}</ref>  Generally, populations with high degrees of [[consanguinity]] or with [[Founder mutation|founder variants]] have a higher prevalence of DADA2. For example, the [[History of the Jews in Georgia|Georgian-Jewish]] and [[Turkey|Turkish]] populations are estimated to have a 1:10 and 1:500 likelihood of carrying the G47R mutation respectively.  The R169Q variant is also more common in northern Europe, with a carrier frequency of 1:500.<ref name = "Aksentijevich_1993" />
 ==Diagnosis==
-Currently, screening for DADA2 is initiated upon a physician's judgement. Criteria to trigger screening have been proposed however, including at least one sign of inflammation and vasculitis.<ref>{{cite journal | vauthors = Rama M, Duflos C, Melki I, Bessis D, Bonhomme A, Martin H, Doummar D, Valence S, Rodriguez D, Carme E, Genevieve D, Heimdal K, Insalaco A, Franck N, Queyrel-Moranne V, Tieulie N, London J, Uettwiller F, Georgin-Lavialle S, Belot A, Koné-Paut I, Hentgen V, Boursier G, Touitou I, Sarrabay G | display-authors = 6 | title = A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience | journal = European Journal of Human Genetics | volume = 26 | issue = 7 | pages = 960–971 | date = July 2018 | pmid = 29681619 | pmc = 6018671 | doi = 10.1038/s41431-018-0130-6 }}</ref> The specific diagnosis of DADA2 requires either confirmation of known pathogenic mutations in ADA2 or low ADA2 enzymatic activity in patient blood.<ref name=":11" />  Genetic testing for DADA2 has been performed as either a single-gene test through [[Sanger sequencing]], or a multi-gene test through [[Elective genetic and genomic testing|panel testing]], [[Exome sequencing|whole exome sequencing]], or [[whole genome sequencing]].<ref name=":11" /> These techniques vary in cost, intensity, and detection, and mutations have been missed due to the technique initially used.<ref>{{cite journal | vauthors = Vairo FP, Koster MJ, Kemppainen JL, Thomas BC, Warrington KJ | title = Comment on: Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2) | journal = Rheumatology | issue = keab081 | date = January 2021 | pmid = 33515254 | doi = 10.1093/rheumatology/keab081 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Claassen D, Boals M, Bowling KM, Cooper GM, Cox J, Hershfield M, Lewis S, Wlodarski M, Weiss MJ, Estepp JH | display-authors = 6 | title = Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia | journal = Cold Spring Harbor Molecular Case Studies | volume = 4 | issue = 6 | date = December 2018 | pmid = 30559313 | pmc = 6318771 | doi = 10.1101/mcs.a003384 }}</ref> As such, more extensive analysis is sometimes necessary if suspicion of DADA2 remains. Enzymatic activity analysis can confirm whether or not the ADA2 gene should be investigated further in these situations, and has been recommended by some as the premier diagnostic technique.<ref>{{cite journal| vauthors = Moura N | date=2019-05-16|title=10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID) |journal=Pediatric Rheumatology Online Journal|volume=17|issue=Suppl 1|doi=10.1186/s12969-019-0313-x |pmc=7103907}}</ref>
+Currently, screening for DADA2 is initiated upon a physician's judgement. Criteria to trigger screening have been proposed however, including at least one sign of inflammation and vasculitis.<ref>{{cite journal | vauthors = Rama M, Duflos C, Melki I, Bessis D, Bonhomme A, Martin H, Doummar D, Valence S, Rodriguez D, Carme E, Genevieve D, Heimdal K, Insalaco A, Franck N, Queyrel-Moranne V, Tieulie N, London J, Uettwiller F, Georgin-Lavialle S, Belot A, Koné-Paut I, Hentgen V, Boursier G, Touitou I, Sarrabay G | display-authors = 6 | title = A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience | journal = European Journal of Human Genetics | volume = 26 | issue = 7 | pages = 960–971 | date = July 2018 | pmid = 29681619 | pmc = 6018671 | doi = 10.1038/s41431-018-0130-6 }}</ref> The specific diagnosis of DADA2 requires either confirmation of known pathogenic mutations in ADA2 or low ADA2 enzymatic activity in patient blood.<ref name=":11" />  Genetic testing for DADA2 has been performed as either a single-gene test through [[Sanger sequencing]], or a multi-gene test through [[Elective genetic and genomic testing|panel testing]], [[Exome sequencing|whole exome sequencing]], or [[whole genome sequencing]].<ref name=":11" /> These techniques vary in cost, intensity, and detection, and mutations have been missed due to the technique initially used.<ref>{{cite journal | vauthors = Vairo FP, Koster MJ, Kemppainen JL, Thomas BC, Warrington KJ | title = Comment on: Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2) | journal = Rheumatology | issue = keab081 | date = January 2021 | volume = 60 | pages = e218–e219 | pmid = 33515254 | doi = 10.1093/rheumatology/keab081 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Claassen D, Boals M, Bowling KM, Cooper GM, Cox J, Hershfield M, Lewis S, Wlodarski M, Weiss MJ, Estepp JH | display-authors = 6 | title = Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia | journal = Cold Spring Harbor Molecular Case Studies | volume = 4 | issue = 6 | date = December 2018 | pages = a003384 | pmid = 30559313 | pmc = 6318771 | doi = 10.1101/mcs.a003384 }}</ref> As such, more extensive analysis is sometimes necessary if suspicion of DADA2 remains. Enzymatic activity analysis can confirm whether or not the ADA2 gene should be investigated further in these situations, and has been recommended by some as the premier diagnostic technique.<ref>{{cite journal| vauthors = Moura N | date=2019-05-16|title=10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID) |journal=Pediatric Rheumatology Online Journal|volume=17|issue=Suppl 1| page=18|doi=10.1186/s12969-019-0313-x |pmc=7103907}}</ref>
 == Management ==
-The most common management of DADA2 after diagnosis is TNFa inhibition (TNFi). This treatment serves those with vasculitic forms of the disease best, improving most symptoms and significantly preventing strokes.<ref name=":3" /><ref name=":4" /> TNFi is ineffective in those with severe bone marrow dysfunction or immunodeficiency.<ref name=":12">{{cite journal | vauthors = Cooray S, Omyinmi E, Hong Y, Papadopoulou C, Harper L, Al-Abadi E, Goel R, Dubey S, Wood M, Jolles S, Berg S, Ekelund M, Armon K, Eleftheriou D, Brogan PA | display-authors = 6 | title = Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2) | journal = Rheumatology | issue = keaa837 | date = January 2021 | pmid = 33420503 | doi = 10.1093/rheumatology/keaa837 | doi-access = free }}</ref>  In these patients, hematopoietic stem cell transplant is considered and upon successful completion can be curative.<ref name=":12" /><ref name=":5" /> However, the risks associated with this procedure preclude its use in most patients. {{cn|date=September 2021}}
+The most common management of DADA2 after diagnosis is TNFa inhibition (TNFi). This treatment serves those with vasculitic forms of the disease best, improving most symptoms and significantly preventing strokes.<ref name=":3" /><ref name=":4" /> TNFi is ineffective in those with severe bone marrow dysfunction or immunodeficiency.<ref name=":12">{{cite journal | vauthors = Cooray S, Omyinmi E, Hong Y, Papadopoulou C, Harper L, Al-Abadi E, Goel R, Dubey S, Wood M, Jolles S, Berg S, Ekelund M, Armon K, Eleftheriou D, Brogan PA | display-authors = 6 | title = Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2) | journal = Rheumatology | issue = keaa837 | date = January 2021 | volume = 60 | pages = 4373–4378 | pmid = 33420503 | doi = 10.1093/rheumatology/keaa837 | doi-access = free }}</ref>  In these patients, hematopoietic stem cell transplant is considered and upon successful completion can be curative.<ref name=":12" /><ref name=":5" /> However, the risks associated with this procedure preclude its use in most patients. {{cn|date=September 2021}}
-Ongoing pre-clinical studies are researching [[gene therapy]].<ref>{{cite journal| vauthors = Brigida I |date=2019-05-16|title=10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID) |journal=Pediatric Rheumatology Online Journal|volume=17|issue=Suppl 1|doi=10.1186/s12969-019-0313-x|issn=1546-0096|pmc=7103907}}</ref><ref>{{cite journal| vauthors = Hong Y |date=2019-05-16|title=10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID) |journal=Pediatric Rheumatology Online Journal|volume=17|issue=Suppl 1|doi=10.1186/s12969-019-0313-x|issn=1546-0096|pmc=7103907}}</ref> Both gene therapy and [[enzyme replacement therapy]] have been successful in the [[ADA-SCID|adenosine deaminase deficiency]],<ref>{{cite journal|date=1995-09-01|title=PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years |journal=Clinical Immunology and Immunopathology|language=en|volume=76|issue=3|pages=S228–S232|doi=10.1016/S0090-1229(95)90306-2|issn=0090-1229}}</ref><ref>{{cite journal | vauthors = Aiuti A, Roncarolo MG, Naldini L | title = Gene therapy for ADA-SCID, the first marketing approval of an ''exvivo'' gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products | journal = EMBO Molecular Medicine | volume = 9 | issue = 6 | pages = 737–740 | date = June 2017 | pmid = 28396566 | pmc = 5452047 | doi = 10.15252/emmm.201707573 }}</ref> indicating their potential future success in DADA2.
+Ongoing pre-clinical studies are researching [[gene therapy]].<ref>{{cite journal| vauthors = Brigida I |date=2019-05-16|title=10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID) |journal=Pediatric Rheumatology Online Journal|volume=17|issue=Suppl 1|page=18|doi=10.1186/s12969-019-0313-x|issn=1546-0096|pmc=7103907}}</ref><ref>{{cite journal| vauthors = Hong Y |date=2019-05-16|title=10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID) |journal=Pediatric Rheumatology Online Journal|volume=17|issue=Suppl 1|page=18|doi=10.1186/s12969-019-0313-x|issn=1546-0096|pmc=7103907}}</ref> Both gene therapy and [[enzyme replacement therapy]] have been successful in the [[ADA-SCID|adenosine deaminase deficiency]],<ref>{{cite journal|date=1995-09-01|title=PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years |journal=Clinical Immunology and Immunopathology|language=en|volume=76|issue=3|pages=S228–S232|doi=10.1016/S0090-1229(95)90306-2|issn=0090-1229|last1=Hershfield |first1=Michael S. |pmid=7554473 }}</ref><ref>{{cite journal | vauthors = Aiuti A, Roncarolo MG, Naldini L | title = Gene therapy for ADA-SCID, the first marketing approval of an ''exvivo'' gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products | journal = EMBO Molecular Medicine | volume = 9 | issue = 6 | pages = 737–740 | date = June 2017 | pmid = 28396566 | pmc = 5452047 | doi = 10.15252/emmm.201707573 }}</ref> indicating their potential future success in DADA2.
 == History ==