Medicine:Adenosine deaminase 2 deficiency

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Deficiency of Adenosine Deaminase 2
Other namesDADA2
Autosomal recessive - en.svg
Autosomal recessive pattern is the inheritance manner of this condition
SpecialtyMedical genetics, Pediatrics, Rheumatology, Neurology, Dermatology, Immunology, Hematology
Usual onsetVariable, but commonly in early childhood
DurationLifelong
CausesMutations in the ADA2 gene
Diagnostic methodGenetic or Enzymatic Testing

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]

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.[39] The specific diagnosis of DADA2 requires either confirmation of known pathogenic mutations in ADA2 or low ADA2 enzymatic activity in patient blood.[40]  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.[40] These techniques vary in cost, intensity, and detection, and mutations have been missed due to the technique initially used.[41][42] 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.[43]

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.[44]  In these patients, hematopoietic stem cell transplant is considered and upon successful completion can be curative.[44][8] However, the risks associated with this procedure preclude its use in most patients. [citation needed]   

Ongoing pre-clinical studies are researching gene therapy.[45][46] Both gene therapy and enzyme replacement therapy have been successful in the adenosine deaminase deficiency,[47][48] indicating their potential future success in DADA2.

Epidemiology

As of 2020, over 260 cases of DADA2 have been identified since the disease's discovery in 2014.[40] 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.[49]  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.[49]

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, being held in 2016, 2018, 2020 and 2023.[50]

References

  1. ↑ 1.0 1.1 "Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2". Frontiers in Pediatrics 6: 282. 2018. doi:10.3389/fped.2018.00282. PMID 30406060. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment". Journal of Clinical Immunology 38 (5): 569–578. July 2018. doi:10.1007/s10875-018-0525-8. PMID 29951947. 
  3. ↑ "Deficiency of adenosine deaminase 2 diagnosed at 65 years of age". Lancet 397 (10277): 913. March 2021. doi:10.1016/S0140-6736(20)32660-X. PMID 33676630. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)" (in English). The Journal of Allergy and Clinical Immunology 145 (6): 1664–1672.e10. June 2020. doi:10.1016/j.jaci.2019.12.908. PMID 31945408. 
  5. ↑ 5.0 5.1 "Treatment Strategies for Deficiency of Adenosine Deaminase 2". The New England Journal of Medicine 380 (16): 1582–1584. April 2019. doi:10.1056/NEJMc1801927. PMID 30995379. 
  6. ↑ 6.0 6.1 "Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India". Arthritis & Rheumatology 73 (2): 276–285. February 2021. doi:10.1002/art.41500. PMID 32892503. 
  7. ↑ "Biologic drugs in the treatment of polyarteritis nodosa and deficit of adenosine deaminase 2: A narrative review". Autoimmunity Reviews 20 (4): 102784. April 2021. doi:10.1016/j.autrev.2021.102784. PMID 33609794. 
  8. ↑ 8.0 8.1 "Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2". Blood 130 (24): 2682–2688. December 2017. doi:10.1182/blood-2017-07-798660. PMID 28974505. 
  9. ↑ "Diagnosis of deficiency of adenosine deaminase type 2 in adulthood". Scandinavian Journal of Rheumatology 50 (6): 493–496. February 2021. doi:10.1080/03009742.2021.1881156. PMID 33627040. https://lirias.kuleuven.be/bitstream/123456789/671373/3/DADA2_060121.pdf. 
  10. ↑ 10.0 10.1 "Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy". The New England Journal of Medicine 370 (10): 921–31. March 2014. doi:10.1056/NEJMoa1307362. PMID 24552285. 
  11. ↑ 11.0 11.1 11.2 "Early-onset stroke and vasculopathy associated with mutations in ADA2". The New England Journal of Medicine 370 (10): 911–20. March 2014. doi:10.1056/NEJMoa1307361. PMID 24552284. 
  12. ↑ "ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study". Annals of the Rheumatic Diseases 76 (10): 1648–1656. October 2017. doi:10.1136/annrheumdis-2016-210802. PMID 28522451. 
  13. ↑ "Stroke as Initial Manifestation of Adenosine Deaminase 2 Deficiency". Neuropediatrics 48 (2): 111–114. April 2017. doi:10.1055/s-0036-1597611. PMID 28024309. 
  14. ↑ 14.0 14.1 "Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood". Arthritis & Rheumatology 69 (8): 1689–1700. August 2017. doi:10.1002/art.40147. PMID 28493328. 
  15. ↑ "Adenosine Deaminase 2 Deficiency As a Cause of Pure Red Cell Aplasia Mimicking Diamond Blackfan Anemia". Blood 126 (23): 3615. 2015. doi:10.1182/blood.V126.23.3615.3615. https://ashpublications.org/blood/article/126/23/3615/92721/Adenosine-Deaminase-2-Deficiency-As-a-Cause-of. 
  16. ↑ "ADA2 deficiency: Clonal lymphoproliferation in a subset of patients" (in English). The Journal of Allergy and Clinical Immunology 141 (4): 1534–1537.e8. April 2018. doi:10.1016/j.jaci.2018.01.012. PMID 29391253. 
  17. ↑ "Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis". Pediatric Blood & Cancer 65 (4): e26912. April 2018. doi:10.1002/pbc.26912. PMID 29271561. 
  18. ↑ "Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations". Clinical Immunology 218: 108525. September 2020. doi:10.1016/j.clim.2020.108525. PMID 32659374. 
  19. ↑ "Deficiency of Adenosine Deaminase 2 in Adult Siblings: Many Years of a Misdiagnosed Disease With Severe Consequences". Frontiers in Immunology 9: 1361. 2018-06-14. doi:10.3389/fimmu.2018.01361. PMID 29963054. 
  20. ↑ "Youth Hypertension Associated With ada2 Deficiency. About Three Cases". Journal of Hypertension 37: e215. July 2019. doi:10.1097/01.hjh.0000572764.95461.72. 
  21. ↑ "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". Paediatrics and International Child Health 40 (1): 65–68. February 2020. doi:10.1080/20469047.2018.1559495. PMID 30642227. 
  22. ↑ 22.0 22.1 "Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages". Journal of Leukocyte Biology 88 (2): 279–90. August 2010. doi:10.1189/jlb.1109764. PMID 20453107. 
  23. ↑ "Human plasma adenosine deaminase 2 is secreted by activated monocytes". Biological Chemistry 387 (3): 319–21. March 2006. doi:10.1515/BC.2006.042. PMID 16542154. 
  24. ↑ "ADA2 is a lysosomal DNase regulating the type-I interferon response" (in en). bioRxiv: 2020.06.21.162990. 2020-06-22. doi:10.1101/2020.06.21.162990. https://www.biorxiv.org/content/10.1101/2020.06.21.162990v2. 
  25. ↑ 25.0 25.1 "Deficiency of adenosine deaminase triggers adenosine-mediated NETosis and TNF production in patients with DADA2". Blood 134 (4): 395–406. 2019. doi:10.1182/blood.2018892752. PMID 31015188. 
  26. ↑ "The extracellular adenosine deaminase growth factor, ADGF/CECR1, plays a role in Xenopus embryogenesis via the adenosine/P1 receptor" (in English). The Journal of Biological Chemistry 283 (4): 2255–64. January 2008. doi:10.1074/jbc.M709279200. PMID 18032387. 
  27. ↑ "A role for adenosine deaminase in Drosophila larval development". PLOS Biology 3 (7): e201. July 2005. doi:10.1371/journal.pbio.0030201. PMID 15907156. 
  28. ↑ "The emerging role of adenosine deaminases in insects". Insect Biochemistry and Molecular Biology 35 (5): 381–9. May 2005. doi:10.1016/j.ibmb.2004.12.009. PMID 15804573. 
  29. ↑ "Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells". Cellular and Molecular Life Sciences 74 (3): 555–570. February 2017. doi:10.1007/s00018-016-2357-0. PMID 27663683. 
  30. ↑ "ADA2 Gene - GeneCards | ADA2 Protein | ADA2 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=ADA2. 
  31. ↑ "ADA2 Sequence Variants". https://infevers.umai-montpellier.fr/web/search.php?n=20. 
  32. ↑ "Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance". Journal of Clinical Immunology 40 (6): 917–926. August 2020. doi:10.1007/s10875-020-00817-3. PMID 32638197. 
  33. ↑ "Novel variants in Iranian individuals suspected to have inherited red blood cell disorders, including bone marrow failure syndromes". Haematologica 105 (1): e1–e4. January 2020. doi:10.3324/haematol.2019.216069. PMID 31097629. 
  34. ↑ "Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias". Nature Reviews. Genetics 2 (4): 245–55. April 2001. doi:10.1038/35066048. PMID 11283697. 
  35. ↑ "Monogenic traits are not simple: lessons from phenylketonuria" (in en). Trends in Genetics 15 (7): 267–272. July 1999. doi:10.1016/S0168-9525(99)01761-8. PMID 10390625. 
  36. ↑ "Disease-modifying genes and monogenic disorders: experience in cystic fibrosis". The Application of Clinical Genetics 7: 133–46. July 2014. doi:10.2147/TACG.S18675. PMID 25053892. 
  37. ↑ "Exploring genetic modifiers of Gaucher disease: The next horizon". Human Mutation 39 (12): 1739–1751. December 2018. doi:10.1002/humu.23611. PMID 30098107. 
  38. ↑ "A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2". The Journal of Rheumatology 47 (1): 117–125. January 2020. doi:10.3899/jrheum.181384. PMID 31043544. 
  39. ↑ "A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience". European Journal of Human Genetics 26 (7): 960–971. July 2018. doi:10.1038/s41431-018-0130-6. PMID 29681619. 
  40. ↑ 40.0 40.1 40.2 "The Many Faces of a Monogenic Autoinflammatory Disease: Adenosine Deaminase 2 Deficiency". Current Rheumatology Reports 22 (10): 64. August 2020. doi:10.1007/s11926-020-00944-1. PMID 32845415. 
  41. ↑ "Comment on: Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2)". Rheumatology 60 (keab081): e218–e219. January 2021. doi:10.1093/rheumatology/keab081. PMID 33515254. 
  42. ↑ "Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia". Cold Spring Harbor Molecular Case Studies 4 (6): a003384. December 2018. doi:10.1101/mcs.a003384. PMID 30559313. 
  43. ↑ "10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)". Pediatric Rheumatology Online Journal 17 (Suppl 1): 18. 2019-05-16. doi:10.1186/s12969-019-0313-x. 
  44. ↑ 44.0 44.1 "Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2)". Rheumatology 60 (keaa837): 4373–4378. January 2021. doi:10.1093/rheumatology/keaa837. PMID 33420503. 
  45. ↑ "10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)". Pediatric Rheumatology Online Journal 17 (Suppl 1): 18. 2019-05-16. doi:10.1186/s12969-019-0313-x. ISSN 1546-0096. 
  46. ↑ "10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)". Pediatric Rheumatology Online Journal 17 (Suppl 1): 18. 2019-05-16. doi:10.1186/s12969-019-0313-x. ISSN 1546-0096. 
  47. ↑ Hershfield, Michael S. (1995-09-01). "PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years" (in en). Clinical Immunology and Immunopathology 76 (3): S228–S232. doi:10.1016/S0090-1229(95)90306-2. ISSN 0090-1229. PMID 7554473. 
  48. ↑ "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". EMBO Molecular Medicine 9 (6): 737–740. June 2017. doi:10.15252/emmm.201707573. PMID 28396566. 
  49. ↑ 49.0 49.1 "Adenosine Deaminase 2 Deficiency". GeneReviews. University of Washington, Seattle. 1993. http://www.ncbi.nlm.nih.gov/books/NBK544951/. 
  50. ↑ "DADA2 Foundation — Supporting research into ADA2 deficiency." (in en-US). https://www.dada2.org/. 



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