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Muratoglu, Selen, Sofia Georgieva, Gábor Pápai, et al. "Two Different Drosophila ADA2 Homologues Are Present in Distinct GCN5 Histone Acetyltransferase-Containing Complexes." Molecular and Cellular Biology 23, no. 1 (2003): 306–21. http://dx.doi.org/10.1128/mcb.23.1.306-321.2003.
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ABSTRACT We have isolated a novel Drosophila (d) gene coding for two distinct proteins via alternative splicing: a homologue of the yeast adaptor protein ADA2, dADA2a, and a subunit of RNA polymerase II (Pol II), dRPB4. Moreover, we have identified another gene in the Drosophila genome encoding a second ADA2 homologue (dADA2b). The two dADA2 homologues, as well as many putative ADA2 homologues from different species, all contain, in addition to the ZZ and SANT domains, several evolutionarily conserved domains. The dada2a/rpb4 and dada2b genes are differentially expressed at various stages of Drosophila development. Both dADA2a and dADA2b interacted with the GCN5 histone acetyltransferase (HAT) in a yeast two-hybrid assay, and dADA2b, but not dADA2a, also interacted with Drosophila ADA3. Both dADA2s further potentiate transcriptional activation in insect and mammalian cells. Antibodies raised either against dADA2a or dADA2b both immunoprecipitated GCN5 as well as several Drosophila TATA binding protein-associated factors (TAFs). Moreover, following glycerol gradient sedimentation or chromatographic purification combined with gel filtration of Drosophila nuclear extracts, dADA2a and dGCN5 were detected in fractions with an apparent molecular mass of about 0.8 MDa whereas dADA2b was found in fractions corresponding to masses of at least 2 MDa, together with GCN5 and several Drosophila TAFs. Furthermore, in vivo the two dADA2 proteins showed different localizations on polytene X chromosomes. These results, taken together, suggest that the two Drosophila ADA2 homologues are present in distinct GCN5-containing HAT complexes.
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Kozlova, A. L., Z. A. Nesterenko, K. K. Egorova, et al. "THE MANY FACES OF AUTOINFLAMMATION: ADENOSINE DEAMINASE 2 (DADA2) DEFICIENCY IN A 12 YEAR OLD." Pediatria. Journal named after G.N. Speransky 100, no. 2 (2021): 246–53. http://dx.doi.org/10.24110/0031-403x-2021-100-2-246-253.
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This article is dedicated to one of the auto-respiratory syndromes – adenosine deaminase deficiency 2 (deficiency of adenosine deaminase 2 – DADA2) in the 12-year-old. This rare disease is caused by mutations in the ADA2 gene (CECR1), that encodes the ADA2 protein. Clinical manifestations of DADA2 are very diverse and usually include systemic inflammatory reaction in the form of fever attacts, vasculopathy in the form of livedo reticulum, polyarteritis nodosa, ischemic and/or hemorrhagic strokes, as well as signs of immunodeficiency with hypogammaglobulinemia and bone marrow failure. Complex pathogenetic mechanisms, variety of clinical manifestations complicate both diagnosis of the disease and trial of pathogenetic therapy in patients with DADA2. The article describes DADA2 patient care, as well as provides present state analysis of the DADA2 problem in the world, including terminology, historical references, pathogenesis, diagnosis problems and clinical manifestations.
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Hassanzadeh, Shakiba, Mohammad Bahadoram, and Karim Mowla. "Deficiency of adenosine deaminase 2: a challenging differential diagnosis of polyarteritis nodosa." Rheumatology 61, no. 1 (2023): 45–54. http://dx.doi.org/10.5114/reum.2023.124878.
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Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive that was first described in 2014. It is a monogenic disease that is caused by loss-of-function variants in the ADA2 gene. DADA2 involves small- and medium-sized vessels and its clinical presentations include polyarteritis nodosa (PAN)-like features such as livedoid rash, early-onset stroke, hypogammaglobulinemia, hematological abnormalities, and systemic inflammation. Early diagnosis and treatment of DADA2 are crucial as the clinical features could be potentially life-threatening but might be treatable. The first-line treatment of choice in DADA2 is tumor necrosis factor (TNF)-inhibitors. We aimed to give an overview of the known pathophysiology, clinical presentations, diagnosis, and treatment of DADA2. A clearer knowledge of DADA2 may help to better diagnose, manage, and improve the clinical outcome of DADA2 patients. However, further studies are required to investigate the genotype-phenotype associations and exact pathophysiology of DADA2.
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Alabbas, Fahad, Ghaleb Elyamany, Omar Alsharif, Michael Hershfield, and Isabelle Meyts. "Childhood Hodgkin Lymphoma: Think DADA2." Journal of Clinical Immunology 39, no. 1 (2019): 26–29. http://dx.doi.org/10.1007/s10875-019-0590-7.
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Collison, Joanna. "Stem cell transplantation for DADA2." Nature Reviews Rheumatology 13, no. 12 (2017): 694. http://dx.doi.org/10.1038/nrrheum.2017.175.
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Lee, Pui Y., Brad A. Davidson, Roshini S. Abraham, et al. "Evaluation and Management of Deficiency of Adenosine Deaminase 2." JAMA Network Open 6, no. 5 (2023): e2315894. http://dx.doi.org/10.1001/jamanetworkopen.2023.15894.
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ImportanceDeficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management.ObjectiveTo review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2.Evidence ReviewThe DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence.FindingsThe DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined.Conclusions and RelevanceDADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.
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Özen, Seza, Ezgi Deniz Batu, Ekim Z. Taşkıran, et al. "A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2." Journal of Rheumatology 47, no. 1 (2019): 117–25. http://dx.doi.org/10.3899/jrheum.181384.
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Objective.Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder associated with ADA2 mutations. We aimed to investigate the characteristics and ADA2 enzyme activities of patients with DADA2 compared to non-DADA2 patients.Methods.This is a descriptive study of 24 patients with DADA2 who were admitted to the Adult and Pediatric Rheumatology, Pediatric Haematology, and Pediatric Immunology Departments of Hacettepe University. All ADA2 exons were screened by Sanger sequencing. Serum ADA2 enzyme activity was measured by modified spectrophotometric method.Results.Twenty-four patients with DADA2 were included: 14 with polyarteritis nodosa (PAN)-like phenotype (Group 1); 9 with Diamond-Blackfan anemia (DBA)-like features, and 1 with immunodeficiency (Group 2). Fourteen PAN-like DADA2 patients did not have the typical thrombocytosis seen in classic PAN. Inflammatory attacks were evident only in Group 1 patients. Serum ADA2 activity was low in all patients with DADA2 except one, who was tested after hematopoietic stem cell transplantation. There was no significant difference in ADA2 activities between PAN-like and DBA-like patients. In DADA2 patients with one ADA2 mutation, serum ADA2 activities were as low as those of patients with homozygote DADA2. ADA2 activities were normal in non-DADA2 patients. ADA2 mutations were affecting the dimerization domain in Group 1 patients and the catalytic domain in Group 2 patients.Conclusion.We suggest assessing ADA2 activity along with genetic analysis because there are patients with one ADA2 mutation and absent enzyme activity. Our data suggest a possible genotype–phenotype correlation in which dimerization domain mutations are associated with PAN-like phenotype, and catalytic domain mutations are associated with hematological manifestations.
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Kaya Akca, U., E. Sag, Ş. Ünal, M. Kasap-Cuceoglu, Y. Bilginer, and S. Özen. "OP0168 THE ROLE OF VASCULAR INFLAMMATION MARKERS IN DEFICIENCY OF ADENOSINE DEAMINASE 2." Annals of the Rheumatic Diseases 80, Suppl 1 (2021): 100.1–101. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2504.
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Background:Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease whose pathogenesis has not been clearly elucidated.Objectives:To investigate the role of vascular inflammatory factors in the pathogenesis of DADA2, to compare the vascular inflammation profiles of DADA2 patients with different phenotypes, and to compare DADA2 patients with classic polyarteritis nodosa (PAN).Methods:The study included eighteen DADA2 patients, ten PAN patients, and eight healthy controls. Plasma levels of sST2, sRAGE, Tie-2, sCD40L, Tie-1, sFlt-1, LIGHT, TNF-α, PlGF, IL-6, IL-18, IL-10, MCP-1 were studied by cytometric bead-based multiplex assay panel.Results:Among the DADA2 patients, five had hematological manifestations, 13 had vasculitic findings, and accompanying immunological findings were present in seven patients. Nine patients had neurological findings, five of whom had neuropathy. Hematological findings were Diamond-Blackfan anemia-like phenotype in four patients and bicytopenia (anemia and thrombocytopenia) in one patient. Disease characteristics of DADA2 and PAN patients revealed that neurological involvement and livedo reticularis were more frequent in DADA2 patients (p=0.034 and p=0.009, respectively), while myalgia was more common in PAN patients (p:0.001).Plasma levels of Tie-1 and sFlt-1 were higher in the overall DADA2 patients compared to healthy controls and PAN patients (p<0.001 and p=0.004, respectively). DADA2 patients with PAN-like features had higher sRAGE, Tie-2, and TNF-α levels compared to PAN patients (p=0.013, p=0.003, and p=0.001, respectively).There was no significant difference in the levels of vascular inflammation markers between DADA2 patients with vasculitis and hematological involvement except IL-18. The plasma IL-18 levels were higher in the DADA2 patients with hematological findings compared to vasculitic phenotype (p=0.001). Finally DADA2 patients with neuropathy had higher sRAGE concentrations than patients without neuropathy and healthy controls (p=0.03 and p=0.008, respectively).Conclusion:We suggest that the high plasma IL-18 levels may be associated with an activated IFN pathway, the pathogenesis of hematologic manifestations, and unresponsive to anti-TNF treatment. Higher concentrations of Tie-1, Tie-2, sFlt-1, sRAGE, and TNF-α distinguished DADA2 patients with PAN-like features from PAN patients. We identified sRAGE as a potential biomarker of neuropathy in DADA2 patients.References:[1]Pesciotta EN, Lam H-S, Kossenkov A, et al. In-Depth, Label-Free analysis of the erythrocyte cytoplasmic proteome in Diamond Blackfan Anemia identifies a unique inflammatory signature. PLoS One 2015;10(10):e0140036.[2]Haslbeck KM, Bierhaus A, Erwin S, et al. Receptor for advanced glycation endproduct (RAGE)–mediated nuclear factor-κB activation in vasculitic neuropathy. Muscle Nerve 2004;29(6):853-60.Disclosure of Interests:None declared
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Arts, Katrijn, Jenna R. E. Bergerson, Amanda K. Ombrello, et al. "Warts and DADA2: a Mere Coincidence?" Journal of Clinical Immunology 38, no. 8 (2018): 836–43. http://dx.doi.org/10.1007/s10875-018-0565-0.
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Watanabe, Naoki, Shouguo Gao, Sachiko Kajigaya, et al. "Analysis of Deficiency of Adenosine Deaminase 2 Pathogenesis Based on Single Cell RNA Sequencing of Monocytes." Blood 134, Supplement_1 (2019): 2317. http://dx.doi.org/10.1182/blood-2019-123859.
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Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disease caused by loss-of-function mutations in the ADA2 gene. DADA2 typically presents in childhood and is characterized by vasculopathy, stroke, inflammation, and immunodeficiency as well as hematologic manifestations, such as bone marrow failure and lymphoproliferation. The ADA2 protein is predominantly expressed in stimulated monocytes, dendritic cells and macrophages. ADA2 increases in the setting of inflammation and/or infection conditions. ADA2 has been reported to have a critical role in maintaining the balance between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Macrophages of DADA2 patients are polarized towards M1 subset., DADA2 pathogenesis is not well characterized. To elucidate molecular mechanisms in DADA2 deficiency, we analyzed a gene expression profile of CD14+ monocytes derived from peripheral blood using single cell RNA sequencing (scRNA-seq). Blood was collected from DADA2 patients and age- and sex-matched healthy donors; all patients were studied in a registered research protocol (clinicaltrials.gov NCT00071045). Samples were obtained from 14 DADA2 patients and 6 healthy donors; median age of the DADA2 patients was 23 years old (range, 5 - 57 years). Among the 14 patients, 7 had hematological phenotypes: 5 lymphopenia, 3 neutropenia, 3 thrombocytopenia, and 2 with hypocellular bone marrow histology. Low serum immunoglobulins and cutaneous findings were frequent. Nine of the 14 patients had been treated with TNF inhibitors (etanercept and adalimumab). Mutations were distributed throughout the ADA2 gene; although two siblings had the same mutation, even they showed poor genotype-phenotype correlation. Monocytes were isolated by immunomagnetic positive selection with the EasySep™ positive CD14 selection kit Ⅱ, then subjected to scRNA-seq using Single Cell 3' Reagent Kits v2 (10X Genomics). Libraries for scRNA-seq were sequenced on the HiSeq-3000 instrument. Based on scRNA-seq data, we could classify monocytes into three populations by conventional flow cytometric criteria using cell surface protein expression imputed from scRNA-seq: CD14++CD16- classical, CD14++CD16+ intermediate, and CD14+CD16++ nonclassical monocytes (Figure A). CD16 expression was higher in DADA2 patients than in healthy donors (Figure B). A proportion of nonclassical monocytes among total monocytes were significantly higher in DADA2 patients compared to healthy donors (Figure C). On comparison of gene expression of each monocyte subtypes in DADA2 patients with that of healthy donors, there were 215, 237, and 267 differentially expressed upregulated genes in classical, intermediate, and nonclassical monocytes, respectively (at a threshold avg_logFC > 0.2). Approximately 35% of upregulated genes were overlapped among the three monocyte subtypes of DADA2 patients, including immune response genes such as IFITM1, IFITM2, IFITM3, and C3AR1 (Figure D). Common gene pathways were associated with immune function, such as interferon alpha/beta signaling and interferon gamma signaling. Specific genes to classical and intermediate monocytes were less than 10% of all the upregulated genes. Distinctively, the NF-κB pathway was upregulated in nonclassical monocytes, this might contribute to the pathogenesis of DADA2 as inflammatory disease. Overall, each monocyte subtype of DADA2 patients showed upregulation of immune response gene sets compared to controls. DADA2 patients have increased numbers of nonclassical monocytes which may contribute the immune dysregulation and increased inflammation observed in the disease. Figure Disclosures No relevant conflicts of interest to declare.
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Carmona-Rivera, Carmelo, Sami S. Khaznadar, Kyawt W. Shwin, et al. "Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2." Blood 134, no. 4 (2019): 395–406. http://dx.doi.org/10.1182/blood.2018892752.
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Abstract Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation was observed during active disease in DADA2 and were significantly reduced after remission induction by anti–tumor necrosis factor (TNF) therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A1 and A3 adenosine receptors (ARs) and through reactive oxygen species– and peptidylarginine deiminase–dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A1/A3 AR antagonists, or by an A2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-α. Treatment with an A2AAR agonist decreased nuclear translocation of NF-κB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases.
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Bica, P. F., C. Matucci-Cerinic, E. Hysa, et al. "AB1437 NAILFOLD CAPILLAROSCOPY IN DEFICIENCY OF ADENOSINE DEAMINASE 2 (DADA2): A CASE-CONTROL STUDY." Annals of the Rheumatic Diseases 82, Suppl 1 (2023): 1946.3–1947. http://dx.doi.org/10.1136/annrheumdis-2023-eular.5400.
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BackgroundDeficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease characterized by the presence of systemic inflammation, vasculitis, early-onset stroke, and hematologic manifestations such as cytopenia and immunodeficiency. Mucocutaneous and peripheral microvascular manifestations, such as livedo racemosa, cutaneous ulcers and Raynaud’s phenomenon (RP), can occur, in up to 50%, 22% and 8 % of DADA2 patients respectively [1].ObjectivesTo investigate the microvascular architecture in nailfold capillaries of DADA2 patients comparing them with adequate healthy controls (HCs) and primary RP individuals.MethodsThe data of 9 patients with DADA2 followed at Istituto Gaslini were retrospectively retrieved and compared to 11 HCs and 7 RP. Clinical and genetic data were collected for DADA2 patients. Nailfold videocapillaroscopy (NVC) findings were collected in the whole cohort, independently from their current treatment. The capillaroscopic parameters were classified according to the Fast Track Algorithm and distinguished between scleroderma-pattern (encompassing specific NVC alteration, such as the presence of giant capillaries and/or loss of capillaries combined with abnormally shaped capillaries) and non-scleroderma patterns (non-specific NVC alterations) [2]. A validated semiquantitative scale (score 0–3 for each NVC parameter) was used to compare microvascular findings in the three groups [3]ResultsThe patients with DADA2 were diagnosed according to genetic testing. The disease onset was in early infancy, while the mean age at NVC was of 18.8 years. Livedo racemosa was present in 7 patients (78%), digital ulcers in 1 patient, and an ischemic stroke was reported in 5 patients (55%). None of the patients had RP (0%). The NVC showed the presence of non-specific alterations in all DADA2 patients (capillary dilations in 100%, abnormally shaped capillaries and haemorrages in 23% of patients). The capillary density was normal (median = 9) and no scleroderma-like pattern was found. No significant differences in the rates of each microvascular finding were detected between DADA2, RP patients and HCs.ConclusionThis is the first report investigating the NVC findings in DADA2 patients. Microvascular damage in DADA2 does not show a specific capillaroscopic alteration but the presence of non-specific findings might suggest a disease-related endothelial damage.References[1] Meyts I et al. J Clin Immunol 2018[2] Smith V et al. Autoimmun Rev 2019[3] Sulli A et al. Ann Rheum Dis. 2008Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Yap, Jin Yan, Leen Moens, Ming-Wei Lin, et al. "Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency." Journal of Clinical Immunology 41, no. 8 (2021): 1915–35. http://dx.doi.org/10.1007/s10875-021-01141-0.
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Abstract Purpose Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. Methods In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. Results The median age of the patients was 10 years (mean 20.7 years, range 1–44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. Conclusion Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.
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Hashem, Hasan, Ashish R. Kumar, Ingo Müller, et al. "Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2." Blood 130, no. 24 (2017): 2682–88. http://dx.doi.org/10.1182/blood-2017-07-798660.
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Key Points HSCT represents an effective and definitive treatment of DADA2. HSCT can cure the immunological, hematological, and vascular phenotype of DADA2 with 100% survival at median follow-up of 18 months.
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Lee, Pui Y. "NETing the mechanism of inflammation in DADA2." Blood 134, no. 4 (2019): 338–39. http://dx.doi.org/10.1182/blood.2019001251.
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Wang, W., T. Zhang, L. Wang, and H. Song. "FRI0472 DIAGNOSIS AND MANAGEMENT OF ADENOSINE DEAMINASE 2 DEFICIENCY CHILDREN: THE EXPERIENCE FROM CHINA." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 833.1–833. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3481.
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Background:Adenosine deaminase 2 deficiency (DADA2) is a rare antoinflammatory disease caused by mutations in ADA2 gene, few Chinese cases have been reported.Objectives:To describe and compare the clinical features, genotypes, and treatments of Chinese DADA2 patients and foreign cases.Methods:Primary immunodeficiency disease Panel or Whole Exome Sequencing was performed to suspected subjects, and assays for adenosine deaminase 2(ADA2) enzyme activity were also carried out to them and their parents. Case reports of Chinese and foreign patients with DADA2 were searched from PubMed and Chinese domestic databases.Results:Seven unrelated DADA2 children from China were included in our study, 5 were identified at Peking union medical college hospital and 2 had been reported previously (1 on PubMed and 1 in Chinese literatures). 14 mutations in ADA2 were identified, and 9 of which have not been found in other countries. Four children receiving enzymatic analysis had lower ADA2 enzyme activity compared to their parents. Phenotypic manifestations included fever, skin symptoms, vasculitis, neurologic involvement, et al. The treatments varying from steroids, immunosuppressants, and tocilizumab, anti-TNF therapy and hematopoietic stem cell transplantation (HSCT) were effective depending on different phenotype and severity.Conclusion:This study includes the biggest number of Chinese DADA2 patients at present. We recommend combination of enzymatic analysis with gene screening to confirm the diagnosis. Genotypes of patients from China were some different, the clinical manifestations were similar. We suggest anti-TNF therapy may not be necessary for mild case and HSCT should be considered even without hematological phenotype.References:[1]Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370:911-920.[2]Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. J Clin Immunol. 2018;38:569-578.[3]Wang XN, Zhou ZX, Li SN, Lai JM, Su GX, Kang M, et al. A case report of DADA2. Chin J Rheumatol. 2019;23:476-478.[4]Liu L, Wang W, Wang Y, Hou J, Ying W, Hui X, et al. A Chinese DADA2 patient: report of two novel mutations and successful HSCT. Immunogenetics. 2019;71:299-305.Disclosure of Interests:None declared
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Santo, Gustavo C., Inês Baldeiras, Rita Guerreiro, et al. "Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon’s Syndrome of Unknown Cause." Cerebrovascular Diseases 46, no. 5-6 (2018): 257–64. http://dx.doi.org/10.1159/000495794.
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Background: The association that exists between livedo reticularis (LR) and stroke is known as Sneddon’s syndrome (SnS). The disorder is classified as primary SnS (PSnS), if the cause remains unknown and secondary SnS. The condition is rare and it occurs mainly sporadically. In 2014, 2 independent teams described a new genetic disorder with childhood-onset, which was called deficiency of adenosine deaminase 2 (DADA2), characterized by recurrent fevers and vascular pathologic features that included LR and stroke. All the patients carried recessively inherited mutations in cat eye syndrome chromosome region candidate 1 gene (CECR1), encoding the adenosine deaminase 2 (ADA2) protein. Genetic testing is the standard for the diagnosis of DADA2. However, the diagnostic accuracy of more affordable laboratorial analysis in CECR1-mutated individuals remains to be established. We aim to determine whether plasma ADA2 activity and serum immunoglobulin M (IgM) levels can distinguish (1) DADA2 from other adult patients within the SnS spectrum, and (2) healthy CECR1 heterozygous (HHZ) from healthy controls (HC). Methods: ADA2 activity in plasma and serum IgM concentrations was measured in adult patients within the SnS spectrum, healthy first-degree relatives and HC. Genetic results were used as the reference standard. The primary outcome measures were sensitivity and specificity derived from receiver operating curve analysis. Results: A total of 73 participants were included in the study: 26 patients with PSnS with no CECR1 mutation (PSnS), 6 bi-allelic (DADA2 patients) and 7 HHZ CECR1 mutations and 34 HC. Plasma ADA2 activity and serum IgM levels were significantly lower in DADA2 patients than in PSnS. With the use of the best indexes, plasma ADA2 activity differentiated PSnS from DADA2 with a sensitivity and specificity of 100.0% and HHZ from HC with a sensitivity of 97.1% and specificity of 85.7%. Serum IgM levels also differentiated PSnS from DADA2 with a sensitivity of 85.2% and specificity of 83.3%. Conclusion: Serum IgM levels might be used as a triage tool and plasma ADA2 activity performs perfectly as a diagnostic test for DADA2 in adult patients within the SnS spectrum. ADA2 activity in plasma also reliably distinguishes HHZ from HC.
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Barnes, Christopher J., Linett Rasmussen, Maria Asplund, et al. "Comparing DADA2 and OTU clustering approaches in studying the bacterial communities of atopic dermatitis." Journal of Medical Microbiology 69, no. 11 (2020): 1293–302. http://dx.doi.org/10.1099/jmm.0.001256.
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Introduction. The pathogenesis of atopic dermatitis (AD) is not yet fully understood, but the bacterial composition of AD patients’ skin has been shown to have an increased abundance of Staphylococcus aureus . More recently, coagulase-negative Staphylococcus (CoNS) species were shown to be able to inhibit S. aureus , but further studies are required to determine the effects of Staphylococcus community variation in AD. Aim. Here we investigated whether analysing metabarcoding data with the more recently developed DADA2 approach improves metabarcoding analyses compared to the previously used operational taxonomic unit (OTU) clustering, and can be used to study Staphylococcus community dynamics. Methods. The bacterial 16S rRNA region from tape strip samples of the stratum corneum of AD patients (non-lesional skin) and non-AD controls was metabarcoded. We processed metabarcoding data with two different bioinformatic pipelines (an OTU clustering method and DADA2), which were analysed with and without technical replication (sampling strategy). Results. We found that OTU clustering and DADA2 performed well for community-level studies, as demonstrated by the identification of significant differences in the skin bacterial communities associated with AD. However, the OTU clustering approach inflated bacterial richness, which was worsened by not having technical replication. Data processed with DADA2 likely handled sequencing errors more effectively and thereby did not inflate molecular richness. Conclusion. We believe that DADA2 represents an improvement over an OTU clustering approach, and that biological replication rather than technical replication is a more effective use of resources. However, neither OTU clustering nor DADA2 gave insights into Staphylococcus community dynamics, and caution should remain in not overinterpreting the taxonomic assignments at lower taxonomic ranks.
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Alabbas, Fahad, Omar Alsharief, Isabelle Meyts, et al. "Deficiency of Adenosine Deaminase 2 (DADA2) Presenting As Familial Hodgkin Lymphoma." Blood 132, Supplement 1 (2018): 5373. http://dx.doi.org/10.1182/blood-2018-99-116431.
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Abstract Familial Hodgkin Lymphoma (HL) accounts for 4.5% of HL. Both genetic susceptibility and shared environmental factors can play a role. The usual presentation of HL is cervical lymphadenopathy/ mediastinal mass. Subdiaphragmatic presentation is rare and hepatosplenomegaly is associated with advanced HL. Adenosine deaminase 2 (ADA2) act as an outside extracellular growth factor for integrity of endothelial cells and in the development of certain immune cells. Deficiency of ADA2 (DADA2) is a recently described inborn error of immunity caused by biallelic mutations in adenosine deaminase 2 (ADA2) gene (formerly known as CECR1). It is an auto-inflammatory disorder with a spectrum of vascular, inflammatory, hematological and immunodeficiency phenotypes. The condition is inherited in an autosomal recessive pattern.The association of DADA2 with lymphoproliferation such asT-LGL like condition and ALPS like disease have been reported, however, HL has not previously been reported in DADA2. Herein we describe two siblings with DADA2 who presented with Hodgkin Lymphoma. The first patient is the third child of Saudi first degree related parents. He is known to have bronchial asthma on bronchodilators. At the age of 5 years, he was referred from primary care clinic for investigation of hepatosplenomegaly. He was otherwise well with growth along the fifth centile. His complete blood count (CBC) showed mild lymphopenia, other lab results including liver function tests were within normal. Few months later, he developed non-tender mobile cervical lymph nodes enlargement. Viral serology including EBV was negative based on PCR testing. Lymph node biopsy revealed the diagnosis of HL, mixed cellularity type, EBV negative (Figure 1). Whole exome analysis sequencing identified a homozygous variant in ADA2 gene c.1447_1451del. This variant has been confirmed by Sanger sequencing. Plasma assay of ADA2 enzyme activity revealed undetectable levels compatible with ADA2 deficiency. The patient started on prednisone 2 mg/kg/day, which showed good response in the form of being off blood support and regression of splenomegaly. Few months later, the course was complicated by recurrent infections. The patient remained stable for three years on small dose of prednisone, monthly IVIG due to hypogammaglobulinemia. Recently, etanercept was started to control disease progression. Nine months after the diagnosis of first patient, his younger brother who is known to have mild bronchial asthma on bronchodilators presented at the age of five years with hepatosplenomegaly and generalized lymphadenopathy. Lymph node biopsy revealed the diagnosis of classical HL, lymphocyte-rich subtype. Similar to his sibling, whole exome analysis identified the same mutation (a homozygous variant in ADA2 gene c.1447_1451del). This variant has been confirmed by Sanger sequencing and plasma level of ADA2 enzyme activity was undetectable. After the diagnosis of DADA2, screening for serum immunoglobulin levels showed hypogammaglobulinemia. The patient continues to be off treatment. Both patients were treated with chemotherapy with or without radiotherapy showing good response and they remained in remission at respectively and months after cessation of chemotherapy. This study is important for several reasons. First, this is the first report of HL in the context of DADA2. This again widens the clinical spectrum of DADA2. Interestingly, the boys presented two different forms of HL at the cellular level with no evidence of viral infection. The reported siblings presented with subdiaphragmatic diseases, which is uncommon in HL but in line with the sites of lymphoproliferation in DADA2. In addition, the age of presentation in the two siblings is uncommon in HL (less than 10 years). Second, we report an novel mutation in ADA2 gene. It creates a shift in the reading frame starting at codon Ser483. The new reading frame ends in a stop codon 4 positions downstream. This description and the description of the HL occurrence further expands the spectrum of DADA2. Our data, call for judicious exclusion of ADA2 deficiency in the HL patient with an aberrant course and additional symptoms / signs. In summary, we report familial HL in two patients with a novel deleterious mutation in ADA2 gene. This expands the spectrum of this disease to include cancer and should alert the hemato-oncologist to the possibility of DADA2 as an underlying diagnosis in HL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Lee, Seo-Young, Yeuni Yu, Jin Chung, and Hee Sam Na. "Trimming conditions for DADA2 analysis in QIIME2 platform." International Journal of Oral Biology 46, no. 3 (2021): 146–53. http://dx.doi.org/10.11620/ijob.2021.46.3.146.
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Agajany, Netta, Liran Horev, Netanel Agajany, and Gilad Kenan. "Cerebral Aneurysms and Recurrent TIAs in a 42-Year-Old Patient With DADA2 Mutation." Neurology Genetics 9, no. 5 (2023): e200097. http://dx.doi.org/10.1212/nxg.0000000000200097.
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ObjectivesDeficiency of adenosine deaminase 2 (DADA2) is a rare, recessively inherited autoinflammatory disease with a wide clinical spectrum of manifestations, including strokes and vasculitis.MethodsWe report a case of a patient with DADA2 who presented with neurologic manifestations.ResultsA 42-year-old woman with a known diagnosis of polyarteritis nodosa experienced several episodes of TIAs. Neuroimaging revealed 2 aneurysms in unusual locations. Her young age, ethnic origin, absent of cardiovascular risk factors, and skin involvement raised the suspicion of DADA2. Genetic testing confirmed the diagnosis, and a directed treatment with anti-TNF was initiated.DiscussionDADA2, although thought to be rare, needs to be borne in mind when evaluating patients with a combination of neurologic and systemic symptoms, as early diagnosis and treatment are imperative in preventing permanent disability.
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Schwartz, Daniella Muallem, Moses M. Kitakule, Brian LP Dizon, et al. "Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features." Annals of the Rheumatic Diseases 80, no. 6 (2021): 788–95. http://dx.doi.org/10.1136/annrheumdis-2020-219137.
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Background Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. Objectives We investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy). Methods In this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed. Results Clinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20. Conclusions CAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.
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Zoccolillo, Matteo, Immacolata Brigida, Federica Barzaghi, et al. "Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency." Blood Advances 5, no. 16 (2021): 3174–87. http://dx.doi.org/10.1182/bloodadvances.2020003811.
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Abstract Adenosine deaminase 2 deficiency (DADA2) is a rare inherited disorder that is caused by autosomal recessive mutations in the ADA2 gene. Clinical manifestations include early-onset lacunar strokes, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic defects. Anti–tumor necrosis factor therapy reduces strokes and systemic inflammation. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Autologous HSPC gene therapy may be an alternative curative option for patients with DADA2. We designed a lentiviral vector encoding ADA2 (LV-ADA2) to genetically correct HSPCs. Lentiviral transduction allowed efficient delivery of the functional ADA2 enzyme into HSPCs from healthy donors. Supranormal ADA2 expression in human and mouse HSPCs did not affect their multipotency and engraftment potential in vivo. The LV-ADA2 induced stable ADA2 expression and corrected the enzymatic defect in HSPCs derived from DADA2 patients. Patients’ HSPCs re-expressing ADA2 retained their potential to differentiate into erythroid and myeloid cells. Delivery of ADA2 enzymatic activity in patients’ macrophages led to a complete rescue of the exaggerated inflammatory cytokine production. Our data indicate that HSPCs ectopically expressing ADA2 retain their multipotent differentiation ability, leading to functional correction of macrophage defects. Altogether, these findings support the implementation of HSPC gene therapy for DADA2.
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Pardinhas, Clara, Gustavo Santo, Luís Escada, et al. "A Case of Deficiency of Adenosine Deaminase 2: 28 years of Diagnostic Challenges." Case Reports in Nephrology and Dialysis 11, no. 3 (2021): 340–47. http://dx.doi.org/10.1159/000517141.
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Deficiency of adenosine deaminase 2 (DADA2) is a unique monogenic autoinflammatory disease caused by autosomal recessive loss-of-function mutations in the CECR1 gene which presents as childhood-onset small- and medium-vessel vasculitis. Previously, many of these patients were misdiagnosed and thought to have clinical features of systemic polyarteritis nodosum, which negatively influenced its outcome, since TNF inhibitors seem to have efficacy on the vasculitic phenotype of DADA2. We present a case of a 28-year-old woman with a lifelong unknown syndrome and unique clinical manifestations recently recognized as DADA2. The first manifestation, at 3 months of age, was an episode of facial paralysis during which renovascular hypertension was diagnosed. Later, she developed episodes of prolonged fever, polyarthritis, Raynaud’s phenomenon, gastrointestinal bleeding, and intracerebral hemorrhage. This inflammatory state ultimately led to the development of amyloid A amyloidosis and renal insufficiency.
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Balažiová, Barbora, Gabriela Hrčková, Veronika Dobšinská, and Tomáš Dallos. "Deficiency of adenosine deaminase type 2 (DADA2): clinical picture, diagnosis and treatment." Vnitřní lékařství 70, no. 4 (2024): 233–40. http://dx.doi.org/10.36290/vnl.2024.046.
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Kasap Cuceoglu, Muserref, Seher Sener, Ezgi Deniz Batu, et al. "Systematic review of childhood-onset polyarteritis nodosa and DADA2." Seminars in Arthritis and Rheumatism 51, no. 3 (2021): 559–64. http://dx.doi.org/10.1016/j.semarthrit.2021.04.009.
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Callahan, Benjamin J., Paul J. McMurdie, Michael J. Rosen, Andrew W. Han, Amy Jo A. Johnson, and Susan P. Holmes. "DADA2: High-resolution sample inference from Illumina amplicon data." Nature Methods 13, no. 7 (2016): 581–83. http://dx.doi.org/10.1038/nmeth.3869.
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Michniacki, Thomas F., Mark Hannibal, Charles W. Ross, et al. "Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure." Journal of Clinical Immunology 38, no. 2 (2018): 166–73. http://dx.doi.org/10.1007/s10875-018-0480-4.
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Vai, Silvia, Erika Marin, Roberta Cosso, et al. "A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype." International Journal of Molecular Sciences 22, no. 15 (2021): 8331. http://dx.doi.org/10.3390/ijms22158331.
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Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up.
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Cafaro, Alessia, Federica Pigliasco, Sebastiano Barco, et al. "A Novel LC–MS/MS-Based Method for the Diagnosis of ADA2 Deficiency from Dried Plasma Spot." Molecules 26, no. 18 (2021): 5707. http://dx.doi.org/10.3390/molecules26185707.
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Adenosine Deaminase 2 Deficiency (DADA2) (OMIM: 607575) is a monogenic, autoinflammatory disease caused by the loss of functional homozygous or heterozygous mutations in the ADA 2 gene (previously CECR1, Cat Eye Syndrome Chromosome Region 1). A timely diagnosis is crucial to start Anti-TNF therapies that are efficacious in controlling the disease. The confirmation of DADA2 is based on DNA sequencing and enzymatic assay. It is, thus, very important to have robust and reliable assays that can be rapidly utilized in specialized laboratories that can centralize samples from other centers. In this paper, we show a novel enzymatic assay based on liquid chromatography-tandem mass spectrometry that allows the accurate determination of the ADA2 enzyme activity starting from very small amounts of plasma spotted on filter paper (dried plasma spot). The method allows significantly distinguishing healthy controls from affected patients and carriers and could be of help in implementing the diagnostic workflow of DADA2.
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Balažiová, Barbora, Peter Čižnár, Miroslava Pozdechová, et al. "Deficiency of adenosine deaminase type 2 (DADA2) - first experiences in Slovakia: case reports." Vnitřní lékařství 70, no. 4 (2024): 246–54. http://dx.doi.org/10.36290/vnl.2024.048.
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Szvetnik, Enikoe Amina, Christian Klemann, Ina Hainmann, et al. "Diamond-Blackfan Anemia Phenotype Caused By Deficiency of Adenosine Deaminase 2." Blood 130, Suppl_1 (2017): 874. http://dx.doi.org/10.1182/blood.v130.suppl_1.874.874.
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Abstract Diamond-Blackfan anemia (DBA) is a prototypic ribosomopathy and remains the most common cause of congenital pure red cell aplasia (PRCA). In 2/3 of patients, ribosomal protein haploinsufficiency is disease-causing, while in remaining 1/3 the genetic etiology is unknown. Recently, deficiency of ADA2 (DADA2) due to biallelic CECR1 -mutations was reported in patients with systemic autoinflammatory disease presenting with early onset vasculopathy, strokes, antibody deficiency, and in some cases variable cytopenias. Based on the clinical findings in an ADA2-deficient patient with PRCA resembling DBA, we aimed to define the prevalence and clinical picture of DADA2 within DBA patient cohorts. Patients enrolled in the national observational DBA registry in Germany were evaluated for the presence of mutations in CECR1 gene; additional nonconsecutive patients from the French and Turkish registries within the European DBA (EuroDBA) consortium were part of this study. Functional studies included profiling of polysomes and pre-rRNAs in patient-derived EBV-cell lines, CECR1 RT-PCR, measurements of autophagy and apoptosis, and analysis of erythropoiesis in zebrafish embryos. Systematic mutational and copy number analysis had identified typical ribosomal haploinsufficiency in 169/242 patients (70%). Out of 73 remaining patients, full CECR1 -sequencing was accomplished in 68 cases, of which 4 (6%) carried biallelic CECR1 -mutations. Additional 3 patients with biallelic CECR1 -mutations and DBA phenotype were referred from Germany (the index PRCA case), France and Turkey. In contrast to typical autoinflammatory DADA2 (caused by missense biallelic CECR1 -mutations) all patients studied here had at least one CECR1 -allele affected by truncating/stop-gain/deletion mutation leading to mRNA degradation in patient cells. Low or missing ADA2 enzyme activity in plasma confirmed DADA2, while erythrocyte ADA (eADA) levels and MCV were normal. Transfusion-dependent hypoproliferative anemia developed at a median age of 5 weeks (birth-14 years), while hypogammaglobulinemia developed in all cases either initially or during disease course. Notably, a transient hematologic response to steroids was achieved in 5/7 patients, but no improvement was observed in 2 patients treated with TNF-inhibitor; all patients at one point became heavily transfusion-dependent. Systemic vasculitis or cerebral complications were not observed in our cohort. At the last follow-up, 6/7 patients were alive; 3 had successfully undergone hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning and 1 patient had died due to septic shock. Next, we addressed the question if ribosome biogenesis is affected in ADA2-deficient patient cells. Using pre-rRNA maturation assays, polysome profiling and Western blots we established that ribosome biogenesis is normal in DADA2-related PRCA and there is no increase of TP53 stabilization over basal levels in patient LCLs. Analysis of CECR1 -morpholino zebrafish embryos revealed early anemia with lethal phenotype. Although there was no evidence for extrinsic (e.g. immune-mediated) pathomechanisms in our patients, it remains to be answered if CECR1 loss directly affects erythroid development. Finally, the association between elevated levels of eADA (=ADA1) specific to classical DBA and decreased ADA2 enzyme levels in DADA2-related PRCA remains obscure. In summary, DADA2 can phenotypically mimic DBA and thus extends the spectrum of congenital PRCA. Ribosome synthesis seems not to be affected by CECR1 mutations. DADA2 should be considered in patients with DBA-like phenotype but with normal eADA/MCV and hypogammaglobulinemia, allowing for early stratification aimed at HSCT in affected individuals. Disclosures Grosse: Addmedica: Membership on an entity's Board of Directors or advisory committees.
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Miano, Maurizio, Michela Lupia, Francesca Schena, et al. "Bone Marrow Impairment in Patients with Adenosine Deaminase 2 Deficiency." Blood 144, Supplement 1 (2024): 5396. https://doi.org/10.1182/blood-2024-204733.
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Introduction Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory syndrome caused by biallelic mutations in the ADA2 gene characterized by early-onset inflammatory vasculopathy, strokes and immunodeficiency. Haematologic manifestations include lymphopenia, and bone marrow failure (BMF) mainly pure red cell aplasia. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. TNFα inhibitors control inflammatory symptoms whereas hematopoietic stem cell transplant may be needed to treat refractory cytopenia. Objectives The aim of this study is to characterize the mechanisms of bone marrow damage in DADA2 patients. Methods Bone marrow(BM) samples from DADA2 patients and healthy donors (HD) were analyzed for different in-vitro assays to test in vitro potential therapeutic agents. In-vitro colony forming unit assay were performed from fresh bone marrow mononuclear cells (BMMNCs) in presence of anti-TNFα, human recombinant ADA2 or Eltrombopag. After 14 days CFU colonies were scored. Pro-inflammatory cytokines in the BM plasma were also measured by flow cytometry bead array. Results Fourteen patients (median age 17yo) were studied. Eight /14 (57%) showed reduced erythroid (CFU-E 0.5, normal range 27-81/2 × 104) and myeloid (CFU-GM 3.5, normal range 33-100/2 ×104) progenitor cell growth; The addition of anti-TNFα and eltrombopag 1 ug/ml, had a statistically significant stimulatory effect on the growth of myeloid progenitors (p=0.01 and p= 0.05, respectively). The addition of ADA2 (1 ug/ml and 10 ug/ml) had a stimulatory effect on myeloid progenitors, although not statistically significant. TNFα marrow plasma levels were higher in 4/9 patients (44 %) compared to 1/6 (17%) of healthy controls (p=0,002). No differences were noted in marrow plasma IFNγ levels. Conclusion Our study shows that the bone marrow of DADA2 patients is characterized by an inflammatory milieu and by a reduced growth of marrow progenitor cells, partially rescued in vitro by anti-TNFα and Eltrombopag. Further studies are needed to better understand the mechanisms of BM damage and to develop novel potential therapeutic approaches.
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Pimpale Chavan, Pallavi, Divya Ramadoss, Archana Khan, Pui Y. Lee, and Raju Khubchandani. "Deficiency of Adenosine Deaminase 2 (DADA2): One Disease, Several Faces." Indian Journal of Pediatrics 88, no. 8 (2021): 828–30. http://dx.doi.org/10.1007/s12098-021-03809-2.
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Sönmez, Hafize Emine, Ezgi Deniz Batu, Ekim Z. Taşkıran, Mehmet Alikaşifoğlu, Yelda Bilginer, and Seza Özen. "Genetic testing for DADA2: How can we avoid missing patients?" European Journal of Human Genetics 26, no. 11 (2018): 1563–65. http://dx.doi.org/10.1038/s41431-018-0240-1.
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Insalaco, Antonella, Gian Marco Moneta, Manuela Pardeo, et al. "Variable Clinical Phenotypes and Relation of Interferon Signature with Disease Activity in ADA2 Deficiency." Journal of Rheumatology 46, no. 5 (2019): 523–26. http://dx.doi.org/10.3899/jrheum.180045.
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Objective.An upregulation of type I interferon (IFN) stimulated genes [IFN score (IS)] was described in patients with adenosine deaminase 2 deficiency (DADA2). We describe the clinical course of 5 such patients and the role of IS as a marker of disease activity and severity.Methods.Expression levels of IS were determined by quantitative real-time PCR.Results.Five white patients were identified as carrying CECR1 mutations. The IS before treatment was elevated in 4 out of 5 patients and decreased after treatment.Conclusion.Our data confirm the high variability of DADA2 and suggest type I IS as a biomarker of disease activity.
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Mamadapur, M., S. Mahadevan, A. Singh, R. Chakravarthy C H, R. S, and T. T N. "AB0733 DADA2 VASCULITIS PRESENTING AS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES): AN ATYPICAL PRESENTATION." Annals of the Rheumatic Diseases 80, Suppl 1 (2021): 1396.3–1397. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2660.
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Background:Deficiency of Adenosine Aminase deficiency 2 is monogenic disease presenting with multisystem involvement of vasculitis,Stroke1,hematological manifestations. We hereby present a young child who presented with PRES initially and later diagnosed as DADA2.Only one case of DADA2 presenting as PRES is reported so far2.This case highlights the atypical presentation of DADA2.Objectives:A case report to highlight the rare presentation of DADA2 vasculits.Methods:8 year old developmentally normal male child,born out of consanguineous marriage presented with with fever,abdominal pain, seizures 1 year back.Ultrasound of abdomen revelaed mesenteric lymphadenitis and MRI Brain was suggestive of Meningoencephalitis.He was managed with antivirals and antibiotics then.6 months later,he had fever,skin rash,pain abdomen,status epilepticus,hypertension followed by gangrene of fingers and toes.APLA,ANA,ANCA workup was negative. Complete Hemogram was normal. CRP was 130mg/dl. CT Abdomen was normal and no evidence of aneurysms. Renal Doppler Ultrasound was normal.CT upper limb showed left radial and ulnar artery significant narrowing with patchy occlusion. MRI Brain showed bilateral fronto parietal,occipital,putamen,left insula and subcortical and cortical T2W FLAIR hyperintensity without diffusion restriction suggestive of PRES. He was diagnosed as Childhood Polyarteritis Nodosa and treated with cyclophosphamide. Genetic Analysis of ADA2(CECR1) gene mutation by Sanger Sequencing of exons 2 to 10 showed a known variant (rs202134424) in ADA2 gene.Figure 1.Gangrene of left 1-5th digits and right 4th and 5th digit resorptionFigure 2.T2W FLAIR image showing bilateral fronto parietal,occipital,putamen,left insula and subcortical and cortical hyperintensity without diffusion restriction suggestive of PRES.Results:He was started on Infliximab and is on follow up. No further events noted so far.Rehabilitation of left upper hand was done.Conclusion:DADA2 can present with varied CNS manifestations like infarct,hemorrhage,aneurysms and PRES.High index of suspicion and early recognition can help in maintaining vascular integrity.References:[1]Ganhão S, Loureiro G, Oliveira D, dos-Reis-Maia R, Aguiar F, Quental R et al. Two cases of ADA2 deficiency presenting as childhood polyarteritis nodosa: novel ADA2 variant, atypical CNS manifestations, and literature review. Clinical Rheumatology. 2020;39(12):3853-3860.[2]Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V et al. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India. Arthritis & Rheumatology. 2020;73(2):276-285.Disclosure of Interests:None declared
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Amikishiyev, S., B. Ince, M. Bektas, et al. "AB1300 AA AMYLOIDOSIS IN A PATIENT WITH MUTATIONS IN BOTH ADA2 AND A20 GENES." Annals of the Rheumatic Diseases 81, Suppl 1 (2022): 1756.2–1757. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3346.
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BackgroundAdenosine Deaminase 2 Deficiency (DADA2) and Haploinsufficiency of A20 (HA20) are two recently described monogenic autoinflammatory diseases (AID). The uncontrolled inflammatory response has been associated with an increased risk of AA amyloidosis in other AID, but there are only two reported patients with DADA2-related amyloidosis so far.1,2ObjectivesWe herein report a patient with AA amyloidosis and AID associated with both DADA2 and HA20.MethodsWe used the Ion Torrent platform for deep sequencing.ResultsCase: A 20-year-old male patient born to consanguineous parents (Figure 1), was admitted to our hospital with fever and abdominal pain in June 2014. Peritonitis, hepatomegaly, and a palpable non-tender mass in the right axillary cavity were detected in physical examination, and his laboratory investigations revealed neutrophilic leukocytosis, high acute phase reactants (APR), and nephrotic range proteinuria. CT angiography showed multiple thrombotic microaneurysms in celiac, splenic, superior, and inferior mesenteric and bilateral renal arteries; and MRI documented an additional aneurysm in anterior communicating artery. No finding was detected in hepatitis serology. He had been diagnosed with polyarteritis nodosa, and prednisolone and azathioprine were started. Renal histopathology confirmed the AA amyloidosis. Genetic analysis revealed no pathogenic MEFV variant. Colchicine and anakinra 100 mg/day were added to his treatment. He experienced 1-2 abdominal episodes annually between 2014-2019, and APR were normal between attacks. In March 2019, he was admitted to the hospital because of abdominal pain, high APR, and iron deficiency anemia. No gross pathology was observed in endoscopic examination of gastrointestinal tract, but histopathological investigation of the gastric mucosa and terminal ileum showed AA amyloidosis. Multiple aneurysms were detected in renal arteries with angiography. Deep sequencing of the targeted genes revealed homozygous p.Pro251Leu in ADA2 gene and heterozygous p.Thr647Pro in TNFAIP3 gene encoding A20, confirming the molecular diagnosis of DADA2 and HA20. The patient described oral recurrent aphthous ulcers starting from his childhood, but he had no uveitis or genital ulcers. His mother and brother also had recurrent oral aphthous ulcers. Genetic analyses showed heterozygous p.Pro251Leu variant in ADA2 gene in his mother, and heterozygous p.Gln703Lys variant in NLRP3 gene as well as heterozygous p.Thr647Pro TNFAIP3 variant and heterozygous p.Pro251Leu ADA2 in his brother. An improvement in his findings was observed within 2 weeks after switching his anakinra to adalimumab 40 mg every other week. At his last visit in February 2021, the patient had no complaints with normal APR, and urinalysis analysis showed 200 mg/day proteinuria, which was regressed from 3 g/day.ConclusionThis is the first case of AA amyloidosis associated with ADA2 and TNFAIP3 (A20) variants. ADA2 p.Pro251Leu variant has previously been validated as likely pathogenic, and our patient’s clinical findings were mainly compatible with DADA2. On the other hand, TNFAIP3 gene p.Thr647Pro mutation has been reported as variant of unknown significance, but it may have contributed to the DADA2 associated increased risk of amyloidosis. A better response of proteinuria to adalimumab treatment indicates superiority of anti-TNFs in DADA2 patients compared to anti-IL-1 drugs.References[1]Ekinci RMK, Balci S, Bisgin A, et al. Renal amyloidosis in deficiency of adenosine deaminase 2: successful experience with canakinumab. Pediatrics 2018;142.[2]Batu ED, Karadag O, Taskiran EZ, et al. A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations. The Journal of rheumatology 2015;42:1532-4.Disclosure of InterestsNone declared
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Mortellaro, Alessandra, Matteo Zoccolillo, Cristina Mesa Nuñez, et al. "Lentiviral-Mediated Gene Therapy for the Treatment of Adenosine Deaminase 2 Deficiency." Blood 138, Supplement 1 (2021): 2937. http://dx.doi.org/10.1182/blood-2021-152127.
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Abstract Adenosine deaminase 2 deficiency (DADA2) is a recently defined inborn error of immunity caused by loss-of-function mutations in the ADA2 gene. Patients suffer from severe manifestations, including early-onset lacunar strokes, intracranial hemorrhages, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic abnormalities. The therapeutic benefit of the current treatments is unsatisfactory. Anti-tumor necrosis factor therapy reduces strokes and systemic inflammation but does not correct cytopenia and bone marrow failure. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Therefore, we proposed that autologous HSPC gene therapy may be an alternative curative option for patients who has no compatible donor or cannot receive intense chemotherapy. We performed an in-depth study, using multiparametric flow cytometry, of the bone marrow (BM) cell composition of three adult patients with the hematological phenotype of DADA2. Compared with healthy donors (HDs), patients' BM exhibited a reduced number of mature and immature populations belonging to different hematopoietic lineages. Patients exhibited a substantial reduction in circulating neutrophils and hematopoietic stem cells and progenitor pools in the BM. Severe neutropenia and HSPC defects are direct causes of DADA2. Indeed, ADA2 knock-down in zebrafish - as rodents do not harbor an ADA2 orthologue gene - caused a significant decrease in neutrophil and HSPC numbers, reminiscent of patients' phenotype. Administration of human recombinant ADA2 effectively corrected both neutropenia and defective hematopoiesis in the zebrafish embryo. We used a third-generation LV to restore constitutive ADA2 expression in HSPCs. Transduction of healthy donors' HSPCs allowed efficient delivery of the functional ADA2 enzyme with no toxicity. Supranormal ADA2 expression in healthy donors' and patients' HSPCs was well-tolerated and did not impact HSPC multilineage differentiation potential in vitro and in vivo. We also assessed whether LV-derived ADA2 could correct the hyperinflammatory M1 macrophage phenotype characteristic of DADA2. ADA2 reconstitution in patients' macrophages led to the normalization of IL-6 and TNF release. Similar results were obtained using M1 macrophages differentiated from ADA2-transduced HSPCs. Altogether, our findings indicate that HSPC gene therapy is a promising approach to re-establish stable ADA2 activity and correct the hematological and inflammatory manifestations in patients with DADA2. Disclosures Aiuti: Orchard Therapeutics: Other: PI of clinical trials sponsored by company.
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Motto, Cristina, Federica Teutonico, Nicola Tovaglieri, et al. "Ischemic stroke as presentation of DADA2: Case report and literature review." Journal of the Neurological Sciences 429 (October 2021): 118886. http://dx.doi.org/10.1016/j.jns.2021.118886.
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Pilania, Rakesh Kumar, Aaqib Zaffar Banday, Saniya Sharma, et al. "Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist." Frontiers in Immunology 13 (May 3, 2022). http://dx.doi.org/10.3389/fimmu.2022.869570.
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Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo reticularis. The clinical phenotype of DADA2 is, however, very broad and may involve several organ systems. Apart from vasculitis, children may present with i) Hematological manifestations (ii) Lymphoproliferation and iii) Immunodeficiencies. Patients with DADA2 can have variable patterns of cytopenias and bone marrow failure syndromes. Patients with DADA2 who have predominant haematological manifestations are associated with ADA2 gene variants that result in minimal or no residual ADA2 activity. Lymphoproliferation in patients with DADA2 may range from benign lymphoid hyperplasia to lymphoreticular malignancies. Patients may present with generalized lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome (ALPS) like phenotype, Hodgkin lymphoma, T-cell large granular lymphocytic infiltration of bone marrow and multicentric Castleman disease. Immunodeficiencies associated with DADA are usually mild. Affected patients have variable hypogammaglobulinemia, decrease in B cells, low natural killer cells, common variable immunodeficiency and rarely T cell immunodeficiency. To conclude, DADA2 has an extremely variable phenotype and needs to be considered as a differential diagnosis in diverse clinical conditions. In this review, we describe the evolving clinical phenotypes of DADA2 with a special focus on haematological and immunological manifestations.
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Maximiliano, Barbosa. "Trophic State Drives the Diversity of Protists in a Tropical River (New River, Belize)." December 7, 2022. https://doi.org/10.3390/microorganisms10122425.
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Papatriantafyllou, Maria. "DADA2 prevalence in China." Nature Reviews Rheumatology, December 2, 2024. https://doi.org/10.1038/s41584-024-01191-9.
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Öztürk, Admir, Lara Yağcı, and Serdal Ugurlu. "Mimics and Challenging Presentations of DADA2." Clinical and Experimental Immunology, March 21, 2025. https://doi.org/10.1093/cei/uxaf017.
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Abstract Deficiency of adenosine deaminase 2 (DADA2) has been a challenging diagnosis to make since it was first described in 2014. The disease represents a wide range of phenotypes. Therefore, it may present with various clinical patterns. Throughout the years, several difficult-to-diagnose cases of DADA2 were reported in the literature. Although several studies and reviews were published regarding different phenotypes and manifestations of DADA2, a review of challenging cases with diverse combinations of DADA2 manifestations was needed to integrate the knowledge from the literature into the clinical practice. Immunological, hematologic, autoinflammatory, and adult-onset polyarteritis-nodosa patterns were reported in the literature as cases challenging to diagnose. In this review, we aim to summarize the challenging case reports from the literature, provide an algorithmic approach for these kinds of presentations, and share our perspective and recommendations on the topic. Diagnosing DADA2 on time is a vital issue for preventing fatal and debilitating vascular events with anti-TNF-alpha therapy. Thus, early testing for DADA2 in suspected cases is recommended. Family history and genetic testing of the patient and the first-degree relatives are essential for accurate diagnosis. Thorough systemic examination and imaging might help detect clinically silent findings of vasculitis. Enzymatic activity of ADA2, when available, is also a key diagnostic tool that complements genetic testing and clinical evaluation.
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Asna Ashari, Kosar, Nahid Aslani, Nima Parvaneh, et al. "A case series of ten plus one deficiency of adenosine deaminase 2 (DADA2) patients in Iran." Pediatric Rheumatology 21, no. 1 (2023). http://dx.doi.org/10.1186/s12969-023-00838-3.
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Abstract Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by mutations in the ADA2 gene. DADA2 has a broad spectrum of clinical presentations. Apart from systemic manifestations, we can categorize most of the signs and symptoms of DADA2 into the three groups of vasculitis, hematologic abnormalities, and immunologic dysregulations. The most dominant vasculitis features are skin manifestations, mostly in the form of livedo racemosa/reticularis, and early onset ischemic or hemorrhagic strokes. Hypogammaglobulinemia that is found in many cases of DADA2 brings immunodeficiencies into the differential diagnosis. Cytopenia, pure red cell aplasia (PRCA), and bone marrow failure (BMF) are the hematologic abnormalities commonly found in DADA. Case presentation We introduce eleven patients with DADA2 diagnosis, including two brothers and sisters, one set of twin sisters, and one father and his daughter and son. Ten patients (91%) had consanguineous parents. All the patients manifested livedo racemose/reticularis. Ten patients (91%) reported febrile episodes, and seven (64%) had experienced strokes. Only one patient had hypertension. Two of the patients (11%) presented decreased immunoglobulin levels. One of the patients presented with PRCA. Except for the PRCA patient with G321E mutation, all of our patients delivered G47R mutation, the most common mutation in DADA2 patients. Except for one patient who unfortunately passed away before the diagnosis was made and proper treatment was initiated, the other patients’ symptoms are currently controlled; two of the patients presented with mild symptoms and are now being treated with colchicine, and the eight others responded well to anti-TNFs. The PRCA patient still suffers from hematologic abnormalities and is a candidate for a bone marrow transplant. Conclusions Considering the manifestations and the differential diagnoses, DADA2 is not merely a rheumatologic disease, and introducing this disease to hematologists, neurologists, and immunologists is mandatory to initiate prompt and proper treatment. The efficacy of anti-TNFs in resolving the symptoms of DADA2 patients have been proven, but not for those with hematologic manifestations. Similarly, they were effective in controlling the symptoms of our cohort of patients, except for the one patient with cytopenia.
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Hashem, Hasan, Dimana Dimitrova, and Isabelle Meyts. "Allogeneic Hematopoietic Cell Transplantation for Patients With Deficiency of Adenosine Deaminase 2 (DADA2): Approaches, Obstacles and Special Considerations." Frontiers in Immunology 13 (July 7, 2022). http://dx.doi.org/10.3389/fimmu.2022.932385.
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Deficiency of adenosine deaminase 2 (DADA2) is an inherited autosomal recessive disease characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages, end organ vasculitis), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure. Allogeneic hematopoietic cell transplantation (HCT) is curative for DADA2 as it reverses the hematological, immune and vascular phenotype of DADA2. The primary goal of HCT in DADA2, like in other non-malignant diseases, is engraftment with the establishment of normal hematopoiesis and normal immune function. Strategies in selecting a preparative regimen should take into consideration the specific vulnerabilities to endothelial dysfunction and liver toxicity in DADA2 patients. Overcoming an increased risk of graft rejection while minimizing organ toxicity, graft-versus-host disease, and infections can be particularly challenging in DADA2 patients. This review will discuss approaches to HCT in DADA2 patients including disease-specific considerations, barriers to successful engraftment, post-HCT complications, and clinical outcomes of published patients with DADA2 who have undergone HCT to date.
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Zhao, Xiaozhen, Junmei Zhang, Caifeng Li, et al. "Early onset is an indication of the severity of DADA2 disease." Rheumatology, April 26, 2022. http://dx.doi.org/10.1093/rheumatology/keac233.
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Abstract Objective To find indicators of disease severity and factors of early remission in patients with the deficiency of adenosine deaminase 2 (DADA2). We enrolled 6 DADA2 patients from 6 families. Methods Direct sequencing of ADA2 was performed by Sanger analysis. A literature review was conducted for articles regarding pediatric DADA2. Results We have found that more organs were involved in early-onset DADA2 patients and early-onset patients had high level inflammatory responses, such as elevated ESR, SF, serum amyloid A (SAA) and CRP. Disease severity was not significantly different from missense and frameshift mutation. Early administration of tumor necrosis factor (TNF) inhibitor might result in better remission and reduce recurrence. In the literature, 4 articles describing 51 pediatric DADA2 patients were identified. We also found more organs involved in early onset DADA2 patients. Fever, stroke, peripheral nervous system involvement, hypogammaglobulinemia (HGGN), and hypertension were more frequent in early onset DADA2 patients. Conclusion Early-onset DADA2 may be more severe. Early administration of TNF inhibitor can effectively reduce recurrence and quickly alleviate the disease.
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Dzhus, Mariia, Lisa Ehlers, Marjon Wouters, et al. "A Narrative Review of the Neurological Manifestations of Human Adenosine Deaminase 2 Deficiency." Journal of Clinical Immunology, August 7, 2023. http://dx.doi.org/10.1007/s10875-023-01555-y.
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AbstractDeficiency of human adenosine deaminase type 2 (DADA2) is a complex systemic autoinflammatory disorder characterized by vasculopathy, immune dysregulation, and hematologic abnormalities. The most notable neurological manifestations of DADA2 are strokes that can manifest with various neurological symptoms and are potentially fatal. However, neurological presentations can be diverse. We here present a review of the neurological manifestations of DADA2 to increase clinical awareness of DADA2 as the underlying diagnosis. We reviewed all published cases of DADA2 from 1 January 2014 until 19 July 2022 found via PubMed. A total of 129 articles describing the clinical features of DADA2 were included in the analysis. Six hundred twenty-eight patients diagnosed with DADA2 were included in the review. 50.3% of patients had at least signs of one reported neurological event, which was the initial or sole manifestation in 5.7% and 0.6%, respectively. 77.5% of patients with neurological manifestations had at least signs of one cerebrovascular accident, with lacunar strokes being the most common and 35.9% of them having multiple stroke episodes. There is a remarkable predilection for the brain stem and deep gray matter, with 37.3% and 41.6% of ischemic strokes, respectively. Other neurological involvement included neuropathies, focal neurological deficits, ophthalmological findings, convulsions, and headaches. In summary, neurological manifestations affect a significant proportion of patients with DADA2, and the phenotype is broad. Neurological manifestations can be the first and single manifestation of DADA2. Therefore, stroke, encephalitis, posterior reversible encephalopathy syndrome, mononeuropathy and polyneuropathy, and Behçet’s disease-like presentations should prompt the neurologist to exclude DADA2, especially but not only in childhood.
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Lee, Pui Y., Ezgi D. Batu, and Seza Ozen. "Editorial: DADA2 and other monogenic vasculitides." Frontiers in Immunology 13 (December 8, 2022). http://dx.doi.org/10.3389/fimmu.2022.1108853.
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Gardner, Logan S., Lachlin Vaughan, Danielle T. Avery, et al. "Development of EBV Related Diffuse Large B-cell Lymphoma in Deficiency of Adenosine Deaminase 2 with Uncontrolled EBV Infection." Journal of Clinical Immunology 44, no. 5 (2024). http://dx.doi.org/10.1007/s10875-024-01712-x.
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AbstractDeficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.