THE MANY FACES OF AUTOINFLAMMATION: ADENOSINE DEAMINASE 2 (DADA2) DEFICIENCY IN A 12 YEAR OLD

2021 ◽  
Vol 100 (2) ◽  
pp. 246-253
Author(s):  
A.L. Kozlova ◽  
◽  
Z.A. Nesterenko ◽  
K.K. Egorova ◽  
N.Yu. Kan ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Adenosine Deaminase Deficiency ◽  
Systemic Inflammatory Reaction ◽  
The World ◽  
Pathogenetic Therapy ◽  
Adenosine Deaminase 2 ◽  
The Many ◽  
Historical References

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patient care, as well as provides present state analysis of the DADA2 problem in the world, including terminology, historical references, pathogenesis, diagnosis problems and clinical manifestations.

scholarly journals Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

2021 ◽  
Vol 12 ◽  
Author(s):  
Gianluca Dell’Orso ◽  
Alice Grossi ◽  
Federica Penco ◽  
Roberta Caorsi ◽  
Elena Palmisani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adenosine Deaminase ◽  
Bone Marrow Failure ◽  
Genetic Diagnosis ◽  
Functional Study ◽  
Sequencing Analysis ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Hematopoietic Stem ◽  
Lymphoproliferative Syndrome ◽  
Adenosine Deaminase 2

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.

scholarly journals FRI0472 DIAGNOSIS AND MANAGEMENT OF ADENOSINE DEAMINASE 2 DEFICIENCY CHILDREN: THE EXPERIENCE FROM CHINA

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 833.1-833
Author(s):  
W. Wang ◽  
T. Zhang ◽  
L. Wang ◽  
H. Song
Keyword(s):  
Enzyme Activity ◽  
Adenosine Deaminase ◽  
Case Reports ◽  
Clinical Manifestations ◽  
Primary Immunodeficiency Disease ◽  
Enzymatic Analysis ◽  
College Hospital ◽  
Hematopoietic Stem ◽  
Medical College ◽  
Adenosine Deaminase 2

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

scholarly journals Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients

2021 ◽  
Author(s):  
Hasan Hashem ◽  
Giorgia Bucciol ◽  
Seza Ozen ◽  
Sule Unal ◽  
Ikbal Ok Bozkaya ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Failure ◽  
Hematopoietic Cell ◽  
Recurrent Fever ◽  
Vascular Events ◽  
Livedo Racemosa ◽  
Conditioning Regimens ◽  
Adenosine Deaminase 2

Abstract Purpose Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications HCT is a definitive cure for DADA2 with > 95% survival.

scholarly journals A Case of Deficiency of Adenosine Deaminase 2: 28 years of Diagnostic Challenges

2021 ◽  
pp. 340-347
Author(s):  
Clara Pardinhas ◽  
Gustavo Santo ◽  
Luís Escada ◽  
Jorge Rodrigues ◽  
Maria Rosário Almeida ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Adenosine Deaminase ◽  
Autosomal Recessive ◽  
Autoinflammatory Disease ◽  
Clinical Manifestations ◽  
Loss Of Function ◽  
Childhood Onset ◽  
Amyloid A ◽  
Inflammatory State ◽  
Adenosine Deaminase 2

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.

scholarly journals Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency

2021 ◽  
Vol 5 (16) ◽  
pp. 3174-3187
Author(s):  
Matteo Zoccolillo ◽  
Immacolata Brigida ◽  
Federica Barzaghi ◽  
Serena Scala ◽  
Raisa Jofra Hernández ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Enzymatic Activity ◽  
Adenosine Deaminase ◽  
Systemic Inflammation ◽  
Lentiviral Vector ◽  
Clinical Manifestations ◽  
Hematopoietic Stem ◽  
Functional Correction ◽  
Adenosine Deaminase 2

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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