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 OR13-001 Loss-of-function mutations in CECR1, encoding adenosine deaminase 2 (ADA2), cause recurrent fevers and early onset strokes

2013 ◽  
Vol 11 (Suppl 1) ◽  
pp. A263
Author(s):  
Q Zhou ◽  
A Zavialov ◽  
J Chae ◽  
M Hershfield ◽  
R Sood ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Early Onset ◽  
Loss Of Function ◽  
Adenosine Deaminase 2

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Historical References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 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 Galactosialidosis in a newborn with a novel mutation in the CTSA gene presenting with transient hyperparathyroidism

2017 ◽  
Vol 20 (2) ◽  
pp. 95-97
Author(s):  
E Okulu ◽  
G Tunc ◽  
T Eminoglu ◽  
O Erdeve ◽  
B Atasay ◽  
...  
Keyword(s):  
Lysosomal Storage Disease ◽  
Autosomal Recessive ◽  
Storage Disease ◽  
Age Of Onset ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Inherited Disease ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Infantile Form

Abstract Galactosialidosis is a lysosomal storage disease caused by deficiency of protective protein that is encoded by the cathepsin A (CTSA) gene localized on chromosome 20q13.1. Mutations of this gene are the cause of galactosialidosis that result in loss of function of protective protein. Galactosialidosis is an autosomal recessive inherited disease and has been divided into three subtypes based on age of onset and the severity of clinical manifestations. We report an early infantile form of galactosialidosis in a newborn with a novel mutation on the CTSA gene.

scholarly journals 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

2021 ◽  
Vol 22 (15) ◽  
pp. 8331
Author(s):  
Silvia Vai ◽  
Erika Marin ◽  
Roberta Cosso ◽  
Francesco Saettini ◽  
Sonia Bonanomi ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Systemic Vasculitis ◽  
Systemic Disease ◽  
Loss Of Function ◽  
Mineral Density ◽  
Skeletal Health ◽  
Related Phenotype ◽  
Adenosine Deaminase 2

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.

scholarly journals Dysregulation of myelin synthesis and actomyosin function underlies aberrant myelin in CMT4B1 neuropathy

2021 ◽  
Vol 118 (10) ◽  
pp. e2009469118
Author(s):  
Marta Guerrero-Valero ◽  
Federica Grandi ◽  
Silvia Cipriani ◽  
Valeria Alberizzi ◽  
Roberta Di Guardo ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Loss Of Function ◽  
Childhood Onset ◽  
Demyelinating Neuropathy ◽  
Lipid Turnover ◽  
Cytoskeletal Dynamics ◽  
Catalytically Active ◽  
Tooth Type ◽  
Rhoa Signaling

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P2, with a preference for PtdIns(3,5)P2. A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3′-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P2 levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P2 synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.

scholarly journals Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2

Blood ◽  
2019 ◽  
Vol 134 (4) ◽  
pp. 395-406 ◽  
Author(s):  
Carmelo Carmona-Rivera ◽  
Sami S. Khaznadar ◽  
Kyawt W. Shwin ◽  
Jorge A. Irizarry-Caro ◽  
Liam J. O’Neil ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Nuclear Translocation ◽  
Inflammatory Diseases ◽  
Systemic Vasculitis ◽  
Remission Induction ◽  
Loss Of Function ◽  
Pathogenic Role ◽  
Study Objective ◽  
Adenosine Deaminase 2

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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