Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)

Lee, Pui Y.; Kellner, Erinn S.; Huang, Yuelong; Furutani, Elissa; Huang, Zhengping; Bainter, Wayne; Alosaimi, Mohammed F.; Stafstrom, Kelsey; Platt, Craig D.; Stauber, Tali; Somech, Raz; Tirosh, Irit; Weiss, Aaron R.; Jordan, Michael B.; Krupski, Christa; Eleftheriou, Despina; Brogan, Paul A.; Sobh, Ali; Baz, Zeina; Lefranc, Gérard; Irani, Carla; Kılıç, Sara Şebnem; El-Owaidy, Rasha H.; Lokeshwar, M. R.; Pimpale, Pallavi; Khubchandani, Raju; Chambers, Eugene P.; Chou, Janet; Geha, Raif S.; Nigrović, Peter A.; Zhou, Qing

doi:10.1016/j.jaci.2019.12.908

“…DADA2 is usually a childhood-onset disease, with 24% of cases reported before one year of age, and 77% before the age of 10. DADA2 was rst described in 2014 [1,2], and more than 300 cases have been reported in the literature thus far [3][4][5][6][7]. ADA2 is secreted by monocytes and macrophages, and may have a role in the degradation of extracellular adenosine at the site of in ammation.…”

Section: Introductionmentioning

confidence: 99%

Diagnosis and management of Adenosine Deaminase 2 Deficiency children: the experience from China

Wang

¹

,

Zhang

²

,

Zheng

³

et al. 2020

Preprint

2

1

0

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BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease caused by mutations in the ADA2 gene. Few Chinese cases have been reported. We describe and compare the clinical features, genotypes, and treatments of Chinese DADA2 patients and non-Chinese patients.METHODS: Primary immunodeficiency disease panel or whole-exome sequencing was performed for suspected cases, and assays for adenosine deaminase 2 (ADA2) enzyme activity were also carried out for the patients and their parents. Case reports of Chinese and non-Chinese patients with DADA2 were searched in PubMed and Chinese national databases.RESULTS: Seven unrelated children from China with DADA2 were included in our study. Five were identified at Peking Union Medical College Hospital, and two had been reported previously (1 on PubMed and 1 in Chinese literature). Fourteen mutations in ADA2 were identified, 7 of which have not previously been reported in non-Chinese patients. Four children who underwent enzymatic analysis had lower ADA2 activity compared with their parents. Phenotypic manifestations included fever, skin symptoms, vasculitis, and neurologic involvement. Treatments varying from steroids, immunosuppressants, and tocilizumab, anti-TNF therapy and hematopoietic stem cell transplantation (HSCT) were effective depending on phenotype and severity.CONCLUSION: This study includes the largest number of Chinese DADA2 patients to date. We recommend the combination of enzymatic analysis with gene screening to confirm the diagnosis. Different genotypes were observed among Chinese DADA2 patients; most phenotypes were similar to those of non-Chinese DADA2 patients, except for growth retardation. Disease remission might not be achieved with anti-IL-6 therapy.

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“…In some DADA2 patients, the hematological phenotype may be an accompanying feature., including bone marrow failure and pure red cell aplasia. The commonly used immunosuppressive drugs and TNF-α inhibitors may not reverse the hematological manifestation [7,25], though HSCT has been considered a treatment, speci cally for patients with this phenotype [26]. Indeed, one of our patients underwent HSCT.…”

Section: Comparisonmentioning

confidence: 98%

“…Moreover, some manifestations were not present, such as hepatosplenomegaly, neutropenia, lymphopenia, and low levels of IgA. [7]. The most frequent mutation G47R, which is thought to be more associated with the PAN-like phenotype, in Turkish and Georgian ancestry, and R169Q, which is thought to be associated with susceptibility to stroke, in the European population [4].…”

Section: Comparisonmentioning

confidence: 99%

Diagnosis and management of Adenosine Deaminase 2 Deficiency children: the experience from China

Wang

¹

,

Zhang

²

,

Zheng

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease caused by mutations in the ADA2 gene. Few Chinese cases have been reported. We describe and compare the clinical features, genotypes, and treatments of Chinese DADA2 patients and non-Chinese patients.METHODS: Primary immunodeficiency disease panel or whole-exome sequencing was performed for suspected cases, and assays for adenosine deaminase 2 (ADA2) enzyme activity were also carried out for the patients and their parents. Case reports of Chinese and non-Chinese patients with DADA2 were searched in PubMed and Chinese national databases.RESULTS: Seven unrelated children from China with DADA2 were included in our study. Five were identified at Peking Union Medical College Hospital, and two had been reported previously (1 on PubMed and 1 in Chinese literature). Fourteen mutations in ADA2 were identified, 7 of which have not previously been reported in non-Chinese patients. Four children who underwent enzymatic analysis had lower ADA2 activity compared with their parents. Phenotypic manifestations included fever, skin symptoms, vasculitis, and neurologic involvement. Treatments varying from steroids, immunosuppressants, and tocilizumab, anti-TNF therapy and hematopoietic stem cell transplantation (HSCT) were effective depending on phenotype and severity.CONCLUSION: This study includes the largest number of Chinese DADA2 patients to date. We recommend the combination of enzymatic analysis with gene screening to confirm the diagnosis. Different genotypes were observed among Chinese DADA2 patients; most phenotypes were similar to those of non-Chinese DADA2 patients, except for growth retardation. Disease remission might not be achieved with anti-IL-6 therapy.

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“…106 Mutations with residual ADA2 function tend to be associated with stroke and other inflammatory manifestations responsive to TNF inhibition, whereas mutations that abrogate gene function manifest as profound immunodeficiency and hematologic compromise, often not responsive to TNF inhibitors; bone marrow transplant should be considered for this subset of patients. 107 The physiologic function of ADA2 is not clear, but appears to be different from that of ADA1 and ADAR (doublestranded RNA-specific adenosine deaminase) based on the unique biochemical properties and clinical consequences of mutations in these genes. 108…”

Section: Disorders Of Nf-kb And/or Aberrant Tnf Activitymentioning

confidence: 99%

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

Nigrović

¹

,

Lee

²

,

Hoffman

³

2020

Journal of Allergy and Clinical Immunology

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Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)

Cited by 116 publications

References 39 publications

Diagnosis and management of Adenosine Deaminase 2 Deficiency children: the experience from China

Diagnosis and management of Adenosine Deaminase 2 Deficiency children: the experience from China

Diagnosis and management of Adenosine Deaminase 2 Deficiency children: the experience from China

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

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