Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency

Schepp, Johanna; Bulashevska, Alla; Mannhardt-Laakmann, Wilma; Cao, Hongzhi; Yang, Fang; Seidl, Maximilian; Kelly, Susan J.; Hershfield, Michael S.; Grimbacher, Bodo

doi:10.1007/s10875-016-0245-x

Cited by 78 publications

(75 citation statements)

References 18 publications

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“…A minority of our patients displayed a hypogammaglobulinaemia with a history of recurrent infections, resembling clinical features of patients followed for common variable immunodeficiency (CVID) 21. This finding is likely due to the selection of our patients from the paediatric rheumatology community and should not underestimate the multifaceted phenotype of patients with DADA2, some of whom may display major haematological and/or immunological features of the disease.…”

Section: Discussionmentioning

confidence: 60%

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

et al. 2017

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DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

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Section: Discussionmentioning

confidence: 60%

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

et al. 2017

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“…As other authors have reported, ADA2 activity might be lower in adults that in children [4,14] and an age-adjusted cut-off value would probably be needed. In our study, as in the study of Schepp et al [19], there was no evidence of an influence of the position and type of mutation on ADA2 enzymatic activity. However, this should also be confirmed by the inclusion of patients with other CECR1 mutations.…”

Section: Doi: 101159/000495794supporting

confidence: 81%

“…Other studies have reported on ADA2 activity in CECR1 single-mutation carriers, and while some authors showed a reduction to approximately half [4,19] other reported no difference in relation to HCs [5,14]. Meanwhile, for serum IgM levels, at the best cut-off of 0.92 g/L, AUC was 0.647 (p = 0.225, 95% CI 0.386-0.908), with a sensitivity of 67.6%, and specificity of 71.4 %, which suggests that this test does not accurately identify CECR1 heterozygous.…”

Section: Doi: 101159/000495794mentioning

confidence: 95%

“…Its absence has been associated with a defect in differentiation of M2 macrophages, which leads to a prevalence of pro-inflammatory M1 cells [18], establishing a vicious circle of vasculopathy and inflammation [4]. As previously stated, a mild immunodeficiency can also be observed in DADA2, and indeed, very recently, Schepp et al [19] suggested that patients with antibody deficiency should be screened for DADA2. Some patients present hypogammaglobulinemia that may affect IgM or all Ig subclasses [18].…”

Section: Doi: 101159/000495794mentioning

confidence: 96%

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Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon’s Syndrome of Unknown Cause

et al. 2018

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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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“…In a subsequent study of 48 cases with polyarteritis nodosa associated with livedo reticularis and/or strokes, Gattorno et al performed Sanger sequencing of CECR1 and determined that 15 cases harboured homozygous or compound heterozygous mutations [88]. Since the time of the original description, there has been an expansion of the clinical phenotype of cases with DADA2, from cytopaenias and pure red cell aplasia [89], to lymphoproliferative disease [90–92], and combined immune deficiency, as well as common variable immune deficiency (CVID) [93]. Indeed, a cohort study of 181 cases with antibody deficiency diagnosed 11 individuals with mutation and enzyme activity confirmed DADA2 [94].…”

Section: Classificationmentioning

confidence: 99%

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Moghaddas

Masters

2018

Clinical Science

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Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be ‘autoinflammatory’, but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term ‘autoinflammatory’ is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype–phenotype correlations, with the aim of identifying areas of future research.

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Deficiency of Adenosine Deaminase 2 Causes Antibody Deficiency

Abstract: Deficiency of ADA2 (DADA2) has been reported to cause vasculopathy and early-onset stroke. Our case suggests that it should also be considered when evaluating patients with antibody deficiencies and immune dysregulation syndromes.

Cited by 78 publications

References 18 publications

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon’s Syndrome of Unknown Cause

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

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