Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations

Montfrans, Joris M. van; Hartman, Esther A R; Braun, Kees P.J.; Hennekam, Eric A.M.; Hak, Elisabeth A.; Nederkoorn, Paul J.; Westendorp, Willeke F.; Bredius, Robbert G. M.; Kollen, Wouter J.W.; Schölvinck, Elisabeth H.; Legger, G. Elizabeth; Meyts, Isabelle; Liston, Adrian; Lichtenbelt, Klaske D.; Giltay, Jacques C.; Haaften, Gijs van; Simons, Gaby M. De Vries; Leavis, Helen L.; Sanders, Cornelis J. G.; Bierings, Marc; Nierkens, Stefan; Gijn, M. E. van

doi:10.1093/rheumatology/kev439

Cited by 124 publications

(117 citation statements)

References 11 publications

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“…The clinical presentation of patients with ADA2 deficiency is extremely variable. At present, over 170 patients have been reported with males and females equally affected . The disease onset is usually in childhood with 25% of patients presenting before age 1 year and the majority presenting prior to the age of 10 years.…”

Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 99%

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small‐ and medium‐size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro‐inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti‐TNF therapy with etanercept and that is the first‐line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients’ refractory to anti‐cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine‐tune and steer future therapeutic strategies.

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Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 99%

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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“…As demonstrated in the reports of Van Montfrans et al 47 and Van Eyck et al ,48 successful treatment of patients harbouring the p.Arg169Gln CECR1 mutation further reiterates the origination of ADA2 largely from monocytes and macrophages. Other therapeutic options include anti-TNF therapy, anti-IL-6 therapy and fresh frozen plasma containing ADA2, though the latter's practicality needs further assessment 49…”

Section: Vasculopathy As Manifestation Of Autoinflammatory Processmentioning

confidence: 76%

“…However, the phenotypic variance observed between patients with DADA2, such as localised to severe vasculitis, indicates that both epigenetic and environmental factors may play a role in the development of severe disease manifestations 47. This inherited type of early-onset vasculitis bears resemblances to polyarteritis nodosa; a necrotising vasculopathy with its pathology also poorly understood.…”

Section: Vasculopathy As Manifestation Of Autoinflammatory Processmentioning

confidence: 99%

Autoinflammatory diseases: update on classification diagnosis and management

2016

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The spectrum of systemic autoinflammatory disorders broadens continually. In part, this is due to the more widespread application of massive parallel sequencing, helping with novel gene discovery in this and other areas of rare diseases. Some of the conditions that have been described fit neatly into a conventional idea of autoinflammation. Others, such as Interferon-mediated autoinflammatory diseases, are broadening the concept which we consider to be autoinflammatory disorders. There is also a widening of the clinical phenotypes associated with certain genetic mutations, as genetic testing is used more regularly and increasing numbers of patients are screened. It is also increasingly evident that both autoinflammatory and autoimmune problems are frequently seen as complications of primary immunodeficiency disorders.The aim of this review is to provide an update on some recently discovered conditions, and to discuss how these disorders help to define the concept of autoinflammation. The review will also cover recent discoveries in the biology of innate-immune mediated inflammation, and describe how this has provided the biological rationale for using anti-IL-1 therapies in the treatment of many such conditions. Finally, we discuss the importance of recognising somatic mutations as causes of autoinflammatory clinical phenotypes, and provide practical advice on how this could be tackled in everyday clinical practice.

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“…Hematopoietic stem cell transplantation (HSCT) is another possible therapeutic strategy, because the pathogenesis of DADA2 appears to derive mainly from the myeloid cell lineage. Indeed, the effectiveness of HSCT was initially reported by Van Eyck et al 40 , followed by a number of papers 4137 , in which HSCT normalized the plasma level of ADA2 and suppressed disease manifestations. It will be important to establish the risk-benefit ratios for anti-TNF, HSCT, and other potential therapies in various clinical settings across the widening spectrum of DADA2.…”

Section: Deficiency Of Ada2 (Dada2)mentioning

confidence: 99%

“…The lymphoproliferative picture is shared by a mutation-positive patient who was diagnosed with Castleman's disease and responded to anti IL-6 treatment 36 . Biallelic CECR1 mutations have also been found in patients presenting with anemia, thrombocytopenia, and splenomegaly, leading to the initial clinical diagnosis of Diamond-Blackfan anemia or storage disease 37 . Recently a biallelic 770-kb deletion of chromosome 22q11.1 encompassing both CECR1 and IL17RA (encoding the IL-17 receptor A) was reported in two siblings with a history of both mucocutaneous infection and early-onset systemic vasculitis 38 .…”

Section: Deficiency Of Ada2 (Dada2)mentioning

confidence: 99%

Genomics, Biology, and Human Illness

Oda

Kastner

2017

Rheumatic Disease Clinics of North America

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SYNOPSIS The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically-determined recurrent sterile inflammation, and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines such as IL-1 and TNF and intracellular cytokine signaling pathways have proven effective in many cases. Emerging next generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. In this review we will cover several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies.

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Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations

Cited by 124 publications

References 11 publications

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Autoinflammatory diseases: update on classification diagnosis and management

Genomics, Biology, and Human Illness

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