RARE DISEASE
Adenosine deaminase 2 deficiency
Adenosine deaminase 2 deficiency
Adenosine deaminase 2 deficiency
Synonyms: DADA2, Deficiency of adenosine deaminase 2, Vasculitis due to ADA2 deficiency, Vasculitis due to DADA2
Synonyms: DADA2, Deficiency of adenosine deaminase 2, Vasculitis due to ADA2 deficiency, Vasculitis due to DADA2
Synonyms: DADA2, Deficiency of adenosine deaminase 2, Vasculitis due to ADA2 deficiency, Vasculitis due to DADA2
Drug discovery
2
drugs
With orphan designations
Overview
Adenosine deaminase 2 (ADA2) deficiency is an autosomal recessive disorder caused by ADA2 gene mutations, leading to systemic inflammation, vasculopathy, and multi-organ involvement. Key features include recurrent strokes (often lacunar), livedo racemosa, vasculitis resembling polyarteritis nodosa, cytopenias, and immunodeficiency. Disease onset ranges from infancy to adulthood, with phenotypic variability even within families. Pathogenesis involves dysregulated macrophage polarization and TNF-mediated vascular injury [1][6][16].
Burden
Morbidity: 51% develop strokes (often <5 years), 50% hematologic dysfunction, 30% immunodeficiency [6][13]
Mortality: Predominantly from strokes, infections, or bone marrow failure without treatment [5][14]
Diagnostic delays: Frequent misdiagnosis as polyarteritis nodosa or autoimmune disorders [1][6][13]
Therapies
First-line: TNF inhibitors (etanercept, adalimumab) reduce stroke risk by 78-80% and control vasculitis [8][11][16]
Curative option: Hematopoietic stem cell transplantation for refractory cytopenias, immunodeficiency, or severe vasculitis [3][10][16]
Supportive: Immunosuppressants, IVIG for infections, and avoidance of antiplatelets due to hemorrhage risk [6][14]
Categories: rare circulatory system diseases, rare genetic diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood
Research Papers
263 drug discovery papers about Adenosine deaminase 2 deficiency, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
263 drug discovery papers about Adenosine deaminase 2 deficiency, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-07-01 | Synthetic approaches and biological functions of 2 deoxyadenosine: A review of nucleoside chemistry and cellular dynamics
2′ Deoxyadenosine (dAdo) resides at the critical junction of de novo and salvage deoxyribonucleotide synthesis while salvage phosphorylation of dAdo replenishes the dATP-pool, the de novo pathway via ribonucleotide reductase (RNR) generates dNTPs from ribonucleotides. Disruption of this balance as typified in adenosine deaminase (ADA) deficiency causes intracellular dAdo and dATP accumulation, potent RNR inhibition, dNTP‐pool disruption and replication stress. Concurrently, synthetic modification of the dAdo scaffold has driven the development of analogues that exploit nucleoside transporters, resist deaminative inactivation and selectively accumulate in target cells to modulate DNA repair, immune signalling and mitochondrial DNA maintenance. This review presents a unified account of dAdo’s structural and molecular properties, its role in dNTP homeostasis and cellular dynamics, the pathological consequences of salvage/de novo dysregulation, and the latest synthetic and medicinal chemistry strategies built on the dAdo framework.
2025-06-23 | Inhibition of lysosomal degradation increases expression of mutant ADA2 in DADA2 monocytes.
Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity causing vasculitis and bone marrow failure. Bone marrow failure is mostly unresponsive to TNF-α inhibitors. The limited understanding of the pathomechanisms driving the disease impedes the development of new treatment options. Unlike cellular model systems expressing pathogenic ADA2 variants, primary monocytes from patients with DADA2 lack ADA2 protein expression. This study aimed to analyze the role of protein degradation in the pathogenesis of DADA2 and the therapeutic potential of the lysosomotropic drug hydroxychloroquine in the treatment of patients with DADA2. ADA2 protein expression in CD14+ monocytes from healthy controls (n = 8) and patients with DADA2 (n = 11) was determined by Western blot after inhibition of lysosomal and proteasomal degradation, as well as after hydroxychloroquine treatment in vivo in 1 patient with DADA2. Lipidation of microtubule associated protein 1 light chain 3 beta (LC3B) was analyzed as a measure of autophagic activity. Clinical and laboratory data were recorded in cytopenic patients with DADA2 treated with hydroxychloroquine, 200 mg per day. We demonstrated that inhibition of lysosomal degradation restores ADA2 protein expression in DADA2 monocytes in vitro. DADA2 monocytes exhibited increased autophagic activity. We observed clinical improvement in 2 cytopenic patients with DADA2 who were treated with hydroxychloroquine, and we showed a concomitant increase in ADA2 protein levels in monocytes from one of these patients in vivo. We identified lysosomal protein degradation of ADA2 as a pathomechanism of DADA2 and introduced hydroxychloroquine as a potential treatment option in patients with DADA2 with refractory cytopenia.
2024-11-05 | Bone Marrow Impairment in Patients with Adenosine Deaminase 2 Deficiency
Introduction Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory syndrome caused by biallelic mutations in the ADA2 gene characterized by early-onset inflammatory vasculopathy, strokes and immunodeficiency. Haematologic manifestations include lymphopenia, and bone marrow failure (BMF) mainly pure red cell aplasia. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. TNFα inhibitors control inflammatory symptoms whereas hematopoietic stem cell transplant may be needed to treat refractory cytopenia. Objectives The aim of this study is to characterize the mechanisms of bone marrow damage in DADA2 patients. Methods Bone marrow(BM) samples from DADA2 patients and healthy donors (HD) were analyzed for different in-vitro assays to test in vitro potential therapeutic agents. In-vitro colony forming unit assay were performed from fresh bone marrow mononuclear cells (BMMNCs) in presence of anti-TNFα, human recombinant ADA2 or Eltrombopag. After 14 days CFU colonies were scored. Pro-inflammatory cytokines in the BM plasma were also measured by flow cytometry bead array. Results Fourteen patients (median age 17yo) were studied. Eight /14 (57%) showed reduced erythroid (CFU-E 0.5, normal range 27-81/2 × 104) and myeloid (CFU-GM 3.5, normal range 33-100/2 ×104) progenitor cell growth; The addition of anti-TNFα and eltrombopag 1 ug/ml, had a statistically significant stimulatory effect on the growth of myeloid progenitors (p=0.01 and p= 0.05, respectively). The addition of ADA2 (1 ug/ml and 10 ug/ml) had a stimulatory effect on myeloid progenitors, although not statistically significant. TNFα marrow plasma levels were higher in 4/9 patients (44 %) compared to 1/6 (17%) of healthy controls (p=0,002). No differences were noted in marrow plasma IFNγ levels. Conclusion Our study shows that the bone marrow of DADA2 patients is characterized by an inflammatory milieu and by a reduced growth of marrow progenitor cells, partially rescued in vitro by anti-TNFα and Eltrombopag. Further studies are needed to better understand the mechanisms of BM damage and to develop novel potential therapeutic approaches.
2023-10-18 | Efficacy and safety of thalidomide in children with monogenic autoinflammatory diseases: a single-center, real-world-evidence study.
Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs. This was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses. A total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions. The largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.
2023-07-13 | Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review.
Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes' reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients' long-term recovery.
antibodies
2026-08-06 | Current and future advances in practice: polyarteritis nodosa and related vasculitides.
Polyarteritis nodosa (PAN) is a rare vasculitis affecting predominately medium-sized vessels. Our evolving understanding of PAN, including the role of HBV and discovery of monogenic variants such as deficiency of adenosine deaminase 2 (DADA2), has resulted in idiopathic PAN becoming a very rare condition with an annual incidence of 0.6-19.9/million. The investigative approach is to assess organ involvement and confirm the diagnosis either by imaging or biopsy. Conventional catheter angiography is being replaced by CT or MR angiography, which provide increasingly good resolution of the typical fusiform narrowing and aneurysm. ANCA-associated vasculitis (AAV) should be excluded. DADA2 is being more frequently identified as causing a PAN-like illness, especially in children; cases presenting in adulthood are now recognised. In children and most adults, genotyping for DADA2 should be undertaken. There are no high-quality randomised controlled trials of treatment in idiopathic PAN. Current approaches have been adapted from those used to treat other types of vasculitis. The five-factor score may be used to stratify patients to identify those needing intensive therapy with glucocorticoids combined with CYC. In order to reduce the burden of glucocorticoid toxicity, the ACR has advocated the use of immunosuppressive drugs in addition to steroids in those not initially receiving CYC. Unlike AAV, there appears to be little role for rituximab in the treatment of idiopathic PAN, although it is occasionally used as salvage therapy. HBV-associated PAN is treated with immunosuppression and antiviral therapy. There is reasonably good evidence to support the use of anti-TNF to treat DADA2.
2026-07-27 | Navigating secondary loss of response: breakthrough midbrain ischemia in deficiency of adenosine deaminase 2: a case report
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory vasculopathy that may present in childhood with lacunar infarcts in deep perforator territories. Tumor necrosis factor-alpha (TNF-alpha) inhibitors have changed the outlook for stroke-predominant disease, but ischemic events can still occur during treatment. An 8-year-old girl with recurrent brainstem and deep gray matter lacunar infarcts had normal magnetic resonance angiography and negative autoimmune and antiphospholipid testing. Genetic analysis confirmed a homozygous pathogenic ADA2 variant. She received infliximab 100 mg intravenously every two months with aspirin, but after five doses developed a new right paramedian superior midbrain infarct. Infliximab was stopped and subcutaneous adalimumab 40 mg every two weeks was started. After 18 doses of adalimumab, she has had no further cerebrovascular events. TNF-alpha blockade markedly reduces stroke risk in DADA2, but it does not abolish it. In this child, switching from infliximab to adalimumab was followed by neurological stability. For a vasculitis-predominant patient without hematologic failure, an intra-class switch is a practical option to consider before hematopoietic cell transplantation, with continued neurologic surveillance.
2026-07-07 | Anifrolumab, a potential treatment for ADA2 deficiency.
Adenosine deaminase 2 deficiency (DADA2) is an inborn error of immunity leading to systemic vasculitis, haematological manifestations, immune deficiency and/or autoimmunity. We report the case of a 26-year-old female with an initial diagnosis of systemic lupus erythematosus (SLE). However, atypical evolution patterns for SLE (hypogammaglobulinaemia, moderate B-cell lymphopenia, disappearance of anti-dsDNA) led to the identification of a homozygous class 5 missense variant of CECR1/ADA2, thus to a final diagnosis of DADA2. Strikingly, the patient was treated with anifrolumab (an anti-interferon alpha receptor 1 antibody) that rapidly induced clinical remission and significant corticosteroid tapering. Consistently, we show a lower type I interferon (IFN-I) score and a persistently low tumour necrosis factor α (TNFα) and IL-6 expression levels in whole blood cells of the patient during anifrolumab compared to anti-TNFα. Altogether, this case (1) illustrates the challenging diagnosis of DADA2 (SLE with hypogammaglobulinaemia) and (2) reinforces DADA2 as a disease at the border with type I interferonopathies. Besides, we report here, to our knowledge, the first description of a successful use of anifrolumab in DADA2, paving the way for further studies to validate this therapeutic approach.
2026-06-01 | First Case of Deficiency of Adenosine Deaminase 2 (DADA2) in Oman With a Novel Mutation: A Case Report.
Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disorder that results from biallelic loss-of-function mutations in the ADA2 gene. It is characterized by a spectrum of clinical features, predominantly vasculitis, autoinflammation, dysregulated immune function, and hematologic abnormalities, making it a challenging condition to diagnose. This case report presents the first documented case of DADA2 in Oman, highlighting a novel mutation in the ADA2 gene. It provides insights into the diagnostic process, therapeutic strategies, systemic evaluations, and family-focused management, contributing to the growing understanding of this rare disorder. This is a case of an 18-month-old male toddler who presented with persistent bi-cytopenia and a history of febrile seizures. Genetic testing revealed a novel homozygous pathogenic variant in the ADA2 gene. The patient was managed with infliximab infusions and regular follow-up. This report enhances the understanding of DADA2. The identification of a novel mutation in this case further highlights the growing insight into the pathogenesis of DADA2 and its clinical implications. Effective management requires genetic testing, systemic evaluation, and targeted therapy. Genetic counseling and family screening are crucial for early intervention and disease prevention. Further research is needed to improve diagnostics, treatments, and patient outcomes.
2026-05-26 | Deficiency of Adenosine Deaminase 2 (DADA2): A Single-Center Experience with Diverse Clinical Phenotypes and Outcomes
Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory and immunodysregulatory disorder characterized by vasculopathy, cytopenias, and variable immune dysfunction. Its expanding phenotypic spectrum continues to challenge early recognition and timely intervention. Objective To describe the clinical phenotypes, laboratory features, genetic variants, treatment patterns, and outcomes of patients with DADA2 at a national referral center. Methods We conducted a retrospective review of all genetically confirmed DADA2 cases evaluated over a 5-year period at the Pediatric Allergy, Immunology, and Rheumatology Division at Queen Rania Children’s Hospital (Amman, Jordan). Demographic, clinical, laboratory, and genetic data were extracted, and therapeutic exposures and outcomes were analyzed. Results 10 patients (7 females, 3 males) were identified, all with homozygous pathogenic variants. The c.1471_1472dup mutation was predominant (7/10). The mean age at presentation was 63.7 ± 59.2 months, and the median diagnostic delay was 24.5 months (interquartile range 64.5). Fever was universal, and immune dysregulation was common, including vasculopathy, skin involvement, lymphoproliferation, and cytopenias. Recurrent infections occurred in only three patients. The mean ADA2 level was 1.5 mU/g protein. Two previously unreported phenotypes were observed: nonimmune hydrops fetalis and chronic pancreatitis. Treatments included corticosteroids (10/10), intravenous immunoglobulin (6/10), cyclosporine (6/10), G-CSF (7/10), mycophenolate mofetil (2/10), sirolimus (1/10), anti-TNF therapy (8/10), and hematopoietic stem cell transplantation (3/10). Overall mortality was 40%, with deaths due to sepsis (2), stroke (1), and transplant-related complications (1). Conclusion DADA2 demonstrates marked phenotypic heterogeneity with substantial diagnostic delays. Recognition of atypical presentations, including hydrops fetalis and chronic pancreatitis, may broaden the known disease spectrum. Early diagnosis and timely initiation of anti-TNF therapy or hematopoietic stem cell transplantation remain critical for improving outcomes.
gene therapies
2026-05-28 | Functional characterisation of a novel homozygous p.Y227C ADA2 variant in a child with deficiency of adenosine deaminase type 2.
Deficiency of adenosine deaminase 2 (DADA2) is a rare inflammatory disorder caused by biallelic loss-of-function mutations in ADA2. We sought to functionally characterise a novel homozygous ADA2 variant, p.Y227C (c.680A>G), identified in a six-year-old patient presenting with recurrent fevers, erythema nodosum, and tumor necrosis factor (TNF) inhibitor-responsive myositisMETHODS: Monocyte-derived macrophages from the patient were analysed for ADA2 protein expression, enzymatic activity, and TNFα secretion. To model the inflammatory phenotype in vitro, THP-1 cells were engineered to express the p.Y227C variant. Lentiviral gene correction with wild-type ADA2 was performed to assess rescue of enzymatic function and inflammatory responses. Patient-derived macrophages exhibited markedly reduced ADA2 protein levels and enzymatic activity, accompanied by increased TNFα secretion. THP-1 cells expressing the p.Y227C variant recapitulated this proinflammatory phenotype. Lentiviral reconstitution with wild-type ADA2 restored protein expression and enzymatic activity and normalised TNFα release. The p.Y227C ADA2 variant is pathogenic and promotes inflammation through loss of ADA2 function. Functional rescue following gene correction confirms the causal role of this mutation and underscores the therapeutic potential of restoring ADA2 activity in DADA2.
2025-12-01 | Gene therapy supports long-term reconstitution of patient hematopoietic stem cells in deficiency of adenosine deaminase 2.
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder characterized by systemic inflammation, vasculopathy, immunodeficiency, and bone marrow failure. Current therapies-including anti-TNF agents and allogeneic hematopoietic stem cell transplantation (HSCT)-have limitations, especially for patients with hematologic involvement or no matched donor. We developed a lentiviral vector (LV.ADA2) to restore ADA2 expression in patient hematopoietic stem and progenitor cells (HSPCs) and evaluated its safety and efficacy in preclinical models. LV.ADA2 transduction of mobilized peripheral blood HSPCs from healthy donors resulted in stable ADA2 expression and secretion without impairing clonogenicity, multilineage differentiation, or long-term engraftment in immunodeficient mice. In HSPCs from 12 DADA2 patients, LV.ADA2 restored ADA2 protein and enzymatic activity preserving colony-forming ability and multilineage differentiation in vitro. In vivo, gene-corrected patient-derived HSPCs sustained long-term engraftment and multilineage reconstitution comparable to healthy controls. Integration site analysis confirmed a polyclonal pattern of hematopoietic reconstitution across all experimental settings, with no evidence of clonal dominance. Together, these findings demonstrate that ADA2 gene therapy with a LV is safe, maintains HSPC functionality, and enables durable hematopoietic reconstitution in a mouse model, providing a strong foundation for clinical translation and as a curative alternative to allogeneic HSCT in DADA2.
2025-08-14 | Precision T cell correction platform for Inborn Errors of Immunity.
CRISPR/Cas9 gene editing is a promising tool to correct pathogenic variants for autologous cell therapies targeting Inborn errors of immunity (IEI). Current strategies, such as gene knockout or cDNA knock-in, address many single-gene defects but can disrupt gene expression, highlighting the need for precise correction platforms. While transplanting corrected autologous hematopoietic stem cells is a curative approach, it is unsuitable for patients with advanced disease, inflammation or acute infections. As correcting T cells is an alternative therapeutic strategy for lymphoid IEIs, we present an efficient T cell single nucleotide variant (SNV) correction platform based on homology-directed repair (HDR). By using STAT1 gain-of-function (STAT1-GOF), Cartilage Hair Hypoplasia (CHH), Deficiency of ADA2 (DADA2), and Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as IEI models, we demonstrate that our platform achieves up to 80% correction, with resultant functional correction of the disease phenotype in the selected models. Furthermore, we performed safety profiling using GUIDE-seq, single-cell RNA sequencing, long-read genome sequencing, and proteomics analysis and detected no genomic, transcriptomic, or proteomic aberrations. This study establishes HDR-based SNV editing as a portable method for developing clinical autologous T cell therapies and represents a promising step toward a broad-spectrum gene correction platform for treating diverse monogenic immune disorders.
2025-08-14 | Editing of ADA2 Point Mutation in Human Hematopoietic Stem Cells
Abstract Background The homozygous ADA2 : c.506G>A (p.Arg169Gln; p.R169Q) variant accounts for majority of Deficiency in Adenosine Deaminase 2 (DADA2). This monogenic disorder may be amenable to ex vivo gene therapy by correcting the pathogenic mutation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Objective To apply CRISPR-Cas9 and homology-directed repair (HDR) as a surrogate strategy to model correction of the pathogenic ADA2 c.506G>A variant in healthy cord blood HSPCs. Methods HSPCs were electroporated with optimised CRISPR-Cas9 editing reagents, and editing outcomes, including HDR and on-target deletions, were quantified by ddPCR. Cell functionality was assessed through colony-forming unit (CFU) assays and by xenotransplantation into NOD SCID Gamma (NSG) mice. Two HDR enhancement strategies were tested: (1) genetic inhibitors of p53 and non-homologous end joining (NHEJ) pathways, and (2) pharmacological NHEJ inhibition. Results Small-molecule NHEJ inhibitors increased HDR efficiency approximately two-fold (from ∼40 % to ∼80 %). Edited HSPCs retained normal CFU capacity and successfully engrafted in NSG mice. However, up to 8 % of edited cells exhibited on-target chromosome loss, though this declined over time. Up to 40 % of T cells and fibroblasts demonstrated similar losses under NHEJ inhibitors treatment. In contrast, genetically encoded inhibitors did not improve HDR. Conclusion The ADA2 p. c.506G>A variant can be effectively edited employing surrogate strategy in HSPCs without impairing functionality. Although pharmacological inhibition of NHEJ enhances HDR efficiency, it also increases the risk of on-target chromosome aberrations, highlighting the need for careful consideration of the associated risks and benefits in therapeutic gene editing. Key messages 1) The ADA2 p.R169Q variant can be efficiently corrected via HDR, and the edited CD34+ HSPCs retain their engraftment capability in NSG mice. 2) Pharmacological inhibition of NHEJ using small-molecule inhibitors increases HDR efficiency but is associated with significant on-target deletions and chromosomal arm loss, particularly in differentiated cell types, and in a donor-dependent manner. Capsule summary The ADA2 p.R169Q variant is a viable target for precision gene editing in hematopoietic stem cells. Although inhibition of NHEJ improves HDR efficiency, it concomitantly increases the risk of large on-target deletions, particularly in differentiated cells.
2025-06-25 | Preclinical evaluation of lentiviral gene therapy for adenosine deaminase 2 deficiency (DADA2): engraftment efficiency and biodistribution in humanised NBSGW mice.
Adenosine deaminase type 2 deficiency (DADA2) is caused by bi-allelic loss-of-function mutations in ADA2. While anti-TNF therapy is effective for the autoinflamatory and vasculitic components of the disease it does not correct marrow failure or immunodeficiency. Allogeneic stem cell transplantation (HSCT) offers a potential cure but is limited by challenges such as graft-versus-host-disease and donor availability. We previously demonstrated that lentiviral-mediated ADA2 gene therapy could restore ADA2 enzyme activity in patient-derived cells, correct macrophage inflammatory activation and reduce endothelial activation in vitro. Here, we evaluated the biodistribution and engraftment potential of lentivirally transduced healthy donor and patient-derived haematopoietic stem cells (HSC) in vivo using a humanised NBSGW mouse model. Transduced healthy HSC retained multilineage differentiation and engraftment capacity, without functional impairment. PCR analysis confirmed the absence of viral integration in non-haematopoietic organs, and histology showed no abnormal tissue changes, underscoring the safety and precision of this approach. In DADA2 patient-derived HSC, ADA2 transduction restored protein expression and enzyme activity, supporting improved cellular function and enhanced engraftment potential. These findings provide a strong foundation for advancing ADA2 gene therapy as a therapeutic strategy for DADA2, bringing it closer to clinical application.
proteins
2026-02-28 | Deficiency of Adenosine deaminase Type 2: An Unusual Clinical Presentation
Background:Adenosine deaminase 2(ADA2) deficiency was a systemic autoinflammatory disease characterised by systemic inflammation, vasculitis, early-onset stroke, cytopenias, and immunodeficiency.It is caused by a loss of function due to a mutation in the ADA2 gene and is inherited in an autosomal recessive pattern.Due to its ability to cause early-onset stroke, its vasculitis-like clinical manifestations, and its correlation with immunodeficiency, it is a disease that is difficult to diagnose and treat.Case presentation:In this report, we present a case of a 14-year-old with an unusual clinical onset, where the differential diagnosis involved clinical overlap of several diseases, who was diagnosed with a homozygous mutation in the ADA2 gene, and who came with complaints of abdominal swelling and chest pain.Conclusion:Unlike ADA2 deficiency, which is often considered in differential diagnosis with early-onset stroke, vasculitis, immunodeficiency, and hematological abnormalities, our case contributes to the literature by presenting with liver parenchymal disease and portal hypertension findings.
2026-01-01 | Constitutional Bone Marrow Failure due to Immune Dysregulation Disorders
Abstract Constitutional bone marrow failure (BMF) syndromes caused by immune dysregulation represent a growing subset of hematologic disorders, characterized by complex interactions between hematopoiesis and immune dysfunction. Unlike classical BMF syndromes, these disorders often present with overlapping features of cytopenias, autoimmunity, and immunodeficiency, frequently linked to underlying genetic mutations affecting immune regulatory pathways. Conditions such as GATA2 deficiency, adenosine deaminase 2 (ADA2) deficiency (deficiency of adenosine deaminase 2 (DADA2)), and DNA double-strand break (DSB) repair disorders exemplify this spectrum, with marrow failure arising from both intrinsic stem cell defects and extrinsic immune-mediated destruction. Diagnostic evaluation requires a comprehensive immunologic and genetic workup, including next-generation sequencing and biomarker profiling. Early identification is essential for therapeutic decision-making, particularly in guiding hematopoietic stem cell transplantation (HSCT), the only curative option for many of these disorders. This chapter provides an in-depth overview of the pathophysiology, diagnostic approach, and evolving management strategies for BMF syndromes associated with immune dysregulation.
2025-01-20 | Intracellular concentration of ADA2 is a marker for monocyte differentiation and activation.
Adenosine, a critical molecule regulating cellular function both inside and outside cells, is controlled by two human adenosine deaminases: ADA1 and ADA2. While ADA1 primarily resides in the cytoplasm, ADA2 can be transported to lysosomes within cells or secreted outside the cell. Patients with ADA2 deficiency (DADA2) often suffer from systemic vasculitis due to elevated levels of TNF-α in their blood. Monocytes from DADA2 patients exhibit excessive TNF-α secretion and differentiate into pro-inflammatory M1-type macrophages. Our findings demonstrate that ADA2 localizes to endolysosomes within macrophages, and its intracellular concentration decreases in cells secreting TNF-α. This suggests that ADA2 may function as a lysosomal adenosine deaminase, regulating TNF-α expression by the cells. Interestingly, pneumonia patients exhibit higher ADA2 concentrations in their bronchoalveolar lavage (BAL), correlating with elevated pro-inflammatory cytokine levels. Conversely, cord blood has low ADA2 levels, creating a more immunosuppressive environment. Additionally, secreted ADA2 can bind to apoptotic cells, activating immune cells by reducing extracellular adenosine levels. These findings imply that ADA2 release from monocytes during inflammation, triggered by growth factors, may be crucial for cell activation. Targeting intracellular and extracellular ADA2 activities could pave the way for novel therapies in inflammatory and autoimmune disorders.
2024-11-05 | Unveiling Mysteries: Novel Germline Mutations in Children with Bone Marrow Failure Syndrome and Hematologic Malignancy of Arab Ancestry
Introduction : Inherited predisposition to Hematologic malignancies, due to deleterious germline variants in a variety of genes, is an important clinical entity with implications for the health and management of patients and their family members. We sought to study genetic of Cancer predisposition and or bone marrow failure genes in children treated at King Hussein Cancer Center. Methods: This is a retrospective review of patients who were referred to our Cancer Predisposition clinic that was established in Jan 2020. Referred patients were screened using Jongmans' and McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) for cancer predisposition. Next-generation sequencing of germline DNA was performed using panels of genes suited for patients' diagnosis and family history. Results: 103 patients were screened; all were under age of 18-years .Most of patients fulfilled Jongmans' and/or MIPOGG criteria; sixty patients (58%) had family history of cancer, congenital or other phenotypic anomalies were detected in 45 patients with inherited bone marrow failure syndrome (IBMFS), five patients were referred due the diagnosis of two malignancies, excessive toxicity related to cancer treatment was reported in 10 patients. Primary Hematological malignancies were diagnosed in 58 patients : ALL (n=17), AML (n=11), Myelodysplastic (MDS)/ myeloproliferative diseases (MPD) (n=8) and lymphomas (n=22 ). Pathogenic/Likely pathogenic germline mutations were identified in 25 patients (43%), VUS /likely causative in 27 patients (47% ) with hematologic malignancy across the cancer predisposition (CPS) genes as following: CPS genes in ALL( MSH6,PTCH1,TP53, MET, CDH1, POLE, ERCC6L2, RUNX1, RAD50, ATM, SDHA, RABGAP1, POT1, VHL). CPS genes in AML( ACD, GATA2, MUTYH, BPTF,FANCA, FANCG, HAX1,ELANE and mitochondrial DNA deletion ~5kb in Pearson syndrome). CPS genes in MDS/MPD ( NF1, PTPN11, VPS45, GATA2, ACD,DUT, FANCG, ELANE). CPS genes in Lymphoma(RASGRP1, BRCA1, CHEK2, ATM, MSH3,TNFRSF9, PTCH1, MSH6, NAF1, CASR, DCLRE1C, RASGRP1, RIPK1, ATM, BRCA2, ERBIN, STK4, DOCK8). Pathogenic/Likely pathogenic germline mutations were identified in 36 patients (82%), VUS /likely causative in 8 patients (18%) with IBMFS as following: Fanconi Anemia (FANCA,FANCD2,FANCF,FANCG) Diamond-Blackfan anemia(RPL11, RPS19, RPL5, RPL35A), Dyskeratosis congenita (TINF2, PARN), Shwachman-Diamond Syndrome (SBDS), Severe congenital neutropenia(CSF3R), ERCC6L2 Syndrome (ERCC6L2), Adenosine Deaminase 2 deficiency( ADA2),CBL Syndrome(CBL), Epimerase deficiency galactosemia (GALE), Ghosalhemato diaphyseal dysplasia (TBXAS1),Idiopathic Bone marrow failure ( ALPK3), Bone Marrow Failure Syndrome 4 (MYSM1),THPO-Hereditary Thrombocytopenia (THPO),TUBB1-related Macrothrombocytopenia ( TUBB1), X-linked recessive Wiskott-Aldrich syndrome (WAS). Conclusion: By screening our patients carefully, we were able to identify a significant number of patients with cancer predisposition Syndrome. The early recognition of genetic predispositions for childhood cancers may provide an opportunity of therapy adjustment and specific screening for different syndrome-related malignancies as well as genetic counseling. Further refinement of our testing may require WES to detect structural variations and collaboration with research centers to perform functional testing for patients with VUS.
2024-11-01 | Carrier frequency and incidence estimation of deficiency of adenosine deaminase 2 in the Chinese population based on massive exome sequencing data.
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease characterised by early onset stroke, recurrent fever, and diverse vascular pathologies, caused by loss-of-function homozygous or compound heterozygous variants of ADA2. This research aimed to determine the carrier frequency and expected incidence of DADA2 in China, using massive exome sequencing (ES) data. A total of 50 likely pathogenic/pathogenic variants (LP/PVs) were identified among 69,413 Chinese individuals, including 20 novel and rare variants (<0.0022 % allele frequency), expanding the known spectrum of PVs in ADA2. The overall carrier frequency in the Chinese population was 1.05 % (732/69,413) and the estimated incidence of DADA2 was approximately one in 92,251 individuals. The present study provides an accurate estimation of the prevalence of DADA2 in China, supporting genetic counseling, early diagnosis treatment, and prognostic evaluation.
other
2026-08-04 | Adenosine deaminase type 2 deficiency: From rare to common.
Deficiency of adenosine deaminase type 2 (DADA2) is an inborn error of immunity caused by biallelic pathogenic variants in the ADA2 gene. DADA2 is characterized by a broad spectrum of clinical features, including inflammatory/vasculitic, hematological, and immunodeficient manifestations. Related to this complex clinical phenotype, which overlaps with other diseases, underdiagnosis of DADA2 can be suspected. Several pathophysiological mechanisms causing DADA2 have been described in recent years; however, a unifying pathomechanism explaining all DADA2 disease manifestations is still lacking. Although DADA2 is considered an autosomal recessive disorder, recently several variants in the ADA2 gene were described to cause DADA2 disease in a heterozygous state, via negative dominance. Data from PheWAS studies in large public databases support this observation. Based on these findings, the prevalence of ADA2-associated phenotypes might be much higher than the estimated 1 in 222,146 individuals. As a result, patients with these phenotypes are likely to be encountered by multiple medical disciplines.
2026-07-31 | Immune Dysregulation and Lymphoma Risk in Deficiency of Adenosine Deaminase 2
The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1: Descriptive characteristics and laboratory values of DADA2 patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2026-06-22 | Inborn errors of immunity in children with neuroinflammation.
Inborn errors of immunity (IEIs), an expanding group of monogenic disorders with diverse clinical manifestations, are increasingly recognized to include neuroinflammatory disease. Examples of diseases included under this umbrella are Aicardi-Goutières syndrome, deficiency of adenosine deaminase 2, familial haemophagocytic lymphohistiocytosis, neonatal-onset multisystem inflammatory disease, and acute necrotizing encephalopathy, among others. Children with IEIs may develop encephalopathy, seizures, focal neurological deficits, aseptic meningitis, inflammatory lesions on magnetic resonance imaging, or other central or peripheral nervous system manifestations. While systemic features of autoinflammation or autoimmunity are often present and provide important clues that an underlying IEI may be present, neuroinflammation may be the presenting or sole manifestation in some children. Early recognition of neuroinflammatory presentations of IEIs is critical to prompt immunological and genetic investigations, enabling diagnosis and timely initiation of appropriate immunotherapies, and reducing the risk of long-term neurological outcomes. This review highlights paediatric-onset neuroinflammatory phenotypes associated with IEIs and provides practical frameworks for their recognition and investigation in clinical practice.
2026-05-05 | A Single-Center Study on Childhood Rare Vasculitides: Clinical and Outcome Analysis.
To evaluate rare childhood vasculitides using standardized clinical, laboratory, imaging, and outcome data. A retrospective cohort of 74 children with 8 rare vasculitides was assessed at a single center. Demographics, imaging, and disease activity (Pediatric Vasculitis Activity Score (PVAS)) and damage (Pediatric Vasculitis Damage Index) scores were recorded at diagnosis, 12 months, and last visit. Among 74 patients, 39 (52.7%) were girls. Median diagnosis age was 13.5 years. Subtype distribution was vascular Behçet syndrome 22 (29.7%), Takayasu arteritis (TA) 16 (21.6%), deficiency of adenosine deaminase 2 (DADA2) 14 (18.9%), polyarteritis nodosa 11 (14.9%), granulomatosis with polyangiitis (GPA) 6 (8.1%), primary angiitis of the central nervous system (PACNS) 3 (4.1%), eosinophilic GPA 1 (1.4%), and Cogan syndrome 1 (1.4%). The DADA2 had the longest diagnostic delay (median [IQR]: 20 [6-99.75] months), while PACNS had the youngest median age at onset (4.6 [3.07-7.95] years). Overall, 13.5% (n=10) were diagnosed before age 5, showing recurrent fever (60%, n=6) and anemia (50%, n=5), less skin/mucosal (40%, n=4), musculoskeletal (30%, n=3), cardiovascular (20%, n=2), and pulmonary involvement (20%, n=2), and higher PVAS (median 2.0, IQR 1.25-2.75). At 12 months, all had low disease activity. The TA had the longest corticosteroid use, highest damage, and slower remission. Overall remission was 91.9% (n=68/74), while GPA patients had more flares in the first year (median 1.0, IQR 0.25-1.75). Prognosis was favorable, but TA and monogenic vasculitides showed greater damage. In children <5 years, higher activity but good early response emphasize timely, individualized management.
2026-03-23 | ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances.
Deficiency of adenosine deaminase 2 (DADA2) causes a complex phenotype of autoinflammation and immunodeficiency. Bone marrow failure is often refractory to treatment with tumour necrosis factor-alpha (TNF-alpha) inhibitors and additional treatment options are needed. However, the pathomechanisms underlying the disease remain incompletely understood. The aim of this study was to examine the viability and metabolic profile of ADA2-deficient cells and to characterise the activity of different cell death pathways to advance the mechanistic understanding of DADA2. By flow cytometry and western blot, we showed that ADA2-/- U-937 cells and PBMCs from DADA2 patients showed significantly elevated levels of cell death compared with cells expressing wild-type ADA2. Viability of ADA2-deficient cells was not improved by inhibitors of apoptosis, necroptosis, pyroptosis and ferroptosis. Blocking of TNF-alpha, type I interferon and STING signalling as well as reintroduction of wild-type ADA2 protein did not rescue the cell death phenotype in vitro. ADA2-deficient cells had an aberrant morphology with increased cell size and granularity and were impaired in their proliferative capacity. To identify the cause of the impaired viability, we performed 13C glucose tracer metabolomics experiments which revealed disturbances in the pentose phosphate pathway of ADA2-deficient cells. This tended to be associated with increased exposure to intracellular reactive oxygen species that was attenuated in the PBMCs of a DADA2 patient measured after successful hematopoietic stem cell transplantation. Collectively, our findings established increased levels of cell death as a possible pathomechanism of DADA2 and showed that the absence of ADA2 leads to an impairment of the pentose phosphate pathway which may account for the cellular vulnerability of ADA2-deficient cells.
small molecules
2025-07-01 | Synthetic approaches and biological functions of 2 deoxyadenosine: A review of nucleoside chemistry and cellular dynamics
2′ Deoxyadenosine (dAdo) resides at the critical junction of de novo and salvage deoxyribonucleotide synthesis while salvage phosphorylation of dAdo replenishes the dATP-pool, the de novo pathway via ribonucleotide reductase (RNR) generates dNTPs from ribonucleotides. Disruption of this balance as typified in adenosine deaminase (ADA) deficiency causes intracellular dAdo and dATP accumulation, potent RNR inhibition, dNTP‐pool disruption and replication stress. Concurrently, synthetic modification of the dAdo scaffold has driven the development of analogues that exploit nucleoside transporters, resist deaminative inactivation and selectively accumulate in target cells to modulate DNA repair, immune signalling and mitochondrial DNA maintenance. This review presents a unified account of dAdo’s structural and molecular properties, its role in dNTP homeostasis and cellular dynamics, the pathological consequences of salvage/de novo dysregulation, and the latest synthetic and medicinal chemistry strategies built on the dAdo framework.
2025-06-23 | Inhibition of lysosomal degradation increases expression of mutant ADA2 in DADA2 monocytes.
Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity causing vasculitis and bone marrow failure. Bone marrow failure is mostly unresponsive to TNF-α inhibitors. The limited understanding of the pathomechanisms driving the disease impedes the development of new treatment options. Unlike cellular model systems expressing pathogenic ADA2 variants, primary monocytes from patients with DADA2 lack ADA2 protein expression. This study aimed to analyze the role of protein degradation in the pathogenesis of DADA2 and the therapeutic potential of the lysosomotropic drug hydroxychloroquine in the treatment of patients with DADA2. ADA2 protein expression in CD14+ monocytes from healthy controls (n = 8) and patients with DADA2 (n = 11) was determined by Western blot after inhibition of lysosomal and proteasomal degradation, as well as after hydroxychloroquine treatment in vivo in 1 patient with DADA2. Lipidation of microtubule associated protein 1 light chain 3 beta (LC3B) was analyzed as a measure of autophagic activity. Clinical and laboratory data were recorded in cytopenic patients with DADA2 treated with hydroxychloroquine, 200 mg per day. We demonstrated that inhibition of lysosomal degradation restores ADA2 protein expression in DADA2 monocytes in vitro. DADA2 monocytes exhibited increased autophagic activity. We observed clinical improvement in 2 cytopenic patients with DADA2 who were treated with hydroxychloroquine, and we showed a concomitant increase in ADA2 protein levels in monocytes from one of these patients in vivo. We identified lysosomal protein degradation of ADA2 as a pathomechanism of DADA2 and introduced hydroxychloroquine as a potential treatment option in patients with DADA2 with refractory cytopenia.
2024-11-05 | Bone Marrow Impairment in Patients with Adenosine Deaminase 2 Deficiency
Introduction Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory syndrome caused by biallelic mutations in the ADA2 gene characterized by early-onset inflammatory vasculopathy, strokes and immunodeficiency. Haematologic manifestations include lymphopenia, and bone marrow failure (BMF) mainly pure red cell aplasia. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. TNFα inhibitors control inflammatory symptoms whereas hematopoietic stem cell transplant may be needed to treat refractory cytopenia. Objectives The aim of this study is to characterize the mechanisms of bone marrow damage in DADA2 patients. Methods Bone marrow(BM) samples from DADA2 patients and healthy donors (HD) were analyzed for different in-vitro assays to test in vitro potential therapeutic agents. In-vitro colony forming unit assay were performed from fresh bone marrow mononuclear cells (BMMNCs) in presence of anti-TNFα, human recombinant ADA2 or Eltrombopag. After 14 days CFU colonies were scored. Pro-inflammatory cytokines in the BM plasma were also measured by flow cytometry bead array. Results Fourteen patients (median age 17yo) were studied. Eight /14 (57%) showed reduced erythroid (CFU-E 0.5, normal range 27-81/2 × 104) and myeloid (CFU-GM 3.5, normal range 33-100/2 ×104) progenitor cell growth; The addition of anti-TNFα and eltrombopag 1 ug/ml, had a statistically significant stimulatory effect on the growth of myeloid progenitors (p=0.01 and p= 0.05, respectively). The addition of ADA2 (1 ug/ml and 10 ug/ml) had a stimulatory effect on myeloid progenitors, although not statistically significant. TNFα marrow plasma levels were higher in 4/9 patients (44 %) compared to 1/6 (17%) of healthy controls (p=0,002). No differences were noted in marrow plasma IFNγ levels. Conclusion Our study shows that the bone marrow of DADA2 patients is characterized by an inflammatory milieu and by a reduced growth of marrow progenitor cells, partially rescued in vitro by anti-TNFα and Eltrombopag. Further studies are needed to better understand the mechanisms of BM damage and to develop novel potential therapeutic approaches.
2023-10-18 | Efficacy and safety of thalidomide in children with monogenic autoinflammatory diseases: a single-center, real-world-evidence study.
Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs. This was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses. A total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions. The largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.
2023-07-13 | Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review.
Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes' reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients' long-term recovery.
antibodies
2026-08-06 | Current and future advances in practice: polyarteritis nodosa and related vasculitides.
Polyarteritis nodosa (PAN) is a rare vasculitis affecting predominately medium-sized vessels. Our evolving understanding of PAN, including the role of HBV and discovery of monogenic variants such as deficiency of adenosine deaminase 2 (DADA2), has resulted in idiopathic PAN becoming a very rare condition with an annual incidence of 0.6-19.9/million. The investigative approach is to assess organ involvement and confirm the diagnosis either by imaging or biopsy. Conventional catheter angiography is being replaced by CT or MR angiography, which provide increasingly good resolution of the typical fusiform narrowing and aneurysm. ANCA-associated vasculitis (AAV) should be excluded. DADA2 is being more frequently identified as causing a PAN-like illness, especially in children; cases presenting in adulthood are now recognised. In children and most adults, genotyping for DADA2 should be undertaken. There are no high-quality randomised controlled trials of treatment in idiopathic PAN. Current approaches have been adapted from those used to treat other types of vasculitis. The five-factor score may be used to stratify patients to identify those needing intensive therapy with glucocorticoids combined with CYC. In order to reduce the burden of glucocorticoid toxicity, the ACR has advocated the use of immunosuppressive drugs in addition to steroids in those not initially receiving CYC. Unlike AAV, there appears to be little role for rituximab in the treatment of idiopathic PAN, although it is occasionally used as salvage therapy. HBV-associated PAN is treated with immunosuppression and antiviral therapy. There is reasonably good evidence to support the use of anti-TNF to treat DADA2.
2026-07-27 | Navigating secondary loss of response: breakthrough midbrain ischemia in deficiency of adenosine deaminase 2: a case report
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory vasculopathy that may present in childhood with lacunar infarcts in deep perforator territories. Tumor necrosis factor-alpha (TNF-alpha) inhibitors have changed the outlook for stroke-predominant disease, but ischemic events can still occur during treatment. An 8-year-old girl with recurrent brainstem and deep gray matter lacunar infarcts had normal magnetic resonance angiography and negative autoimmune and antiphospholipid testing. Genetic analysis confirmed a homozygous pathogenic ADA2 variant. She received infliximab 100 mg intravenously every two months with aspirin, but after five doses developed a new right paramedian superior midbrain infarct. Infliximab was stopped and subcutaneous adalimumab 40 mg every two weeks was started. After 18 doses of adalimumab, she has had no further cerebrovascular events. TNF-alpha blockade markedly reduces stroke risk in DADA2, but it does not abolish it. In this child, switching from infliximab to adalimumab was followed by neurological stability. For a vasculitis-predominant patient without hematologic failure, an intra-class switch is a practical option to consider before hematopoietic cell transplantation, with continued neurologic surveillance.
2026-07-07 | Anifrolumab, a potential treatment for ADA2 deficiency.
Adenosine deaminase 2 deficiency (DADA2) is an inborn error of immunity leading to systemic vasculitis, haematological manifestations, immune deficiency and/or autoimmunity. We report the case of a 26-year-old female with an initial diagnosis of systemic lupus erythematosus (SLE). However, atypical evolution patterns for SLE (hypogammaglobulinaemia, moderate B-cell lymphopenia, disappearance of anti-dsDNA) led to the identification of a homozygous class 5 missense variant of CECR1/ADA2, thus to a final diagnosis of DADA2. Strikingly, the patient was treated with anifrolumab (an anti-interferon alpha receptor 1 antibody) that rapidly induced clinical remission and significant corticosteroid tapering. Consistently, we show a lower type I interferon (IFN-I) score and a persistently low tumour necrosis factor α (TNFα) and IL-6 expression levels in whole blood cells of the patient during anifrolumab compared to anti-TNFα. Altogether, this case (1) illustrates the challenging diagnosis of DADA2 (SLE with hypogammaglobulinaemia) and (2) reinforces DADA2 as a disease at the border with type I interferonopathies. Besides, we report here, to our knowledge, the first description of a successful use of anifrolumab in DADA2, paving the way for further studies to validate this therapeutic approach.
2026-06-01 | First Case of Deficiency of Adenosine Deaminase 2 (DADA2) in Oman With a Novel Mutation: A Case Report.
Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disorder that results from biallelic loss-of-function mutations in the ADA2 gene. It is characterized by a spectrum of clinical features, predominantly vasculitis, autoinflammation, dysregulated immune function, and hematologic abnormalities, making it a challenging condition to diagnose. This case report presents the first documented case of DADA2 in Oman, highlighting a novel mutation in the ADA2 gene. It provides insights into the diagnostic process, therapeutic strategies, systemic evaluations, and family-focused management, contributing to the growing understanding of this rare disorder. This is a case of an 18-month-old male toddler who presented with persistent bi-cytopenia and a history of febrile seizures. Genetic testing revealed a novel homozygous pathogenic variant in the ADA2 gene. The patient was managed with infliximab infusions and regular follow-up. This report enhances the understanding of DADA2. The identification of a novel mutation in this case further highlights the growing insight into the pathogenesis of DADA2 and its clinical implications. Effective management requires genetic testing, systemic evaluation, and targeted therapy. Genetic counseling and family screening are crucial for early intervention and disease prevention. Further research is needed to improve diagnostics, treatments, and patient outcomes.
2026-05-26 | Deficiency of Adenosine Deaminase 2 (DADA2): A Single-Center Experience with Diverse Clinical Phenotypes and Outcomes
Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory and immunodysregulatory disorder characterized by vasculopathy, cytopenias, and variable immune dysfunction. Its expanding phenotypic spectrum continues to challenge early recognition and timely intervention. Objective To describe the clinical phenotypes, laboratory features, genetic variants, treatment patterns, and outcomes of patients with DADA2 at a national referral center. Methods We conducted a retrospective review of all genetically confirmed DADA2 cases evaluated over a 5-year period at the Pediatric Allergy, Immunology, and Rheumatology Division at Queen Rania Children’s Hospital (Amman, Jordan). Demographic, clinical, laboratory, and genetic data were extracted, and therapeutic exposures and outcomes were analyzed. Results 10 patients (7 females, 3 males) were identified, all with homozygous pathogenic variants. The c.1471_1472dup mutation was predominant (7/10). The mean age at presentation was 63.7 ± 59.2 months, and the median diagnostic delay was 24.5 months (interquartile range 64.5). Fever was universal, and immune dysregulation was common, including vasculopathy, skin involvement, lymphoproliferation, and cytopenias. Recurrent infections occurred in only three patients. The mean ADA2 level was 1.5 mU/g protein. Two previously unreported phenotypes were observed: nonimmune hydrops fetalis and chronic pancreatitis. Treatments included corticosteroids (10/10), intravenous immunoglobulin (6/10), cyclosporine (6/10), G-CSF (7/10), mycophenolate mofetil (2/10), sirolimus (1/10), anti-TNF therapy (8/10), and hematopoietic stem cell transplantation (3/10). Overall mortality was 40%, with deaths due to sepsis (2), stroke (1), and transplant-related complications (1). Conclusion DADA2 demonstrates marked phenotypic heterogeneity with substantial diagnostic delays. Recognition of atypical presentations, including hydrops fetalis and chronic pancreatitis, may broaden the known disease spectrum. Early diagnosis and timely initiation of anti-TNF therapy or hematopoietic stem cell transplantation remain critical for improving outcomes.
gene therapies
2026-05-28 | Functional characterisation of a novel homozygous p.Y227C ADA2 variant in a child with deficiency of adenosine deaminase type 2.
Deficiency of adenosine deaminase 2 (DADA2) is a rare inflammatory disorder caused by biallelic loss-of-function mutations in ADA2. We sought to functionally characterise a novel homozygous ADA2 variant, p.Y227C (c.680A>G), identified in a six-year-old patient presenting with recurrent fevers, erythema nodosum, and tumor necrosis factor (TNF) inhibitor-responsive myositisMETHODS: Monocyte-derived macrophages from the patient were analysed for ADA2 protein expression, enzymatic activity, and TNFα secretion. To model the inflammatory phenotype in vitro, THP-1 cells were engineered to express the p.Y227C variant. Lentiviral gene correction with wild-type ADA2 was performed to assess rescue of enzymatic function and inflammatory responses. Patient-derived macrophages exhibited markedly reduced ADA2 protein levels and enzymatic activity, accompanied by increased TNFα secretion. THP-1 cells expressing the p.Y227C variant recapitulated this proinflammatory phenotype. Lentiviral reconstitution with wild-type ADA2 restored protein expression and enzymatic activity and normalised TNFα release. The p.Y227C ADA2 variant is pathogenic and promotes inflammation through loss of ADA2 function. Functional rescue following gene correction confirms the causal role of this mutation and underscores the therapeutic potential of restoring ADA2 activity in DADA2.
2025-12-01 | Gene therapy supports long-term reconstitution of patient hematopoietic stem cells in deficiency of adenosine deaminase 2.
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder characterized by systemic inflammation, vasculopathy, immunodeficiency, and bone marrow failure. Current therapies-including anti-TNF agents and allogeneic hematopoietic stem cell transplantation (HSCT)-have limitations, especially for patients with hematologic involvement or no matched donor. We developed a lentiviral vector (LV.ADA2) to restore ADA2 expression in patient hematopoietic stem and progenitor cells (HSPCs) and evaluated its safety and efficacy in preclinical models. LV.ADA2 transduction of mobilized peripheral blood HSPCs from healthy donors resulted in stable ADA2 expression and secretion without impairing clonogenicity, multilineage differentiation, or long-term engraftment in immunodeficient mice. In HSPCs from 12 DADA2 patients, LV.ADA2 restored ADA2 protein and enzymatic activity preserving colony-forming ability and multilineage differentiation in vitro. In vivo, gene-corrected patient-derived HSPCs sustained long-term engraftment and multilineage reconstitution comparable to healthy controls. Integration site analysis confirmed a polyclonal pattern of hematopoietic reconstitution across all experimental settings, with no evidence of clonal dominance. Together, these findings demonstrate that ADA2 gene therapy with a LV is safe, maintains HSPC functionality, and enables durable hematopoietic reconstitution in a mouse model, providing a strong foundation for clinical translation and as a curative alternative to allogeneic HSCT in DADA2.
2025-08-14 | Precision T cell correction platform for Inborn Errors of Immunity.
CRISPR/Cas9 gene editing is a promising tool to correct pathogenic variants for autologous cell therapies targeting Inborn errors of immunity (IEI). Current strategies, such as gene knockout or cDNA knock-in, address many single-gene defects but can disrupt gene expression, highlighting the need for precise correction platforms. While transplanting corrected autologous hematopoietic stem cells is a curative approach, it is unsuitable for patients with advanced disease, inflammation or acute infections. As correcting T cells is an alternative therapeutic strategy for lymphoid IEIs, we present an efficient T cell single nucleotide variant (SNV) correction platform based on homology-directed repair (HDR). By using STAT1 gain-of-function (STAT1-GOF), Cartilage Hair Hypoplasia (CHH), Deficiency of ADA2 (DADA2), and Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as IEI models, we demonstrate that our platform achieves up to 80% correction, with resultant functional correction of the disease phenotype in the selected models. Furthermore, we performed safety profiling using GUIDE-seq, single-cell RNA sequencing, long-read genome sequencing, and proteomics analysis and detected no genomic, transcriptomic, or proteomic aberrations. This study establishes HDR-based SNV editing as a portable method for developing clinical autologous T cell therapies and represents a promising step toward a broad-spectrum gene correction platform for treating diverse monogenic immune disorders.
2025-08-14 | Editing of ADA2 Point Mutation in Human Hematopoietic Stem Cells
Abstract Background The homozygous ADA2 : c.506G>A (p.Arg169Gln; p.R169Q) variant accounts for majority of Deficiency in Adenosine Deaminase 2 (DADA2). This monogenic disorder may be amenable to ex vivo gene therapy by correcting the pathogenic mutation in CD34+ hematopoietic stem and progenitor cells (HSPCs). Objective To apply CRISPR-Cas9 and homology-directed repair (HDR) as a surrogate strategy to model correction of the pathogenic ADA2 c.506G>A variant in healthy cord blood HSPCs. Methods HSPCs were electroporated with optimised CRISPR-Cas9 editing reagents, and editing outcomes, including HDR and on-target deletions, were quantified by ddPCR. Cell functionality was assessed through colony-forming unit (CFU) assays and by xenotransplantation into NOD SCID Gamma (NSG) mice. Two HDR enhancement strategies were tested: (1) genetic inhibitors of p53 and non-homologous end joining (NHEJ) pathways, and (2) pharmacological NHEJ inhibition. Results Small-molecule NHEJ inhibitors increased HDR efficiency approximately two-fold (from ∼40 % to ∼80 %). Edited HSPCs retained normal CFU capacity and successfully engrafted in NSG mice. However, up to 8 % of edited cells exhibited on-target chromosome loss, though this declined over time. Up to 40 % of T cells and fibroblasts demonstrated similar losses under NHEJ inhibitors treatment. In contrast, genetically encoded inhibitors did not improve HDR. Conclusion The ADA2 p. c.506G>A variant can be effectively edited employing surrogate strategy in HSPCs without impairing functionality. Although pharmacological inhibition of NHEJ enhances HDR efficiency, it also increases the risk of on-target chromosome aberrations, highlighting the need for careful consideration of the associated risks and benefits in therapeutic gene editing. Key messages 1) The ADA2 p.R169Q variant can be efficiently corrected via HDR, and the edited CD34+ HSPCs retain their engraftment capability in NSG mice. 2) Pharmacological inhibition of NHEJ using small-molecule inhibitors increases HDR efficiency but is associated with significant on-target deletions and chromosomal arm loss, particularly in differentiated cell types, and in a donor-dependent manner. Capsule summary The ADA2 p.R169Q variant is a viable target for precision gene editing in hematopoietic stem cells. Although inhibition of NHEJ improves HDR efficiency, it concomitantly increases the risk of large on-target deletions, particularly in differentiated cells.
2025-06-25 | Preclinical evaluation of lentiviral gene therapy for adenosine deaminase 2 deficiency (DADA2): engraftment efficiency and biodistribution in humanised NBSGW mice.
Adenosine deaminase type 2 deficiency (DADA2) is caused by bi-allelic loss-of-function mutations in ADA2. While anti-TNF therapy is effective for the autoinflamatory and vasculitic components of the disease it does not correct marrow failure or immunodeficiency. Allogeneic stem cell transplantation (HSCT) offers a potential cure but is limited by challenges such as graft-versus-host-disease and donor availability. We previously demonstrated that lentiviral-mediated ADA2 gene therapy could restore ADA2 enzyme activity in patient-derived cells, correct macrophage inflammatory activation and reduce endothelial activation in vitro. Here, we evaluated the biodistribution and engraftment potential of lentivirally transduced healthy donor and patient-derived haematopoietic stem cells (HSC) in vivo using a humanised NBSGW mouse model. Transduced healthy HSC retained multilineage differentiation and engraftment capacity, without functional impairment. PCR analysis confirmed the absence of viral integration in non-haematopoietic organs, and histology showed no abnormal tissue changes, underscoring the safety and precision of this approach. In DADA2 patient-derived HSC, ADA2 transduction restored protein expression and enzyme activity, supporting improved cellular function and enhanced engraftment potential. These findings provide a strong foundation for advancing ADA2 gene therapy as a therapeutic strategy for DADA2, bringing it closer to clinical application.
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2026-02-28 | Deficiency of Adenosine deaminase Type 2: An Unusual Clinical Presentation
Background:Adenosine deaminase 2(ADA2) deficiency was a systemic autoinflammatory disease characterised by systemic inflammation, vasculitis, early-onset stroke, cytopenias, and immunodeficiency.It is caused by a loss of function due to a mutation in the ADA2 gene and is inherited in an autosomal recessive pattern.Due to its ability to cause early-onset stroke, its vasculitis-like clinical manifestations, and its correlation with immunodeficiency, it is a disease that is difficult to diagnose and treat.Case presentation:In this report, we present a case of a 14-year-old with an unusual clinical onset, where the differential diagnosis involved clinical overlap of several diseases, who was diagnosed with a homozygous mutation in the ADA2 gene, and who came with complaints of abdominal swelling and chest pain.Conclusion:Unlike ADA2 deficiency, which is often considered in differential diagnosis with early-onset stroke, vasculitis, immunodeficiency, and hematological abnormalities, our case contributes to the literature by presenting with liver parenchymal disease and portal hypertension findings.
2026-01-01 | Constitutional Bone Marrow Failure due to Immune Dysregulation Disorders
Abstract Constitutional bone marrow failure (BMF) syndromes caused by immune dysregulation represent a growing subset of hematologic disorders, characterized by complex interactions between hematopoiesis and immune dysfunction. Unlike classical BMF syndromes, these disorders often present with overlapping features of cytopenias, autoimmunity, and immunodeficiency, frequently linked to underlying genetic mutations affecting immune regulatory pathways. Conditions such as GATA2 deficiency, adenosine deaminase 2 (ADA2) deficiency (deficiency of adenosine deaminase 2 (DADA2)), and DNA double-strand break (DSB) repair disorders exemplify this spectrum, with marrow failure arising from both intrinsic stem cell defects and extrinsic immune-mediated destruction. Diagnostic evaluation requires a comprehensive immunologic and genetic workup, including next-generation sequencing and biomarker profiling. Early identification is essential for therapeutic decision-making, particularly in guiding hematopoietic stem cell transplantation (HSCT), the only curative option for many of these disorders. This chapter provides an in-depth overview of the pathophysiology, diagnostic approach, and evolving management strategies for BMF syndromes associated with immune dysregulation.
2025-01-20 | Intracellular concentration of ADA2 is a marker for monocyte differentiation and activation.
Adenosine, a critical molecule regulating cellular function both inside and outside cells, is controlled by two human adenosine deaminases: ADA1 and ADA2. While ADA1 primarily resides in the cytoplasm, ADA2 can be transported to lysosomes within cells or secreted outside the cell. Patients with ADA2 deficiency (DADA2) often suffer from systemic vasculitis due to elevated levels of TNF-α in their blood. Monocytes from DADA2 patients exhibit excessive TNF-α secretion and differentiate into pro-inflammatory M1-type macrophages. Our findings demonstrate that ADA2 localizes to endolysosomes within macrophages, and its intracellular concentration decreases in cells secreting TNF-α. This suggests that ADA2 may function as a lysosomal adenosine deaminase, regulating TNF-α expression by the cells. Interestingly, pneumonia patients exhibit higher ADA2 concentrations in their bronchoalveolar lavage (BAL), correlating with elevated pro-inflammatory cytokine levels. Conversely, cord blood has low ADA2 levels, creating a more immunosuppressive environment. Additionally, secreted ADA2 can bind to apoptotic cells, activating immune cells by reducing extracellular adenosine levels. These findings imply that ADA2 release from monocytes during inflammation, triggered by growth factors, may be crucial for cell activation. Targeting intracellular and extracellular ADA2 activities could pave the way for novel therapies in inflammatory and autoimmune disorders.
2024-11-05 | Unveiling Mysteries: Novel Germline Mutations in Children with Bone Marrow Failure Syndrome and Hematologic Malignancy of Arab Ancestry
Introduction : Inherited predisposition to Hematologic malignancies, due to deleterious germline variants in a variety of genes, is an important clinical entity with implications for the health and management of patients and their family members. We sought to study genetic of Cancer predisposition and or bone marrow failure genes in children treated at King Hussein Cancer Center. Methods: This is a retrospective review of patients who were referred to our Cancer Predisposition clinic that was established in Jan 2020. Referred patients were screened using Jongmans' and McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) for cancer predisposition. Next-generation sequencing of germline DNA was performed using panels of genes suited for patients' diagnosis and family history. Results: 103 patients were screened; all were under age of 18-years .Most of patients fulfilled Jongmans' and/or MIPOGG criteria; sixty patients (58%) had family history of cancer, congenital or other phenotypic anomalies were detected in 45 patients with inherited bone marrow failure syndrome (IBMFS), five patients were referred due the diagnosis of two malignancies, excessive toxicity related to cancer treatment was reported in 10 patients. Primary Hematological malignancies were diagnosed in 58 patients : ALL (n=17), AML (n=11), Myelodysplastic (MDS)/ myeloproliferative diseases (MPD) (n=8) and lymphomas (n=22 ). Pathogenic/Likely pathogenic germline mutations were identified in 25 patients (43%), VUS /likely causative in 27 patients (47% ) with hematologic malignancy across the cancer predisposition (CPS) genes as following: CPS genes in ALL( MSH6,PTCH1,TP53, MET, CDH1, POLE, ERCC6L2, RUNX1, RAD50, ATM, SDHA, RABGAP1, POT1, VHL). CPS genes in AML( ACD, GATA2, MUTYH, BPTF,FANCA, FANCG, HAX1,ELANE and mitochondrial DNA deletion ~5kb in Pearson syndrome). CPS genes in MDS/MPD ( NF1, PTPN11, VPS45, GATA2, ACD,DUT, FANCG, ELANE). CPS genes in Lymphoma(RASGRP1, BRCA1, CHEK2, ATM, MSH3,TNFRSF9, PTCH1, MSH6, NAF1, CASR, DCLRE1C, RASGRP1, RIPK1, ATM, BRCA2, ERBIN, STK4, DOCK8). Pathogenic/Likely pathogenic germline mutations were identified in 36 patients (82%), VUS /likely causative in 8 patients (18%) with IBMFS as following: Fanconi Anemia (FANCA,FANCD2,FANCF,FANCG) Diamond-Blackfan anemia(RPL11, RPS19, RPL5, RPL35A), Dyskeratosis congenita (TINF2, PARN), Shwachman-Diamond Syndrome (SBDS), Severe congenital neutropenia(CSF3R), ERCC6L2 Syndrome (ERCC6L2), Adenosine Deaminase 2 deficiency( ADA2),CBL Syndrome(CBL), Epimerase deficiency galactosemia (GALE), Ghosalhemato diaphyseal dysplasia (TBXAS1),Idiopathic Bone marrow failure ( ALPK3), Bone Marrow Failure Syndrome 4 (MYSM1),THPO-Hereditary Thrombocytopenia (THPO),TUBB1-related Macrothrombocytopenia ( TUBB1), X-linked recessive Wiskott-Aldrich syndrome (WAS). Conclusion: By screening our patients carefully, we were able to identify a significant number of patients with cancer predisposition Syndrome. The early recognition of genetic predispositions for childhood cancers may provide an opportunity of therapy adjustment and specific screening for different syndrome-related malignancies as well as genetic counseling. Further refinement of our testing may require WES to detect structural variations and collaboration with research centers to perform functional testing for patients with VUS.
2024-11-01 | Carrier frequency and incidence estimation of deficiency of adenosine deaminase 2 in the Chinese population based on massive exome sequencing data.
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease characterised by early onset stroke, recurrent fever, and diverse vascular pathologies, caused by loss-of-function homozygous or compound heterozygous variants of ADA2. This research aimed to determine the carrier frequency and expected incidence of DADA2 in China, using massive exome sequencing (ES) data. A total of 50 likely pathogenic/pathogenic variants (LP/PVs) were identified among 69,413 Chinese individuals, including 20 novel and rare variants (<0.0022 % allele frequency), expanding the known spectrum of PVs in ADA2. The overall carrier frequency in the Chinese population was 1.05 % (732/69,413) and the estimated incidence of DADA2 was approximately one in 92,251 individuals. The present study provides an accurate estimation of the prevalence of DADA2 in China, supporting genetic counseling, early diagnosis treatment, and prognostic evaluation.
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2026-08-04 | Adenosine deaminase type 2 deficiency: From rare to common.
Deficiency of adenosine deaminase type 2 (DADA2) is an inborn error of immunity caused by biallelic pathogenic variants in the ADA2 gene. DADA2 is characterized by a broad spectrum of clinical features, including inflammatory/vasculitic, hematological, and immunodeficient manifestations. Related to this complex clinical phenotype, which overlaps with other diseases, underdiagnosis of DADA2 can be suspected. Several pathophysiological mechanisms causing DADA2 have been described in recent years; however, a unifying pathomechanism explaining all DADA2 disease manifestations is still lacking. Although DADA2 is considered an autosomal recessive disorder, recently several variants in the ADA2 gene were described to cause DADA2 disease in a heterozygous state, via negative dominance. Data from PheWAS studies in large public databases support this observation. Based on these findings, the prevalence of ADA2-associated phenotypes might be much higher than the estimated 1 in 222,146 individuals. As a result, patients with these phenotypes are likely to be encountered by multiple medical disciplines.
2026-07-31 | Immune Dysregulation and Lymphoma Risk in Deficiency of Adenosine Deaminase 2
The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1: Descriptive characteristics and laboratory values of DADA2 patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2026-06-22 | Inborn errors of immunity in children with neuroinflammation.
Inborn errors of immunity (IEIs), an expanding group of monogenic disorders with diverse clinical manifestations, are increasingly recognized to include neuroinflammatory disease. Examples of diseases included under this umbrella are Aicardi-Goutières syndrome, deficiency of adenosine deaminase 2, familial haemophagocytic lymphohistiocytosis, neonatal-onset multisystem inflammatory disease, and acute necrotizing encephalopathy, among others. Children with IEIs may develop encephalopathy, seizures, focal neurological deficits, aseptic meningitis, inflammatory lesions on magnetic resonance imaging, or other central or peripheral nervous system manifestations. While systemic features of autoinflammation or autoimmunity are often present and provide important clues that an underlying IEI may be present, neuroinflammation may be the presenting or sole manifestation in some children. Early recognition of neuroinflammatory presentations of IEIs is critical to prompt immunological and genetic investigations, enabling diagnosis and timely initiation of appropriate immunotherapies, and reducing the risk of long-term neurological outcomes. This review highlights paediatric-onset neuroinflammatory phenotypes associated with IEIs and provides practical frameworks for their recognition and investigation in clinical practice.
2026-05-05 | A Single-Center Study on Childhood Rare Vasculitides: Clinical and Outcome Analysis.
To evaluate rare childhood vasculitides using standardized clinical, laboratory, imaging, and outcome data. A retrospective cohort of 74 children with 8 rare vasculitides was assessed at a single center. Demographics, imaging, and disease activity (Pediatric Vasculitis Activity Score (PVAS)) and damage (Pediatric Vasculitis Damage Index) scores were recorded at diagnosis, 12 months, and last visit. Among 74 patients, 39 (52.7%) were girls. Median diagnosis age was 13.5 years. Subtype distribution was vascular Behçet syndrome 22 (29.7%), Takayasu arteritis (TA) 16 (21.6%), deficiency of adenosine deaminase 2 (DADA2) 14 (18.9%), polyarteritis nodosa 11 (14.9%), granulomatosis with polyangiitis (GPA) 6 (8.1%), primary angiitis of the central nervous system (PACNS) 3 (4.1%), eosinophilic GPA 1 (1.4%), and Cogan syndrome 1 (1.4%). The DADA2 had the longest diagnostic delay (median [IQR]: 20 [6-99.75] months), while PACNS had the youngest median age at onset (4.6 [3.07-7.95] years). Overall, 13.5% (n=10) were diagnosed before age 5, showing recurrent fever (60%, n=6) and anemia (50%, n=5), less skin/mucosal (40%, n=4), musculoskeletal (30%, n=3), cardiovascular (20%, n=2), and pulmonary involvement (20%, n=2), and higher PVAS (median 2.0, IQR 1.25-2.75). At 12 months, all had low disease activity. The TA had the longest corticosteroid use, highest damage, and slower remission. Overall remission was 91.9% (n=68/74), while GPA patients had more flares in the first year (median 1.0, IQR 0.25-1.75). Prognosis was favorable, but TA and monogenic vasculitides showed greater damage. In children <5 years, higher activity but good early response emphasize timely, individualized management.
2026-03-23 | ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances.
Deficiency of adenosine deaminase 2 (DADA2) causes a complex phenotype of autoinflammation and immunodeficiency. Bone marrow failure is often refractory to treatment with tumour necrosis factor-alpha (TNF-alpha) inhibitors and additional treatment options are needed. However, the pathomechanisms underlying the disease remain incompletely understood. The aim of this study was to examine the viability and metabolic profile of ADA2-deficient cells and to characterise the activity of different cell death pathways to advance the mechanistic understanding of DADA2. By flow cytometry and western blot, we showed that ADA2-/- U-937 cells and PBMCs from DADA2 patients showed significantly elevated levels of cell death compared with cells expressing wild-type ADA2. Viability of ADA2-deficient cells was not improved by inhibitors of apoptosis, necroptosis, pyroptosis and ferroptosis. Blocking of TNF-alpha, type I interferon and STING signalling as well as reintroduction of wild-type ADA2 protein did not rescue the cell death phenotype in vitro. ADA2-deficient cells had an aberrant morphology with increased cell size and granularity and were impaired in their proliferative capacity. To identify the cause of the impaired viability, we performed 13C glucose tracer metabolomics experiments which revealed disturbances in the pentose phosphate pathway of ADA2-deficient cells. This tended to be associated with increased exposure to intracellular reactive oxygen species that was attenuated in the PBMCs of a DADA2 patient measured after successful hematopoietic stem cell transplantation. Collectively, our findings established increased levels of cell death as a possible pathomechanism of DADA2 and showed that the absence of ADA2 leads to an impairment of the pentose phosphate pathway which may account for the cellular vulnerability of ADA2-deficient cells.
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2 orphan drug designations for Adenosine deaminase 2 deficiency.
2 orphan drug designations for Adenosine deaminase 2 deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous CD34+ cell enriched population containing haematopoietic stem and progenitor cells transduced ex vivo with a lentiviral vector encoding the human ADA2 gene | gene therapies | EMA | 2025-02-26 | — | UCL Research Limited |
Autologous CD34+ cell enriched population containing haematopoietic stem and progenitor cells transduced ex vivo with a lentiviral vector encoding the human ADA2 gene | cell therapies | EMA | 2021-08-20 | — | Fondazione Telethon Ets |
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