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:
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.
2026-08-04 | 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.
2026-07-27 | 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.
2026-08-06 | 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.
2026-08-04 | 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.
2026-07-27 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
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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