Adenosine deaminase 2 deficiency

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This article is about a vasculitis syndrome caused by ADA2 gene mutations. For the metabolic disorder caused by ADA1 gene mutations, see Adenosine deaminase deficiency.
Deficiency of Adenosine Deaminase 2
Other namesDADA2
Autosomal recessive pattern is the inheritance manner of this condition
SpecialtyMedical genetics, Pediatrics, Rheumatology, Neurology, Dermatology, Immunology, Hematology
Usual onsetVariable, but commonly in early childhood
DurationLifelong
CausesMutations in the ADA2 gene
Diagnostic methodGenetic or Enzymatic Testing

Deficiency of Adenosine deaminase 2 (DADA2) is a

vasculopathy that affects a wide variety of organs in different patients. As a result, it is hard to characterize a patient with this disorder. Manifestations of the disease include but are not limited to recurrent fever, livedoid rash (reticularis or racemosa), various cytopenias, stroke, immunodeficiency, and bone marrow failure.[1][2] Symptoms often onset during early childhood, but some cases have been discovered as late as 65 years old.[3]

DADA2 is caused by

enzymatic activity in patient blood, leading to disease manifestations. However, mutational status and residual enzyme activity levels do not explicitly correlate with the type of disease a patient displays.[4][2][1]

The most common treatment for DADA2 is TNF inhibitors. This therapy tends to prevent vasculitis-related manifestations such as rash and stroke,[5][6] but does not perform well in individuals presenting with severe hematologic and immunologic abnormalities such as bone marrow failure or severe recurrent infections.[7] In these cases, hematopoietic stem cell transplantation has led to major improvements in the vascular, hematologic, and immunologic manifestations of disease.[8]

Signs and symptoms

The signs and symptoms of disease are wide-ranging in severity, but can be grouped into vascular, immunologic, and hematologic manifestations. Individual patients typically present with disease of only one of these subtypes, but this is not always the case.  Symptoms have also been known to abate and recur even without treatment.[9] Twenty-four percent of patients have disease onset before 1 year of age, and 77% of patients have disease onset before 10 years of age.[2]

Vasculopathy is the hallmark of DADA2, and was the most prominent feature of the disease upon its initial discovery.[10][11] The vasculitis seen in DADA2 is similar to polyarteritis nodosa (PAN), often leading to misdiagnosis. However, DADA2 patients typically have earlier disease onset, and a greater prevalence of skin and neurologic manifestations.[12] The systemic inflammation present in DADA2 leads to this vasculopathy, with symptoms involving but not limited to skin, brain, gastrointestinal tract, and kidneys. Livedo racemosa and livedo reticularis are the most common manifestations in skin, although other symptoms such as digital necrosis, subcutaneous nodules, and non-specific rash have been seen.  The most common neurological manifestations of DADA2 are secondary to vasculitis.  Fifty-one percent of patients present with neurologic disease, typically in the form of lacunar stroke.[2] In some patients, stroke can be the first indication of disease.[13]

Approximately 50% of patients have some form of immunologic or hematologic disease.

intestinal and urinary tract infections have been seen alongside various more rare infections such as viral encephalitis.[14]

There are a variety of rare DADA2 symptoms that have only been reported in a handful of patients.  For example, lymphoproliferation and large granular lymphocytic leukemia have been reported.[16][17][18] Other symptoms are becoming more known over time – reports of hypertension associated with DADA2 have increased in recent years.[19][20][21]

Pathophysiology

The mechanism by which mutations in ADA2 lead to disease manifestations is not fully clear.  ADA2 is a primarily

chronic inflammatory phenotype associated with DADA2.  Less is known about the role of ADA2 dysfunction in the immunologic and hematologic aspects of the disease.[citation needed
]

ADA2 catalyzes the reaction of adenosine to inosine and

TNFa.  TNFa likely plays a major role in the vasculitic phenotype of DADA2 due the efficacy of TNFa targeting drugs in treating symptoms.  However, the enzymatic activity of ADA2 is 100 fold lesser than that of the intracellular adenosine deaminase ADA1, and at physiological concentrations of adenosine the enzymatic activity of ADA2 is near zero.[2] This indicates that loss of ADA2 may cause disease by other mechanisms.[citation needed
]

Endothelial cell activation and damage is a further source of inflammation and vascular symptoms caused by DADA2. Endothelial cells from patients are extensively damaged and secrete pro-inflammatory cytokines. However, endothelial cells themselves don't express the ADA2 protein, so this phenotype is likely mediated by the effects of mutant ADA2 on other cell types feeding back onto endothelial cells. For example, ADA2 mutant monocytes display abnormal differentiation into macrophages, and endothelial cells grown in the presence of ADA2 deficient monocytes are similarly extensively damaged.[11]
 

The molecular underpinnings of the immunologic disease are unclear, but the upregulation of

CD4+ T cells to increase monocyte differentiation and T cell proliferation when present together.[22] Thus, DADA2 might lead to poor immune cell development directly or through the generally high inflammation.[citation needed
]

Genetics

DADA2 is caused by mutations in

deletions, and duplications. As of 2021, there are 117 known mutations, although classification into disease-causing and benign is ongoing.[31] This disease is inherited in an autosomal recessive fashion meaning that both versions of this gene, one inherited from each parent, must be defective in a patient.  While those with only one known mutant allele have been found to have disease manifestations, it is thought that those individuals have a mutation not found upon initial genomic sequencing.[citation needed
]

While there is some relationship between the genetic mutations a patient displays and their experience with the disease, the relationship is not one to one. Patients with DADA2 that share the same mutation are more likely to experience similar disease, but even family members with the same mutations have had entirely different disease courses.

catalytic domain lead to the Diamond Blackfan anemia-like phenotype.[38] In another study, specific mutations segregated perfectly into groups based on the type of the disease the patient displayed. In this analysis, the common G47R mutation always found in individuals with vasculitic disease, and the G358R mutation always seen in those with severe hematologic disease. However, some mutations did not separate as well. For example, the R169Q mutation was found in both vasculitic- and hematologic-forward disease subtypes.[4]  An analysis of the enzymatic activity of mutated ADA2 enzyme in vitro found that mutations yielding greater enzyme activity favored vasculitis, whereas mutations with less residual activity favored hematologic manifestations.[4]

Diagnosis

Currently, screening for DADA2 is initiated upon a physician's judgement. Criteria to trigger screening have been proposed however, including at least one sign of inflammation and vasculitis.[39] The specific diagnosis of DADA2 requires either confirmation of known pathogenic mutations in ADA2 or low ADA2 enzymatic activity in patient blood.[40]  Genetic testing for DADA2 has been performed as either a single-gene test through Sanger sequencing, or a multi-gene test through panel testing, whole exome sequencing, or whole genome sequencing.[40] These techniques vary in cost, intensity, and detection, and mutations have been missed due to the technique initially used.[41][42] As such, more extensive analysis is sometimes necessary if suspicion of DADA2 remains. Enzymatic activity analysis can confirm whether or not the ADA2 gene should be investigated further in these situations, and has been recommended by some as the premier diagnostic technique.[43]

Management

The most common management of DADA2 after diagnosis is TNFa inhibition (TNFi). This treatment serves those with vasculitic forms of the disease best, improving most symptoms and significantly preventing strokes.[5][6] TNFi is ineffective in those with severe bone marrow dysfunction or immunodeficiency.[44]  In these patients, hematopoietic stem cell transplant is considered and upon successful completion can be curative.[44][8] However, the risks associated with this procedure preclude its use in most patients. [citation needed]   

Ongoing pre-clinical studies are researching

adenosine deaminase deficiency,[47][48]
indicating their potential future success in DADA2.

Epidemiology

As of 2020, over 260 cases of DADA2 have been identified since the disease's discovery in 2014.

Georgian-Jewish and Turkish populations are estimated to have a 1:10 and 1:500 likelihood of carrying the G47R mutation respectively.  The R169Q variant is also more common in northern Europe, with a carrier frequency of 1:500.[49]

History

DADA2 was discovered in 2014 by two independent groups at the NIH and in Jerusalem, each reporting systemic inflammation and vasculitis syndromes caused by mutations in ADA2.[10][11] The DADA2 Foundation was formed in 2016 to serve patients with DADA2 by providing information and spurring research progress. The Foundation has organized an international DADA2 Conference, being held in 2016, 2018, 2020 and 2023.[50]

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