Deficiency of Adenosine Deaminase 2 - Causes, Diagnosis, and Treatment

What Is the Deficiency of Adenosine Deaminase 2?

Adenosine deaminase 2 (ADA2) deficiency is a systemic inflammatory disorder characterized by abnormal inflammation of various tissues and organs. Signs and symptoms usually appear in early childhood but can develop in late adulthood also. Affected individuals in the same family can show different degrees of severity of the same disorder.

Inflammation is a normal reaction exhibited by the host’s immune system in response to any kind of injury or foreign invasive agents (such as viruses and bacteria). However, a deficiency of adenosine deaminase 2 causes abnormal inflammation that causes damage and destruction to the tissues and organs of the body, blood vessels, in particular. Inflammation of the blood vessels is called vasculitis. Skin, gastrointestinal tract, liver, kidneys, and brain are some of the tissues affected by abnormal inflammation. The disorder can be debilitating and life-threatening depending on the severity and site of inflammation.

What Are the Other Names of the Deficiency of Adenosine Deaminase 2?

• Childhood-onset polyarteritis nodosa.

• Adenosine deaminase 2 (ADA2) deficiency.

• Sneddon syndrome.

What Is the Frequency of the Deficiency of Adenosine Deaminase 2?

Deficiency of Adenosine deaminase 2 is a rare disease with not more than 150 cases reported in the medical literature. However, researchers are working hard to identify whether this disorder is more common and could underlie more common forms of vasculitis and stroke. The disease is an autosomal recessive disorder.

What Are the Causes of the Deficiency of Adenosine Deaminase 2?

The deficiency of Adenosine deaminase 2 is caused by genetic mutations in the adenosine deaminase 2 gene. This gene is responsible for providing instructions to synthesize an enzyme called adenosine deaminase 2. This enzyme plays a crucial role in the growth and development of certain immune cells, including macrophages (a type of white blood cell that plays an essential role in inflammation). However, some macrophages are pro-inflammatory, meaning they catalyze the inflammatory reaction, while other macrophages are anti-inflammatory, meaning they minimize the inflammation.

Genetic mutations in the adenosine deaminase gene severely alter (reduces) the activity of the enzyme adenosine deaminase 2. Researchers believe that the deficiency of the enzyme may alter the balance between the pro-inflammatory and anti-inflammatory macrophages in multiple tissues, leading to an increase in the number of pro-inflammatory macrophages thereby causing abnormal inflammation.

What Is the Inheritance Pattern of the Deficiency of Adenosine Deaminase 2?

The disorder is inherited in an autosomal recessive form which means each cell carries both copies of the mutated gene. Each parent of the affected individual with an autosomal recessive disorder carries one copy of the gene that is mutated, but the parents typically do not present with any signs and symptoms of the disease.

What Are the Signs and Symptoms of the Deficiency of Adenosine Deaminase 2?

The signs and symptoms associated with adenosine deaminase 2 deficiency include the following:

• Intermittent fevers.

• Enlargement of the liver and spleen.

• Systemic portal hypertension.

• Web-like, mottled skin discoloration (livedo racemosa).

• Recurrent brain strokes.

• Recurrent hemorrhagic strokes.

• Increased risk of viral and bacterial infections.

• Usually, the symptoms appear in early childhood.

• Immunodeficiency state.

• Lymphadenopathy.

What Are the Diagnostic Findings of the Deficiency of Adenosine Deaminase 2?

The laboratory findings of the disorder include the following:

• Increased C-reactive protein (CRP) and erythrocyte sedimentation rate at the time of inflammatory response.

• Increased level of transaminases.

• Absence of antineutrophil cytoplasmic antibodies.

The imaging diagnostic findings of the disorder include the following:

• Magnetic Resonance Imaging- Lacunar ischemic infarcts (either acute or chronic) are present in the deep brain nuclei or the brain stem. The white cortical matter is spared. Hemorrhagic stroke and bleeding within the skull can also be diagnosed.

• Angiography- Aneurysm or stenosis (narrowing) in medium-sized arteries.

• Hypogammaglobulinemia has low levels of IgM, IgG, and IgA. Low serum immunoglobulin levels are usually associated with inflammatory disease activity.

• Decreased synthesis of both transitional and switched memory B cells.

• In some cases, defective T-cell proliferation, profound CD4+ lymphopenia, and low natural killer cell counts have been determined.

• Positive lupus anticoagulants may also be reported.

• Lymphopenia - Decreased lymphocyte count has been seen.

• Neutropenia - Reduced neutrophil count observed in some cases.

• Thrombocytopenia - Decreased production of platelets.

• Pancytopenia - Overall reduction in the production of white blood cells, red blood cells, and platelets.

• Red Cell Aplasia - The bone marrow fails to produce red blood cells resulting in anemia.

• Bone Marrow Biopsy - Biopsy may exhibit hypocellularity or hypercellularity, mild myelofibrosis, and lymphocytic cell infiltrate.

What Is the Treatment of the Deficiency of Adenosine Deaminase 2?

• Anti-tumor necrosis factor agents such as Adalimumab, Golimumab, Infliximab, and Certolizumab are the drugs of choice for the affected individuals (symptomatic and asymptomatic). These drugs eliminate the clinical manifestations of autoinflammatory vasculitis, thereby reducing the risk of hemorrhagic stroke, reducing the inflammatory response, and relieving the conditions of immunodeficiency, hepatosplenomegaly, and neutropenia. These drugs also improve the rate of growth and development in affected children and increase red blood cell and platelet counts.

• The relatives or other family members of the affected person who are at risk of acquiring the disease should be evaluated. Carrier testing for relatives at risk can be performed.

• Genetic counseling of the affected person and his family members is also recommended.

• Prenatal testing of the fetus for a pregnant lady who is at high risk should be done.

What Are the Precautions to Be Taken by the Patient?

• Certain drugs or medications need to be avoided such as antiplatelet medications including Aspirin.

• The affected individual should avoid smoking since it may exacerbate the peripheral arterial disease.

• Prenatal testing of the fetus should be carried out on a pregnant woman who is at higher risk.

Conclusion:

The deficiency of adenosine deaminase is a rare systemic inflammatory disorder that causes damage to the host’s immune system. It is an autosomal recessive disorder caused due to genetic mutation in the adenosine deaminase 2 gene. Newborn screening, blood, and genetic tests can be used to diagnose the disorder. Early detection leads to better management of the affected patients. Genetic counseling of the affected individual, parents, or their family members is important to deal with this rare genetic disorder.