ADA

Adenosine deaminase (ADA) is an enzyme encoded by the ADA gene, crucial for the breakdown of deoxyadenosine into deoxyinosine, thus preventing toxic accumulation in cells. 

Found in high levels in lymphocytes, ADA is important in immune system regulation and homeostasis. Mutations in the ADA gene can lead to ADA deficiency, resulting in immune system impairments such as severe combined immunodeficiency (ADA-SCID). 

ADA activity is also involved in various autoimmune diseases, often serving as a biomarker due to its altered levels in conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). 

Additionally, ADA's role extends to influencing inflammatory responses and immune activation, making it significant in the diagnosis and monitoring of autoimmune and infectious diseases. 

The enzyme exists in two isoforms, ADA1 and ADA2, with distinct functions and distributions within the body. 

What is ADA? [1., 2., 8.]

The ADA gene encodes the enzyme adenosine deaminase. This enzyme is found in all cells but is present at highest levels in lymphocytes, which are immune cells that defend the body against foreign invaders.

The main function of adenosine deaminase is to break down a molecule called deoxyadenosine, which is generated when DNA is broken down. Specifically, it converts deoxyadenosine to deoxyinosine, which is not harmful to cells. This process is crucial because a buildup of deoxyadenosine can lead to early cell death, especially in lymphocytes.

Mutations in the ADA gene can lead to adenosine deaminase deficiency, a condition that impairs the immune system. The severity of the condition depends on how much functional enzyme is available. 

Individuals with no enzyme activity have a severe form called ADA-SCID (severe combined immunodeficiency), while those with reduced enzyme activity may have delayed-onset or partial ADA deficiency.

Adenosine deaminase deficiency is inherited in an autosomal recessive manner. It is a rare disorder, with an estimated incidence of about 1 in 200,000 to 1,000,000 newborns worldwide.

Research has demonstrated that levels of ADA immunoreactive protein and translatable ADA mRNA are 6 to 8 times higher in T-lymphoblast lines compared to B-lymphoblast lines. This corresponds to increased ADA catalytic activity and protein in T cells relative to B cells. [4.]

The ADA enzyme plays a crucial role in the purine salvage pathway and is essential for the development and proper functioning of the immune system. Its deficiency leads to the accumulation of toxic metabolites that primarily affect lymphocyte development and viability. [8.]

ADA1 and ADA2 [LEE>>>

There are two isoforms of the ADA enzyme, ADA1 (an intracellular version) and ADA2 (found in the plasma, secreted by monocytes and macrophages).  

ADA1 is an intracellular enzyme that is ubiquitously expressed and crucial for metabolizing adenosine and 2’-deoxyadenosine in the purine salvage pathway. ADA1 deficiency in humans leads to defective lymphocyte development and severe combined immunodeficiency (SCID).

The ADA2 enzyme is a plasma protein secreted primarily by monocytes and macrophages. 

ADA2 has a much lower substrate affinity compared to ADA1, and its exact physiological role remains unclear. 

ADA2 levels are higher in children than adults and are notably elevated in conditions involving macrophage activation, such as macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA).

ADA in Health and Disease

Adenosine Deaminase (ADA) Deficiency [8.]

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. 

It manifests as a spectrum of immune deficiencies, from early-onset severe combined immunodeficiency (ADA-SCID) diagnosed in infancy to milder late-onset combined immunodeficiency (ADA-CID) in older children and adults. 

ADA-SCID, the most severe form, leads to life-threatening infections, poor growth, and skeletal abnormalities. Without treatment, children with ADA-SCID rarely survive past infancy. 

ADA deficiency can be diagnosed through newborn screening and confirmed by detecting reduced ADA activity or identifying pathogenic ADA gene variants. 

Management includes enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), or gene therapy to restore immune function and prevent severe infections. Carrier testing and genetic counseling are essential for at-risk families.

Adult-onset Still's disease (AOSD) [14.]

Serum ADA activity was significantly increased in patients with AOSD compared to healthy controls. Higher ADA activity was correlated with disease activity and specific clinical manifestations such as fever, skin rash, splenomegaly, pleuritis, and pericarditis.

Research has shown that ADA activity in AOSD patients is significantly higher compared to healthy controls and as well as patients with other autoimmune diseases like systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis. [14.]

Adult-onset Still's disease (AOSD) is characterized by a range of symptoms including spiking fevers that typically occur once or twice daily, a salmon-pink rash that may come and go, often coinciding with fevers, and persistent or recurrent sore throat. 

Patients also experience severe joint pain affecting multiple joints (arthralgia or arthritis), generalized muscle pain (myalgia), and swollen lymph nodes (lymphadenopathy). 

The disease can cause an enlarged liver or abnormal liver function tests (hepatomegaly or abnormal liver function), inflammation of the pleura leading to chest pain (pleuritis), and inflammation of the pericardium, also causing chest pain (pericarditis). 

Additional symptoms include an enlarged spleen (splenomegaly), as well as generalized fatigue, weight loss, and malaise. 

Laboratory findings often show elevated white blood cell count, increased serum ferritin, and abnormal liver function tests.

Macrophage Activation Syndrome [9., 14.]

Excess adenosine deaminase (ADA) activity, particularly ADA2, has been linked to macrophage activation syndrome (MAS), a severe hyperinflammatory condition often associated with systemic juvenile idiopathic arthritis (JIA) as well as adult-onset Still's disease (AOSD). 

Elevated ADA2 levels in the plasma can serve as a biomarker for MAS, reflecting the enzyme's role in modulating immune responses. [14.]

ADA2 influences the degradation of adenosine, an immunosuppressive molecule, thus reducing its concentration and potentially leading to excessive activation of immune cells, including macrophages. 

This heightened immune activity can contribute to the hyperinflammatory state characteristic of MAS, making ADA2 a critical indicator in diagnosing and understanding the disease's pathophysiology.

Male Fertility [5., 11.]

Adenosine deaminase, or ADA, an enzyme that catalyzes the conversion of adenosine to inosine, plays a significant role in the human reproductive system by affecting adenosine metabolism. 

A study compared the plasma activities of total adenosine deaminase (ADAT) and its isoenzymes, ADA1 and ADA2, between 55 fertile and 70 infertile men. [11.]

The findings showed that infertile men had significantly higher activities of ADAT, ADA1, and ADA2 compared to fertile men (P < 0.01). [11.] Elevated ADA activity may lead to reduced adenosine levels, potentially disrupting fertility.

Tuberculosis [10.]

Pleural tuberculosis (TB) is a frequent cause of pleural exudates, especially in TB-endemic areas and among HIV-positive individuals. Most TB pleural effusions are exudates that are high in adenosine deaminase (ADA), lymphocyte-rich, straw-colored, and free-flowing, but they have a low yield on mycobacterial culture. 

Lymphoma [12.]

Elevated adenosine deaminase (ADA) levels in pleural effusion are commonly used to diagnose tuberculosis (TB), but they are not exclusive to TB and can also indicate other conditions, such as lymphoma. 

Increased Inflammation and Immune Response [13.]

Elevated adenosine deaminase (ADA) activity is associated with increased immune system function and inflammation. 

The elevation in ADA activity is attributed to the proliferation of T lymphocytes and monocytes/macrophage activity in response to infection. Therefore, ADA serves as a marker for cellular immune responses.

Autoimmune Conditions [6.]

ADA is a significant immune regulatory molecule with altered activity in various autoimmune diseases. Its elevated levels are associated with increased immune response and inflammation, making it a valuable marker for the diagnosis and monitoring of autoimmune conditions. 

ADA activity is altered in various autoimmune diseases; often elevated, but sometimes decreased.

Systemic Lupus Erythematosus (SLE)

Elevated serum ADA and ADA2 activities are noted in SLE patients.

Rheumatoid Arthritis (RA)

Studies show inconsistent results, with some reporting increased ADA levels in RA patients.

Juvenile Idiopathic Arthritis (JIA)

ADA activity varies among different subtypes of JIA, although limited studies are available.

Autoimmune Liver Diseases (AILD)

Higher ADA activity is observed in conditions like Autoimmune Hepatitis (AIH) and is correlated with inflammatory activity.

Adult-Onset Still's Disease (AOSD)

ADA activity is higher in AOSD patients compared to SLE and healthy controls.

Systemic Sclerosis (SSc)

Increased serum ADA activity is associated with progressive systemic sclerosis.

Autoimmune Nervous System Diseases

ADA activity is elevated in the cerebrospinal fluid of patients with certain autoimmune nervous system disorders.

Genetic Alterations in the ADA Gene

The gene for the ADA protein may contain alterations or mutations that cause increase or decrease of function of the ADA protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Specific SNPs Associated with Alterations in the ADA Gene

rs452159 [7.]

The rs452159 polymorphism is significantly associated with susceptibility to CHF. 

This SNP was also significantly associated with CHF dyslipidemia, suggesting its potential influence on lipid metabolism.

rs73598374 (22G>A) [7.]

General Information: The 22G>A (rs73598374) has been linked to human life expectancy in males, schizophrenia, sleep intensity, and potentially coronary artery disease. However, its role in cardiovascular effects remains unclear.

Laboratory Testing for ADA

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

ADA enzyme testing may also be assessed as an RBC adenosine deaminase assay, which requires a blood draw.  

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing. Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

Frequently Asked Questions (FAQs) on ADA

What Is ADA?

ADA stands for adenosine deaminase, an enzyme involved in the metabolism of adenosine, a nucleoside that plays a key role in various physiological processes, including energy transfer, signal transduction, and immune response.

Why Is ADA Important?

ADA is important because it is crucial for the breakdown of adenosine into inosine, which is further processed in the purine metabolism pathway. This enzyme is essential for maintaining proper immune function and cellular homeostasis.

What Is the Function of ADA?

The primary function of ADA is to catalyze the deamination of adenosine to inosine, a reaction that is vital for the proper functioning of the immune system. ADA activity helps regulate levels of adenosine, preventing its accumulation, which can be toxic to cells.

How Is ADA Measured?

The ADA gene is typically tested to assess for specific mutations that can cause alterations in function.  Genetic testing is commonly done via blood or cheek swab.  

ADA enzyme testing may also be assessed as an RBC adenosine deaminase assay, which requires a blood draw.  

What Are Normal Levels of ADA?

Normal levels of ADA activity vary depending on age, sex, and overall health. Reference ranges are provided by the testing laboratory and should be interpreted by a healthcare provider within the context of the patient's health status and medical history.

What Can Cause Elevated Levels of ADA?

Elevated levels of ADA can be associated with various conditions, including active tuberculosis, autoimmunity, and certain types of lymphoma. High ADA levels may indicate increased immune system activity or inflammation.

What Can Cause Low Levels of ADA?

Low levels of ADA activity may indicate ADA deficiency, a rare genetic disorder that can lead to severe combined immunodeficiency (SCID). This condition results in a compromised immune system, making individuals highly susceptible to infections.

What Are the Symptoms of Abnormal ADA Levels?

Symptoms of abnormal ADA levels depend on whether the levels are high or low. 

Elevated ADA levels may be associated with symptoms of the underlying condition such as fever, fatigue, and lymphadenopathy in tuberculosis or leukemia. 

Low ADA levels can result in symptoms of immunodeficiency, such as frequent infections, failure to thrive, and chronic diarrhea.

How Are Abnormal Levels of ADA Treated?

Treatment for abnormal levels of ADA depends on the underlying cause. 

For elevated ADA levels due to infections, addressing the primary condition is essential. 

For ADA deficiency, treatment may involve enzyme replacement therapy, bone marrow transplantation, or gene therapy. It is important to consult with a healthcare provider for an accurate diagnosis and appropriate treatment plan.

‍

Why Might a Doctor Order an ADA Test?

A doctor might order an ADA test to evaluate a patient for conditions like tuberculosis, lymphoma, or autoimmune diseases. 

It can also be used to diagnose ADA deficiency in individuals with symptoms of immunodeficiency. The test helps in assessing immune system function and guiding treatment decisions.

Is the ADA Test Safe?

Yes, the ADA test is safe. Blood tests involve a minor risk of discomfort or bruising at the site where blood is drawn. The procedure is generally well-tolerated and poses minimal risk to the patient.

Order Genetic Testing

Click here to compare genetic test panels and order genetic testing for health-related SNPs.