Adenosine Deaminase Deficiency- An Overview

Introduction

A genetic condition known as adenosine deaminase (ADA) deficiency harms the immune system and results in severe combined immunodeficiency (SCID). Virtually all immunological defenses against bacteria, viruses, and fungi are absent in people with SCID. They are vulnerable to recurrent, chronic infections that can be extremely harmful or fatal. These infections are frequently brought on by "opportunistic" microorganisms, which generally do not infect people with healthy immune systems. This condition is also called as

• ADA deficiency.

• ADA-SCID.

• Adenosine deaminase deficient severe combined immunodeficiency.

• SCID due to ADA deficiency.

• Severe combined immunodeficiency due to ADA deficiency.

What Are the Causes of Adenosine Deaminase Deficiency?

Mutations in the ADA gene are the root cause of adenosine deaminase deficiency. The adenosine deaminase gene contains instructions for making the enzyme. Although this enzyme is present throughout the body, lymphocytes, a subgroup of white blood cells, are where it is most active. These cells produce immunity proteins called antibodies or target infected cells to defend the body from potentially hazardous intruders like bacteria and viruses. The thymus, a gland situated beneath the breastbone, and lymph nodes present throughout the body are examples of specialized lymphoid tissues that create lymphocytes. The immune system comprises lymphocytes found in lymphoid tissues and the blood.

What Happens in Adenosine Deaminase Deficiency?

The adenosine deaminase enzyme's job is to eliminate the deoxyadenosine molecule produced when DNA is broken down. Deoxyadenosine, which can be hazardous to lymphocytes, is changed into harmless deoxyinosine by the enzyme adenosine deaminase. Adenosine deaminase activity is decreased or eliminated by mutations in the ADA gene, allowing deoxyadenosine to accumulate to lethal amounts for lymphocytes. The thymus' immature lymphocytes are especially susceptible to a toxic accumulation of deoxyadenosine. These cells die before they can develop to aid in infection defense. Other lymphoid tissues likewise have significantly fewer lymphocytes. The symptoms and signs of SCID are brought on by the loss of cells that fight infections.

What Is the Inheritance Pattern of Adenosine Deaminase Deficiency?

This condition has an autosomal recessive pattern of inheritance. All people receive the majority of their genes in pairs. The number of gene copies with a disease-causing variation determines how an illness is passed down through the family. This disease is inherited in an autosomal recessive manner. An autosomal gene can be found on any chromosome other than the X or Y (sex chromosomes). Like chromosomes, genes often exist in pairs. Recessive means that for a person to develop a disorder, both copies of the disease-causing gene (pathogenic variation) must possess the disease-causing alteration. Pathogenic variations have historically been referred to as mutations, an older term. A gene with a harmful mutation is inherited from each parent by a child with an autosomal recessive disorder. Each parent is a carrier of the pathogenic variation of the gene since each has one copy of it. Usually, carriers of autosomal recessive diseases do not exhibit any disease symptoms. The probability of having a kid with an autosomal recessive disease increases by 25 percent when two carriers are pregnant (1 in 4).

What Are the Symptoms of Adenosine Deaminase Deficiency?

Individuals may experience various variations of these symptoms. Symptoms can range from moderate to severe; some people experience them more frequently than others. For example, these signs of this condition could manifest as:

• Humoral Immunity Abnormality - A malfunction of the humoral immune system, including the complement system and the antibodies B cells make.

• Lymph Node Germinal Center Defect - No germinal centers are present in lymph nodes. B lymphocytes multiply, develop, undergo somatic hypermutation, and switch classes during antibody reactions in the lymph nodes' germinal centers.

• Tonsillar Hypoplasia - No evident tonsillar tissue.

• Allergy - An immunological response or reaction to substances that are typically not toxic.

• Anti-thyroid Peroxidase Antibody Positivity - The presence of thyroid peroxidase-reacting autoantibodies (immunoglobulins) in serum.

• Autoimmunity - The manifestation of an immune response against an individual's cells or tissues.

• B Lymphocytopenia - An unnatural drop in B cell count compared to the normal.

• Diarrhea - Irregularly more frequent loose or watery bowel motions.

• Failure to Thrive - A child that fails to thrive (FTT) has a noticeably below-average physical development.

• Skin Inflammation - The existence of skin irritation. Specifically, a skin anomaly brought on by a localized buildup of fluid, plasma proteins, and leukocytes.

• Lymphopenia - Abnormally low lymphocytes in the blood.

• Pulmonary Insufficiency - The pulmonary valve allows blood to flow retrogradely (backward) into the right ventricle during diastole.

• Recurrent Opportunistic Infections - Increased sensitivity to opportunistic infections, as seen by recurrent episodes of infection by opportunistic agents or by microorganisms that can infect a host with a compromised immune system but do not often cause disease in a healthy host.

• Recurrent Otitis Media - Inflammation of the middle ear indicates increased vulnerability to the condition.

• Recurrent Pneumonia - Frequent episodes of pneumonia (inflammation of air sac in the lungs caused by infection).

• Recurrent Upper Respiratory Tract Infections - Indicate a higher vulnerability to these infections (sinusitis, pharyngitis, tonsillitis).

• Sinusitis - Inflammation of the paranasal sinuses brought on by a bacterial, viral, or fungal infection, an allergy, or an autoimmune reaction.

• T Lymphocytopenia - An unusual drop of T cells in the blood.

How Is Adenosine Deaminase Deficiency Diagnosed?

In a proband (the first person suspected of hereditary risk), the diagnosis of ADA deficiency is made:

• When dried blood spots (DBS) are extracted using EDTA- or heparin-anticoagulated blood, they have less than one percent of regular ADA catalytic activity.

• When biallelic pathogenic mutations in ADA are found through molecular genetic testing.

Supportive Laboratory Findings:

1. Immune System

   1. At birth, lymphopenia is present. Typically, there are 500 or fewer total blood lymphocytes per liter (2,000 to 5,000 or more for neonates).

   2. Flow cytometry has shown that the significant lymphoid lineages (T-, B-, and NK-cells) are all severely reduced.

   3. Proliferative response to mitogens and antigens, a measure of in vitro lymphocyte activity, is minimal or nonexistent.

   4. There is no detectable specific antibody response to illnesses or vaccinations due to low serum immunoglobulin levels. However, higher serum IgE levels may be present in people with delayed or late phenotypes.

2. Increased levels of erythrocyte deoxyadenosine (dAdo) triphosphate (dATP) or total dAdo nucleotides (dAXP, calculated as the sum of dAMP+dADP+dATP)

   1. dATP and total dAXP were increased, a finding pathognomonic for ADA insufficiency.

   2. The quantity of dAXP in hemolysates or dried blood spot (DBS) extracts correlates with clinical phenotype in untreated afflicted patients (SCID > "delayed/late" onset > "partial ADA deficiency").

   3. The persistence of some erythrocyte dAXP rise following transfusion suggests underlying ADA insufficiency.

3. Reduced (usually five percent of normal) S-adenosylhomocysteine hydrolase (AdoHcyase, SAHase) activity in erythrocytes.

4. Elevated urine dAdo in those who are not receiving treatment.

5. Tandem mass spectrometry was used to measure the elevated levels of adenosine (Ado) and dAdo in dried blood spots (DBS) extracts.

How Is Adenosine Deaminase Deficiency Treated?

Intravenous immunoglobulin (IVIg) is administered to treat infections with particular antibiotic, antifungal, and antiviral medications; prophylaxis is recommended for Pneumocystis jiroveci infection.

Prevention of Primary Symptoms: Restoring a working immune system is crucial. Bone marrow or stem cell transplantation (BMT or SCT) from an HLA-identical healthy sibling or close relative is the chosen course of treatment. However, most patients with ADA-deficient SCID do not have a related HLA-identical donor. Alternative therapy for these people could include:

• BMT or SCT using "non-ideal" donors, such as umbilical cord-derived stem cells, an unrelated donor who is HLA-matched, or a parent who is HLA-haploidentical.

• PEG-ADA, a bovine adenosine deaminase modified with polyethylene glycol, is used as an enzyme replacement therapy in the experimental field of gene therapy (ERT).

Conclusion

People with all types of ADA must begin therapy as soon as feasible. Early detection and intervention reduce complications and enhance prognosis in a condition that might otherwise be fatal in infancy. In addition, the method of treating ADA has been impacted by improvements in transplantation, gene therapy, and enzyme replacement therapy (ERT).