Adenosine Deaminase Severe Combined Immunodeficiency(ADA-SCID)

ADA-SCID (Adenosine deaminase severe combined immunodeficiency), a rare inherited disorder, weakens the immune system, making individuals prone to recurring and potentially deadly fungal, bacterial, and viral infections. This immune deficiency also leads to a low white blood cell count and abnormal cell development. If left untreated, it frequently proves fatal in affected individuals.

ADA-SCID disease Mechanism

The ADA-SCID (Adenosine deaminase severe combined immunodeficiency) disease mechanisms are as follows:

Cell Division

• Every day, cells undergo division in the body, which is a normal aspect of life for all individuals.

Role of ADA in Purine Metabolism

• ADA serves as a crucial enzyme in the purine metabolic recycling and synthesis pathway.
• Present in all human tissues, ADA exhibits its highest levels and activity in the lymphatic system.
• ADA is responsible for irreversibly deaminating adenosine and 2’deoxyadenosine into inosine and 2’deoxyinosine, respectively.

Metabolite Accumulation in ADA SCID

• Loss or impairment of ADA function in patients with ADA SCID results in the excessive accumulation of metabolites, including adenosine (Ado), 2’deoxyadenosine (dAdo), and deoxyadenosine triphosphate (dATP), leading to cytotoxicity.

Impact on DNA Synthesis and Repair:

• Elevated levels of dAdo and dATP obstruct normal DNA synthesis and repair processes.
• Increased Ado levels can induce disordered immune responses in various body tissues.
• Abnormal lymphatic development and function, crucial for infection defense, are observed in ADA SCID patients due to the highest levels of ADA in lymphoid tissue.

Non-Immune System Manifestations:

• People with ADA-SCID can experience symptoms beyond a weak immune system, such as bone problems, delays in brain development, breathing issues, organ damage, changes in their bone marrow, rare skin tumors, and liver and kidney disease.

These mechanisms highlight the multifaceted impact of ADA-SCID on various physiological processes beyond the immune system.

Symptoms of ADA-SCID

When ADA (adenosine deaminase) is abnormal, it results in immunodeficiency, causing the immune system to be incapable of effectively combating infections. This leads to common symptoms associated with ADA-SCID, a condition typically diagnosed in infancy. ADA-SCID manifests in three different types, each presenting distinct symptoms:

1. Severe Combined Immunodeficiency Disease with ADA Deficiency (Most Common):
   • Age at diagnosis (most common): <6 months
   • Most common symptoms:
     • Opportunistic infections
     • Chronic diarrhea
     • Recurrent pneumonia
     • Skin rash
     • Non-communicable lung disease
   • Other symptoms:
     • Pulmonary insufficiency
     • Developmental delay
     • Skeletal abnormalities
     • Bone marrow abnormalities
     • Liver function abnormalities
     • Nervous system abnormalities
     • Skin tumors
2. Delayed/Late-Onset ADA Deficiency:
   • 15-20% of children diagnosed
   • Age at diagnosis (most common): 1 to 10 years
   • Most common symptoms:
     • Chronic ear infections
     • Sinus infections
     • Upper respiratory tract infections
     • Palm/plantar warts
     • Chronic pulmonary insufficiency (leaky heart valves)
     • Autoimmune diseases
     • Allergies
   • Other symptoms:
     • Papillomavirus infection
     • Developmental delay
3. Some ADA Deficiencies (Very Rare):
   • Age at diagnosis: Any
   • Most common symptoms:
     • None
   • Demonstration:
     • Individuals with very low or absent ADA activity in red blood cells but high ADA activity in nucleated cells have normal immune function.
   • Certain lung abnormalities in ADA-SCID and other forms of severe combined immunodeficiency (SCID) may be caused by metabolic deficiencies
4. While some individuals with ADA-SCID may develop symptoms later in life, they tend to be milder compared to those experienced in infancy.

Diagnosis of ADA-SCID

Untreated ADA-SCID poses a serious threat, often proving fatal by the age of two. Timely diagnosis and intervention are critical for managing ADA-SCID effectively.

ADA SCID is typically diagnosed through a blood test measuring ADA enzyme activity. If red blood cells have almost no ADA activity (less than 1% of normal) and there’s a lot of adenosine and dAdo in the blood, it’s a strong sign of ADA-SCID. Genetic testing may also be employed to confirm the diagnosis by identifying biallelic mutations in ADA genes.

Genetic Factors and Family Planning

People with ADA-SCID inherit two copies of the mutated ADA gene, one from each parent. Even if both parents carry a copy of the mutated gene, they usually do not exhibit symptoms. Family planning decisions involve a 25% chance of having a child without ADA mutations, a 50% chance of having a child with a mutation, and a 25% chance of having a child with ADA-SCID. Understanding family history aids in prenatal screening decisions.

Challenges in Managing ADA-SCID Patients

Managing patients with ADA-SCID daily presents challenges due to the life-threatening nature of infections. Family members may be at risk, and careful family planning is crucial. Daily life adjustments are necessary, and with appropriate treatment and management, a return to normalcy is possible.

Support and Education for Patients and Families

Newly diagnosed patients and their families may find the situation overwhelming. Support and educational resources can assist in coping with ADA-SCID. Life after treatment involves ongoing care, regular examinations, and adjustments for transitioning into adulthood.

Mental Health and Support

Caring for a child with ADA-SCID can be mentally taxing. Parents and caregivers need to prioritize mental health and seek support from groups specializing in severe combined immunodeficiency. Healthcare providers can offer guidance, and open communication is crucial.

Early Treatment and Infection Prevention

While accepting the diagnosis may be challenging, early treatment is imperative. Measures to reduce bacterial infections, such as minimizing germ exposure, are essential. Informing family and friends about ADA-SCID and the need for isolation can be helpful. Three powerful ways to fight ADA-SCID are enzyme replacement therapy (ERT), hematopoietic stem cell transplant (HSCT), and gene therapy (GT). If there is suspicion or confirmation of ADA-SCID, it is crucial to consult with a local doctor for appropriate guidance and management.

Impact on Daily Life and Resources for Support

ADA-SCID significantly affects daily life, but discussions with healthcare providers and access to organizational support can aid in coping. Resources are available to educate family and friends about living with ADA-SCID and the associated treatment plan.