ADA Deficiency (Adenosine Deaminase Deficiency)

Adenosine Deaminase (ADA) Deficiency – Treatment Options

Introduction
Adenosine deaminase (ADA) deficiency is a rare autosomal recessive metabolic disorder that leads to accumulation of toxic metabolites (adenosine and deoxyadenosine), resulting in impaired lymphocyte development and function. It is one of the most common causes of severe combined immunodeficiency (SCID), typically presenting in infancy with recurrent infections, failure to thrive, and developmental delay. Without treatment, ADA deficiency is usually fatal within the first two years of life, but several therapeutic options are available, including enzyme replacement, hematopoietic stem cell transplantation, and gene therapy.

1. Supportive Management

• Infection control: Prompt treatment of bacterial, viral, and fungal infections.

• Prophylaxis: Trimethoprim-sulfamethoxazole for Pneumocystis jirovecii, antifungals and antivirals as indicated.

• Immunoglobulin replacement therapy: IVIG or SCIG to provide passive immunity.

• Protective environment: Limiting exposure to infectious agents, particularly before definitive therapy.

2. Enzyme Replacement Therapy (ERT)

• Pegademase bovine (PEG-ADA):

  • Polyethylene glycol–modified bovine ADA enzyme given intramuscularly.

  • Reduces toxic metabolite levels, partially restores immune function.

  • Often used as bridging therapy before curative treatment (HSCT or gene therapy).

  • Limitations: Life-long treatment required, risk of reduced efficacy over time, high cost.

3. Hematopoietic Stem Cell Transplantation (HSCT)

• Allogeneic HSCT:

  • The current treatment of choice and potentially curative.

  • Best outcomes with HLA-matched sibling donors.

  • Restores normal immune function by replacing defective hematopoietic stem cells.

  • Risks: Graft-versus-host disease (GVHD), graft rejection, infections, and chemotherapy-related toxicity.

4. Gene Therapy

• Autologous hematopoietic stem cell gene therapy:

  • Patient’s own hematopoietic stem cells are harvested, corrected with a functional ADA gene (via retroviral or lentiviral vector), and reinfused.

  • Shown to restore immune function with reduced risk of GVHD compared to HSCT.

  • Approved gene therapies (e.g., Strimvelis in Europe) have demonstrated long-term efficacy.

  • Limitations: Availability, high cost, and requirement for specialized centers.

5. Experimental/Adjunctive Approaches

• CRISPR-based genome editing: Investigational, aiming for precise correction of the ADA gene.

• Bone marrow–sparing conditioning regimens: To reduce HSCT toxicity in infants.

6. Monitoring and Long-Term Care

• Immune function testing: Regular monitoring of lymphocyte subsets, immunoglobulin levels, and ADA activity.

• Toxic metabolite levels: Adenosine and deoxyadenosine monitoring to assess therapy response.

• Growth and development assessments: To address complications like developmental delay or hearing loss.

• Psychosocial support: Counseling for families coping with chronic or genetic illness.

7. Multidisciplinary Care

• Immunologists: For diagnosis, monitoring, and long-term follow-up.

• Transplant specialists: For HSCT planning and post-transplant care.

• Geneticists and gene therapy teams: For genetic counseling and advanced therapies.

• Infectious disease specialists: For infection prevention and management.

• Nutritionists and developmental specialists: For growth and neurocognitive support.