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Sunday, September 14, 2025

Adenosine Deaminase Deficiency


Adenosine Deaminase Deficiency – Treatment Options

Introduction
Adenosine deaminase (ADA) deficiency is a rare autosomal recessive disorder of purine metabolism. It leads to accumulation of deoxyadenosine and deoxyadenosine triphosphate, which are toxic to lymphocytes, resulting in impaired T-cell, B-cell, and NK-cell development. ADA deficiency is one of the most common causes of severe combined immunodeficiency (SCID). Infants typically present with recurrent severe infections, failure to thrive, and developmental delay. Without intervention, it is often fatal in early life. Several therapeutic approaches are available that can restore immune function and improve survival.

1. Supportive Therapy

  • Infection prophylaxis and treatment:

    • Broad-spectrum antibiotics for acute infections.

    • Trimethoprim-sulfamethoxazole for Pneumocystis jirovecii.

    • Antifungal and antiviral prophylaxis in high-risk patients.

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

  • Protective measures: Infection control, avoidance of live vaccines, isolation in severe cases.

2. Enzyme Replacement Therapy (ERT)

  • Pegademase bovine (PEG-ADA):

    • Intramuscular injections of polyethylene glycol–modified bovine ADA enzyme.

    • Decreases toxic metabolite accumulation and partially restores immune function.

    • Useful as bridging therapy until definitive cure (HSCT or gene therapy).

    • Limitations: Requires lifelong therapy, risk of antibody development, high cost.

3. Hematopoietic Stem Cell Transplantation (HSCT)

  • Allogeneic HSCT:

    • Gold standard and potentially curative if an HLA-matched sibling donor is available.

    • Restores ADA activity by replacing defective hematopoietic stem cells.

    • Conditioning regimens tailored to minimize toxicity in infants.

    • Risks: Graft-versus-host disease (GVHD), graft rejection, infection.

4. Gene Therapy

  • Autologous hematopoietic stem cell gene therapy:

    • Patient’s own stem cells are corrected ex vivo with a functional ADA gene using viral vectors.

    • Cells are reinfused, leading to long-term immune reconstitution.

    • Example: Strimvelis (approved in Europe) has shown durable benefit.

    • Advantage: Avoids GVHD, suitable for patients without matched donors.

    • Limitations: Limited availability, high cost, requires specialized centers.

5. Monitoring and Long-Term Care

  • Immune function tests: T-cell counts, immunoglobulin levels, ADA activity.

  • Metabolite monitoring: Adenosine and deoxyadenosine levels.

  • Growth and neurodevelopmental follow-up: Detect and manage developmental delays.

  • Psychosocial support: For families coping with a chronic, inherited condition.

6. Multidisciplinary Care

  • Immunologists: For diagnosis and ongoing management.

  • Transplant specialists: For HSCT evaluation and care.

  • Gene therapy experts: For patient selection and advanced care.

  • Infectious disease specialists: For prophylaxis and acute infection treatment.

  • Genetic counselors: For family planning and recurrence risk counseling.



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