Adenosine Deaminase Deficiency

Adenosine deaminase (ADA) deficiency is an autosomal recessive metabolic disorder that causes combined immunodeficiency. It is the cause of about 10 to 15% of severe combined immunodeficiency and presents with T, B and NK cell lymphopenia (T-B-NK-).

Pathophysiology. Loss of ADA lets deoxyadenosine and deoxyadenosine nucleotides (dAXP) accumulate, and these are toxic to lymphocytes and also affect liver, bone, brain and lung.

The incidence is about 1 in 200,000 to 1 in 1,000,000 births. Most present at 3 to 6 months of age.

Partial or delayed forms present in later childhood or adulthood with milder lymphopenia, recurrent infection and autoimmunity.

• Recurrent severe infection in the first months: pneumonia (including Pneumocystis), oral thrush, chronic diarrhoea
• Failure to thrive
• Small or absent thymus and lymph nodes
• Skeletal abnormalities, such as costochondral cupping
• Sensorineural deafness, behavioural problems and neurological delay
• Hepatic dysfunction, pulmonary alveolar proteinosis, renal disease
• Complications of live vaccines (BCG, rotavirus)
• Partial forms: autoimmunity, allergy, recurrent sinopulmonary infection

• Lymphocyte subsets: very low T, B and NK cells (absolute lymphocyte count often under 0.5 x 109/L).
• ADA enzyme activity in red cells or leucocytes (under 1% of normal in severe forms), with raised dAXP in red cells and raised deoxyadenosine.
• Genetic testing of ADA for confirmation, family testing and prenatal diagnosis.
• TREC newborn screening, where available, usually shows low values.
• Immunoglobulins: low or absent, with poor specific antibody responses.
• Chest X-ray: absent thymic shadow, and skeletal survey for rib cupping.
• Infection workup: viral and Pneumocystis PCR, cultures.
• Hearing test, liver enzymes and neurodevelopmental assessment.

Differential diagnosis.

• Other types of severe combined immunodeficiency
• Purine nucleoside phosphorylase deficiency
• Reticular dysgenesis and Omenn syndrome
• HIV infection (infants)
• Secondary lymphopenia (maternal immunosuppressants, malnutrition)
• DiGeorge syndrome

This is a medical emergency in infants.

• Protective isolation, avoidance of live vaccines, and irradiated, leukodepleted, CMV-safe blood products.
• Enzyme replacement: elapegademase (pegylated ADA) 0.2 mg/kg intramuscularly once weekly at the start, adjusted to keep trough plasma ADA activity at 30 mmol/h/L or more and red cell dAXP under 0.02 mmol/L, usually by 0.033 mg/kg steps. It restores metabolic control and partly restores immunity, and acts as a bridge to definitive treatment.
• Definitive treatment: haematopoietic stem cell transplantation from a matched sibling donor (best results), a matched unrelated donor, or autologous gene therapy using the patient's own corrected stem cells where available. Enzyme replacement is stopped after successful engraftment or gene therapy.
• Pneumocystis prophylaxis: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week.
• Antifungal prophylaxis: fluconazole 3 to 6 mg/kg orally daily (maximum 400 mg); check liver enzymes.
• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Infections: treat promptly by culture and PCR; CMV disease with ganciclovir 5 mg/kg intravenously every 12 hours (adjust to renal function), then valganciclovir.
• Nutrition and supportive care: high energy feeds, enteral or parenteral support, and hearing and developmental support.

Special groups.

• Late onset or partial deficiency: enzyme replacement or transplantation is still considered, depending on infection, autoimmunity and dAXP levels.
• Families with a known variant: carrier testing and prenatal diagnosis.

Monitoring. Plasma ADA activity and red cell dAXP before the next dose, monthly at first, then every 3 months. Lymphocyte subsets, trough IgG, full blood count and liver enzymes every 3 months. Growth, hearing and neurodevelopment yearly.

Referral and escalation. Refer urgently to a paediatric immunology and transplant centre at diagnosis. Emergency for respiratory distress, sepsis, or severe diarrhoea.