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Severe combined immunodeficiency and adenosine deaminase deficiency: failure of enzyme replacement therapy
Insights
Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency presents challenges. Enzyme replacement therapy showed limited immunological reconstitution in a patient with severe skeletal abnormalities.
Area of Science:
- Immunology
- Biochemistry
- Pediatrics
Background:
- Severe combined immunodeficiency (SCID) is a group of rare genetic disorders characterized by profound defects in the development and function of both cellular and humoral immunity.
- Adenosine deaminase (ADA) deficiency is a specific metabolic cause of SCID, leading to the accumulation of toxic metabolites that impair lymphocyte function.
- Early diagnosis and treatment are crucial for improving outcomes in SCID patients.
Observation:
- A 3-month-old infant presented with failure to thrive, persistent diarrhea, and recurrent infections, indicative of SCID.
- Extensive skeletal abnormalities suggested a potential metabolic etiology, later confirmed as adenosine deaminase (ADA) deficiency.
- The patient exhibited extremely low ADA activity (< 0.005 nmol/h per mg protein) in erythrocytes and leukocytes.
Findings:
- Enzyme replacement therapy using plasma and erythrocyte infusions normalized blood ADA levels (> 30 nmol/h per mg hemoglobin).
- While interstitial pneumonitis and skeletal abnormalities improved, there was no significant immunological reconstitution.
- The patient ultimately succumbed to a parainfluenza pneumonitis at 17 months of age.
Implications:
- Early presentation with severe skeletal abnormalities and minimal residual ADA activity may predict a poor response to erythrocyte-based ADA enzyme replacement therapy.
- Lack of in vitro response to exogenous ADA in peripheral blood mononuclear cells could indicate a lack of therapeutic benefit.
- This case highlights the limitations of current enzyme replacement strategies for ADA-SCID and underscores the need for alternative or adjunctive therapies, such as hematopoietic stem cell transplantation or gene therapy.
Abstract:
A first-born baby boy presented at age 3 months with persistent diarrhoea, failure to thrive, and recurrent bacterial and fungal infections. Severe combined immunodeficiency was demonstrated. A deficiency of adenosine deaminase (ADA) activity was suggested by the presence of extensive skeletal abnormalities, and the ADA activity in erythrocyte and leucocyte lysates was < 0.005 nmol/h per mg protein. Culture of ADA-negative peripheral blood mononuclear cells, together with purified calf ADA, did not alter the absent phytohaemagglutinin response. Treatment with immunoglobulin, pentamidine, and co-trimoxazole was started and a programme of ADA enzyme replacement, with infusions of plasma and frozen irradiated erythrocytes, was begun at age 4 months and achieved blood ADA levels in excess of 30 nmol/h per mg haemoglobin. Although resolution of the interstitial pneumonitis and skeletal abnormalities was observed, there was no evidence of immunological reconstitution. The patient died at age 17 months after a parainfluenza pneumonitis. Features of importance in predicting lack of benefit from enzyme replacement by erythrocyte infusion in ADA-negative severe combined immunodeficiency appear to be early clinical presentation with associated severe skeletal abnormalities, a very low level of residual ADA activity in peripheral blood mononuclear cells, and lack of effect of exogenous ADA on the absent in vitro mitogen response of ADA-negative blood mononuclear cells.