Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy.

Adenosine deaminase (ADA) deficiency is the first known cause of severe combined immunodeficiency disease (SCID). Over the past 25 years, the metabolic basis for immune deficiency has largely been established. The clinical spectrum associated with ADA deficiency is now quite broad, including older children and adults. The ADA gene has been sequenced, the structure of the enzyme has been determined, and over 50 ADA gene mutations have been identified. There appears to be a quantitative relationship between residual ADA activity, determined by genotype, and both metabolic and clinical phenotype. ADA deficiency has become a focus for novel approaches to enzyme replacement and gene therapy. Enzyme replacement with polyethylene glycol (PEG)-modified ADA, used to treat patients who lack a human leukocyte antigen (HLA)-matched bone marrow donor, is safe and effective, but expensive. Several approaches to gene therapy have been investigated in patients receiving PEG-ADA. Persistent expression of transduced ADA cDNA in T lymphocytes and myeloid cells has occurred in a few patients, but significant improvement in immune function because of the transduced cells has not been shown. The major barrier to effective gene therapy remains the low efficiency of stem cell transduction with retroviral vectors.