Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations

Deficiency of adenosine deaminase( ADA, EC3.5.4.4), a housekeepingenzyme of purine metabolismencoded by the Adagene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutationsoccurring in the ADAgene have been found in patients with profound lymphopenia (T− B− NK−), thus underscoring the importance of functional purine metabolismfor the development of the immune defense. While untreated ADASCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADAactivity and reconstitute protective immunity, including enzyme replacement therapy(ERT), allogeneic hematopoietic stem celltransplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells(HSC). We review the pathogenic mechanisms and clinical manifestations of ADASCID.