Metabolic Disorders in Purine Biosynthesis Gout * Caused by various genetic defect in PRPP synthase * elevated Vmax, increased affinity for ribose 5-phosphate, or resistance to feedback inhibition—results in overproduction and overexcretion of purine catabolites. * When serum urate levels exceed the solubility limit, sodium urate crystalizes in soft tissues and joints and causes an inflammatory reaction, gouty arthritis. * Most cases of gout reflect abnormalities in renal handling of uric acid. Lesch-Nyhan Syndrome * Defect in the HGPRT enzyme of the salvage pathway Symptoms include: an overproduction hyperuricemia characterized by frequent episodes of uric acid lithiasis and a bizarre syndrome of self-mutilation * rise in intracellular PRPP result in purine overproduction Von Gierke’s disease * glucose-6-phosphate deficiency * occurs secondary to enhanced generation of the PRPP precursor ribose 5-phosphate * lactic acidosis (due to decreased blood glucose) elevates the renal threshold for urate, elevating total body urates.
Hypouricemia * results in overexcretion of hypoxanthine and xanthine * due to xanthine oxidase deficiency caused by genetic defect or severe liver damage Adenosine deaminase deficiency * associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells) are sparse and dysfunctional. Purine nucleoside phosphorylase deficiency * associated with a severe deficiency of T cells but apparently normal B cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, * this inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors.