Gout does not occur in the absence of hyperuricemia. Hyperuricemia is defined as a serum urate concentration exceeding 7.0mg/dL in men and 6.0mg/dL in women. However, it should be noted that serum urate concentrations vary markedly among different populations and the values are influenced by such things as age, sex, ethnicity, body weight and the surface area of the body. Hyperuricemia can result from either excess uric acid production or reduced excretion or a combination of both mechanisms. Primary gout is a biochemically and genetically heterogeneous disorder resulting from inborn metabolic errors that alter uric acid homeostasis.
There are at least three different inherited defects that lead to early development of severe hyperuricemia and gout: glucose-6-phosphatase (gene symbol = G6PT) deficiency; severe and partial hypoxanthine-guanine phosphoribosyltransferase (HGPRT, gene symbol = HPRT) deficiency; and elevated 5'-phosphoribosyl-1'-pyrophosphate synthetase (PRPP synthetase, gene symbol = PRPS) activity.
The familial association of gout was recognized hundreds of years ago but defining the exact genetic mechanisms wasn't possible until the advent of modern genetic tools. Gout was included as an inherited disorder in the seminal work of Archibald E. Garrod in his 1931 publication on inborn errors in metabolism. Garrod considered gout to be a dominantly inherited trait. However, we now know that G6PT deficiencies are inherited as autosomal recessive traits and HPRT and PRPS defects are X-linked traits.
PRPP synthetase is the enzyme responsible for the synthesis of the activated ribose (5'-phosphoribosyl-1'-pyrophosphate, PRPP) necessary for the de novo synthesis of purine and pyrimidine nucleotides. Regulation of PRPP synthesis is effected through complex allosteric regulation of PRPP synthetase. At least three different isoforms of PRPP synthetase have been identified and are encoded by three distinct, yet highly homologous PRPS genes, identified as PRPS1, PRPS2, and PRPS3. The PRPS1 and PRPS2 genes are found on the X chromosome (Xq22–q24 and Xp22.2–p22.3, respectively) and the PRPS3 gene is found on chromosome 7. The PRPS3 gene appears to be expressed exclusively in the testes. All three PRPP synthetase isoforms differ in kinetic and physical characteristics such as isoelectric points (pI), pH optima, activators and inhibitors. Mutations in the PRPS genes that result in superactivity lead to enhanced production of PRPP. Increased levels of PRPP, in turn, drive enhanced de novo synthesis of purine nucleotides in excess of the needs of the body. Thus, the excess purine nucleotides are catabolized resulting in elevated production of uric acid and consequent hyperuricemia and gout.
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme involved in the salvage of purine nucleotides. HGPRT catalyzes the following two interconversions:
hypoxanthine + PRPP <——> IMP + PPi
guanine + PRPP <——> GMP + PPi
A complete or virtually complete loss of HGPRT activity results in the severe disorder, Lesch-Nyhan syndrome. Although Lesch-Nyhan syndrome is known more for the associated bizarre emotional behaviors, there is also overproduction and excretion of uric acid and gouty manifestation. Less dramatic reductions in HGPRT activity do cause hyperuricemia and gout due to the reduced salvage of hypoxanthine and guanine leading to increased uric acid production.
Deficiencies in glucose-6-phosphatase result in type I glycogen storage disease (von Gierke disease). However, associated with this defect is increased uric acid production and symptoms of gout. The inability to dephosphorylate glucose 6-phosphate leads to an increase in the diversion of this sugar into the pentose phosphate pathway (PPP). One major product of the PPP is ribose 5-phosphate. An increase in the production of ribose 5-phosphate results in substrate-level activation of PRPP synthetase. Increased activity of PRPP synthetase, in this circumstance, has the same consequences as defects in the PRPS gene that lead to superactivity of PRPP synthetase described above.
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