Introduction
This topic covers inherited defects of purine nucleotide metabolism: how purines are made and broken down, which enzyme defects cause hyperuricemia and gout, which defects cause neurological or immune disease, and how these disorders are inherited and counselled. Purine metabolism is a common exam topic because several of its disorders are classic examples of X-linked and autosomal recessive inheritance.
Basic biochemistry of purine metabolism
Purines (adenine and guanine) are built de novo from ribose-5-phosphate in a pathway that starts with PRPP synthetase and is regulated by feedback from the end products. Purines are also recycled through the salvage pathway, in which hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and adenine phosphoribosyltransferase (APRT) reattach bases to PRPP. Catabolism ends with uric acid, formed by xanthine oxidase from hypoxanthine and xanthine. Humans excrete uric acid rather than converting it further, so any block in this chain tends to raise either uric acid or the precursors upstream of it.
Gout and hyperuricemia
Gout is the most common inflammatory arthritis caused by purine metabolism. Hyperuricemia is the underlying cause, and most cases are primary and polygenic, with diet, alcohol, obesity, renal urate excretion and drugs such as diuretics contributing. A small number of familial forms are monogenic: PRPP synthetase superactivity is X-linked and causes overproduction of uric acid, and partial HGPRT deficiency causes a milder picture.
- Clinical picture: acute monoarthritis, classically of the first metatarsophalangeal joint (podagra), caused by monosodium urate crystals; later tophi, chronic arthropathy and urate nephrolithiasis.
- Diagnosis: serum uric acid (hyperuricemia is above about 420 µmol/L in men and 360 µmol/L in women), joint aspiration showing negatively birefringent needle-shaped crystals, and imaging for tophi.
- Differential diagnosis: septic arthritis, pseudogout (calcium pyrophosphate crystals, positively birefringent), rheumatoid arthritis and reactive arthritis.
- Treatment: NSAIDs, colchicine or glucocorticoids for acute attacks; urate-lowering therapy with allopurinol or febuxostat (xanthine oxidase inhibitors) aiming at serum urate below about 360 µmol/L once attacks are controlled.