There are 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 was not possible until the advancement of modern genetic tools. Gout and Garrod have been linked in medical literature for more ^{than a century. He identified uric acid as a normal constituent of the serum of healthy persons and devised a method for detecting its increased concentration in gouty subjects.}

Overactivity of PRS is also an X-linked dominant disorder that can produce hyperuricemia. It is characterized by an overproduction of phosphoribosyl pyrophosphate (PRPP) and uric acid, which can cause hyperuricemia, nephrolithiasis, and gout at an early age. Overactivity of PRS is related to an accelerated transcription of the PRS-I gene, acting as a major determinant of synthesis of PRPP, purine nucleotides, and uric acid. 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. Phosphoribosylpyrophosphate synthetase (PRS) superactivity is characterized by hyperuricemia and hyperuricosuria and is divided into a severe phenotype with infantile or early-childhood onset and a milder phenotype with late-juvenile or early-adult onset. Variable combinations of sensorineural hearing loss, hypotonia, and ataxia observed in the severe type are not usually present in the mild type. In the mild type, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled.

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme involved in the salvage of purine nucleotides. HGPRT catalyzes the following two interconversions:

hypoxanthine + PRPP <——> IMP + PP_i

guanine + PRPP <——> GMP + PP_i

A complete or virtually complete loss of HGPRT activity results in the severe disorder, Lesch-Nyhan syndrome. Lesch-Nyhan syndrome is inherited as an x linked trait. Persons with this syndrome are missing or are severely lacking an enzyme called hypoxanthine guanine phosphoribosyltransferase 1 (HGP). The body needs this enzyme to recycle purines. Without it, abnormally high levels of uric acid build up in the body.

Hyperuricemia results from a combination of increased generation and decreased excretion of uric acid which is generated when increased amounts of G6P are metabolized via the pentose phosphate pathway. It is also a byproduct of purine degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue.

Foods high in uric acid play a major role in the development of Gout. In association with a healthy lifestyle and changes in diet, it can actually be easier to manage than many people believe, as long as the sufferer is willing to make some significant changes in their eating habits. Diets that have high contents of purine are extremely important. Restrictions of diet containing higher level of purine will help in reducing serum uric acid level. Normally, uric acid is eliminated from the body by the kidneys. However, some people are more sensitive to high levels of uric acid, and their bodies will form crystals that accumulate in the joints and cause painful gout symptoms. The main goals of treatment for acute gout are to get rid the pain that comes with this disease as well as prevention of future gout attacks. If untreated, it can also lead to joint disability and, ultimately, kidney damage. Diets to reduce uric acid also benefit gout sufferers by helping them lose weight, which has also been shown to help lower concentrations of uric acid in the blood. Foods containing purine and the compounds that metabolize into uric acid include most animal meats, such as beef, pork and seafood. White meat is better than red meat and can have some degree of purine content and should be eaten very sparingly, but they are not as detrimental as the red meats. Alcohol and foods that have high content purine should be kept out of the diet. Black cherry juice, is recommended as herbal therapy for treatment of gout. Celery seed extract and bromelain are some popular alternative medicine remedies that have been used as natural anti-inflammatories and have been well tolerated by those who suffer chronic inflammation. Adding eicosapentaenoic acid (EPA) and folic acid to the diet can also assist in relieving symptoms of gouty arthritis.

Three treatments are available for patients with acute gouty arthritis. Colchicine is commonly used for treatment of acute gouty arthritis. Nonsteroidal antiinflammatory drugs, which are currently prescribed, are rapidly effective but may have serious side effects. Corticosteroids administered either intraarticularly or parenterally, are used increasingly in patients with monarticular gout, especially if oral drug therapy is not feasible. Urate lowering drugs should not be initiated or changed as long as any gouty joint inflammation persists, because such treatment may delay the recovery.

Colchicine is the most popular treatment for acute gout. The high dose of colchicine, up to 6 mg, usually advised for the treatment of gout may cause unnecessary toxicity; a lower dose of 0.5 mg every eight hours may be more appropriate. The toxicity of intravenous colchicine is too high to justify its use.

Most potent nonsteroidal antiinflammatory drugs are rapidly effective in relieving pain and reducing inflammation in patients with acute gout, particularly if the drugs are taken soon after the onset of the attack. Indomethacin, the first of these drugs to be used extensively, provides some pain relief within two to four hours. Depending on the severity of the attack and its duration, the appropriate dose ranges from 150 to 300 mg per day, given in divided doses, with a gradual reduction during a period of five to seven days as the attack subsides. Most other nonsteroidal antiinflammatory drugs are effective but no better than indomethacin, although few comparative data are available. The usefulness of nonsteroidal antiinflammatory drugs is limited by their side effects, but in general, the risks are greatest in elderly patients, particularly those with renal dysfunction.

Corticosteroids such as prednisone can be used as a last resort for gout therapy, when neither NSAIDs nor colchicine can be used. As well, intra-articular steroids can be useful when medium to large joints are affected. Steroids are used to control pain and inflammation. Normally patients taking corticosteroids are given tapered doses when coming off of treatment. However, tapering is not usually necessary for gout patients because of the short duration of therapy.

Gout can be prevented by identifying and correcting the cause of hyperuricemia or by administering drugs that inhibit the synthesis of urate or increase its excretion. Gout may be prevented by reducing serum urate concentrations to values less than 6.0 mg per deciliter (360 μmol per liter). A reduction to less than 5.0 mg per deciliter (300 μmol per liter) may be required for the resorption of tophi. Two classes of drugs are available: uricosuric drugs and xanthine oxidase inhibitors. Uricosuric drugs increase the urinary excretion of urate, thereby lowering the serum urate concentration. In contrast, xanthine oxidase inhibitors block the final step in urate synthesis, reducing the production of urate while increasing that of its precursors, xanthine and hypoxanthine (the oxypurines). In general, a xanthine oxidase inhibitor is indicated in patients with increased urate production, and a uricosuric drug in those with low urate clearance. A potential complication of these drugs is the precipitation of acute attacks of gout. The mechanism is poorly understood, but it is usually attributed to the sudden change in the serum urate concentration. The risk can be minimized by concurrently administering prophylactic drugs, delaying urate-lowering therapy until several weeks after the last attack of gout, and commencing therapy with a low dose of the drug that is chosen.

Uricosurics like probenecid and sulfinpyrazone increase renal excretion of uric acid by inhibiting tubular reabsorption in the kidneys. It is important to start at low doses because large amounts of uric acid passing through the kidneys will increase the risk of forming uric acid stones. The anti-hypertensive drug losartan has been shown to have a uricosuric effect, but this effect decreases drastically once the drug has reach steady state. It can also worsen preexisting renal impairment. Uricosuric drugs are contraindicated for patients with kidney stones and renal insufficiency. Those patients should use a drug that will function independently of kidney function.

Allopurinol, a xanthine oxidase inhibitor, is the most commonly prescribed of these agents. The average dose is 300 mg per day, although dosing recommendations range from 100 to 800 mg per day, titrated to serum urate and creatinine clearance. The side effects of allopurinol, although uncommon, may be severe or life-threatening and occur more often in patients with renal insufficiency. Allopurinol has been considered the drug of choice for hyperuricemia because it can be conveniently administered once daily, and might prevent urolithiasis. Allopurinol and uricosuric drug may be used simultaneously in a few patients who can not be controlled with a single medication.