Unusual Clinical Presentations of Gout

Tony C. Ning; Robert T. Keenan

Disclosures

Curr Opin Rheumatol. 2010;22(2):181 

In This Article

Early Onset Gout

Gout is a disease of middle-aged men, but it can present much earlier in life. Deficiencies in certain enzymes can cause overproduction and excessive levels of serum urate in childhood and early adulthood. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) is involved in the purine salvage pathway and catalyzes the reutilization of hypoxanthine and guanine to purine nucleotides. Complete and partial deficiencies of HPRT are X-linked and although the prevalence is not known, some speculate that it may be as prevalent as one in 380 000 in some populations.[8,9] In addition to hyperuricemia, severe gout and nephropathy, complete deficiency of HPRT manifests as Lesch-Nyhan syndrome with spasticity, choreoathetosis, mental retardation, and self-mutilation.[9] Partial HPRT deficiency, also known as Kelley–Seegmiller syndrome, results in a spectrum of neurological disorders in addition to early onset hyperuricemia and gout.[9] Interestingly, these patients may not present with elevated plasma uric-acid levels until puberty, as uric-acid secretion increases two-to-four times greater than the average adult.

Another genetic disorder that results in elevated levels of serum urate and gouty arthropathy is super activity of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase, an enzyme that is a cosubstrate for HPRT.[10] Increased activity of this enzyme leads to increased synthesis of purine nucleotides, which are then catabolized into uric acid. Approximately 20 cases of PRPP synthetase super activity have been reported, but this X-linked disease should be suspected in cases where the patient presents with early onset gout and sensorineural deafness.[11]

Glycogen storage diseases can also result in elevated urate levels. Glycogen storage enzyme type I disease (von Gierke's glycogen storage disease) is an autosomal-recessive disorder that is a result of glucose-6-phosphatase deficiency.[12] These patients have an accelerated purine production, which predisposes them to elevated levels of serum urate and gout. These patients may present with a classic picture of gout[12] with involvement of the first MTP in addition to myopathies. There have been cases reported when the presence of gouty tenosynovitis of the achilles tendon was the first clinical manifestation of glycogen-storage disease Ia.[13]

A small number of gouty arthropathy cases are a result of familial gout. In these patients gout can present as early as the initial teenage years to late third decade of life. Gout manifesting in the early teens is a result of a group of autosomal-dominant diseases, which include familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney type II disease.[14] These diseases feature a mutant gene that interrupts the tertiary structure of uromodulin, also known as the Tamm-Horsfall protein. The clinical presentation of these diseases not only includes early onset gout, but also progressive renal failure and polyuria. The development of hyperuricemia and gout is probably related to the volume contraction that results from the interruption of renal and water transport from the mutant uromodulin protein.[15] A study[14] that examined homozygosity in these disorders did not note increased uric acid levels in the homozygotes for medullary cystic disease versus the heterozygotes.

In addition to uromodulin defects, a large number of familial cases of gout are the deficiency of fructose-1-phosphate aldolase.[16] Homozygous deficiency in fructose-1-phosphate aldolase results in hypoglycemia, proximal tubular dysfunction and liver failure in very young children. Heterozygous carriers develop hyperuricemia, and many of those will develop gout.[16]

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