Introduction:
Xanthinuria is a condition with a large amount of purine base xanthine excretion. This incidence is primarily seen due to the deficiency of an enzyme called xanthine dehydrogenase (responsible for degrading hypoxanthine and xanthine to uric acid). Hereditary xanthinuria is a condition frequently seen affecting the kidneys. It can be characterized by high levels of a substance called xanthine and very low levels of another substance called uric acid in the blood and urine.
What Is Xanthinuria?
Xanthinuria occurs when there is too much excretion of purine base xanthine by urinary means. Two inherited forms of xanthinuria exist. These occur due to a deficiency of the enzyme xanthine dehydrogenase. This enzyme is responsible for degrading hypoxanthine and xanthine to uric acid.
A deficiency of xanthine dehydrogenase can cause accumulation of plasma and excess urinary excretion of the highly insoluble xanthine, which might lead to arthropathy, myopathy, crystal nephropathy, urolithiasis, or renal failure.
Hypoxanthine accumulation, to an appreciable degree, does not occur as it is recycled through a salvage pathway by an enzyme called hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Xanthine keeps accumulating, despite hypoxanthine recycling, because the metabolism of guanine to xanthine by an enzyme called guanase takes place.
What Is Hereditary Xanthinuria?
Hereditary xanthinuria is a condition frequently seen affecting the kidneys. It can be characterized by high levels of a substance called xanthine and very low levels of another substance called uric acid in the blood and urine. The excess amount of xanthine can accumulate in the kidneys and other tissues.
In the kidneys, small crystals are formed by xanthine that sometimes build up to form kidney stones. These stones can be responsible for the impairment of the function of the kidney and ultimately result in kidney failure. The signs and symptoms associated with it can be abdominal pain, recurring UTIs or urinary tract infections, and the presence of blood in the urine (hematuria).
Less commonly, xanthine crystals are formed in the muscles, resulting in pain and cramping. The condition does not cause health problems in some people with hereditary xanthinuria. It is an autosomal recessive genetic abnormality that causes the excretion of too much xanthine (a metabolic byproduct) in the urine. This elevates the risk for the formation of xanthine bladder or stones in the kidney and can cause significant kidney disease. Hereditary xanthinuria occurs due to mutations (changes) in either xanthine dehydrogenase (XDH, type 1 xanthinuria) or molybdenum cofactor sulfurase (MOCOS, type 2 xanthinuria).
Xanthinuria can also occur due to non-genetic factors like drug exposure that inhibit the XDH (e.g., allopurinol). This is referred to as iatrogenic xanthinuria. The combined prevalence of hereditary xanthinuria types I and II is estimated to be around 1 in 69,000 people worldwide. However, studies also suggest that the incidence might be higher as some affected individuals remain asymptomatic and are never diagnosed with this condition. Some of the other names of this condition are Combined deficiency of xanthine dehydrogenase and aldehyde oxidase.
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Xanthine dehydrogenase deficiency.
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Xanthinuria.
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XDH deficiency.
What Causes Xanthinuria?
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Type I hereditary xanthinuria is caused because of mutations in the XDH gene. This gene is responsible for instructing the formation of an enzyme, xanthine dehydrogenase. This enzyme is indulged in the breakdown of purines normally, which are the building blocks of DNA and RNA, its chemical cousin. Particularly, xanthine dehydrogenase takes the final two steps in the process, including the conversion of xanthine to uric acid (that is excreted in urine and feces). Mutations or changes in the XDH gene decrease or eliminate the activity of xanthine dehydrogenase. As a result of this, the enzyme is not available to help in carrying out the last two steps of purine breakdown. As xanthine is not converted into uric acid, the individuals affected have higher levels of xanthine, and uric acid’s level is lower in their blood and urine. This excess xanthine might result in damaging the kidneys and other tissues.
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Mutations in the MOCOS gene cause type II hereditary xanthinuria. This gene instructs the formation of an enzyme called molybdenum cofactor sulfurase. This enzyme is required for the proper functioning of xanthine dehydrogenase, as described above, and one more enzyme called aldehyde oxidase. Mutations in the MOCOS gene prevent the activation of xanthine dehydrogenase and aldehyde oxidase. The loss of xanthine dehydrogenase activity inhibits the conversion of xanthine to uric acid, this causes the deposition of xanthine in the kidneys and other tissues. The loss of aldehyde oxidase activity will not result in causing any health issues.
What Are the Signs of Hereditary Xanthinuria?
Xanthinuria is responsible for the formation of urinary stones. This results in irritation that might manifest as straining to urinate, frequent urination, the urgency of urination, blood in the urine, or life-threatening urinary problems. Microscopic crystals, too, can accumulate in the kidney and lead to kidney disease. Patients with xanthinuria can be of any age from a few months onwards. Many patients have serious consequences, while some remain asymptomatic. Males are more likely to develop stones than females.
How Is Hereditary Xanthinuria Diagnosed?
Hereditary xanthinuria can be diagnosed by estimating uric acid in the blood and urine. If hyperuricemia is confirmed, a detailed purine metabolic investigation is done, including evaluating xanthine and hypoxanthine in urine and plasma.
High urinary levels of xanthine are usual for classical hereditary xanthinuria. In around half of the patients, ultrasonography identifies the presence of xanthine urolithiasis.
Other methods that can be used to confirm or identify the type of xanthinuria are the allopurinol loading test, xanthine oxidase assay, and molecular analysis.
What Is the Differential Diagnosis of Hereditary Xanthinuria?
Hereditary xanthinuria is regarded as a clinical feature of molybdenum cofactor deficiency. Clinically, this disease is more severe, as it is associated with neurological damage and frequent infant death. Hypouricemia is also considered a biochemical marker for primary hereditary renal hypouricemia. The excretion fraction of uric acid is higher in renal hypouricemia.
How Is Hereditary Xanthinuria Managed?
There is no definitive treatment for hereditary xanthinuria. A diet that is low in purine and more fluid intake is advised. As the solubility of xanthine is not affected by the pH of the urine, alkalization is of no importance. In case of any calculi, a pyelolithotomy might be advised.
Conclusion:
Hereditary xanthinuria is a condition in which a purine-based xanthine is removed excessively by the urinary means. It is a genetically inherited disease. An estimation of the uric acid present in the blood and urine can diagnose it. A low purine diet and higher fluid intake can manage it.
