Hereditary xanthinuria

ALSO KNOWN AS: Xanthine dehydrogenase (XDH) deficiency; xanthine oxidoreductase (XOR) deficiency; xanthine oxidase (XO) deficiency; classical xanthinuria

DEFINITION: Hereditary xanthinuria is an extremely rare autosomal recessive disease characterized by high levels of xanthine in the urine and blood. It is caused by a deficiency of xanthine dehydrogenase (XDH) as a result of abnormalities either in XDH, the gene that encodes this enzyme, or in a gene necessary for the synthesis of a cofactor required by XDH.

Risk Factors

This disease is so rare and underreported that the actual incidence is unknown, as are the relative incidences in different ethnic populations. Only around 150 cases have been described to date, and the estimated annual incidence is between approximately 1 in 6,000 and 1 in 69,000. Risk, however, is very low for all except those with histories of the disease in both the paternal and maternal sides of their families.

Etiology and Genetics

There are two types of hereditary xanthinuria: type I, where XDH is the only inactive enzyme, and type II, where both XDH and aldehyde oxidase (AO) are inactive. The two types of this disease are clinically alike because AO function is required only in highly unusual circumstances. Both types are inherited in an autosomally recessive manner.

Although XDH and AO are functionally different, both require molybdenum cofactor sulfurase (MCOS) for activity. All but one of the genetic alterations responsible for type I xanthinuria that have been subjected to sequence analysis reside at various locations within the part of the genome that codes for XDH—on chromosome 2 at position 2p23.1. (The exception is thought to be a regulatory mutation.) All genetic alterations responsible for xanthinuria type II sequenced thus far are found in the gene that encodes MCOS on chromosome 18 at position 18q12. A single genetic abnormality can eliminate the activities of two enzymes since both require the same cofactor.

Functional XDH is required to convert xanthine to uric acid (the last step in the breakdown of purines before elimination from the body). Thus, the absence of functional XDH in either type of xanthinuria leads to excessive xanthine in the blood and urine. The low solubility of xanthine can lead to its crystallization and deposition on urinary tract tissues and sometimes in muscles and joints. Hence, the low solubility of xanthine generates the clinical symptoms of xanthinuria, namely irritation, inflammation, bloody urine, muscle and joint pain, xanthine stones in the urinary tract, and urinary tract blockages, which can lead to acute and chronic kidney failure.

Symptoms

The primary clinical problem for xanthinuria patients is the formation of xanthine stones in the urinary tract. Other difficulties in approximate order of frequency include irritation, inflammation, susceptibility to infection, blood in the urine, muscle and joint pain, and rarely, renal failure. At least half of patients are asymptomatic.

Screening and Diagnosis

The near absence of uric acid in blood and urine, coupled with elevated xanthine in urine, is diagnostic for xanthinuria. The presence of stones that can be seen by ultrasonography but not by x-rays supports the diagnosis.

To distinguish between xanthinuria types I and II, the conversion of allopurinol to oxypurinol, which requires AO, is measured. If oxypurinol is detected in the blood after allopurinol administration, then the patient has type I. If it is not, the patient has type II. Prenatal screening is not available.

Treatment and Therapy

High fluid intake and a diet that restricts high-purine foods (such as organ meats) are the only recommended therapies. Vigorous exercise and extremely warm weather should be avoided if possible. Xanthine stones can be surgically removed or shattered by ultrasound (lithotripsy).

Prevention and Outcomes

The disease cannot be prevented, but its complications can be minimized. The wide variability in outcomes amongst xanthinuria patients, with about half being asymptomatic, suggests that factors apart from defective xanthine dehydrogenase genes can have a significant impact on outcome. Accordingly, the damage caused by xanthine may be diminished by low-purine diets and high fluid intake. A low-purine diet is expected to decrease the amount of xanthine to be eliminated, and the increased amount of fluid should dilute xanthine and decrease the likelihood of crystallization.

It is important to test potentially xanthinuric individuals at an early age. Urine and blood tests for uric acid are recommended for people who have xanthinuria in their families or who have any of its symptoms.

Bibliography

Eggermann, T., et al. "Multi-Exon Deletion in the XDH Gene As a Cause of Classical Xanthinuria." Clinical Nephrology. 79.1 (2013): 78–80. Digital file.

Genetics Home Reference. "XDH." Genetics Home Reference. US NLM, 21 July 2014. Web. 25 July 2014.

"Hereditary Xanthinuria." Orphanet, Apr. 2012, www.orpha.net/en/disease/detail/3467. Accessed 9 Sept. 2024.

Ichida, Kimiyoshi, Yoshihiro Amaya, Ken Okamoto, and Takeshi Nishino. "Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans." Intl. Jour. of Molecular Sciences 13.11 (2012): 15475–15495. Digital file.

Peretz, H., M. S. Naamati, and D. Levartovsky, et al. “Identification and Characterization of the First Mutation (Arg776Cys) in the C-terminal Domain of the Human Molybdenum Cofactor Sulfurase (HMCS) Associated with Type II Classical Xanthinuria.” Molecular Genetics and Metabolism 91 (2007): 23–29. Print.

Rimoin, David L., J. Michael Connor, and Reed E. Pyeritz, et al. Emery and Rimoin’s Principles and Practice of Medical Genetics. 6th ed. Oxford: Academic, 2013. Print.

Scriver, Charles R., Arthur L. Beaudet, and David Valle, et al. Metabolic and Molecular Bases of Inherited Diseases. 8th ed. 4 vols. New York: McGraw, 2001. Print.