Alternative titles; symbols
SNOMEDCT: 124147007, 836343001; ORPHA: 3467, 93601; DO: 0070452;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p23.1 | Xanthinuria, type I | 278300 | Autosomal recessive | 3 | XDH | 607633 |
A number sign (#) is used with this entry because of evidence that type I xanthinuria (XAN1) is caused by homozygous or compound heterozygous mutation in the gene encoding xanthine dehydrogenase (XDH; 607633) on chromosome 2p23.
Xanthinuria, which was first described by Dent and Philpot (1954), is characterized by excretion of large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. Two clinically similar but distinct forms of xanthinuria are recognized. In type I (XAN1) there is an isolated deficiency of xanthine dehydrogenase, and in type II (XAN2; 603592) there is a dual deficiency of xanthine dehydrogenase and aldehyde oxidase (603592). Type I patients can metabolize allopurinol, whereas type II patients cannot (Simmonds et al., 1995). Xanthinuria also occurs in molybdenum cofactor deficiency (252150).
Type II xanthinuria is caused by mutation in the MOCOS gene (613274), which encodes the enzyme that sulfurates the molybdenum cofactor for XDH and AOX1 (602841).
Dickinson and Smellie (1959) described a well-studied single case, a child of unrelated, unaffected parents. Watts et al. (1964) described a 23-year-old woman in whom the disorder was suspected because of very low serum uric acid. There were no urinary calculi. Enzyme assays showed very little oxidation of both hypoxanthine and xanthine, presumably due to a defect in xanthine oxidase (EC 1.1.3.22), which catalyzes the oxidation of hypoxanthine to xanthine and also of xanthine to uric acid (Engelman et al., 1964; Sperling et al., 1971). Affected brothers have been observed (Wyngaarden, 1978). In the eighth known patient, a black male, studied by Chalmers et al. (1969), crystalline deposits occurred in skeletal muscle. A myopathy with crystalline deposits was described also by Engelman et al. (1964). An increased frequency of xanthinuria was reported in persons of Lebanese ancestry (Frayha et al., 1977).
Mateos et al. (1987) presented evidence of enhanced hypoxanthine salvage in studies of 2 sibs whose parents were first cousins. One, a boy aged 13, had passed multiple brownish-yellow stones during his first year of life and at 2 years of age had right ureteral lithiasis requiring surgical extraction. At age 6, reoperation for multiple pelvic and ureteral xanthine calculi was required. With increased water intake and sodium bicarbonate, he remained asymptomatic. His 22-year-old sister had been in good health since birth. Mateos et al. (1987) presented data indicating that xanthine is mainly derived from GTP to GMP degradation in hereditary xanthinuria both in the basal state and after intravenous fructose. This bypass of the hypoxanthine salvage pathway may explain why xanthine is the predominant urinary purine excreted in xanthinuria.
Maynard and Benson (1988) described hereditary xanthinuria in a 3-year-old Pakistani girl and her 5-year-old sister. The former had end-stage pyelonephritis and nonfunctioning hydronephrotic right kidney due to a xanthine calculus impacted in the right ureter. The older sister, who also had beta-thalassemia, was asymptomatic.
Fildes (1989) observed the unusual occurrence of urolithiasis due to hereditary xanthinuria in a 7-month-old Kuwaiti girl. Renal stones usually occur in older children or in adults.
Roca et al. (1992) reported an 80-year-old man with hereditary xanthinuria. He had coralliform lithiasis of the left kidney and a history of a surgical procedure on the left kidney at the age of 6 years. He also had a form of the Ehlers-Danlos syndrome (see EDS1; 130000).
Mayaudon et al. (1998) described 2 unrelated adults with xanthinuria discovered incidentally because of hypouricemia. One was a 36-year-old man; the second was a 76-year-old woman who was found to have a radiotransparent renal stone.
The transmission pattern of xanthinuria in the patients reported by Ichida et al. (1997) was consistent with autosomal dominant inheritance.
Ichida et al. (1997) studied 4 individuals with classic xanthinuria to discover the molecular cause of the enzyme deficiency. One subject had a C-to-T transition at nucleotide 682 of the XHD gene that caused an arg228-to-ter nonsense substitution (607633.0001). The duodenal mucosa from this subject had no xanthine dehydrogenase protein, while the mRNA level was not reduced. Two other subjects who were sibs were homozygous for this mutation, while another subject was found to carry the same mutation in heterozygous state. The fourth subject had a deletion of C at nucleotide 2567 in cDNA that was predicted to generate a termination codon from nucleotide 2783 (607633.0002). This subject was homozygous for the mutation and the level of mRNA in the duodenal mucosa was not reduced.
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Chalmers, R. A., Johnson, M., Pallis, C., Watts, R. W. E. Xanthinuria with myopathy. Quart. J. Med. 38: 493-512, 1969. [PubMed: 5355540]
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Engelman, K., Watts, R. W. E., Klinenberg, J. R., Sjoerdsma, A., Seegmiller, J. E. Clinical, physiological and biochemical studies of a patient with xanthinuria and pheochromocytoma. Am. J. Med. 37: 839-861, 1964. [PubMed: 14246087] [Full Text: https://doi.org/10.1016/0002-9343(64)90128-7]
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Frayha, R. A., Salti, I. S., Arnaout, A., Khatchadurian, A., Uthman, S. M. Hereditary xanthinuria: report on three patients and short review of the literature. Nephron 19: 328-332, 1977. [PubMed: 927625] [Full Text: https://doi.org/10.1159/000180910]
Ichida, K., Amaya, Y., Kamatani, N., Nishino, T., Hosoya, T., Sakai, O. Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J. Clin. Invest. 99: 2391-2397, 1997. [PubMed: 9153281] [Full Text: https://doi.org/10.1172/JCI119421]
Mateos, F. A., Puig, J. G., Jimenez, M. L., Fox, I. H. Hereditary xanthinuria: evidence for enhanced hypoxanthine salvage. J. Clin. Invest. 79: 847-852, 1987. [PubMed: 3818951] [Full Text: https://doi.org/10.1172/JCI112893]
Mayaudon, H., Burnat, P., Eulry, F., Payen, C., Dupuy, O., Ducorps, M., Bauduceau, B. La xanthinurie hereditaire, cause rare d'hypo-uricemie: 2 observations. Presse Med. 27: 661-663, 1998. [PubMed: 9767921]
Maynard, J., Benson, P. Hereditary xanthinuria in 2 Pakistani sisters: asymptomatic in one with beta-thalassemia but causing xanthine stone, obstructive uropathy and hypertension in the other. J. Urol. 139: 338-339, 1988. [PubMed: 3339736] [Full Text: https://doi.org/10.1016/s0022-5347(17)42404-9]
Roca, B., Calabuig, C., Sastre, J., Arenas, M. Hereditary xanthinuria and Ehlers-Danlos syndrome. J. Inherit. Metab. Dis. 15: 881-882, 1992. [PubMed: 1293384] [Full Text: https://doi.org/10.1007/BF01800226]
Simmonds, H. A., Reiter, S., Nishino, T. Hereditary xanthinuria. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. 2 New York: McGraw-Hill 1995. P. 1781.
Sorensen, L. B., Tesar, J. T., Ellman, M. H., Cowell, J. A new case of xanthinuria. Am. J. Med. 53: 690-692, 1972. [PubMed: 5079766] [Full Text: https://doi.org/10.1016/0002-9343(72)90164-7]
Sperling, O., Liberman, U. A., Frank, M., De Vries, A. Xanthinuria: an additional case with demonstration of xanthine oxidase deficiency. Am. J. Clin. Path. 55: 351-354, 1971. [PubMed: 5549903] [Full Text: https://doi.org/10.1093/ajcp/55.3.351]
Watts, R. W. E., Engelman, K., Klinenberg, J. R., Seegmiller, J. E., Sjoerdsma, A. Enzyme defect in a case of xanthinuria. Nature 201: 395-396, 1964. [PubMed: 14110004] [Full Text: https://doi.org/10.1038/201395a0]
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