RARE DISEASE
Hereditary xanthinuria
Hereditary xanthinuria
Hereditary xanthinuria
Synonyms: Classic xanthinuria, Xanthic urolithiasis, Xanthine stone disease
Synonyms: Classic xanthinuria, Xanthic urolithiasis, Xanthine stone disease
Synonyms: Classic xanthinuria, Xanthic urolithiasis, Xanthine stone disease
Drug discovery
0
drugs
With orphan designations
Overview
Hereditary xanthinuria is a rare autosomal recessive disorder caused by mutations in XDH (type I) or MOCOS (type II), leading to xanthine dehydrogenase/oxidase deficiency. This disrupts purine metabolism, resulting in hypouricemia, elevated serum/urinary xanthine, and xanthine urolithiasis. While ~50% of patients remain asymptomatic, manifestations include nephrolithiasis, hematuria, recurrent UTIs, and rare progression to renal failure [1][2][11]. Diagnosis involves hypouricemia confirmation, urinary xanthine quantification, and genetic testing [1][4][12].
Burden
Therapies
Dietary: Low-purine diet (avoiding organ meats, seafood) and high fluid intake (>3 L/day) [3][8][12].
Surgical: Pyelolithotomy or minimally invasive techniques for obstructing xanthine stones [1][7].
Emerging: Experimental use of methylxanthines (e.g., theobromine derivatives) to inhibit xanthine crystallization [3][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare renal diseases
Research Papers
57 drug discovery papers about Hereditary xanthinuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
57 drug discovery papers about Hereditary xanthinuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-09-24 | XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell.
Xanthine dehydrogenase (XDH) is a molybdenum cofactor (Moco) requiring enzyme that catabolizes hypoxanthine into xanthine and xanthine into uric acid, the final steps in purine catabolism. Human patients with mutations in XDH develop xanthinuria which can lead to xanthine stones in the kidney, recurrent urinary tract infections, and renal failure. Currently, there are no therapies for treating human XDH deficiency. Thus, understanding mechanisms that maintain purine homeostasis is an important goal of human health. Here, we used the nematode Caenorhabditis elegans to model human XDH deficiency using two clinically relevant paradigms: Moco deficiency or loss-of-function mutations in xdh-1, the C. elegans ortholog of XDH. Both Moco deficiency and xdh-1 loss of function caused the formation of autofluorescent xanthine stones in C. elegans. Surprisingly, only 2% of xdh-1 null mutant C. elegans developed a xanthine stone, suggesting additional pathways may regulate this process. To uncover such pathways, we performed a forward genetic screen for mutations that enhance the penetrance of xanthine stone formation in xdh-1 null mutant C. elegans. We isolated multiple loss-of-function mutations in the gene sulp-4 which encodes a sulfate permease homologous to human SLC26 anion exchange proteins. We demonstrated that SULP-4 acts cell-nonautonomously in the excretory cell to limit xanthine stone accumulation. Interestingly, sulp-4 mutant phenotypes were suppressed by mutations in genes that encode for cystathionase (cth-2) or cysteine dioxygenase (cdo-1), members of the sulfur amino acid catabolism pathway required for production of sulfate, a substrate of SULP-4. We propose that sulfate accumulation caused by sulp-4 loss of function promotes xanthine stone accumulation. We speculate that sulfate accumulation causes osmotic imbalance, creating conditions in the intestinal lumen that favor xanthine stone accumulation. Supporting this model, a mutation in osm-8 that constitutively activates the osmotic stress response also promoted xanthine stone accumulation in an xdh-1 mutant background. Thus, our work establishes a C. elegans model for human XDH deficiency and identifies the sulfate permease sulp-4 as a critical player controlling xanthine stone accumulation.
2025-08-14 | [Long-standing myalgia and hypouricemia in a young woman : Case report and review of the literature].
A 46-year-old female patient had been suffering from multiple symptoms such as arthralgia, myalgia, general fatigue, exhaustion, concentration problems, forgetfulness, difficulty falling asleep and sleeping through the night and depression since the age of 27 years old. Rheumatological preliminary findings revealed rheumatoid arthritis with a lack of response to basic treatment as well as secondary fibromyalgia. Supplementary metabolic examinations were carried out in the case of laboratory tests for hypouricemia, which showed massively increased xanthine levels in the urine. With normal renal function and unremarkable urine sediment, small concrements were sonographically visualized in the renal pelvic calyceal system on both sides. The diagnosis of xanthinuria was made. This is a rare hereditary disorder of purine metabolism with a lack of conversion of hypoxanthine via xanthine to uric acid via the enzyme xanthine oxidoreductase. Clinical courses range from asymptomatic to symptomatic urolithiasis with increased renal xanthine excretion and myalgia with intramuscular xanthine deposits. In addition, non-specific arthralgia and progressive renal insufficiency are described during the course of the disease. Clinically, the overlapping symptoms of fibromyalgia and xanthinuria make it impossible to reliably differentiate between the two entities.
2025-02-20 | XDH-1 inactivation causes xanthine stone formation in C. elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell.
Xanthine dehydrogenase (XDH) is a molybdenum cofactor (Moco) requiring enzyme that catabolizes hypoxanthine into xanthine and xanthine into uric acid, the final steps in purine catabolism. Human patients with mutations in XDH develop xanthinuria which can lead to xanthine stones in the kidney, recurrent urinary tract infections, and renal failure. Currently there are no therapies for treating human XDH deficiency. Thus, understanding mechanisms that maintain purine homeostasis is an important goal of human health. Here, we used the nematode C. elegans to model human XDH deficiency using 2 clinically relevant paradigms: Moco deficiency or loss-of-function mutations in xdh-1, the C. elegans ortholog of XDH. Both Moco deficiency and xdh-1 loss of function caused the formation of autofluorescent xanthine stones in C. elegans. Surprisingly, only 2% of xdh-1 null mutant C. elegans developed a xanthine stone, suggesting additional pathways may regulate this process. To uncover such pathways, we performed a forward genetic screen for mutations that enhance the penetrance of xanthine stone formation in xdh-1 null mutant C. elegans. We isolated multiple loss-of-function mutations in the gene sulp-4 which encodes a sulfate permease homologous to human SLC26 anion exchange proteins. We demonstrated that SULP-4 acts cell-nonautonomously in the excretory cell to limit xanthine stone accumulation. Interestingly, sulp-4 mutant phenotypes were suppressed by mutations in genes that encode for cystathionase (cth-2) or cysteine dioxygenase (cdo-1), members of the sulfur amino acid catabolism pathway required for production of sulfate, a substrate of SULP-4. We propose that sulfate accumulation caused by sulp-4 loss of function promotes xanthine stone accumulation. We speculate that sulfate accumulation causes osmotic imbalance, creating conditions in the intestinal lumen that favor xanthine stone accumulation. Supporting this model, a mutation in osm-8 that constitutively activates the osmotic stress response also promoted xanthine stone accumulation in an xdh-1 mutant background. Thus, our work establishes a C. elegans model for human XDH deficiency and identifies the sulfate permease sulp-4 as a critical player controlling xanthine stone accumulation.
2025-01-26 | Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice.
In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene (XDH), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh(- / -) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or xanthine levels become excessive and thus toxic in Xdh(- / -) mice because enhancing the activity of hypoxanthine phosphoribosyl transferase (HPRT), which is an enzyme that uses hypoxanthine as a substrate, slightly increases the life span of these mice. In this study, we targeted the mouse intestinal sodium-dependent nucleobase transporter (SNBT) gene (Slc23a4), which is a pseudogene in humans. Hprt(high)Xdh(- / -)Slc23a4(- / -) mice had a longer life span and reached adulthood. The urinary xanthine excretion of these mice was 20-fold greater than that of patients with type 1 xanthinuria. The urinary hypoxanthine/xanthine ratio of Hprt(high)Xdh(- / -)Slc23a4(- / -) mice was lower than that of patients with type 1 xanthinuria. Hprt(high)Xdh(- / -)Slc23a4(- / -) mice exhibited renal impairment, accompanied by high plasma creatinine levels and anemia. Moreover, female Hprt(high)Xdh(- / -)Slc23a4(- / -) mice produced offspring that did not survive. In conclusion, for the first time, we established that Xdh(- / -) mice survive to adulthood.
2024-12-18 | Theobromine for treatment of uric acid stones and other diseases.
Theobromine (or 3,7-dimethylxanthine) is a natural alkaloid present in cocoa plant and its derivatives, such as chocolate. About 20% of ingested theobromine is excreted unchanged in the urine. Theobromine also derived from caffeine that is metabolized into theobromine by 12%. The primary metabolites of theobromine are 3-methylxantine, 7-methylxantine, 7-methyluric acid and 3,7-dimethyluric acid. Theobromine has an inhibitory activity of uric acid crystallization, because it has a structural pattern very similar to uric acid and can substitute uric acid molecules in the corresponding uric acid crystals, making them longer and thinner and decreasing their growth rate. Theobromine also favors the dissolution of crystals by decreasing supersaturation of uric acid by forming aggregates with uric acid through hydrogen bonds and aromatic stacking interactions (-stacking bonds) increasing urinary solubility of uric acid. Theobromine can be used for uric acid stone dissolution in combination with alkalinization to reduce the dose of citrate, thus preventing excessive alkalinization and the risk of formation of sodium urate crystals. Theobromine could also be used to treat patient with xanthine stones that cannot be dissolved by alkalinization because the solubility of xanthine is relatively independent of urinary pH. A metabolite of theobromine, 7-methylxanthine, has the potential to be used for the prevention of the formation of sodium urate crystals in the synovial fluid of gouty patients.
2025-09-24 | XDH-1 inactivation causes xanthine stone formation in Caenorhabditis elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell.
Xanthine dehydrogenase (XDH) is a molybdenum cofactor (Moco) requiring enzyme that catabolizes hypoxanthine into xanthine and xanthine into uric acid, the final steps in purine catabolism. Human patients with mutations in XDH develop xanthinuria which can lead to xanthine stones in the kidney, recurrent urinary tract infections, and renal failure. Currently, there are no therapies for treating human XDH deficiency. Thus, understanding mechanisms that maintain purine homeostasis is an important goal of human health. Here, we used the nematode Caenorhabditis elegans to model human XDH deficiency using two clinically relevant paradigms: Moco deficiency or loss-of-function mutations in xdh-1, the C. elegans ortholog of XDH. Both Moco deficiency and xdh-1 loss of function caused the formation of autofluorescent xanthine stones in C. elegans. Surprisingly, only 2% of xdh-1 null mutant C. elegans developed a xanthine stone, suggesting additional pathways may regulate this process. To uncover such pathways, we performed a forward genetic screen for mutations that enhance the penetrance of xanthine stone formation in xdh-1 null mutant C. elegans. We isolated multiple loss-of-function mutations in the gene sulp-4 which encodes a sulfate permease homologous to human SLC26 anion exchange proteins. We demonstrated that SULP-4 acts cell-nonautonomously in the excretory cell to limit xanthine stone accumulation. Interestingly, sulp-4 mutant phenotypes were suppressed by mutations in genes that encode for cystathionase (cth-2) or cysteine dioxygenase (cdo-1), members of the sulfur amino acid catabolism pathway required for production of sulfate, a substrate of SULP-4. We propose that sulfate accumulation caused by sulp-4 loss of function promotes xanthine stone accumulation. We speculate that sulfate accumulation causes osmotic imbalance, creating conditions in the intestinal lumen that favor xanthine stone accumulation. Supporting this model, a mutation in osm-8 that constitutively activates the osmotic stress response also promoted xanthine stone accumulation in an xdh-1 mutant background. Thus, our work establishes a C. elegans model for human XDH deficiency and identifies the sulfate permease sulp-4 as a critical player controlling xanthine stone accumulation.
2025-08-14 | [Long-standing myalgia and hypouricemia in a young woman : Case report and review of the literature].
A 46-year-old female patient had been suffering from multiple symptoms such as arthralgia, myalgia, general fatigue, exhaustion, concentration problems, forgetfulness, difficulty falling asleep and sleeping through the night and depression since the age of 27 years old. Rheumatological preliminary findings revealed rheumatoid arthritis with a lack of response to basic treatment as well as secondary fibromyalgia. Supplementary metabolic examinations were carried out in the case of laboratory tests for hypouricemia, which showed massively increased xanthine levels in the urine. With normal renal function and unremarkable urine sediment, small concrements were sonographically visualized in the renal pelvic calyceal system on both sides. The diagnosis of xanthinuria was made. This is a rare hereditary disorder of purine metabolism with a lack of conversion of hypoxanthine via xanthine to uric acid via the enzyme xanthine oxidoreductase. Clinical courses range from asymptomatic to symptomatic urolithiasis with increased renal xanthine excretion and myalgia with intramuscular xanthine deposits. In addition, non-specific arthralgia and progressive renal insufficiency are described during the course of the disease. Clinically, the overlapping symptoms of fibromyalgia and xanthinuria make it impossible to reliably differentiate between the two entities.
2025-02-20 | XDH-1 inactivation causes xanthine stone formation in C. elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell.
Xanthine dehydrogenase (XDH) is a molybdenum cofactor (Moco) requiring enzyme that catabolizes hypoxanthine into xanthine and xanthine into uric acid, the final steps in purine catabolism. Human patients with mutations in XDH develop xanthinuria which can lead to xanthine stones in the kidney, recurrent urinary tract infections, and renal failure. Currently there are no therapies for treating human XDH deficiency. Thus, understanding mechanisms that maintain purine homeostasis is an important goal of human health. Here, we used the nematode C. elegans to model human XDH deficiency using 2 clinically relevant paradigms: Moco deficiency or loss-of-function mutations in xdh-1, the C. elegans ortholog of XDH. Both Moco deficiency and xdh-1 loss of function caused the formation of autofluorescent xanthine stones in C. elegans. Surprisingly, only 2% of xdh-1 null mutant C. elegans developed a xanthine stone, suggesting additional pathways may regulate this process. To uncover such pathways, we performed a forward genetic screen for mutations that enhance the penetrance of xanthine stone formation in xdh-1 null mutant C. elegans. We isolated multiple loss-of-function mutations in the gene sulp-4 which encodes a sulfate permease homologous to human SLC26 anion exchange proteins. We demonstrated that SULP-4 acts cell-nonautonomously in the excretory cell to limit xanthine stone accumulation. Interestingly, sulp-4 mutant phenotypes were suppressed by mutations in genes that encode for cystathionase (cth-2) or cysteine dioxygenase (cdo-1), members of the sulfur amino acid catabolism pathway required for production of sulfate, a substrate of SULP-4. We propose that sulfate accumulation caused by sulp-4 loss of function promotes xanthine stone accumulation. We speculate that sulfate accumulation causes osmotic imbalance, creating conditions in the intestinal lumen that favor xanthine stone accumulation. Supporting this model, a mutation in osm-8 that constitutively activates the osmotic stress response also promoted xanthine stone accumulation in an xdh-1 mutant background. Thus, our work establishes a C. elegans model for human XDH deficiency and identifies the sulfate permease sulp-4 as a critical player controlling xanthine stone accumulation.
2025-01-26 | Pseudogenization of the Slc23a4 gene is necessary for the survival of Xdh-deficient mice.
In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene (XDH), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh(- / -) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or xanthine levels become excessive and thus toxic in Xdh(- / -) mice because enhancing the activity of hypoxanthine phosphoribosyl transferase (HPRT), which is an enzyme that uses hypoxanthine as a substrate, slightly increases the life span of these mice. In this study, we targeted the mouse intestinal sodium-dependent nucleobase transporter (SNBT) gene (Slc23a4), which is a pseudogene in humans. Hprt(high)Xdh(- / -)Slc23a4(- / -) mice had a longer life span and reached adulthood. The urinary xanthine excretion of these mice was 20-fold greater than that of patients with type 1 xanthinuria. The urinary hypoxanthine/xanthine ratio of Hprt(high)Xdh(- / -)Slc23a4(- / -) mice was lower than that of patients with type 1 xanthinuria. Hprt(high)Xdh(- / -)Slc23a4(- / -) mice exhibited renal impairment, accompanied by high plasma creatinine levels and anemia. Moreover, female Hprt(high)Xdh(- / -)Slc23a4(- / -) mice produced offspring that did not survive. In conclusion, for the first time, we established that Xdh(- / -) mice survive to adulthood.
2024-12-18 | Theobromine for treatment of uric acid stones and other diseases.
Theobromine (or 3,7-dimethylxanthine) is a natural alkaloid present in cocoa plant and its derivatives, such as chocolate. About 20% of ingested theobromine is excreted unchanged in the urine. Theobromine also derived from caffeine that is metabolized into theobromine by 12%. The primary metabolites of theobromine are 3-methylxantine, 7-methylxantine, 7-methyluric acid and 3,7-dimethyluric acid. Theobromine has an inhibitory activity of uric acid crystallization, because it has a structural pattern very similar to uric acid and can substitute uric acid molecules in the corresponding uric acid crystals, making them longer and thinner and decreasing their growth rate. Theobromine also favors the dissolution of crystals by decreasing supersaturation of uric acid by forming aggregates with uric acid through hydrogen bonds and aromatic stacking interactions (-stacking bonds) increasing urinary solubility of uric acid. Theobromine can be used for uric acid stone dissolution in combination with alkalinization to reduce the dose of citrate, thus preventing excessive alkalinization and the risk of formation of sodium urate crystals. Theobromine could also be used to treat patient with xanthine stones that cannot be dissolved by alkalinization because the solubility of xanthine is relatively independent of urinary pH. A metabolite of theobromine, 7-methylxanthine, has the potential to be used for the prevention of the formation of sodium urate crystals in the synovial fluid of gouty patients.
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