Xanthinuria is a hereditary disease with two major forms- types I and II. Both forms show an autosomal recessive mode of inheritance and are differentiated by the purine metabolism enzyme that is deficient. The enzyme xanthine dehydrogenase is deficient in type I xanthinuria while a dual deficiency of xanthine dehydrogenase and aldehyde oxidase occurs in type II xanthinuria. The third type of xanthinuria, associated with molybdenum cofactor deficiency, has been described as a separate clinical entity due to the neurological involvement. In addition, iatrogenic xanthinuria may be rarely observed in patients treated with allopurinol during the course of aggressive chemotherapy [1] [2].

There is no difference in the clinical presentations of xanthinuria type I and type II. The enzyme deficiencies which are seen in xanthinuria prevent the transformation of hypoxanthine to xanthine and xanthine to uric acid. There is a salvage pathway for hypoxanthine, while a similar pathway for xanthine does not exist. Consequently, the xanthine accumulates and is excreted in the urine. Furthermore, excessive xanthine accumulates mostly within the kidneys, leading to nephropathy and urolithiasis, making the kidneys more prone to infections. Renal failure is the most severe consequence of xanthinuria [3] [4] [5].

Symptoms in patients with xanthinuria mimic the symptoms seen in any other condition presenting with the stone formation or urinary infection. Renal colic, dysuria, nocturia, polyuria, microscopic or macroscopic hematuria, and pyuria may be commonly observed in such patients.

Other less common sites of xanthine deposits are the muscles and the joints. Myopathy mainly occurs in older patients and results in muscle cramps and pain. The involvement of the joints clinically results in joint pain and stiffness [6].

Non-specific symptoms such as abdominal pain, nausea, vomiting, and irritability may be present in young children. Some pediatric patients may have growth retardation as a consequence of xanthinuria. However, two-thirds of patients may not have any symptoms at all and the disease is revealed accidentally [6] [7].

• Recurrent Urinary Tract Infection

  Some signs and symptoms related may include abdominal pain, recurrent urinary tract infections and hematuria. Less often, xanthine crystals accumulate in the muscles, causing pain and cramps. [ivami.com]

  Related signs and symptoms can include abdominal pain, recurrent urinary tract infections, and blood in the urine (hematuria). Less commonly, xanthine crystals build up in the muscles, causing pain and cramping. [ghr.nlm.nih.gov]

• Failure to Thrive

  Young children [4] may present with nonspecific symptoms such as crying, vomiting, poor feeding and failure to thrive. Family history of renal and ureteric stones This is hereditary condition with a genetic basis. [1] [explainmedicine.com]

• Muscle Cramp

  Muscle cramps, muscle pain, muscle stiffness Accumulation of xanthine inside the muscles can cause muscle pathology-"myopathy". [3] This might be aggravated after exercise. [explainmedicine.com]

  Clinical manifestations of the myopathy (eg, muscle cramps, muscle pain, muscle stiffness) are believed to be the result of long-term accumulation of xanthine and hypoxanthine crystals in the muscle; this has been demonstrated in skeletal muscle biopsies [thehealthscience.com]

  Myopathy mainly occurs in older patients and results in muscle cramps and pain. The involvement of the joints clinically results in joint pain and stiffness. [symptoma.com]

• Suggestibility

  Similar findings were observed in at least 6 other relatives, a finding that suggested that they were heterozygotes. [ncbi.nlm.nih.gov]

• Frequency of Micturition

  […] of micturition due to the calculi formation. [explainmedicine.com]

• Hyperreflexia

  Molybdenum cofactor deficiency The other inherited form of xanthinuria, termed molybdenum cofactor deficiency, presents in the neonatal period with microcephaly, hyperreflexia, and other CNS manifestations. [emedicine.medscape.com]

• Neurologic Manifestation

  Xanthinuria is only a marker in this setting because (1) the clinical presentation is overshadowed by neurologic manifestations and (2) death in the first year of life is caused by the deficiency of sulfite oxidase, which is the final step in cysteine [emedicine.medscape.com]

• Intracranial Hemorrhage

  Other reported manifestations include severe metabolic acidosis and intracranial hemorrhage. [emedicine.medscape.com]

Xanthinuria is a rare cause of renal disease and other more common disorders must be ruled out first. However, if the diagnosis is suspected, it can be confirmed through laboratory and imaging techniques.

Urinalysis may reveal the presence of xanthine crystals along with other findings suggestive of kidney damage such as hematuria and pyuria. The levels of uric acid are extremely low. The 24-hour urine levels of xanthine and hypoxanthine, on the other hand, are significantly high. A urine culture may detect the microorganisms responsible for superadded infection [8].

Changes in serum chemistry are analogous to those seen in the urine. A low serum uric acid, coupled with increased levels of xanthine and hypoxanthine are usually seen. Other causes of a low serum uric acid should be considered while making a diagnosis of xanthinuria.

Imaging studies help support the diagnosis. Ultrasonography may detect stones larger than 1 cm in diameter. Xanthine stones are radiolucent and cannot be revealed via an X-ray. Computed tomography (CT) or magnetic resonance imaging (MRI) scans are recommended for patients presenting with the typical clinical features of nephrolithiasis but with a negative result on ultrasonography [9]. Histology may reveal renal parenchymal xanthine deposits, thereby leading to renal damage and fibrosis.

• Nephrolithiasis

  […] abnormality Metabolism abnormality [ more ] 0001939 Autosomal recessive inheritance 0000007 Hydronephrosis 0000126 Hyperxanthinemia 0010933 Myopathy Muscle tissue disease 0003198 Pyelonephritis 0012330 Reduced xanthine dehydrogenase activity 0003534 Xanthine nephrolithiasis [rarediseases.info.nih.gov]

  Evidence for enhanced hypoxanthine salvage. ( 3818951 ) Mateos F.A....Fox I.H. 1987 31 Effect of fructose infusion in hereditary xanthinuria. ( 3728145 ) Mateos F.A....Fox I.H. 1986 32 Hereditary xanthinuria presenting in infancy with nephrolithiasis. [malacards.org]

  Computed tomography (CT) or magnetic resonance imaging (MRI) scans are recommended for patients presenting with the typical clinical features of nephrolithiasis but with a negative result on ultrasonography. [symptoma.com]

• Hypouricemia

  Abstract A 43-year-old xanthinuric female was referred to our department because of hypouricemia. [ncbi.nlm.nih.gov]

  Hypouricemia is also a biochemical marker for primary hereditary renal hypouricemia (see this term). Unlike hereditary xanthinuria, the excretion fraction of uric acid is elevated in renal hypouricemia. [orpha.net]

• Liver Biopsy

  We advocate for this safe and non-invasive diagnostic algorithm instead of the traditional allopurinol loading test and intestinal or liver biopsy used in the past. [ncbi.nlm.nih.gov]

Patients with Lesch-Nyhan syndrome or patients with partial HGPRT deficiency have developed xanthine nephropathy, acute kidney failure, and stones following treatment with allopurinol. [3] A few incidents of xanthine nephropathy and renal failure have [emedicine.medscape.com]

There is no specific treatment beyond maintaining a high fluid intake and avoiding foods that are high in purine. Xanthinuria at NIH's Office of Rare Diseases [en.wikipedia.org]

Management and treatment There is no curative treatment. Low purine diet and high fluid intake is recommended. Since the solubility of xanthine is not affected by urinary pH, alkalization is of no value. [orpha.net]

Treatment Currently, there is no treatment available for Xanthinuria. However, there are treatment and maintenance needed to keep a balance fluid in the body and avoiding high purine foods. [medigest.uk]

Prognosis The overall prognosis is favorable, even though, in some cases, the disease progresses to end-stage renal insufficiency. The documents contained in this web site are presented for information purposes only. [orpha.net]

The word "symptoms of Xanthinuria" is the more general meaning; Prognosis - Xanthinuria Not supplied. Treatment - Xanthinuria Not supplied. Resources - Xanthinuria Not supplied. [checkorphan.org]

The prognosis for our patient with hereditary type II xanthinuria is excellent, if his renal function can be conserved. 1 Moreover, this child was not hypericosuric but hypouricaemic and hypouricosuric. [jmg.bmj.com]

As our case and other studies on genetic alterations in kidney diseases show, large deletions (and duplications) significantly contribute to the etiology of these entities, specific assays to discover these imbalances should therefore be included in genetic [ncbi.nlm.nih.gov]

Etiology Hereditary xanthinuria is due to mutations in the xanthine dehydrogenase ( XDH, 2p23.1) or molybdenum cofactor sulfurase ( MOCOS, 18q12.2) genes, resulting in failure to degrade hypoxanthine and xanthine to uric acid and leading to the accumulation [orpha.net]

[…] shows that the notion of a single condition known as 'autism' is no longer tenable, and challenges current trends in the diagnosis and management of these behaviours as a homogenous group by drawing on recent research into brain function, genetics, epidemiology [books.google.com]

Summary Epidemiology Prevalence of hereditary xanthinuria is not known, but about 150 patients have been described so far. Annual incidence has been estimated to be between 1:6,000 and 1:69,000. [orpha.net]

Epidemiology Frequency United StatesTrue incidence of classic xanthinuria is unknown because it is rarely reported. Surveys suggest a population incidence of 1 case per 6,000 population to 1 case per 69,000 population. [thehealthscience.com]

Author information 1 Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachiouji-shi, Tokyo 192-0392, Japan. [ncbi.nlm.nih.gov]

Pathophysiology The primary organs affected in xanthinuria are the kidney and, to a lesser extent, skeletal muscle and joints. [thehealthscience.com]

Xanthine oxidoreductase - Role in human pathophysiology and hereditary xanthinuria. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease. New York: McGraw Hill, 2001 : 2653 –62. [jmg.bmj.com]

It is possible that the excessive re-utilization of hypoxanthine and xanthine in this disease prevents the allopurinol-induced inhibition of de novo purine biosynthesis that is seen in normal subjects. [ncbi.nlm.nih.gov]

Drinking water at night is important to prevent the usual development of a concentrated morning urine. Dehydration prevention: Educate the patient about the importance of preventing dehydration. [emedicine.medscape.com]

Mutations in the gene Moços prevent xanthine dehydrogenase and aldehyde oxidase are activated. [ivami.com]

Prevention - Xanthinuria Not supplied. Diagnosis - Xanthinuria The phrase "signs of Xanthinuria" should, strictly speaking, refer only to those signs and symptoms of Xanthinuria that are not readily apparent to the patient. [checkorphan.org]

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2. Ichida K, Matsumura T, Sakuma R, Hosoya T, Nishino T. Mutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II. Biochem Biophys Res Commun. 2001;282(5):1194-200.
3. Simmons A, Reiter S, Nishino T. Hereditary Xanthinuria, in The Metabolic and Molecular Bases of Inherited Diseases, 5. 1995;2:1781–1797.
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8. Carpenter TO, Lebowitz RL, Nelson D, Bauer S. Hereditary xanthinuria presenting in infancy with nephrolithiasis. J Pediatr. 1986;109(2):307-309.
9. Mraz M, Hurba O, Bartl J, et al. Modern diagnostic approach to hereditary xanthinuria. Urolithiasis. 2015;43(1):61-67.