Xanthinuria

Hypouricemia and increased excretion of hypoxanthine and xanthine are associated with xanthine oxidase deficiency due to a genetic defect or to severe liver damage. Patients with a severe enzyme deficiency may exhibit xanthinuria and xanthine lithiasis. 

Hypouricemia. Deficiency of uric acid in the blood, along with xanthinuria, resulting from deficiency of xanthineoxidase, the enzyme required for conversion of hypoxan-thine to xanthine and of xanthine to uric acid. 

B-5) Xanthine oxidase deficiency. The inability to change xanthine to urate results in xanthinuria with decreased blood and urine urate levels. Sometimes urinary xanthine stones may form. The absent enzyme may be confirmed on liver biopsy. 

Diagnosis of renal problems, xanthinuria, and toxemia of pregnancy via determination of the ratio of hypoxanthine to xanthine in plasma is facilitated by the use of biosensors. Xanthine oxidase immobilized on aminopropyl-CPG (controlled pore glass) activated with glutaraldehyde oxidizes hypoxanthine first to xanthine and then to uric acid. Use of an IMER with biosensors for hypoxanthine, xanthine, and uric acid provides the necessary data. Pre- or postcolumn enzymatic reactions catalyzed by creatinine deiminase, urease, alkaline phosphatase, ATPase, inorganic pyrophosphatase, or arylsufatase facilitate analysis of uremic toxins (simultaneous detection of electrolytes, serum urea, uric acid, creatinine, and methylguanidine). 

The reaction mechanism is incompletely understood. Molybdenum, an essential cofactor, is the initial acceptor of electrons during purine oxidation and undergoes reduction from Mo + to Mo" +. Deficiency of molybdenum can result in xanthinuria. The electrons from molybdenum are passed successively to the iron-sulfur center, to FAD, and finally to oxygen. The oxygen incorporated into xanthine and uric acid originates in water. Xanthine oxidase also yields the superoxide radical, O2, which is then converted to hydrogen peroxide by superoxide dismutase (Chapter 14). This may yield free radicals,... 

There have been reports in the literature of hypouricemia coincident with specific inborn metabolic errors, but many of these cases are attributable to defects in the kidney leading to failure of renal tubular reabsorption. It was mentioned above that the excretion of uric acid by the Dalmatian coach hound can be attributed to such a mechanism (Fll). Similarly, the hypouricemia found in the Fanconi syndrome (L4) and Wilson s disease (B12) can be attributed to kidney malfunction. These are not true examples of underproduction of oxypurines, including uric acid, since the daily output of uric acid is normal. The large number of healthy people who have extremely low serum urate values, however, may indicate that there are individuals who underproduce oxypurines but suffer no ill effects because of this. The one well-documented inborn error that results in underproduction of uric acid is xanthinuria. It has been reported in relatively few cases, probably because individuals with this metabolic abnormality who suffer no ill effects would not come to the attention of a physician. 

The patients with xanthinuria who have been studied came to the attention of clinicians because of secondary ailments or because of the fact that relatives had the disease. Since the absence of xanthine oxidase... 

Methods have been devised for the determination of these compounds in the presence of uric acid through the use of uricase. The uricase is destroyed and the xanthine and hypoxanthine determined enzymatically. In the absence of uric acid (e.g., patients with xanthinuria), addition of xanthine oxidase converts the hypoxanthine and xanthine to uric acid and any method for uric acid determination could then be employed. The determination of hypoxanthine and xanthine by any method is complicated if the patient has received allopurinol, since allopurinol does not separate well from xanthine on ion-exchange resins and both allopurinol and alloxanthine are inhibitors of xanthine oxidase. Carefully... 

Cystine stones are rare except in cases of an inborn error of metabolism (cystinuria). Cystine, like uric acid, is more soluble in alkaline urine that in acidic urine. Xanthine stones are very rare except in cases of an inborn error of metabolism (xanthinuria). 

Ichida, K., Amaya, Y., Kamatani, N., Nishino, T., Hosoya, T., and Sakai, O. (1997) Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J. Clin. Invest. 99 (10), 2391-2397. 

Yamamoto, T., Moriwaki, Y., Shibutani, Y., Matsui, K., Ueo, T., Takahashi, S., Tsutsumi, Z., and Hada, T. (2001) Human xanthine dehydrogenase cDNA sequence and protein in an atypical case of type I xanthinuria in comparison with normal subjects. Clin. Chim. Acta 304 (1-2), 153-158. 

Peretz, H., Naamati, M. S., Levartovsky, D., Lagziel, A., Shani, E., Horn, I., Shalev, H., and Landau, D. (2007) 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. Mol. Genet. Metab. 91 (1), 23-29. 

Moco is essential for the activity of sulfite oxidase, XDH, and AO, the three molybdoenzymes present in humans. Human Moco deficiency leads to the pleiotropic loss of all three of these molybdoenzymes and usually progresses to death at an early age. In humans, a combined deficiency of sulfite oxidase and XDH was first described by Duran et al To date, more than 100 cases of Moco deficiency or isolated sulfite oxidase deficiency are known worldwide. Isolated sulfite oxidase deficiency is a related disease in which molybdenum cofactor biosynthesis is normal, but sulfite oxidase activity is altered. The clinical symptoms of Moco deficiency are indistinguishable from those of isolated sulfite oxidase deficiency with a notable exception that xanthinuria is absent in the latter. In both cases, affected neonates show feeding difficulties, neurological abnormalities such as attenuated brain growth, untreatable seizures, dislocated ocular lenses in most cases, and death in early childhood. Although milder symptoms are occasionally observed, none of the treatments tested... 

Mutation of the human molybdenum cofactor sulfurase gene seems to be responsible for classical xanthinuria type II (Ichida et al. 2001). A mutation in the gene for the neurotransmitter receptor-dustering protein gephyrin may cause a novel form of molybdenum cofactor deficiency (Reiss et al. 2001)... 

IchidaK, Matsumaea T, Sakuma R, HosoYATand Nishino T (2001) Mutation of human molybdenum cofactor sulfurasc gene is rcsonsiblcfor classical xanthinuria type II. Biochem Biophys Res Commun 282 1194-1200. 

XDH deficiency is also observed in xanthinuria, a genetic disease in humans characterized by low urinary output of uric acid and high levels of xanthine and hypoxan-thine in the blood and urine. Clinical manifestations develop only after the formation of renal calculi or deposition of xanthine and hypoxanthine in muscles has resulted in a mild myopathy. To date, some 50 cases of this disease have been reported. 

An inborn defect of metabolism that is closely related to sulfite oxidase deficiency and is more prevalent in the human population is that of molybdenum cofactor deficiency (Johnson 1997). In this disease syndrome, the activities of all molybdenum enzymes are affected owing to a lack of functional molybdopterin. The absence of sulfite oxidase is clearly most devastating. A number of individuals have been identified with xanthinuria (specific loss of XHD), and the resultant clinical symptoms are generally mild (Simmonds et al. 1995). A smaller class of patients has more recently been described with deficiencies in XHD and aldehyde oxidase, with mild clinical symptoms (Reiter et al. 1990). 

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