allopurinol and Lesch-Nyhan-Syndrome

Topics: Adenylosuccinate Lyase; Allopurinol; Humans; Lesch-Nyhan Syndrome; Psychomotor Disorders; Purine-Pyrimidine Metabolism, Inborn Errors; Seizures; Self Mutilation

Uric acid stones are the consequences of abnormalities in purine metabolism, urate/uric acid renal handling, or excess dietary protein. Treatment is aimed at preventing additional formation by decreasing the degree of urate and uric acid supersaturation in urine, by altering diet, fluid intake, and the urine pH, and by blocking steps in uric acid production.

Topics: Adenine Phosphoribosyltransferase; Humans; Kidney Calculi; Lesch-Nyhan Syndrome; Purines; Risk Factors; Uric Acid; Urinary Calculi; Xanthine Oxidase

Topics: Adolescent; Adult; Allopurinol; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Behavior Therapy; Child; Humans; Lesch-Nyhan Syndrome; Narcotic Antagonists; Psychotropic Drugs; Self Mutilation; Syndrome

Topics: 5'-Nucleotidase; Adenine Phosphoribosyltransferase; Adenosine Deaminase; Amidophosphoribosyltransferase; AMP Deaminase; Genes; Humans; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Nucleotidases; Orotic Acid; Oxidoreductases Acting on Sulfur Group Donors; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Pyrimidines; Xanthine Oxidase

Topics: Allopurinol; Biological Transport; Diuretics; Glomerular Filtration Rate; Gout; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Diseases; Kidney Tubules; Lactates; Lesch-Nyhan Syndrome; Nucleosides; Nucleotides; Purines; Risk; Sodium; Uric Acid

Genetic defects in purine metabolism are associated with severe immunodeficiency. Adenosine deaminase deficiency impairs the function of both B- and T-lymphocytes whereas in purine nucleoside (inosine) phosphorylase deficiency there is more severe impairment of T-lymphocyte functions than of B-lymphocyte functions. The relative unimportance of the salvage pathway catalysed by hypoxanthine-guanine phosphoribosyltransferase is shown by the normal responses of T-lymphocytes from patients with the Lesch-Nyhan syndrome to antigenic and mitogenic stimulation. A mild deficiency of B-lymphocyte function is found in these patients. Agents inhibiting the de novo pathway of purine synthesis, including azaserine, 6-mercaptopurine and azathioprine in low doses, block the responses of normal human lymphocytes to mitogenic stimulation. These observations emphasize the importance of the de novo pathway of purine synthesis in lymphocyte responses to antigenic and mitogenic stimulation. There is considerable heterogeneity in the amount of labelled uridine incorporated into human and rat lymphocytes. This does not appear to reflect only a difference between T- and B-lymphocytes

Topics: Adenine Phosphoribosyltransferase; Adenosine Deaminase; Adolescent; Adult; Allopurinol; Azaserine; B-Lymphocytes; Child; Child, Preschool; Humans; Hypoxanthine Phosphoribosyltransferase; Immunoglobulins; Lectins; Lesch-Nyhan Syndrome; Lymphocyte Activation; Male; Mercaptopurine; Mitogens; Phosphoribosyl Pyrophosphate; Purine-Nucleoside Phosphorylase; Purines; RNA; T-Lymphocytes; Thymidine; Uridine

Topics: Adenine; Allopurinol; Carbon Radioisotopes; Erythrocytes; Fibroblasts; Glucosephosphate Dehydrogenase; Glutamine; Glutathione Reductase; Gout; Guanine; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Liver; Metabolic Diseases; Molecular Weight; Orotic Acid; Pentosyltransferases; Purines; Uric Acid; Xanthine Oxidase

Topics: Adenine Nucleotides; Anemia, Hemolytic, Congenital Nonspherocytic; Glutamate Dehydrogenase; Glutaminase; Glutathione Reductase; Glycogen Storage Disease; Gout; Guanine Nucleotides; Humans; Hypoxanthines; Immunologic Deficiency Syndromes; Kinetics; Lesch-Nyhan Syndrome; Molecular Weight; Mutation; Pentosephosphates; Pentosyltransferases; Purine-Pyrimidine Metabolism, Inborn Errors; Ribose; Species Specificity; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Bile Acids and Salts; Calcium; Diuretics; Humans; Hydrogen-Ion Concentration; Hyperparathyroidism; Kidney; Lesch-Nyhan Syndrome; Purines; Uric Acid; Urinary Calculi

Topics: Amidophosphoribosyltransferase; Chemical Phenomena; Chemistry; Glucosephosphate Dehydrogenase Deficiency; Glutathione Reductase; Gout; Humans; Inosine Monophosphate; Lesch-Nyhan Syndrome; Phosphoribosyl Pyrophosphate; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Uric Acid; Xanthine Oxidase; Xanthines; Xeroderma Pigmentosum

Topics: Humans; Lesch-Nyhan Syndrome; Metabolism, Inborn Errors; Pentosyltransferases; Purines; Rheumatic Diseases; Xanthine Oxidase

Topics: Allopurinol; Animals; Brain; Chromosome Aberrations; Chromosome Disorders; Guanine; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Male; Metabolism, Inborn Errors; Pentosyltransferases; Purines; Rabbits; Rats; Uric Acid

Topics: Allopurinol; Creatinine; Diet Therapy; Erythrocytes; Gout; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Metabolism, Inborn Errors; Myeloproliferative Disorders; Pentosyltransferases; Prenatal Diagnosis; Protein Binding; Purines; Uric Acid

Topics: Allopurinol; Amniocentesis; Athetosis; Brain; Erythrocytes; Fibroblasts; Humans; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Pentosyltransferases; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Uric Acid

Topics: Adenine; Adrenocorticotropic Hormone; Allopurinol; Animals; Glycogen; Gout; Humans; Lesch-Nyhan Syndrome; Methylene Blue; Orotic Acid; Pentosephosphates; Phosphoric Acids; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Ribose; Thiadiazoles; Thyrotropin; Transferases; Urate Oxidase; Uric Acid

Topics: Allopurinol; Colchicine; Glycogen Storage Disease Type I; Gout; Humans; Lesch-Nyhan Syndrome; Metabolism, Inborn Errors; Pentosyltransferases; Purine Nucleotides; Purines; Uric Acid

Topics: Adolescent; Allopurinol; Cerebral Palsy; Delayed Diagnosis; Exons; Gout Suppressants; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Failure, Chronic; Lesch-Nyhan Syndrome; Male; Radiography, Thoracic; Renal Dialysis; Scoliosis; Uric Acid

Lesch-Nyhan disease (LND) is a rare monogenic disease caused by deficiency of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). LND is characterized by severe neuropsychiatric symptoms that currently cannot be treated. Predictive in vivo models are lacking for screening and evaluating candidate drugs because LND-associated neurological symptoms are not recapitulated in HGPRT-deficient animals. Here, we used human neural stem cells and neurons derived from induced pluripotent stem cells (iPSCs) of children affected with LND to identify neural phenotypes of interest associated with HGPRT deficiency to develop a target-agnostic-based drug screening system. We screened more than 3000 molecules and identified 6 pharmacological compounds, all possessing an adenosine moiety, that corrected HGPRT deficiency-associated neuronal phenotypes by promoting metabolism compensations in an HGPRT-independent manner. This included S-adenosylmethionine, a compound that had already been used as a compassionate approach to ease the neuropsychiatric symptoms in LND. Interestingly, these compounds compensate abnormal metabolism in a manner complementary to the gold standard allopurinol and can be provided to patients with LND via simple food supplementation. This experimental paradigm can be easily adapted to other metabolic disorders affecting normal brain development and functioning in the absence of a relevant animal model.

Topics: Allopurinol; Animals; Case-Control Studies; Cell Differentiation; Disease Models, Animal; Humans; Hypoxanthine Phosphoribosyltransferase; Induced Pluripotent Stem Cells; Lesch-Nyhan Syndrome; Neural Stem Cells; Phenotype

Topics: Allopurinol; Child, Preschool; Humans; Kidney; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Recurrence; Treatment Failure; Ultrasonography

Topics: Allopurinol; Child, Preschool; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Hypoxanthine Phosphoribosyltransferase; Kidney; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Mutation; Potassium Citrate; Recurrence; Renal Elimination; Ultrasonography; Urine; Xanthine; Xanthine Oxidase

Lesch-Nyhan disease (LND) is a rare X-linked genetic disorder, with complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing renal failure, is commonly decreased by xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, yielding a xanthine and hypoxanthine increase. Xanthine accumulation may result in renal stones, while hypoxanthine excess seems involved in the neurological disorder. Inhibition of purine nucleoside phosphorylase (PNP) represents a different strategy for lowering urate. PNP catalyzes the cleavage of purine ribo- and d-ribo-nucleosides into ribose/deoxyribose phosphate and free bases, starting catabolism to uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with allopurinol. The present study tested the reliability of an analogue of immucillin-G (C1a), a PNP inhibitor, as a therapy for urate, hypoxanthine, and xanthine excess in LND patients by blocking hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d-nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia.

Topics: Allopurinol; Cells, Cultured; Enzyme Inhibitors; Humans; Hyperuricemia; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Purine-Nucleoside Phosphorylase; Purines; Pyrimidinones; Pyrroles; Reproducibility of Results; Uric Acid; Xanthine

Patients with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity present hyperuricemia and/or hyperuricosuria, with a variable degree of neurological manifestations. Hyperuricemia in HPRT deficiency is due to uric acid overproduction and is frequently treated with allopurinol. Renal uric acid excretion is sharply increased in these patients. In recent years, several renal tubular urate transporter single nucleotide polymorphisms (SNPs), including those of the GLUT9, ABCG2 and URAT1 genes, have been described that influence the renal handling of uric acid and modulate serum urate levels. In the present study, we analyzed whether GLUT9, ABCG2 and URAT1 gene SNPs are able to influence uric acid levels and allopurinol response in patients with HPRT deficiency.. Three SNPs, URAT1 rs11231825, GLUT9 rs16890979 and ABCG2 rs2231142, previously associated in our population with hyperuricemia and gout, were analyzed in 27 patients with HPRT deficiency treated with allopurinol for at least 5 years.. Patients with HPRT deficiency having allele A of rs16890979 in the GLUT9 gene present with a lower serum urate concentration at diagnosis, before allopurinol treatment is instituted, and need lower allopurinol doses to maintain serum urate levels between 268 and 446 μmol/L (4.5 and 7.5 mg/dL). No relationship between rs2231142 in the ABCG2 gene or rs11231825 in the URAT1 gene and serum urate levels or allopurinol response was found in our patients with HPRT deficiency.. GLUT9 SNPs influence the renal handling of uric acid and modulate serum urate levels and the response to treatment in patients with uric acid overproduction due to HPRT deficiency.

Topics: Adolescent; Adult; Allopurinol; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biomarkers; Child; Child, Preschool; Genetic Predisposition to Disease; Glucose Transport Proteins, Facilitative; Gout; Gout Suppressants; Humans; Hyperuricemia; Lesch-Nyhan Syndrome; Middle Aged; Neoplasm Proteins; Organic Anion Transporters; Organic Cation Transport Proteins; Phenotype; Polymorphism, Single Nucleotide; Renal Elimination; Treatment Outcome; Uric Acid; Young Adult

Lesch-Nyhan syndrome is a rare inborn error of purine metabolism marked by a complete deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Inherited as an X-linked recessive genetic disorder that primarily affects males, patients with Lesch-Nyhan syndrome exhibit severe neurological impairments, including choreoathetosis, ballismus, cognitive dysfunction, and self-injurious behavior. Uric acid levels are usually abnormally high, leading to kidney and bladder stones which often necessitate urological intervention. Factor V Leiden is an autosomal dominant disorder of blood clotting associated with hypercoagulability, thrombophilia, and renal disease.. We present the first reported case of xanthine calculi in a patient with Lesch-Nyhan syndrome and Factor V Leiden who was treated with allopurinol. A renal ultrasound and CT scan demonstrated bilateral staghorn calculi in the kidneys as well as nephrocalcinosis. Two years earlier the patient underwent cystoscopy with bilateral ureteroscopy and laser lithotripsy, and he was stone free afterwards. The patient subsequently underwent bilateral percutaneous nephrolithotomy (PCNL) and was stone free following the procedure. Patients with endogenous overproduction of uric acid who are being treated with allopurinol have a higher chance of developing xanthine stones.. Pediatricians treating these children should be aware of these rare conditions and promptly manage the potential complications that may require medical or surgical intervention.

Topics: Allopurinol; Antimetabolites; Child; Factor V; Humans; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Point Mutation; Xanthine; Xanthine Oxidase

Excess of uric acid is mainly treated with xanthine oxidase (XO) inhibitors, also called uricostatics because they block the conversion of hypoxanthine and xanthine into urate. Normally, accumulation of upstream metabolites is prevented by the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The recycling pathway, however, is impaired in the presence of HPRT deficiency, as observed in Lesch-Nyhan disease. To gain insights into the consequences of purine accumulation with HPRT deficiency, we investigated the effects of the XO inhibitor allopurinol in Hprt-lacking (HPRT-/-) mice. Allopurinol was administered in the drinking water of E12-E14 pregnant mothers at dosages of 150 or 75 μg/ml, and mice sacrificed after weaning. The drug was well tolerated by wild-type animals and heterozygous HPRT+/- mice. Instead, a profound alteration of the renal function was observed in the HPRT-/- model. Increased hypoxanthine and xanthine concentrations were found in the blood. The kidneys showed a yellowish appearance, diffuse interstitial nephritis, with dilated tubules, inflammatory and fibrotic changes of the interstitium. There were numerous xanthine tubular crystals, as determined by HPLC analysis. Oil red O staining demonstrated lipid accumulation in the same location of xanthine deposits. mRNA analysis showed increased expression of adipogenesis-related molecules as well as profibrotic and proinflammatory pathways. Immunostaining showed numerous monocyte-macrophages and overexpression of alpha-smooth muscle actin in the tubulointerstitium. In vitro, addition of xanthine to tubular cells caused diffuse oil red O positivity and modification of the cell phenotype, with loss of epithelial features and appearance of mesenchymal characteristics, similarly to what was observed in vivo. Our results indicate that in the absence of HPRT, blockade of XO by allopurinol causes rapidly developing renal failure due to xanthine deposition within the mouse kidney. Xanthine seems to be directly involved in promoting lipid accumulation and subsequent phenotype changes of tubular cells, with activation of inflammation and fibrosis.

Topics: Allopurinol; Animals; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Mice; Mice, Knockout; Nephritis; Xanthine; Xanthine Oxidase

We report on a male patient with Tuberous Sclerosis Complex (TSC), which was prenatally diagnosed. At the age of 3 months the patient developed acute renal failure with excessive hyperuricemia. Kidney function improved after rehydration and application of rasburicase, however without full recovery. Due to the inappropriate high levels of uric acid compared to kidney function, screening of hypoxanthine-guanine phosphoribosyltransferase (HPRT) related diseases was initiated. Mutation analysis revealed a deletion of exon 2 and 3 of the HPRT gene confirming the diagnosis of Lesch-Nyhan Disease (LND). After initiation of allopurinol therapy renal function further improved. In the following months the patient developed clinically a typical neurological phenotype of LND and TSC with seizures, severe dystonia and developmental delay.. Acute renal failure is a rare complication of HPRT related diseases. Combination of two inherited diseases may lead to a delayed diagnosis due to a mixed and maybe misleading phenotype.

Topics: Acute Kidney Injury; Allopurinol; Developmental Disabilities; Dystonia; Exons; Fluid Therapy; Gout Suppressants; Humans; Hyperuricemia; Hypoxanthine Phosphoribosyltransferase; Infant; Lesch-Nyhan Syndrome; Male; Phenotype; Seizures; Tuberous Sclerosis; Urate Oxidase

A 30-year-old man was referred for investigation and management of hyperuricaemia. History included recurrent nephrolithiasis and chronic gout with poor response to medical management. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) enzyme activity was investigated and found to be deficient confirming the diagnosis of Lesch-Nyhan disease. Hyperuricaemia was treated with allopurinol. To prevent nephrolithiasis, the patient was instructed to avoid dehydration and aim for a minimum urine output of 2 L/day. Urinary alkalinisation with potassium citrate was started. The patient was referred for genetic counselling. This case discusses the genetics, pathophysiology, clinical manifestations, diagnosis and management of HGPRT deficiency.

Topics: Adult; Allopurinol; Diuretics; Genetic Counseling; Gout; Gout Suppressants; Humans; Hyperuricemia; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Male; Nephrolithiasis; Potassium Citrate; Uric Acid

In the present study, we investigate the in vitro effect of hypoxanthine on acetylcholinesterase and butyrylcholinesterase activities in the hippocampus, striatum, cerebral cortex and serum of 15-, 30- and 60-day-old rats. Furthermore, we also evaluated the influence of antioxidants, namely α-tocopherol (trolox) and ascorbic acid, and allopurinol to investigate the possible participation of free radicals and uric acid in the effects elicited by hypoxanthine on these parameters. Acetylcholinesterase and butyrylcholinesterase activities were determined according to Ellman et al. (Biochem Pharmacol 7:88-95, 1961), with some modifications. Hypoxanthine (10.0 μM), when added to the incubation medium, enhanced acetylcholinesterase activity in the hippocampus and striatum of 15- and 30-day-old rats and reduced butyrylcholinesterase activity in the serum of 60-day-old rats. The administration of allopurinol and/or antioxidants partially prevented the alterations caused by hypoxanthine in acetylcholinesterase and butyrylcholinesterase activities in the cerebrum and serum of rats. Data indicate that hypoxanthine alters cholinesterase activities, probably through free radicals and uric acid production since the alterations were prevented by the administration of allopurinol and antioxidants. It is presumed that the cholinesterase system may be associated, at least in part, with the neuronal dysfunction observed in patients affected by Lesch-Nyhan disease. In addition, although extrapolation of findings from animal experiments to humans is difficult, it is conceivable that these vitamins and allopurinol might serve as an adjuvant therapy to avoid progression of brain damage in patients affected by this disease.

Topics: Acetylcholinesterase; Allopurinol; alpha-Tocopherol; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Butyrylcholinesterase; Cholinesterases; Enzyme Inhibitors; Free Radicals; Hypoxanthine; Lesch-Nyhan Syndrome; Rats; Rats, Wistar; Uric Acid

Lesch-Nyhan syndrome is a rare sex-linked disorder of purine metabolism that is caused by a mutation in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene which causes marked hyperuricemia and hyperuricosuria, with signs of gouty arthritis and uric acid stone disease in early childhood. We report a case of renal pelvis calculi which was dissolved within 10 days of urine alkalinization and hydration.

Topics: Allopurinol; Child; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Hypoxanthine Phosphoribosyltransferase; Kidney Calculi; Kidney Pelvis; Lesch-Nyhan Syndrome; Male; Mutation; Tomography, X-Ray Computed; Urine

Topics: Allopurinol; Antimetabolites; Fatal Outcome; Humans; Hypoxanthine Phosphoribosyltransferase; Infant; Lesch-Nyhan Syndrome; Male; Mutation; Phenotype; Uric Acid

Topics: Allopurinol; Carbamazepine; Child, Preschool; DNA Mutational Analysis; Erythrocytes; Family Health; Female; Gout Suppressants; Humans; Hypoxanthine Phosphoribosyltransferase; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Mutation; Peritoneal Dialysis; Treatment Outcome

We have studied 36 patients with HPRT deficiency, 25 with Lesch-Nyhan syndrome and 11 with partial HPRT deficiency (grades 1 to 3). Patients diagnosed with HPRT deficiency have increased 50% since 2000. The most relevant recent advances have been made in molecular diagnosis. Nevertheless, enzyme determinations are still essential for the diagnosis of HPRT deficiency. Therapy for the neurological manifestations of HPRT deficiency has not advanced. Allopurinol remains the drug of choice to diminish uric acid overproduction, but the optimal allopurinol dose must be established in each patient to prevent xanthine or uric acid urolithiasis, a process aided by sequential determination of urinary oxypurines and uric acid.

Topics: Adolescent; Allopurinol; Child, Preschool; Humans; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Mutation; Purines

We describe the case of a 1-year-old boy with partial hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. At his first visit to the hospital, he was diagnosed with hyperuricemia and irreversible renal failure. The misssense mutation Asp185Gly (554A>G) was identified in exon 8 of his HPRT gene, and this mutation was inherited from the mother.

Topics: Allopurinol; Antimetabolites; Creatinine; Electrophoresis, Agar Gel; Humans; Hypoxanthine Phosphoribosyltransferase; Infant; Lesch-Nyhan Syndrome; Male; Metabolic Clearance Rate; Mutation, Missense; Polymorphism, Restriction Fragment Length; Renal Insufficiency; Uric Acid

We report on a rare case of hypoxanthine guanine phosphoribosyl transferase (HGPRT) deficiency that presented in the newborn period with acute renal failure (ARF). The clinical diagnosis was made on the basis of non-oliguric ARF and evidence of crystal nephropathy on renal biopsy. HGPRT deficiency was eventually confirmed by enzymatic and genetic testing, showing a novel point mutation, 293 A>G. Immediate treatment consisted of peritoneal dialysis with, initially, lactate- then bicarbonate-buffered 1.36% glucose solution together with oral administration of allopurinol. Follow-up after more than 4 years continued to show hyper-echogenic kidneys with almost normal renal glomerular function. There continues to be no neurobehavioural abnormalities.

Topics: Acute Kidney Injury; Allopurinol; Combined Modality Therapy; Follow-Up Studies; Gout Suppressants; Hemodialysis Solutions; Humans; Hypoxanthine Phosphoribosyltransferase; Infant, Newborn; Kidney; Lesch-Nyhan Syndrome; Male; Peritoneal Dialysis; Point Mutation; Treatment Outcome; Ultrasonography

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a genetic disease of purine metabolism resulting in uric acid overproduction. Allopurinol, which inhibits the enzyme xanthine oxidase and reduces uric acid synthesis, is widely used for the treatment of gout and uric acid overproduction. The aim of the study was to analyze the long-term efficacy and safety of allopurinol in patients with HPRT deficiency. Nineteen patients (13 with Lesch-Nyhan syndrome and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.4 mg/kg body weight per day; range, 3.7-9.7 mg/kg body weight per day) and followed up for at least 12 months (mean follow-up, 7.6 years). The efficacy of allopurinol was evaluated by serial measurement of purine metabolic parameters and renal function as well as by clinical manifestations. Safety was assessed by recording adverse events. Treatment with allopurinol normalized serum urate level in all patients and resulted in a mean reduction in serum urate of 47%. Allopurinol treatment was associated with a mean 74% reduction in urinary uric acid-to-creatinine ratio. In contrast, allopurinol treatment increased mean hypoxanthine and xanthine urinary excretion rates 5.4- and 9.5-fold, respectively, compared with baseline levels. The decrease in uric acid excretion in complete and partial HPRT-deficient patients was not accompanied by a stoichiometric substitution of hypoxanthine and xanthine excretion rates. Allopurinol-related biochemical changes were similar in patients with either complete or partial HPRT deficiency. Renal function remained stable or improved with treatment. Three patients had urolithiasis during allopurinol treatment. In 2 patients, xanthine stones were documented and they required allopurinol dose adjustments aimed at reducing excessive oxypurine excretion rates. No allopurinol hypersensitivity reactions occurred. Neurologic manifestations were not influenced by allopurinol therapy. In conclusion, allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiencies. Xanthine lithiasis, developing as a consequence of allopurinol therapy, should be preventable by adjustment of allopurinol dose.

Topics: Adolescent; Adult; Allopurinol; Antimetabolites; Child; Child, Preschool; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Hypoxanthine Phosphoribosyltransferase; Infant; Kidney; Lesch-Nyhan Syndrome; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Retrospective Studies; Treatment Outcome; Uric Acid

Xanthine calculi are uncommonly encountered stones. When they occur, they typically do so in association with inborn metabolic disorders such as hereditary xanthinuria or Lesch-Nyhan syndrome. They may also occur in association with states of profound hyperuricemia such as myeloproliferative disease after treatment with allopurinol. If the underlying disorder is not addressed, a high risk of stone recurrence exists. Therefore, to raise clinical awareness, we reviewed and report our experience in the treatment of patients with these stones, discussing the underlying pathophysiology and approach to treatment.

Topics: Adolescent; Allopurinol; Child; Enzyme Inhibitors; Female; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Kidney Calculi; Lesch-Nyhan Syndrome; Lithotripsy, Laser; Male; Nephrostomy, Percutaneous; Potassium Citrate; Renal Agents; Urine; Xanthine

Lesch-Nyhan syndrome is a very rare X-linked recessive disorder caused by mutation in the gene encoding enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A complete deficiency of HPRT leads to severe purine overproduction and to uric acid renal lithiasis as a consequence. This may be effectively prevented by administration of allopurinol; however, its overdosage may result in xanthinuria and xanthine urolithiasis. We report on a 9-year-old boy with Lesch-Nyhan syndrome who developed acute renal failure due to bilateral staghorn xanthine urolithiasis resulting from long-term treatment with excessive doses of allopurinol. To the best of our knowledge, the presented case is the first one in the literature.

Topics: Acute Kidney Injury; Allopurinol; Child; Humans; Lesch-Nyhan Syndrome; Male; Urolithiasis; Xanthine Oxidase; Xanthines

Topics: Adolescent; Adult; Allopurinol; Child; Child, Preschool; France; Gout Suppressants; Humans; Lesch-Nyhan Syndrome; Psychotropic Drugs; Surveys and Questionnaires

Allopurinol is used widely for the treatment of purine disorders such as gout, but efficacy and safety of allopurinol has not been analyzed systematically in an extensive series of patients with HPRT deficiency. From 1984 to 2004 we have diagnosed 30 patients with HPRT deficiency. Eighteen patients (12 with Lesch-Nyhan syndrome or complete HPRT deficiency, and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.44 mg/Kg of weight per day) and followed-up for at least 12 months (mean follow-up 7,6 years per patient). Mean age at diagnosis was 7 years (range, 5 months to 35 years). Treatment with allopurinol was associated to a mean reduction of serum urate concentration of 50%, and was normalized in all patients. Mean urinary uric acid excretion was reduced by 75% from baseline values, and uric acid to creatinine ratio was close or under 1.0 in all patients. In contrast, hypoxanthine and xanthine urinary excretion rates increased by a mean of 6 and 10 times, respectively, compared to baseline levels. These modifications were similar in patients with complete or partial HPRT deficiency. In 2 patients xanthine stones were documented despite allopurinol dose adjustments to prevent markedly increased oxypurine excretion rates. Neurological manifestations did not appear to be influenced by allopurinol therapy. Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis.

Topics: Adolescent; Adult; Allopurinol; Child; Child, Preschool; Follow-Up Studies; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Infant; Lesch-Nyhan Syndrome; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Spain; Uric Acid; Xanthine

Hypoxanthine phosphoribosyltransferase (HPRT) deficiency is an inherited disorder. Complete deficiency of HPRT activity is phenotypically expressed as the devastating Lesch-Nyhan syndrome. Partial HPRT deficiency usually causes hyperuricemia, precocious gout, and uric acid nephrolithiasis. We describe an 18-year follow-up of a 5-year old boy with partial HPRT deficiency and report a novel mutation in his HPRT gene. He presented with overproduction of uric acid and passage of uric acid renal stones, and without gout or neurological and behavioral abnormalities. Treatment with allopurinol, adequate hydration, urinary alkalization, and a low-purine diet was started. No subsequent nephrolithiasis has occurred. After 18-year of this therapy his physical and neuropsychological status were normal, merely his glomerular filtration rate (GFR, normal 97-137 mL min(-1)/1.73 m(2)) fell from normal to 65.1 mL min(-1). The most likely cause of initial renal impairment in our patient is uric and/or xanthine crystalluria. A missense and transition mutation 169A>G (57ATG>GTG, 57met>val) in exon 3 of the patient's HPRT gene was identified and the mother was the carrier of the mutation. As far as we are aware, the identified mutation has not previously been reported. We named the mutant HPRT Maribor.

Topics: Allopurinol; Child, Preschool; Enzyme Inhibitors; Follow-Up Studies; Humans; Hyperuricemia; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Male; Point Mutation; Treatment Outcome; Uric Acid; Urinary Calculi

It is the intention of this report to identify appropriate analytical tests which allow for the monitoring of allopurinol treatment of patients with Lesch-Nyhan syndrome and the prevention of uric acid or xanthine lithiasis.. A 12 year old boy with Lesch-Nyhan syndrome presented with signs of compulsive automutilation, motoric and mental retardation and cerebral palsy. Paraclinical patient showed hyperuricemia and significant hyperuricosuria. During administration of allopurinol (200 mg/d) he developed fever, an urinary tract infection and dilatation of pelviureteric junction which was suspected of being nephrolithiasis. During hospitalisation, the purine metabolism was intensively monitored. The allopurinol treatment was adjusted according to clinical and laboratory data.. The renal scanning diagnostic showed the develepment of a functionally impaired left kidney. Later this kidney had no part in tubulo-secretorical function. It was necessary to remove surgical two renal stones. The composition of the stones was exclusively xanthine. Serum concentration and urinary excretion of xanthine and hypoxanthine were massively enlarged. The elimination of uric acid in urine was normal. But subsequently, the left kidney had to be removed despite intensive care.. Lesch-Nyhan syndrome is a disorder caused by congenital absence of the enzyme hypoxanthineguanine phosphoribosyltransferase and an increase of the enzyme activity of adenine phosphoribosyltransferase. Treatment should be adjusted to patient's age and weight. An adapt treatment with allopurinol and optimal fluid intake reduce the risk of uric acid or xanthine lithiasis. Laboratory monitoring includes testings for serum concentration and urinary excretion of uric acid, xanthine and hypoxanthine. Sole a normal concentration of uric acid is not sufficient for therapy control. Assessment of the urine sediment by microscopy or infrared spectroscopy will enable early detection of uric acid or xanthine lithiasis.

Topics: Allopurinol; Child; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Hypoxanthine; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Uric Acid; Xanthine

The authors report a case of xanthine stones in a 12-year-old child with Lesh Nyhan syndrome treated by allopurinol at the dose of 10 mg/kg/24 hours. This type of urinary stone is unusual and its structure was confirmed by spectrophotometric analysis. This type of stone, in the context of Lesh Nyhan syndrome, suggests the presence of allopurinol treatment. Discontinuation of this treatment prevents recurrence of xanthine stones.

Topics: Allopurinol; Antimetabolites; Child; Enzyme Inhibitors; Follow-Up Studies; Humans; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Oxypurinol; Spectrophotometry; Urinary Bladder Calculi; Xanthine; Xanthines

Topics: Acids; Alkaloids; Allopurinol; Anilino Naphthalenesulfonates; Animals; Blood Proteins; Electrophoresis; Electrophoresis, Capillary; Glucuronates; Humans; Hydrogen-Ion Concentration; Ions; Lesch-Nyhan Syndrome; Muramidase; Nucleotides; Peptide Fragments; Phosphates; Phosphoric Diester Hydrolases; Proteins; Thioglycolates; Vinyl Chloride

Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.

Topics: Adenine; Adenine Phosphoribosyltransferase; Alleles; Allopurinol; Animals; Blotting, Southern; Chromatography, High Pressure Liquid; Cloning, Molecular; Crystallization; Disease Models, Animal; Genotype; Humans; Hypoxanthine; Kidney; Lesch-Nyhan Syndrome; Mice; Mice, Transgenic; Polymerase Chain Reaction; Purines

We report a case of Lesch-Nyhan syndrome (LNS) with urinary xanthine calculi. At eight years of age calculi in the renal pelvis were successfully disintegrated by extracorporeal shock wave lithotripsy (ESWL) without any complications. Follow-up sonography is very useful for management of patients with LNS, particularly when they are on allopurinol therapy.

Topics: Allopurinol; Humans; Infant; Kidney Calculi; Lesch-Nyhan Syndrome; Lithotripsy; Male; Xanthine; Xanthines

1. A compound identified as orotidine has been found in the erythrocytes of all subjects on allopurinol. 2. The erythrocyte orotidine concentrations were much higher in patients with renal failure or with the Lesch-Nyhan syndrome. 3. In addition, increased amounts of oxypurinol-7-riboside were excreted in the urine by both of these groups compared with control subjects or with patients with normal renal function on allopurinol. 4. A good correlation was found between urinary oxypurinol-7-riboside excretion and erythrocyte orotidine concentrations. 5. Increased erythrocyte levels of the pyrimidine-sugar UDP-glucose were also found in patients with the highest orotidine levels. 6. The combined results suggest a derangement of pyrimidine nucleotide metabolism during allopurinol therapy. We propose that erythrocyte orotidine formation results primarily from inhibition of orotidine-5'-monophosphate decarboxylase by oxypurinol-7-ribotide.

Topics: Allopurinol; Erythrocytes; Female; Humans; Kidney Failure, Chronic; Lesch-Nyhan Syndrome; Male; Nucleotides; Oxypurinol; Ribonucleosides; Uridine

The Lesch-Nyhan syndrome is an x-linked defect of purine metabolism resulting in its classical form in major neurodevelopmental abnormality, hyperuricaemia, and hyperuricosuria. Uric acid calculi and crystalluria are common. Allopurinol is the main method of reducing serum and urinary uric acid levels, but results in xanthinuria and oxypurinoluria, both of which may cause crystal nephropathy and calculi. The variable ultrasonic appearances of multiple calculi and increased medullary echogenicity in four cases of long-standing treated disease and the nature of the renal disorder, which is at least partially iatrogenic, are described.

Topics: Adolescent; Adult; Allopurinol; Child; Humans; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Time Factors; Ultrasonography

Topics: Capsules; Child, Preschool; Humans; Lesch-Nyhan Syndrome; Male; Xanthine Oxidase

Lesch-Nyhan syndrome is a rare X-linked recessive disorder of purine metabolism associated with a virtually complete deficiency of the enzyme hypoxanthine-guanine phosphoribosyl-transferase (HPRT). The disease is characterized by hyperuricemia, self-multilation, choreoathetosis, spasticity, and mental retardation. The abnormalities of purine metabolism are present at birth and may lead to uric acid crystalluria and stone formation early in life. Radiographic findings described in Lesch-Nyhan syndrome include faintly radio-opaque stones on abdominal radiographs or, if renal disease is present, small kidneys with poor function on intravenous urogram. Radiolucent stones are usually composed of uric acid; however, several cases of xanthine and hypoxanthine-containing calculi in Lesch-Nyhan patients receiving allopurinl therapy have also been described. Oxypurine is the collective name for the compounds hypoxanthine, xanthine, and uric acid, and all may be radiolucent. We report a case of Lesch-Nyhan syndrome with presumed renal parenchymal oxypurine deposition demonstrated readily by ultrasonography but not detected on standard radiographs or intravenous urograms.

Topics: Allopurinol; Child; Humans; Hypoxanthine; Hypoxanthines; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Ultrasonography; Uric Acid; Xanthine; Xanthines

Two healthy volunteers were treated with hypoxanthine 3 x 1 g and allopurinol 3 x 100 mg daily for 1 week. During this treatment serum oxypurine concentration and urinary oxypurine excretion increased as expected. No side effects were observed except for some mild daytime drowsiness and lethargy. Measurements of urinary serotonin (5-HT) excretion showed decreases to as much as 60% below initial values. Decreased urinary 5-HT excretion was also found in a patient with incomplete Lesch-Nyhan syndrome during treatment with high doses of hypoxanthine. His neurological symptoms improved slightly. The results suggest that high doses of hypoxanthine exert a nonspecific sedative effect on both patients with Lesch-Nyhan syndrome and healthy controls. The cause is probably a reduced synthesis or release of 5-HT.

Topics: Adult; Allopurinol; Dose-Response Relationship, Drug; Humans; Hydrocortisone; Hypoxanthine; Hypoxanthines; Lesch-Nyhan Syndrome; Serotonin

The transfer of purines through the hematoencephalic barrier is poorly understood. Allopurinol inhibits the enzyme xanthine oxidase and increases xanthine and hypoxanthine plasma levels, but it should not increase the cerebrospinal fluid (CSF) levels of these purines owing to the absence of xanthine oxidase in the central nervous system (CNS). In the present study we evaluated the plasma and CSF concentrations of uric acid, hypoxanthine, xanthine and inosine in the baseline state and after 7 days of allopurinol administration (5-10 mg/kg/24 h) in 4 patients with hypoxanthine phosphoribosyltransferase (HPRT) deficiency. The CSF uric acid level was positively correlated with its plasma level (r = 0.93, p less than 0.01). The CSF hypoxanthine and xanthine concentrations were, as a mean, 5 and 2 times higher, respectively, in patients with HPRT deficiency than in 4 control individuals. As hypoxanthine basically comes from adenine nucleotides, while xanthine comes from guanine nucleotides, this finding suggests that in the CNS of patients with HPRT deficiency there is a higher degradation level of adenine nucleotides than of guanine nucleotides. Allopurinol increased plasma concentration of hypoxanthine, xanthine and inosine 4, 10 and 3 times, respectively, in relation to baseline values. In CSF, the mean increase of hypoxanthine and xanthine concentration was 17.5 mumol and 7.7 mumol, respectively, whereas inosine level was unchanged. These results suggest that in HPRT deficiency hypoxanthine and xanthine may be transferred to the brain.

Topics: Adolescent; Adult; Allopurinol; Blood-Brain Barrier; Child; Child, Preschool; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Lesch-Nyhan Syndrome; Male; Purines; Xanthine; Xanthines

Purine metabolism in the Lesch-Nyhan syndrome has been re-examined in 10 patients. Hypoxanthine and xanthine concentrations in plasma and CSF and urinary excretion have been studied, on and off allopurinol treatment, using high performance liquid chromatographic methods. Accumulation of the substrate, hypoxanthine, of the missing hypoxanthine guanine phosphoribosyltransferase (HPRT) enzyme, is more marked in urine and in CSF than in plasma. The greater increase in CSF is consistent with the most metabolically active tissue, brain, showing the most marked functional changes. The function of HPRT seems to be the recycling of hypoxanthine which is released from tissues in increasing quantities as energy use, ATP 'turnover', in the tissue increases. The existing screening method for HPRT deficiency, the ratio of the urinary concentration of urate to that of creatinine, shows overlap between the values in severe HPRT deficiency and in controls; this overlap is not found with a urinary hypoxanthine/creatinine molar concentration ratio.

Topics: Allopurinol; Child; Child, Preschool; Creatinine; Female; Heterozygote; Humans; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Infant; Infant, Newborn; Lesch-Nyhan Syndrome; Male; Purines; Uridine; Xanthines

Topics: Adolescent; Allopurinol; Calculi; Humans; Lesch-Nyhan Syndrome; Male; Xanthine; Xanthines

Topics: Adult; Allopurinol; Biopterins; Drug Administration Schedule; Humans; Hypoxanthine; Hypoxanthines; Lesch-Nyhan Syndrome; Male; Pteridines; Serotonin

Topics: Adolescent; Allopurinol; Child; Child, Preschool; Humans; Hypoxanthine Phosphoribosyltransferase; Infant; Lesch-Nyhan Syndrome; Purines; Uric Acid

A Japanese boy with Lesch-Nyhan syndrome who passed xanthine calculi is reported. After pyelolithotomy for a left renal stone, made up of ammonium urate, associated with urinary tract infection, a high dose of allopurinol was given because of the persistence of pyuria. In the present case, the administration of a high dose of allopurinol, given for the prevention of ammonium urate stone formation in infected urine, induced xanthine calculi formation and we had difficulty in the management of this patient with Lesch-Nyhan syndrome associated with urinary tract infection. However, we believe it a basic necessity to cure our patient of his urinary tract infection and prevent recurrent ammonium urate stone formation because of the risk of renal deterioration.

Topics: Allopurinol; Child; Combined Modality Therapy; Enterococcus faecalis; Humans; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Proteus Infections; Quaternary Ammonium Compounds; Streptococcal Infections; Uric Acid; Urinary Tract Infections; Xanthine; Xanthines

We report a case of urate overproduction owing to the Lesch-Nyhan syndrome (deficiency of hypoxanthine-guanine phosphoribosyltransferase). Urate crystalluria was controlled by allopurinol therapy but renal calculi developed, which contained a variety of purines, particularly the relatively insoluble xanthine, as well as oxypurinol and hypoxanthine. The potential hazard from the increased amounts of xanthine that are produced during allopurinol therapy for urate overproduction is stressed, as well as the importance of maintaining a high urine flow rate even during such therapy.

Topics: Adult; Allopurinol; Humans; Hypoxanthine; Hypoxanthines; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Oxypurinol; Uric Acid; Xanthine; Xanthines

A rare case of renal xanthine stone in association with the Lesch-Nyhan syndrome is presented. The xanthine stone is thought to be a complication of allopurinol therapy.

Topics: Allopurinol; Child; Humans; Kidney; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Uric Acid; Xanthines

In a 7-year-old patient with Lesch-Nyhan syndrome (LNS) the 15N excess frequency was determined in the excreted uric acid after oral application of 27 mg 15N glycine/kg body weight, using emission spectrometry. Incorporation of glycine into uric acid was considerably increased in untreated LNS in comparison with the control. This was due to the extremely increased endogenous de novo synthesis of purine. Allopurinol therapy caused only a gradual decrease of uric acid excretion. The pattern of purine excretion changed in favour of the better soluble oxipurines hypoxanthine and xanthine, by competitive inhibition of xanthine oxidase. In LNS, however, allopurinol had no uricostatic effect. Therapy with adenine is an alternative to influence the de novo synthesis. After adenine application a decrease of the cumulative 15N uric acid excretion occurs and the percentual proportion of 15N uric acid in total 15N excretion decreases. These changes are due to an inhibition of de novo purine biosynthesis. Adenine, however, must be applied in combination with allopurinol in order to avoid the formation of nephrotoxic 2,8-dioxiadenine by xanthine oxidase. Adenine therapy led to an improvement of the clinical course. No side-effects were observed.

Topics: Adenine; Allopurinol; Child; Drug Therapy, Combination; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Purines; Uric Acid

Classically it is considered that vital prognosis of Lesch-Nyhan syndrome depends on renal affectation secondary to uric nephropathy. A case of Lesch-Nyhan syndrome treated with Allopurinol is described which presented multiple and bilateral renal stones by precipitation of xanthine. Treatment with Allopurinol inhibits the formation of uric acid and qualitatively renal excretion of oxypurines modifies. In special circumstances (disminution of urinary output and pH), they can precipitate and originate a radiotransparent lithiasis with uric lithiasis. Interest of this case, lies in being alert to possible xanthine stone formation in patients with a large excretion of purinics metabolites, who are treated with Allopurinol.

Topics: Allopurinol; Child; Humans; Kidney Calculi; Lesch-Nyhan Syndrome; Male; Xanthines

Urinary tract calculi composed primarily of xanthine are rare in adults and children. However, there is risk of xanthine calculi formation in children with hereditary xanthinuria and children on xanthine oxidase inhibitor therapy for hyperuricemia. We describe the clinical presentation and management of 2 children with the Lesch-Nyhan syndrome (a congenital disorder of purine metabolism) and xanthine calculi. Little information has been available to direct the urologic management of such patients. We have based a plan for management upon our clinical experience with these children, as well as upon in vitro dissolution studies of the calculi. We have had some clinical success using an alternating acid/base dissolution therapy developed in the laboratory.

Topics: Adolescent; Allopurinol; Child; Humans; Lesch-Nyhan Syndrome; Male; Urinary Calculi; Xanthines

We analyzed Michaelis--Menten pharmacokinetic parameters of phenytoin with and without the coadministration of allopurinol (150 and 200 mg/day) in a child with Lesch--Nyhan syndrome. The Vmax and Km were estimated from at least two different sets of serum concentration--dosage data of phenytoin. The Vmax values (mg/kg/day) were 16.1 without allopurinol, and 12.4 and 10.9 with allopurinol (150 and 200 mg/day), respectively, whereas those for Km remained relatively constant (3.9 to 4.9 microgram/ml). Our results suggest that allopurinol is a drug that inhibits the hepatic metabolism of phenytoin.

Topics: Adolescent; Allopurinol; Body Weight; Child; Child, Preschool; Drug Interactions; Humans; Kinetics; Lesch-Nyhan Syndrome; Male; Phenytoin

Topics: Allopurinol; Erythrocytes; Fibroblasts; Follow-Up Studies; Genetic Carrier Screening; Humans; Hypoxanthine Phosphoribosyltransferase; Immune Sera; Immunoassay; Infant, Newborn; Kinetics; Lesch-Nyhan Syndrome; Male; Mutation; Purines

Purine metabolism was studied and an enzymatic deficiency was detected in 6 girls with Lesh - Nyhan syndrome/LNS/. In erythrocytes of the patients with LNS and of their parents alterations were found in activities of hypoxanthine guanine phosphoribosyl transferase/HGPRT/ and adenine phosphoribosyl transferase/APRT/. A form of LNS was observed, which exhibited a decrease in stability of HGRPT and alteration in sensitivity of the enzyme to inhibitors. Treatment with allopurinol did not affect the HGRPT and APRT activities. Heterogeneity of the Lesh Nyhan syndrome is discussed.

Topics: Adenine Phosphoribosyltransferase; Allopurinol; Child; Child, Preschool; Erythrocytes; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Infant; Lesch-Nyhan Syndrome; Pentosyltransferases; Sodium Fluoride; Uric Acid

An isotachophoretic system is described for the separation and identification of urinary purine and pyrimidine bases and nucleosides. For a better discrimination and interpretation of the UV profiles, well-defined non-UV-absorbing substances were introduced as spacers. Treatment of urine samples with purified enzymes before analysis resulted in specific shifts in the metabolite profiles, providing a sensitive and specific means of identifying a number of metabolites. With an injected volume of 3 microliters (untreated urine diluted 1:5) the present method allows reproducible separations within 20 min of at least twenty different nucleosides and bases.

Topics: Allopurinol; Electrophoresis; Humans; Lesch-Nyhan Syndrome; Nucleosides; Purines; Pyrimidines

Topics: Allopurinol; Child; Humans; Lesch-Nyhan Syndrome; Male; Urate Oxidase; Xanthines

A method is presented for the two-dimensional thin-layer chromatographic screening of purines, pyrimidines and their nucleosides in the urine. Prior to chromatography, isolation of these substances from the urine is performed by anion-exchange column chromatography. Purines and pyramidines are quantitatively eluted with formic acid 0.01 M and 4 M respectively. The results of recovery and stability experiments are given. Normal excretory patterns are presented. Also results in patients with various diseases are shown: ornithine transcarbamylase deficiency, adenosine deaminase deficiency, purine nucleoside phosphorylase deficiency, adenine phosphoribosyltransferase deficiency, xanthine oxidase deficiency and hypoxanthine-guanine phosphoribosyltransferase deficiency. Finally the pattern of a patient on treatment with allopurinol is given.

Topics: Adenosine Deaminase; Allopurinol; ATP Phosphoribosyltransferase; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Chromatography, Thin Layer; Humans; Lesch-Nyhan Syndrome; Ornithine Carbamoyltransferase Deficiency Disease; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Pyrimidines; Xanthine Oxidase

Topics: 5-Hydroxytryptophan; Adolescent; Aggression; Allopurinol; Behavior Therapy; Child; Child Behavior Disorders; Child Development; Child, Preschool; Humans; Hypoxanthine Phosphoribosyltransferase; Infant; Lesch-Nyhan Syndrome; Male; Restraint, Physical; Self Mutilation; Stereotyped Behavior; Uric Acid

Topics: Allopurinol; Child; Humans; Lesch-Nyhan Syndrome; Male

Topics: Adenosine; Adenosine Triphosphate; Allopurinol; Animals; Ascorbic Acid; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Methylene Blue; Phosphoribosyl Pyrophosphate; Purines; Pyrimidines; Ribosemonophosphates; Uric Acid

Two brothers were found to have athetoid cerebral palsy, mental and growth retardation and evidence of self mutilation. One had passed a renal calculus and both had high serum uric acid levels. The diagnosis of Lesch-Nyhan syndrome was confirmed by the finding of low levels of hypoxanthine-guanine phosphoribosyl transferase in erythrocytes and by autoradiography of fibriblasts. The mother, maternal grandmother, a female sibling and a maternal aunt were identified as carriers of the X-linked mutation which was responsible for the enzyme deficiency in the two male siblings.

Topics: Allopurinol; Child; Female; Heterozygote; Humans; Infant; Lesch-Nyhan Syndrome; Male; Pedigree

Topics: Adenine Phosphoribosyltransferase; Carbohydrate Metabolism; Feedback; Gout; Humans; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Models, Chemical; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Uric Acid; Xanthine Oxidase

Asymptomatic hyperuricemia should be treated only if the plasma uric acid levels are around 10 mg/100 ml or more on several determinations. In addition, patients on a purine-free diet who excrete more than 600 mg uric acid per 24 h should be treated. In both cases, treatment is intended to be prophylactic against gouty nephropathy. At present there is no evidence that primary hyperuricemia alone is a risk factor for early atherosclerosis and especially coronary artery disease. However, more attention should be paid to the accompanying risk factors such as obesity, hyperlipoproteinemia, diabetes mellitus and hypertension.

Topics: Allopurinol; Benzbromarone; Citrates; Coronary Disease; Gout; Humans; Hyperlipidemias; Hypertension; Hypoxanthine Phosphoribosyltransferase; Kidney Diseases; Lesch-Nyhan Syndrome; Obesity; Uric Acid

Topics: Adenine; Allopurinol; Humans; Infant; Lesch-Nyhan Syndrome; Male; Uric Acid

Topics: Adolescent; Adult; Allopurinol; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Lesch-Nyhan Syndrome; Male; Uric Acid

Topics: Allopurinol; Athetosis; Child; Compulsive Behavior; Diet Therapy; Humans; Huntington Disease; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Uric Acid

Topics: Allopurinol; Humans; Infant; Lesch-Nyhan Syndrome; Male; Uric Acid

Topics: Adenine; Allopurinol; Body Weight; Child, Preschool; Chlorpromazine; Creatinine; Exchange Transfusion, Whole Blood; Humans; Language Development; Lesch-Nyhan Syndrome; Male; Motor Skills; Movement Disorders; Pedigree; Pentosyltransferases; Phenothiazines; Tetrabenazine; Uric Acid

Topics: Allopurinol; Carbon Dioxide; Carbon Radioisotopes; Carboxy-Lyases; Child; DNA; Erythrocytes; Gout; Humans; Lesch-Nyhan Syndrome; Orotic Acid; Pentosyltransferases; Pyrazoles; Pyrimidines; Respiration; RNA; Time Factors

Topics: Adenine; Allopurinol; Erythrocytes; Female; Gout; Guanine; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Male; Pentosephosphates; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Pyrazoles; Pyrimidines; Sulfhydryl Compounds; Time Factors; Uric Acid; Xanthines

Topics: Acute Kidney Injury; Adenine; Allopurinol; Child; Child Behavior; Humans; Lesch-Nyhan Syndrome; Male; Phonetics; Verbal Behavior

Topics: Adenosine; Alkaline Phosphatase; Amidinotransferases; Amidohydrolases; Glomerular Filtration Rate; Glucosephosphate Dehydrogenase; Gout; Guanine Nucleotides; Humans; Hypoxanthines; Kinetics; Lesch-Nyhan Syndrome; Pentosephosphates; Pentosyltransferases; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Ribose; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Animals; Chemical Phenomena; Chemistry; Chickens; Electron Transport; Flavin-Adenine Dinucleotide; Gout; Humans; Hydroxylation; Hypoxanthines; Iron; Ketone Oxidoreductases; Lesch-Nyhan Syndrome; Liver; Mice; Milk; Molecular Weight; Molybdenum; Purines; Rats; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Adenine; Adolescent; Allopurinol; Carbon Isotopes; Carboxy-Lyases; Child; Child, Preschool; Diphosphates; Erythrocyte Aging; Erythrocytes; Hot Temperature; Humans; Infant; Lesch-Nyhan Syndrome; Orotic Acid; Pentosyltransferases

Topics: Allopurinol; Anemia; Anti-Bacterial Agents; Humans; Infant; Intellectual Disability; Lesch-Nyhan Syndrome; Neurologic Manifestations; Uric Acid; Urinary Calculi; Urinary Tract Infections

Topics: Adenine; Allopurinol; Carbon Radioisotopes; Diet; Diet Therapy; Drug Stability; Erythrocytes; Hot Temperature; Humans; Imidazoles; Inosine Nucleotides; Lesch-Nyhan Syndrome; Pentosephosphates; Pentosyltransferases; Purines; Time Factors

Topics: Adenine; Adolescent; Adult; Allopurinol; Child; Erythrocytes; Female; Gout; Guanine Nucleotides; Humans; Hypoxanthines; Inosine Nucleotides; Lesch-Nyhan Syndrome; Male; Middle Aged; Pedigree; Pentosephosphates; Pentosyltransferases

Topics: Adenine; Adolescent; Adult; Allopurinol; Athetosis; Australia; Child; Humans; Hypoxanthines; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Phosphotransferases; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Uric Acid; Xanthines

Topics: Adenine Nucleotides; Allopurinol; Feedback; Gout; Guanosine; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Orotic Acid; Pentosyltransferases; Pyrazoles; Pyrimidines; Sulfhydryl Compounds; Uric Acid; Xanthine Oxidase

Topics: Gout; Humans; Lesch-Nyhan Syndrome; Purine-Pyrimidine Metabolism, Inborn Errors; Sex Factors; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Athetosis; Child, Preschool; Humans; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Sex Factors; Syndrome

Topics: Adolescent; Allopurinol; Athetosis; Child, Preschool; Humans; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Sex Chromosomes; Uric Acid

Topics: Allopurinol; Athetosis; Basal Ganglia; Diphosphates; Erythrocytes; Fibroblasts; Guanine; Humans; Hypoxanthines; Infant; Intellectual Disability; Lesch-Nyhan Syndrome; Liver; Pentosephosphates; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Ribose; Self Mutilation; Transferases; Xanthines

Topics: Adolescent; Allopurinol; Athetosis; Child; Humans; Hypoxanthines; Intellectual Disability; Lesch-Nyhan Syndrome; Male; Probenecid; Purine-Pyrimidine Metabolism, Inborn Errors; Pyelonephritis; Self Mutilation; Uric Acid; Urinary Calculi; Xanthines

Topics: Allopurinol; Carbon Dioxide; Carbon Isotopes; Carboxy-Lyases; Chromatography, Paper; Depression, Chemical; Erythrocytes; Gout; Humans; Hypoxanthines; In Vitro Techniques; Lesch-Nyhan Syndrome; Male; Orotic Acid; Pentosyltransferases; Pyrazoles; Pyrimidines; Spirometry; Time Factors

A coordinate relationship between the activities of two sequential enzymes in the de novo pyrimidine biosynthetic pathway has been demonstrated in human red cells. The two enzymes, orotidylate phosphoribosyltransferase and decarboxylase are responsible for the conversion of orotic acid to uridine-5'-monophosphate. Fractionation of red cells, on the basis of increase of specific gravity with cell age, has revealed that these two enzymes have a marked but equal degree of lability in the ageing red cell. It is postulated that orotidylate phosphoribosyltransferase and decarboxylase form an enzyme-enzyme complex, and that the sequential deficiency of these two enzymes in hereditary orotic aciduria may reflect a structural abnormality in this complex. In patients receiving allopurinol, the activities of both enzymes are coordinately increased, and this increase appears to be due, at least in part, to stabilization of both orotidylate phosphoribosyltransferase and decarboxylase in the ageing red cell. Allopurinol ribonucleotide is an in vitro inhibitor of orotidine-5'-monophosphate decarboxylase and requires the enzyme hypoxanthineguanine phosphoribosyltransferase for its synthesis. However, the administration of allopurinol to patients lacking this enzyme results in orotidinuria and these patients have elevated orotidylate phosphoribosyltransferase and decarboxylase activities in their erythrocytes. Evidence is presented that the chief metabolite of allopurinol, oxipurinol, with a 2,4-diketo pyrimidine ring is capable of acting as an analogue of orotic acid. It is postulated that the in vivo formation of oxipurinol ribonucleotide, catalyzed by orotidylate phosphoribosyltransferase, after allopurinol administration, leads to inhibition of orotidine-5'-monophosphate decarboxylase. This inhibition results in the urinary excretion of excessive amounts of orotidine and orotic acid, and "pseudo-substrate" stabilization of orotidylate phosphoribosyltransferase and decarboxylase.

Topics: Adenine; Allopurinol; Carbon Isotopes; Carboxy-Lyases; Centrifugation, Density Gradient; Depression, Chemical; Erythrocytes; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Nucleosides; Orotic Acid; Transferases; Uracil Nucleotides

Topics: Allopurinol; Athetosis; Benzofurans; Brain; Child; Child, Preschool; Chorea; Compulsive Behavior; Erythrocytes; Female; Guanine; Humans; Hypoxanthines; Infant; Intellectual Disability; Japan; Kidney; Lesch-Nyhan Syndrome; Liver; Male; Proteinuria; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Transferases; Uric Acid

Topics: Allopurinol; Athetosis; Azathioprine; Benzofurans; Child; Child, Preschool; Guanine; Humans; Hypoxanthines; Intellectual Disability; Japan; Ketones; Lesch-Nyhan Syndrome; Male; Paraplegia; Pentosyltransferases; Phenols; Purine-Pyrimidine Metabolism, Inborn Errors; Self Mutilation; Spasm; Uric Acid; Xanthines