Hereditary xanthinuria (type I) is caused by an inherited deficiency of the xanthine oxidorectase (XDH/XO), and is characterized by very low concentration of uric acid in blood and urine and high concentration of urinary xanthine, leading to urolithiasis. Type II results from a combined deficiency of XDH/XO and aldehyde oxidase. Patients present with hematuria, renal colic, urolithiasis or even acute renal failure. Clinical symptoms are the same for both types. In a third type, clinically distinct, sulfite oxidase activity is missing as well as XDH/XO and aldehyde oxidase. The prevalence is not known, but about 150 cases have been described so far. Hypouricemia is sometimes overlooked, that´s why we have set up the diagnostic flowchart. This consists of a) evaluation of uric acid concentrations in serum and urine with exclusion of primary renal hypouricemia, b) estimation of urinary xanthine, c) allopurinol loading test, which enables to distinguish type I and II; and finally assay of xanthine oxidoreductase activity in plasma with molecular genetic analysis. Following this diagnostic procedure we were able to find first patients with hereditary xanthinuria in our Czech population. We have detected nine cases, which is one of the largest group worldwide. Four patients were asymptomatic. All had profound hypouricemia, which was the first sign and led to referral to our department. Urinary concentrations of xanthine were in the range of 170-598 mmol/mol creatinine (normal < 30 mmol/mol creatinine). Hereditary xanthinuria is still unrecognized disorder and subjects with unexplained hypouricemia need detailed purine metabolic investigation.

• MeSH
• aldehydoxidasa krev   nedostatek   moč   MeSH
• alopurinol metabolismus   MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• dospělí MeSH
• kyselina močová krev   moč   MeSH
• lidé MeSH
• močové kameny krev   epidemiologie   moč   MeSH
• poruchy metabolismu purinů a pyrimidinů krev   diagnóza   epidemiologie   moč   MeSH
• předškolní dítě MeSH
• puriny metabolismus   MeSH
• vrozené poruchy metabolismu krev   diagnóza   epidemiologie   moč   MeSH
• vrozené poruchy tubulárního transportu krev   epidemiologie   moč   MeSH
• xanthin krev   moč   MeSH
• xanthindehydrogenasa krev   nedostatek   metabolismus   moč   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: The article describes the clinical, biochemical, enzymological and molecular genetics findings in two patients from two families with xanthinuria type I. METHODS: Biochemical analysis using high performance liquid chromatography, allopurinol loading test and analysis of xanthine oxidase activity in plasma and of uromodulin excretion in urine were performed. Sequencing analysis of the xanthine dehydrogenase gene and the haplotype and statistical analyses of consanguinity were performed. RESULTS: Probands showed extremely low concentrations of uric acid, on seven occasions under the limit of detection. The concentration of uric acid in 38-year-old female was 15 μmol/L in serum and 0.04 mmol/L in urine. Excretion of xanthine in urine was 170 mmol/mol creatinine. The concentration of uric acid in 25-year-old male was 0.03 mmol/L in urine. Excretion of xanthine in urine was 141 mmol/mol creatinine. The allopurinol loading test confirmed xanthinuria type I. The xanthine oxidase activities in patients were 0 and 0.4 pmol/h/mL of plasma. We found three nonsense changes: p.P214QfsX4 and unpublished p.R825X and p.R881X. CONCLUSIONS: We found two nonconsanguineous compound heterozygotes with xanthinuria type I caused by three nonsense changes. The methods used did not confirm consanguinity in the probands, thus there might be an unconfirmed biological relationship or mutational hotspot.

• MeSH
• DNA primery MeSH
• dospělí MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• haplotypy MeSH
• kyselina močová krev   MeSH
• lidé MeSH
• mikrosatelitní repetice MeSH
• mutace MeSH
• sekvence nukleotidů MeSH
• western blotting MeSH
• xanthin moč   MeSH
• xanthindehydrogenasa genetika   MeSH
• xanthinoxidasa genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: The aim of our study was to identify the genetic background of thiopurine-induced toxicity in a patient with a wild-type thiopurine methyltransferase genotype and activity. A 38-year-old Caucasian woman presented with cutaneous necrotizing vasculitis pancytopenia one month after starting azathioprine therapy. METHODS: During a routine biochemical follow-up of the patient, undetectable serum uric acid (<10 μl) was observed. A high performance liquid chromatography analysis of urinary purines revealed increased levels of xanthine (137 mmol/mol creatinine). The suspected diagnosis of hereditary xanthinuria, a rare autosomal recessive disorder of the last two steps of purine metabolism, was confirmed by sequence analysis. RESULTS: An analysis of XDH/XO and AOX1 revealed common polymorphisms, while analysis of the MOCOS gene identified a rare homozygous variant c.362C > T. Dysfunction of this variant was confirmed by significantly decreased xanthine dehydrogenase/oxidase activity in the patient's plasma (<2% of control mean activity). CONCLUSIONS: We present a biochemical, enzymatic, and molecular genetic case study suggesting an important association between a hitherto undescribed dysfunction variant in the MOCOS gene and thiopurine-induced toxicity. The identified variant c.362C > T results in slower thiopurine metabolism caused by inhibition of 6-mercaptopurine oxidation (catabolism) to 6-thioxanthine and 6-thiouric acid, which increases the formation of the nucleotide 6-thioguanine, which is toxic. This is the first clinical case to identify the crucial role of the MOCOS gene in thiopurine intolerance and confirm the impact of genetic variability of purine enzymes on different therapeutic outcomes in patients undergoing thiopurine treatment.

• MeSH
• aldehydoxidasa nedostatek   genetika   MeSH
• dospělí MeSH
• kyselina močová krev   MeSH
• lidé MeSH
• merkaptopurin škodlivé účinky   analogy a deriváty   metabolismus   MeSH
• methyltransferasy genetika   MeSH
• polymorfismus genetický genetika   MeSH
• poruchy metabolismu purinů a pyrimidinů genetika   MeSH
• sulfurtransferasy genetika   MeSH
• xanthin moč   MeSH
• xanthindehydrogenasa nedostatek   genetika   MeSH
• xanthinoxidasa genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty MeSH

Hypouricemia is defined as a serum urate levels less than 2 mg/dL (119 µmol/L). Primary hypouricemia is caused by disorders of purine metabolism and transport. This laboratory finding is sometimes overlooked and, following two genetic defects, should be considered in differential diagnosis of unexplained hypouricemia. Hereditary xanthinuria is autosomal recessive and due to mutations in xanthine oxidase, leading to over-production of xanthine and minimal production of urate. Patients have very low serum urate levels and suffer from elevated levels of xanthine in the urine, leading to xanthine stones, haematuria, and sometimes occult chronic kidney failure. Hypouricemia is the key to diagnosis. Hereditary renal hypouricemia is a new genetic defect of renal transport of uric acid. Two types were distinguished: a) renal hypouricemia type 1, caused by the defects in the SLC22A12 gene coding the human urate transporter 1 (hURAT1) and b) renal hypouricemia type 2, caused by the defects in the SLC2A9 gene, which encodes GLUT9 transporter. This disorder predisposes patients to exercise-induced acute renal failure and/or nephrolithiasis. Diagnosis is based on two markers: hypouricemia (<119 µmol/L) and increased fractional excretion of uric acid (>10%). Over one hundred cases were identified in Japan and and this number is unique worldwide. Several patients were described in Macedonia. We were able to detect four Czech families with hereditary xanthinuria and eight cases of hereditary renal hypouricemia. In conclusion, hereditary xanthinuria and hereditary renal hypouricemia are still unrecognized conditions. Patients with unexplained hypouricemia need detailed purine metabolic investigations.

• MeSH
• dítě MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• kyselina močová metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• močové kameny genetika   metabolismus   MeSH
• poruchy metabolismu purinů a pyrimidinů genetika   metabolismus   MeSH
• puriny metabolismus   MeSH
• vrozené poruchy tubulárního transportu genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Renal hypouricemia is a disease caused by the dysfunction of renal urate transporters. This disease is known to cause exercise-induced acute kidney injury, but its mechanism has not yet been established. To analyze the mechanism by which hypouricemia causes renal failure, we conducted a semi-ischemic forearm exercise stress test to mimic exercise conditions in five healthy subjects, six patients with renal hypouricemia, and one patient with xanthinuria and analyzed the changes in purine metabolites. The results showed that the subjects with renal hypouricemia had significantly lower blood hypoxanthine levels and increased urinary hypoxanthine excretion after exercise than healthy subjects. Oxidative stress markers did not differ between healthy subjects and hypouricemic subjects before and after exercise, and no effect of uric acid as a radical scavenger was observed. As hypoxanthine is a precursor for adenosine triphosphate (ATP) production via the salvage pathway, loss of hypoxanthine after exercise in patients with renal hypouricemia may cause ATP loss in the renal tubules and consequent tissue damage.

• Publikační typ
• časopisecké články MeSH

Renal hypouricemia sometimes leads to exercise-induced acute kidney injury (EIAKI) of unknown pathogenesis. In order to elucidate the various pathological conditions associated with hypouricemia, we analyzed the effects of low uric acid level on energy metabolism. We have modified semi-ischemic forearm exercise test and performed this test in one Japanese healthy volunteer, three patients with hereditary renal hypouricemia and one patient with hereditary xanthinuria of Czech origin. Forearm exercise was performed by squeezing a hand dynamometer with the sphygmomanometer cuff pressure kept at the mean arterial pressure. Venous blood was drawn five times (before exercise, 3, 10, 30, 45 minutes after the start of exercise) in each tests. The mean plasma lactate concentration increased from a baseline of 1.3 (range 0.7-1.8 mmol/L) to 4.0 (range 2.0-5.5 mmol/L) at 3 minutes after the start of exercise. The plasma hypoxanthine concentrations were quite low before exercise (0-2.9 μmol/L), but increased markedly to a range of 13.6-28.8 μmol/L after 10 minute forearm ischemia. Our protocol allowed us to conclude that the load was sufficient for observing metabolic changes in temporally hypoxia and in following recovery phase. The test was well tolerated and safe, we did not observe any adverse reactions including EIAKI.

• MeSH
• dospělí MeSH
• hypoxanthin krev   MeSH
• ischemie komplikace   patofyziologie   MeSH
• kyselina mléčná krev   MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• močové kameny komplikace   MeSH
• předloktí krevní zásobení   patofyziologie   MeSH
• vrozené poruchy tubulárního transportu komplikace   MeSH
• zátěžový test * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Obsáhlá práce, místy nejnověji upravená, charakterizuje biochemické procesy v nemoci a naznačuje správnou interpretaci biochemických nálezů. Ustavuje biochemickou syndromologii a poukazuje na využití takové analýzy při zkoumání a léčení vnitřních chorob. Vykládá onemocnění systému zabezpečujícího metabolické vztahy organismu i k okolí a systému pro metabolickou integraci zevního a vnitřního prostředí, cirkulačního ústrojí, systému zajišťujícího homeostasu a rozebírá problematiku výrazně metabolických poruch a biochemii malignity, přičemž pamatuje i na představy o proteosynthese.

• Klíčová slova
• Biochemie, Lékařství vnitřní,
• MeSH
• biochemie MeSH
• vnitřní lékařství MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biochemie

Odborná příručka uvádí údaje potřebné pro rychlou orientaci v oblasti prevence, diagnostiky a léčby dědičných metabolických poruch.

Publikace se zabývá genetickými poznatky vrozených metabolických poruch, jejich diagnostikou a možností léčby.

• Konspekt
• Fyziologie člověka a srovnávací fyziologie
• NLK Obory
• vnitřní lékařství