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
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: X-linked hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in an inherited disorder of purine metabolism is usually associated with the clinical manifestations of hyperuricemia. A variable spectrum of neurological involvement occurs predominantly in males. Females are usually asymptomatic. Carrier status cannot be confirmed by biochemical and enzymatic methods reliably. METHODS: We studied clinical, biochemical and molecular genetic characteristics of Czech families with hyperuricemia and HPRT deficiency. We analyzed age at diagnosis, clinical symptoms, uricemia, urinary hypoxanthine and xanthine, HPRT activity in erythrocytes, mutation in the HPRT1 gene, X-inactivation, and major urate transporters. RESULTS: A mutation in the HPRT1 gene in family A was confirmed in one boy and four females. Three females with hyperuricemia had normal excretion of purine. One female was normouricemic. An 8-month-old boy with neurological symptoms showed hyperuricemia, increased excretion of urinary hypoxanthine and xanthine and a very low HPRT activity in erythrocytes. We have found three other unrelated female carriers with hyperuricemia and normal excretion of hypoxanthine and xanthine among other families with HPRT deficiency. CONCLUSIONS: HPRT deficiency needs to be considered in females with hyperuricemia with normal excretion of purine metabolites. Familiar hyperuricemia and/or nonfamiliar gout should always be further investigated, especially in children.
- MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- dna (nemoc) etiologie genetika MeSH
- dospělí MeSH
- heterozygot MeSH
- hyperurikemie diagnóza etiologie MeSH
- hypoxanthin moč MeSH
- hypoxanthinfosforibosyltransferasa nedostatek genetika MeSH
- lidé MeSH
- mutace * MeSH
- novorozenec MeSH
- rodokmen MeSH
- xanthin moč MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem 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
