Thymine-uraciluria

Genetic mutations are a major cause of DPD impairment (24,58). Polymorphism of the DPYD gene has been well characterized as an autosomal recessive disease, with 0.5% and 3%-5% of the Caucasian population being subsequently affected by total and partial deficiencies, respectively (7,59,60). Thymine uraciluria is a condition caused by inherited total DPD deficiency that can be either associated with neurological disorders or be asymptomatic (61,62,63). 

Wadman SK, Berger R, Duran M et al. Dihydropyrimidine dehydrogenase defieieney leading to thymine-uraciluria an inborn error of pyrimidine metabolism. J Inherit Metab Dis 1985 8 Suppl 2 113-114. 

Au KM, Lai CK, Yuen YP et al. Diagnosis of dihydropyrimidine dehydrogenase defieieney in a neonate with thymine-uraciluria. Hong Kong Med J 2003 9 130-132. 

Yokota H, Fernandez-Salguero P, Furuya H et al. cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria. J Biol Chem 1994 269 23192-23196. 

Nauek M, Gierens H, Marz W et al. Rapid deteetion of a common dihydropyrimidine dehydrogenase mutation assoeiated with 5-fluorouraeil toxicity and congenital thymine uraciluria using fluorogenic hybridization probes. Clin Biochem 2001 34 103-105. 

Bacterial contamination of the urine may result in strongly increased levels of uracil due to the bacterial degradation of pseudouridine. Thymine-uraciluria, which is indicative of a dihydropyrimidine dehydrogenase or dihydropyrimidinase deficiency, may also result from increased tissue degradation. However, the latter situation is also characterized by hyper-/l-aminoisobutyric aciduria and hyper-/f-alaninuria [6]. Under alkaline conditions, due to the presence of bacterial contamination, the de-oxynucleosides may be hydrolyzed toward their corresponding nucleoside bases. 

R.E. (m), with thymine-uraciluria, is the third child of healthy parents. The first child is healthy but the second one died of perinatal asphyxia. A few hours after birth the patient developed cyanosis with a mild respiratory distress. On the third day he developed also a pneumothorax. Furthermore there was a hyperbilirubinemia. Treatment was successful and at 3h weeks he was discharged. Psycho-motor development was normal until the age of Ih years. Then he de/eloped petit mal seizures which were treated. After one month treatment could be discontinued. The parents noticed that behavioural changes occurred after the onset of the seizures. Speech did not develop and his behaviour became solitary. At admission for evaluation of his developmental problems no physical abnormalities were seen. Psychological investigations revealed a normal intelligence with autistic features and the absence of auditory defects. 

Thymine-uraciluria in R.E, The gas chromatogram of the trimethyl si lylated organic acids displayed two mediimi size abnormal peaks, which turned out to be due to uracil and thymine according to GLC-MS analysis. The two-dimensional thin-layer chromatogram showed except uracil and thymine a third abnormal spot. Isolation of this compound from a two-dimensional chromatogram, followed by trimethylsilylation and GLC-MS showed the compound to be 5-hydroxy-methyluracil. This compound is not extracted with ethylacetate and is therefore absent in the gas chromatogram. 

As far as we know persistent thymine-uraciluria has been described once before, in a child with a fatal medulloblastoma (10). It seemed likely that the brain tumor caused the high excretion of uracil and thymine, because there was a correlation between their excretion rates and the clinical progress of symptoms, remission after therapy and relapse. In our patient, however, no signs of malignancy have developed during the four years of observation. Therefore an inherited enzyme defect is held as the most probable cause. 

With our routine GLC-system for iirinary organic acid analysis in use for the screening for inborn errors of metabolism we detected persistent uraciluria in a few children. One of these patients will be described briefly here. Another patient showed a persistent excretion of thymine and uracil both. This child has been studied more in detail the results will be given in the present paper. 

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