Tetrahydrobiopterin (BH(4)) deficiency is an autosomal recessive disorder caused by enzyme defects in the biosynthesis or recycling of BH(4). Patients with BH(4) deficiency present with severe neurological signs and symptoms and require a different treatment from classical phenylketonuria. During the last 12 years, 31 cases of BH(4) deficiency were identified in our department. They were all classified as 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. They were diagnosed at the ages of 2.5-48 months and treated with BH(4), L-dopa and 5-hydroxytryptophan immediately after diagnosis. The average development quotients (DQ) at diagnosis and after treatment for more than 3 years were 53+/- 16, and 78+/- 15, respectively. A significant negative correlation was observed between the level of the DQ and the age at which treatment was commenced (r = -0.751, p = 0.002). Developmental profiles were uneven. Language, adaptability and at later age mathematics were particularly weak areas. Only two patients achieved a good performance in mathematics. Eleven patients who were treated with drugs from ages of 2.9-48 months had neuroradiological scanning. Computed tomography disclosed calcification in lentiform nuclei in one patient and magnetic resonance imaging disclosed delayed myelination and abnormal high intensity signal in cerebral white matter in all of them. Even though most of abnormalities were reversible, small patchy or spotted areas were still present on these regions after treatment for 10-46 months. In summary, our study supports the substantial efficacy of the current therapeutic approach in PTPS deficiency of normalizing amine neurotransmitters with three drugs as early as possible. For the first time, calcifications could be detected in patients with PTPS deficiency. Abnormalities in white matter on magnetic resonance imaging were not related to clinical manifestations and most were reversible.
A rapid and sensitive biological monitoring (BM) method for assessing exposure to the environmental carcinogen safrole has been developed. The method is an isocratic high-performance liquid chromatographic (HPLC) analysis of urinary dihydroxychavicol (DHAB) and eugenol, the urinary metabolites of safrole. Good linearity, precision, and accuracy were demonstrated. A recovery of 98.8 +/- 5.4% (SD, n = 3) was found for DHAB and 84.1 +/- 3.4% (n = 3) for eugenol. The quantitation limits of the method were 8 ng for DHAB and 10 ng for eugenol. The validity of the method was demonstrated by a linear dose-response relationship observed in rats given oral doses of safrole at 30, 75, and 150 mg/kg body weight. The method was also used to monitor the environmental exposure to the Taiwanese betel quid (TBQ) chewing, because TBQ used in Taiwan not only contains areca (betel) nut, slaked lime, and catechu but also Piper betle inflorescence or its leaves. Both of the latter have a high content of safrole. The feasibility of the method to monitor TBQ chewing was demonstrated by an analysis of 153 spot human urine samples. The results showed that the p value of the nonparametric group comparison was < 0.001 for DHAB and 0.832 for eugenol. The TBQ chewers also exhibited a significantly higher rate of urinary DHAB (but not eugenol) than the nonchewers with an odd ratio of 3.47 (95% CI, 1.61-7.51). However, when only the eugenol-positive subjects were taken into analysis, the ratio rose to 24.38 (95% CI, 3.00-197.90).
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