Molecular Genetics and Metabolism 86 (2005) S81–S85 www.elsevier.com/locate/ymgme 1096-7192/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2005.06.008 Tetrahydrobiopterin-responsive phenylketonuria: The New South Wales experience John J. Mitchell a,¤ , Bridget Wilcken b,c,d , Ian Alexander c,d , Carolyn Ellaway c,d , Helen O’Grady c , Veronica Wiley b , John Earl e , John Christodoulou c,d a Department of Genetics, Montreal Children’s Hospital, Montreal, Canada H3H 1P3 b NSW Newborn Screening Programme, Western Sydney Genetics Program, University of Sydney, Australia c Genetic Metabolic Diseases Service, Western Sydney Genetics Program, University of Sydney, Australia d Discipline of Pediatrics and Child Health, University of Sydney, Australia e Clinical Biochemistry, Royal Alexandra Hospital for Children, Westmead, Sydney, Australia Received 30 April 2005; received in revised form 10 June 2005; accepted 13 June 2005 Available online 8 August 2005 Abstract Recent studies have shown that a subgroup of phenylketonuric patients respond to high doses of BH 4 (20 mg/kg) by a decrease of plasma phenylalanine. A clinically signiWcant response has been deWned as a decrease in phenylalanine by more than 30% within 24 h, after a BH 4 challenge. We report our experience with 37 patients diagnosed with hyperphenylalaninemia, mild, moderate, or classical Phenylketonuria (PKU) using a seven day combined BH 4 and phenylalanine load. Nine of the 37 patients responded with a 30% decrease in their phenylalanine levels in the Wrst 8 h of treatment. A total of 17 patients (46%) had a decrease of at least 30% during the study period. This study conWrms that a signiWcant number of patients with mild to moderate PKU will respond to a BH 4 load. Furthermore, it conWrms that the seven-day phenylalanine test is more sensitive in detecting BH 4 responsive patients.  2005 Elsevier Inc. All rights reserved. Keywords: Phenylketonuria; Phenylalanine; Phenylalanine hydroxylase; Tetrahydrobiopterin Introduction Early treatment with a diet restricted in phenylalanine has been the core treatment for phenylketonuria (PKU) for almost 40 years and has succeeded in preventing intellectual disability in aVected patients. While the diet is eVective, it is diYcult for children and adolescents to follow because of its restrictive nature, poor palatability, and social pressures. An exciting alternative to phenylal- anine restriction was proposed by Kure et al. [1] when they reported that tetrahydrobiopterin (BH 4 ) given to four patients with phenylalanine hydroxylase deWciency reduced the blood phenylalanine concentration over an 8 h period. Other reports of BH 4 responsive phenylala- nine hydroxylase deWciency patients have since been reported and up to 70% of hyperphenylalaninemic patients and mild PKU patients are responsive [2–5]. The frequency of responsiveness in classical PKU patients is much lower [6,7]. The optimal way to detect patients with BH 4 respon- siveness remains to be determined and several protocols have been described for detecting BH 4 responsive patients. The loading dose of BH 4 has ranged from 10 to 20 mg/kg and the duration of the trial has varied from 8 h to 1 week. [2–4,8]. A one-week trial of BH 4 has proven the most sensitive test to determine BH 4 respon- siveness as it may detect slow responders who would otherwise be missed [8]. Additionally, some protocols use a combination of BH 4 and either phenylalanine load or * Corresponding author. Fax: +1 514 412 4329. E-mail address: john.mitchell@muhc.mcgill.ca (J.J. Mitchell).