, Volume 32, Issue 4, pp 514-522
Date: 10 Jun 2009

Blood phenylalanine concentrations in patients with PAH-deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control

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Tetrahydrobiopterin (BH4) cofactor loading is a standard procedure to differentiate defects of BH4 metabolism from phenylalanine hydroxylase (PAH) deficiency. BH4 responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH4 responsive, too. BH4 responsiveness has been defined either by a ≥30% reduction of blood Phe concentration after a single BH4 dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH4 responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH4 applied in a double-blind randomized cross-over design. Results are compared for ≥30% reduction and SPC. The effect of BH4 by ≥30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH4 responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH4 doses) and between the two models. We conclude that a comparison of protein loadings without and with BH4 combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.

Communicating editor: John Walter
Competing interests: Projects in the authors’ institution have been sponsored by Milupa Germany and SHS Germany. The first and senior author have received compensation for educational or scientific lectures from both companies.
References to electronic databases: Phenylketonuria: OMIM #261600. Phenylalanine hydroxylase: EC