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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
Author(s) -
Lindner M.,
Gramer G.,
Garbade S. F.,
Burgard P.
Publication year - 2009
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-009-1070-7
Subject(s) - tetrahydrobiopterin , phenylalanine , hyperphenylalaninemia , phenylalanine hydroxylase , phenylketonurias , medicine , endocrinology , chemistry , biochemistry , amino acid , nitric oxide synthase , nitric oxide
Summary Tetrahydrobiopterin (BH 4 ) cofactor loading is a standard procedure to differentiate defects of BH 4 metabolism from phenylalanine hydroxylase (PAH) deficiency. BH 4 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 BH 4 responsive, too. BH 4 responsiveness has been defined either by a ≥30% reduction of blood Phe concentration after a single BH 4 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 BH 4 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 BH 4 applied in a double‐blind randomized cross‐over design. Results are compared for ≥30% reduction and SPC. The effect of BH 4 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 BH 4 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 BH 4 doses) and between the two models. We conclude that a comparison of protein loadings without and with BH 4 combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.