Journal of Inherited Metabolic Disease

, Volume 32, Issue 4, pp 514–522

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

Original Article

Summary

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.

Abbreviations

BH4

tetrahydrobiopterin

bw

bodyweight

HPA

hyperphenylalaninaemia

MHP

mild hyperphenylalaninaemia

PAH

phenylalanine hydroxylase

Phe

phenylalanine

PKU

phenylketonuria

SDS

standard deviation score

SPC

statistical process control

Tyr

tyrosine

U(L)CL

upper (lower) control limit

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • M. Lindner
    • 1
  • G. Gramer
    • 1
  • S. F. Garbade
    • 1
  • P. Burgard
    • 1
  1. 1.Division of Metabolic Disorders, Department of General PaediatricsUniversity Children’s HospitalHeidelbergGermany

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