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.
(June 2009)DOI: 10.1007/s10545-009-1070-7
Abstract
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.