Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias.
BACKGROUND
A significant percentage of patients with hyperphenylalaninaemia (HPA) due to primary deficiency of the phenylalanine hydroxylase enzyme (PAH) respond to a dose of tetrahydrobiopterin (BH(4)) with an increased rate of phenylalanine (Phe) disposal. The effect is exploited therapeutically, with some patients on BH(4) even tolerating a normal diet.


OBJECTIVE
Classification of the Phe blood level response to a BH(4) load by percentage reduction (PR) suffers from loss of information: only part of usually more extensive test data is used, and PR values for different times after load cannot be compared directly. Calculation of half-life (t (1/2)) of blood Phe is proposed as an alternative. This classic measure unifies interpretation of tests of different duration (e.g. 8 or 15 h). t (1/2) subsumes first-order formation of tyrosine, of Phe metabolites, and renal Phe excretion; zero-order net protein synthesis can be neglected during short-time tests.


METHODS
t (1/2) is easily and robustly obtained by fit-ting the total set of (3-4) data points to a log-linear regression.


RESULTS
The advantage of calculating t (1/2) is exemplified by the analysis of selected published data. The results clearly speak in favour of an 8 h test period because so-called 'slow' responders could also be detected within this time window and because tests of longer duration are less reliable kinetically. Sequential Phe and Phe/BH(4) loading tests appear advantageous because the 'natural' t (1/2) (without supplementation of BH(4)) is not normally known beforehand.


CONCLUSIONS
With t (1/2) as a reliable parameter of BH(4) responsiveness, therapeutic decisions would be more rational and genotype-phenotype analysis may also profit.
Langenbeck
U
U
Institute of Human Genetics, University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt/Main, Germany. u.langenbeck@em.uni-frankfurt.de
D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019937:Diagnostic Techniques and Procedures; D006207:Half-Life; D006801:Humans; D007231:Infant, Newborn; D008962:Models, Theoretical; D010649:Phenylalanine / Q000097:blood* / Q000378:metabolism; D010651:Phenylalanine Hydroxylase / Q000378:metabolism; D010661:Phenylketonurias / Q000145:classification* / Q000175:diagnosis* / Q000188:drug therapy; D013997:Time Factors
D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin