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.

AIM: 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.

METHOD: 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.

CONCLUSION: 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.