Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias
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A significant percentage of patients with hyperphenylalaninaemia (HPA) due to primary deficiency of the phenylalanine hydroxylase enzyme (PAH) respond to a dose of tetrahydrobiopterin (BH4) with an increased rate of phenylalanine (Phe) disposal. The effect is exploited therapeutically, with some patients on BH4 even tolerating a normal diet.
Classification of the Phe blood level response to a BH4 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 (t1/2) of blood Phe is proposed as an alternative. This classic measure unifies interpretation of tests of different duration (e.g. 8 or 15 h). t1/2 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.
t1/2 is easily and robustly obtained by fit-ting the total set of (3–4) data points to a log-linear regression.
The advantage of calculating t1/2 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/BH4 loading tests appear advantageous because the ‘natural’ t1/2 (without supplementation of BH4) is not normally known beforehand.
With t1/2 as a reliable parameter of BH4 responsiveness, therapeutic decisions would be more rational and genotype–phenotype analysis may also profit.
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