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Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Summary

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 (BH4) with an increased rate of phenylalanine (Phe) disposal. The effect is exploited therapeutically, with some patients on BH4 even tolerating a normal diet.

Aim

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 (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/BH4 loading tests appear advantageous because the ‘natural’ t 1/2 (without supplementation of BH4) is not normally known beforehand.

Conclusion

With t 1/2 as a reliable parameter of BH4 responsiveness, therapeutic decisions would be more rational and genotype–phenotype analysis may also profit.

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Authors and Affiliations

  1. Institute of Human Genetics, University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt/Main, Germany

    U. Langenbeck

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  1. U. Langenbeck
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Correspondence to U. Langenbeck.

Additional information

Communicating editor: Johannes Zschocke

Competing interests: None declared

References to electronic databases: Phenylketonuria: OMIM +261600. Phenylalanine hydroxylase: EC 1.14.16.1.

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Langenbeck, U. Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias. J Inherit Metab Dis 31, 67–72 (2008). https://doi.org/10.1007/s10545-007-0572-4

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  • DOI: https://doi.org/10.1007/s10545-007-0572-4

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