Defining tetrahydrobiopterin responsiveness in phenylketonuria: Survey results from 38 countries

R A F Evers, A M J van Wegberg, K Ahring, S Beblo, A Bélanger-Quintana, A M Bosch, A Burlina, J Campistol, T Coskun, F Feillet, M Giżewska, S C J Huijbregts, S Kearney, M Langeveld, V Leuzzi, F Maillot, A C Muntau, J C Rocha, C Romani, F K TrefzA MacDonald, F J van Spronsen

Research output: Contribution to journalArticlepeer-review


Background: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH 4), although there is no consensus on the definition of BH 4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH 4 responsiveness being used around the world. Methods: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). Results: We analysed 166 responses. Long-term BH 4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH 4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. Conclusion: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH 4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH 4 treatment.

Original languageEnglish
Pages (from-to)215-219
Number of pages5
JournalMolecular genetics and metabolism
Issue number4
Early online date4 Feb 2021
Publication statusPublished - Apr 2021

Bibliographical note

© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license


  • International
  • Phenylketonuria
  • Survey
  • Tetrahydrobiopterin


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