The first European guidelines on phenylketonuria: Usefulness and implications for BH4 responsiveness testing
Communicating Editor: Wilcken Bridget
Funding information: Tyrosinemia Foundation; Stichting PKU research; Stofwisselkracht; NPKUA; Metakids; ESPKU; Vitaflo; SoBi; Nutricia; Codexis; Alexion; Rare Disease Foundation; Merck Serono; Nutricia, honoraria; Biomarin
Abstract
Objective
This study aimed to investigate and improve the usefulness of the 48-hour BH4 loading test and to assess genotype for BH4 responsiveness prediction, using the new definition of BH4 responsiveness from the European guidelines, as well as an amended definition.
Method
Applying the definition of the European guidelines (≥100% increase in natural protein tolerance) and an amended definition (≥100% increase in natural protein tolerance or tolerating a safe natural protein intake) to a previous dataset, we first assessed the positive predictive value (PPV) of the 48-hour BH4 loading test using a cutoff value of 30%. Then, we tried to improve this PPV by using different cutoff values and separate time points. Last, using the BIOPKU database, we compared predicted BH4 responsiveness (according to genotype) and genotypic phenotype values (GPVs) in BH4-responsive and BH4-unresponsive patients.
Results
The PPV of the 48-hour loading test was 50.0% using the definition of the European guidelines, and 69.4% when applying the amended definition of BH4 responsiveness. Higher cutoff values led to a higher PPV, but resulted in an increase in false-negative tests. Parameters for genotype overlapped between BH4-responsive and BH4-unresponsive patients, although BH4 responsiveness was not observed in patients with a GPV below 2.4.
Conclusion
The 48-hour BH4 loading test is not as useful as previously considered and cannot be improved easily, whereas genotype seems mainly helpful in excluding BH4 responsiveness. Overall, the definition of BH4 responsiveness and BH4 responsiveness testing require further attention.
CONFLICTS OF INTEREST
R.A.F.E. has received financial support from Biomarin for attending symposia. A.M.J.v.W. has received a research grant from Nutricia, honoraria from Biomarin as speaker, and travel grants from Nutricia, and Vitaflo K.A. has received research funding from Merck Serono. C.M.A.L. has received a speaker fee from the Recordati Rare Disease Foundation. E.v.D. has received advisory board fees from Merck Serono and Biomarin. D.v.V. has received speaker's honoraria from Biomarin. N.B. has no conflicts of interest to declare. F.J.v.S. is a member of scientific advisory boards for defects in amino acid metabolism of APR, Arla Food International, BioMarin, Eurocept Int, Lucana, Moderna TX, Nutricia, Rivium, and SoBi, has received research grants from Alexion, Biomarin, Codexis, Nutricia, SoBi, and Vitaflo, has received grants from patient organizations ESPKU, Metakids, NPKUA, Stofwisselkracht, Stichting PKU research and Tyrosinemia Foundation, and has received honoraria as consultant and speaker from APR, Biomarin, MendeliKABS, and Nutricia.
