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The first European guidelines on phenylketonuria: Usefulness and implications for BH 4 responsiveness testing
Author(s) -
Evers Roeland A. F.,
Wegberg Annemiek M. J.,
Anjema Karen,
Lubout Charlotte M. A.,
Dam Esther,
Vliet Danique,
Blau Nenad,
Spronsen Francjan J.
Publication year - 2020
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12173
Subject(s) - human genetics , medicine , phenylketonurias , genetic testing , pediatrics , medline , genetics , biology , phenylalanine , biochemistry , gene , amino acid
Objective This study aimed to investigate and improve the usefulness of the 48‐hour BH 4 loading test and to assess genotype for BH 4 responsiveness prediction, using the new definition of BH 4 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 BH 4 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 BH 4 responsiveness (according to genotype) and genotypic phenotype values (GPVs) in BH 4 ‐responsive and BH 4 ‐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 BH 4 responsiveness. Higher cutoff values led to a higher PPV, but resulted in an increase in false‐negative tests. Parameters for genotype overlapped between BH 4 ‐responsive and BH 4 ‐unresponsive patients, although BH 4 responsiveness was not observed in patients with a GPV below 2.4. Conclusion The 48‐hour BH 4 loading test is not as useful as previously considered and cannot be improved easily, whereas genotype seems mainly helpful in excluding BH 4 responsiveness. Overall, the definition of BH 4 responsiveness and BH 4 responsiveness testing require further attention.