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.
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.
Authors: Alicia Hillert; Yair Anikster; Amaya Belanger-Quintana; Alberto Burlina; Barbara K Burton; Carla Carducci; Ana E Chiesa; John Christodoulou; Maja Đorđević; Lourdes R Desviat; Aviva Eliyahu; Roeland A F Evers; Lena Fajkusova; François Feillet; Pedro E Bonfim-Freitas; Maria Giżewska; Polina Gundorova; Daniela Karall; Katya Kneller; Sergey I Kutsev; Vincenzo Leuzzi; Harvey L Levy; Uta Lichter-Konecki; Ania C Muntau; Fares Namour; Mariusz Oltarzewski; Andrea Paras; Belen Perez; Emil Polak; Alexander V Polyakov; Francesco Porta; Marianne Rohrbach; Sabine Scholl-Bürgi; Norma Spécola; Maja Stojiljković; Nan Shen; Luiz C Santana-da Silva; Anastasia Skouma; Francjan van Spronsen; Vera Stoppioni; Beat Thöny; Friedrich K Trefz; Jerry Vockley; Youngguo Yu; Johannes Zschocke; Georg F Hoffmann; Sven F Garbade; Nenad Blau Journal: Am J Hum Genet Date: 2020-07-14 Impact factor: 11.025
Authors: Tao Yan; Shun Guo; Tian Zhang; Zhimin Zhang; An Liu; Song Zhang; Yuan Xu; Yuhong Qi; Weihe Zhao; Qinhui Wang; Lei Shi; Linna Liu Journal: Front Pharmacol Date: 2021-04-22 Impact factor: 5.810
Authors: A MacDonald; A M J van Wegberg; K Ahring; S Beblo; A Bélanger-Quintana; A Burlina; J Campistol; T Coşkun; F Feillet; M Giżewska; S C Huijbregts; V Leuzzi; F Maillot; A C Muntau; J C Rocha; C Romani; F Trefz; F J van Spronsen Journal: Orphanet J Rare Dis Date: 2020-06-30 Impact factor: 4.123
Authors: María José de Castro; Carmela de Lamas; Paula Sánchez-Pintos; Domingo González-Lamuño; María Luz Couce Journal: Nutrients Date: 2020-07-20 Impact factor: 5.717