The first European guidelines on phenylketonuria: Usefulness and implications for BH₄ responsiveness testing

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.

PKU dietary handbook to accompany PKU guidelines

“…Most patients on diet treatment tolerate less than 500 mg/ day phenylalanine [5]. It is expected that patients who are responsive to sapropterin should at least double their phenylalanine tolerance or tolerate a safe level of protein intake as defined by the WHO/ FAO/UNU 2007 [6,7].…”

Bone Status in Patients with Phenylketonuria: A Systematic Review

“…Intake of glycomacropeptide or large neutral amino acids can also improve the variety and convenience of the dietary therapy [ 6 ]. Since 2007, a synthetic form of tetrahydrobiopterin (6R-BH4) has been used to treat selected patients who have moderate forms of PKU and respond to the BH4 loading test [ 7 , 8 ]. More recently, enzyme substitution therapy has been approved to treat PKU in patients aged 16 years or older [ 9 ].…”

An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations

“…The clinical picture of patients with homozygous genotypes c. [60 + 5G > T]; [60 + 5G > T] coincides with that described for cPKU patients, consisting of early, severe and progressive neurological manifestations, and symptomatology worsening if the start of dietary treatment is delayed. Therefore, these findings emphasize the importance of starting treatment in the first days of life, preferably in the first week [8], to prevent brain damage that leads to neurodevelopmental delay and permanent intellectual disability [38]. At least in two c. 60 + 5G > T-homozygous and lately diagnosed patients (CD group), we documented central nervous system sequelae (Figure 4), consisting of basal ganglia and white matter brain damage.…”