International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria

Muntau, Ania C.; Adams, Darius; Bélanger-Quintana, Amaya; Бушуева, Т. В.; Cerone, R.; Chien, Yin‐Hsiu; Chiesa, Ana; Coşkun, Turgay; Heras, Javier de las; Feillet, François; Katz, Rachel; Lagler, Florian B.; Piazzon, Flávia Balbo; Rohr, Fran; Spronsen, Francjan J. van; Vargas, Paula; Wilcox, Gisela; Bhattacharya, Kaustuv

doi:10.1016/j.ymgme.2019.04.004

Cited by 46 publications

(48 citation statements)

References 57 publications

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“…Table 1 shows information on genotype, calculated SUM AVs for both alleles,phe tolerance mg/day, phenotype assessed clinically and classified by Guldberg´s, concordance with predicted genotype (Yes/No), GPVs and results of the 48hs BH 4 test when performed, considering as a positive response a decrease ≥30% of the Phe basal levels under a stable Phe consumption. [15] The p.Arg261Gln was the most frequent mutation in our cohort, affecting 18 (17.4%) of our patients.Two patients were homozygous with classic and moderate phenotypes. The other 16 were heterozygous and showed phenotypes that covered the whole clinical spectrum, depending on the second mutation found.…”

Section: Genotype: Pah Mutation Spectrummentioning

confidence: 70%

“…It is now accepted that a subset of patients would benefit from using this drug. [15,34] As the genotype determines PAH activity and the metabolic phenotype, it is also useful to select patients to be tested or treated. Moreover, the presence of two null mutations makes the testing unnecessary.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the presence of two null mutations makes the testing unnecessary. [11,15] In Argentina, diet is the first treatment offered to PKU patients. Nevertheless, sapropterin has become available, and BH4 testing if possible, is performed in the neonatal period mainly because it provides the possibility of assessing BH4 deficiencies that are difficult to exclude rapidly because of unavailable biochemical studies.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, sapropterin has become available, and BH4 testing if possible, is performed in the neonatal period mainly because it provides the possibility of assessing BH4 deficiencies that are difficult to exclude rapidly because of unavailable biochemical studies. [15] In this context, phenotype would complement the information in each patient helping to select the adequate treatment .Thus, though it may seem in some way sophisticated in our medium and still not available for every patient, genotype indeed allows for personalized treatment and follow-up. [32] Our results highlight the utility of genotype in the provision of appropriate genetic counseling for PKU patients.…”

Section: Discussionmentioning

confidence: 99%

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Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

Enacan

Miñana

Fernández

et al. 2019

J. inborn errors metab. screen.

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Phenylketonuria (PKU, OMIM 261600) is predominantly caused by mutations in the PAH gene. One hundred and three Argentine PKU patients were studied by Sanger sequencing; 101 were completely characterized (90.3% were compound heterozygotes). Fifty-four different pathogenic variants were identified. Mutations were distributed all along the PAH gene but concentrated in exon 7 (26%), 12 (12%), 11 (10%), and 6 (10%). 77% were missense, and 77% affected the enzyme catalytic domain, nine mutations accounted for 57% of 179 studied alleles: p.

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Section: Genotype: Pah Mutation Spectrummentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

Enacan

Miñana

Fernández

et al. 2019

J. inborn errors metab. screen.

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“…On this topic, a comparison between the outcomes of the BH 4 testing regime in Europe (using a 48‐hour BH 4 loading test) and the United States (using a 28‐days BH 4 loading test) would be interesting. Recently, a group of experts proposed a BH 4 testing algorithm which combines the 48‐hour BH 4 loading tests with testing periods up to 4 weeks . Apart from the fact that Muntau et al did not recommend a specific definition of long‐term BH 4 responsiveness, the value of the recommended testing protocol remains to be established.…”

Section: Discussionmentioning

confidence: 99%

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

Evers

Wegberg

Anjema

et al. 2019

J of Inher Metab Disea

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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.

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Current Advances and Material Innovations in the Search for Novel Treatments of Phenylketonuria

Delbreil,

Dhondt,

Kenaan El Rahbani

et al. 2024

Adv Healthcare Materials

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Phenylketonuria (PKU) is a genetically inherited disease caused by a mutation of the gene encoding phenylalanine hydroxylase (PAH) and is the most common inborn error of amino acid metabolism. A deficiency of PAH leads to increased blood and brain levels of phenylalanine (Phe), which may cause permanent neurocognitive symptoms and developmental delays if untreated. Current management strategies for PKU consist of early detection through neonatal screening and implementation of a restrictive diet with minimal amounts of natural protein in combination with Phe‐free supplements and low‐protein foods to meet nutritional requirements. For milder forms of PKU, oral treatment with synthetic sapropterin (BH4), the cofactor of PAH, may improve metabolic control of Phe and allow for more natural protein to be included in the patient's diet. For more severe forms, daily injections of pegvaliase, a PEGylated variant of phenylalanine ammonia‐lyase (PAL), may allow for normalization of blood Phe levels. However, the latter treatment has considerable drawbacks, notably a strong immunogenicity of the exogenous enzyme and the attached polymeric chains. Research for novel therapies of PKU has made use of innovative materials for drug delivery and state‐of‐the‐art protein engineering techniques to develop treatments which are safer, more effective, and potentially permanent.This article is protected by copyright. All rights reserved

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International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria

Cited by 46 publications

References 57 publications

Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

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

Current Advances and Material Innovations in the Search for Novel Treatments of Phenylketonuria

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International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria

Cited by 46 publications

References 57 publications

Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

Phenylalanine Hydroxylase (PAH) Genotyping in PKU Argentine Patients

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

Current Advances and Material Innovations in the Search for Novel Treatments of Phenylketonuria

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Product

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