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The first European guidelines on phenylketonuria: Usefulness and implications for BH 4 responsiveness testing


Evers, Roeland A F; Wegberg, Annemiek M J; Anjema, Karen; Lubout, Charlotte M A; Dam, Esther; Vliet, Danique; Blau, Nenad; Spronsen, Francjan J (2020). The first European guidelines on phenylketonuria: Usefulness and implications for BH 4 responsiveness testing. Journal of Inherited Metabolic Disease, 43(2):244-250.

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 (Anjema et al 2013), we firstly 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. Lastly, 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. This article is protected by copyright. All rights reserved.

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 (Anjema et al 2013), we firstly 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. Lastly, 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. This article is protected by copyright. All rights reserved.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Genetics(clinical), Genetics
Language:English
Date:1 March 2020
Deposited On:28 Jan 2020 17:16
Last Modified:04 Mar 2020 02:05
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0141-8955
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/jimd.12173
PubMed ID:31503351

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