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Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype


Anjema, Karen; van Rijn, Margreet; Hofstede, Floris C; Bosch, Annet M; Hollak, Carla Em; Rubio-Gozalbo, Estela; de Vries, Maaike C; Janssen, Mirian Ch; Boelen, Carolien Ca; Burgerhof, Johannes Gm; Blau, Nenad; Heiner-Fokkema, M Rebecca; van Spronsen, Francjan J (2013). Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype. Orphanet Journal of Rare Diseases, 8:103.

Abstract

BACKGROUND: How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. METHODS: Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with >=30% phenylalanine reduction at >=1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term >=30% reduction in mean phenylalanine concentration and/or >=4 g/day and/or >=50% increase of natural protein intake. Genotype was collected if available. RESULTS: 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with >=1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. CONCLUSIONS: The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing.

BACKGROUND: How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. METHODS: Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with >=30% phenylalanine reduction at >=1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term >=30% reduction in mean phenylalanine concentration and/or >=4 g/day and/or >=50% increase of natural protein intake. Genotype was collected if available. RESULTS: 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with >=1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. CONCLUSIONS: The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing.

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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
Language:English
Date:2013
Deposited On:10 Feb 2014 09:53
Last Modified:08 Nov 2016 13:33
Publisher:BioMed Central
ISSN:1750-1172
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1186/1750-1172-8-103
PubMed ID:23842451
Permanent URL: https://doi.org/10.5167/uzh-90192

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