Dataset Information

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

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.

SUBMITTER: Anjema K

PROVIDER: S-EPMC3711849 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Anjema Karen K van Rijn Margreet M Hofstede Floris C FC Bosch Annet M AM Hollak Carla E M CE Rubio-Gozalbo Estela E de Vries Maaike C MC Janssen Mirian C H MC Boelen Carolien C A CC Burgerhof Johannes G M JG Blau Nenad N Heiner-Fokkema M Rebecca MR van Spronsen Francjan J FJ

Orphanet journal of rare diseases 20130710

<h4>Background</h4>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.<h4>Methods</h4>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 in ...[more]

PMID: 23842451

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Project description:A need exists to expand the characterization of tetrahydrobiopterin (BH(4)) responsiveness in patients with phenylketonuria (PKU), beyond simply evaluating change in blood phenylalanine concentrations. The clinical interpretation of BH(4) responsiveness should be evaluated within the context of phenylalanine hydroxylase (PAH) genotype.This investigation seeks to use a modified version of a previously developed PAH genotype severity tool, the assigned value (AV) sum, to assess the molecular basis of responsiveness in a clinical cohort and to explore the tool's ability to differentiate BH(4) responsive groups.BH(4) response was previously clinically classified in 58 patients with PKU, with three response groups emerging: definitive responders, provisional responders, and non-responders. Provisional responders represented a clinically ambiguous group, with an initial decrease in plasma phenylalanine concentrations, but limited ability to improve dietary phenylalanine tolerance. In this retrospective analysis, mutations in the PAH gene were identified in each patient. PAH genotype was characterized through the AV sum approach, in which each mutation is given an AV of 1, 2, 4, or 8; the sum of both mutations' AV corresponds to genotype severity, with a lower number representing a more severe phenotype. An AV sum cutoff of 2 (indicative of the most severe genotypes) was used to dichotomize patients and predict BH(4) responsiveness. Provisional responders were classified with the definitive responders then the non-responders to see with which group they best aligned.In 17/19 definitive responders, at least one mutation was mild or moderate in severity (AV sum>2). In contrast, 7/9 provisional responders carried two severe or null mutations (AV sum=2), suggesting little molecular basis for responsiveness. Non-responders represent a heterogeneous group with 15/25 patients carrying two severe mutations (AV sum=2), 5/25 patients carrying one moderate or mild mutation in combination with a severe or null mutation (AV sum>2), and the remaining five patients carrying an uncharacterized mutation in combination with a severe mutation. Predictive sensitivity of the AV sum was maximized (89.5% vs. 67.9%) with limited detriment to specificity (79.4% vs. 80.0%), by classifying provisional responders with the non-responders rather than with the definitive responders.In our clinical cohort, the AV sum tool was able to identify definitive responders with a high degree of sensitivity. As demonstrated by both the provisional responder group and the substantial number of non-responders with AV sums>2, a potential exists for misclassification when BH(4) response is determined by relying solely on change in plasma phenylalanine concentrations. PAH genotype should be incorporated in the clinical evaluation of BH(4) responsiveness.

Project description:Tetrahydrobiopterin (BH(4)) responsiveness is currently defined as a decrease in plasma phenylalanine concentrations in patients with phenylketonuria (PKU). This definition does not offer insight beyond the initial assessment of patients, which may lead to treatment ambiguity in patients who only experience an initial decrease in plasma phenylalanine concentrations. We present our experience with a novel classification approach using sequentially-applied criteria. Plasma phenylalanine concentrations were measured at baseline and after one month of BH(4) therapy (20 mg/kg/day) in 58 PKU patients (34 M, 24 F; age 17.3±11.0 years). Thirty-two patients (55.2%) were classified as "preliminary responders" at one month, experiencing at least a 15% decrease in plasma phenylalanine concentrations. Preliminary responders' ability to liberalize their dietary restrictions was then systematically assessed. "Definitive responders" were defined as preliminary responders who could increase their dietary phenylalanine tolerance by at least 300 mg/day and lower prescribed medical food needs by at least 25% while maintaining metabolic control (plasma phenylalanine ≤360 μmol/L) and consuming adequate dietary protein. Preliminary responders who could not liberalize their diets according to these criteria were classified as "provisional responders." Nineteen patients (32.8% of patients initiating BH(4) therapy) met the definitive responder criteria, increasing dietary phenylalanine tolerance from 704±518 mg/day to 1922±612 mg/day and reducing medical food to 16.7±19.5% of their baseline prescription. Nine patients (15.5% of patients initiating BH(4) therapy) were classified as provisional responders, all remaining on 100% of their baseline medical food prescription. From this classification approach, a subgroup of provisionally responsive patients emerged who experienced an initial decrease in plasma phenylalanine concentrations but who could not substantially increase their dietary phenylalanine tolerance or decrease medical food needs. Diet liberalization is an essential component of BH(4)-responsiveness classification.

Dataset Information

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

Publications

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

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