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The neonatal tetrahydrobiopterin loading test in phenylketonuria: what is the predictive value?

ABSTRACT: It is unknown whether the neonatal tetrahydrobiopterin (BH4) loading test is adequate to diagnose long-term BH4 responsiveness in PKU. Therefore we compared the predictive value of the neonatal (test I) versus the 48-h BH4 loading test (test II) and long-term BH4 responsiveness.Data on test I (>1991, 20 mg/kg) at T?=?8 (n?=?85) and T?=?24 (n?=?5) were collected and compared with test II and long-term BH4 responsiveness at later age, with ?30% Phe decrease used as the cut-off.The median (IQR) age at hospital diagnosis was 9 (7-11) days and the age at test II was 11.8 (6.6-13.7) years. The baseline Phe concentrations at test I were significantly higher compared to test II (1309 (834-1710) versus 514 (402-689) ?mol/L, respectively, P?=?0.000). 15/85 patients had a positive test I T?=?8. All, except one patient who was not tested for long-term BH4 responsiveness, showed long-term BH4 responsiveness. In 20/70 patients with a negative test I T?=?8, long-term BH4 responsiveness was confirmed. Of 5 patients with a test I T?=?24, 1/5 was positive at both tests and showed long-term BH4 responsiveness, 2/5 had negative results at both tests and 2/5 showed a negative test I T?=?24, but a positive test II with 1/2 showing long-term BH4 responsiveness.Both a positive neonatal 8- and 24-h BH4 loading test are predictive for long-term BH4 responsiveness. However, a negative test does not rule out long-term BH4 responsiveness. Other alternatives to test for BH4 responsiveness at neonatal age should be investigated.

SUBMITTER: Anjema K

PROVIDER: S-EPMC4731980 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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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.

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The neonatal tetrahydrobiopterin loading test in phenylketonuria: what is the predictive value?

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