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Author Notes:

Corresponding author at: Department of Human Genetics, 2165 North Decatur Road, Decatur, GA 30033 USA. Fax: +1 404 778 8562. rsingh@emory.edu (R.H. Singh).

Current Affiliation: Children’s Hospital of Pittsburgh, Department of Pathology, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, Pennsylvania, USA.

We would like to acknowledge the contributions of the medical and research staff who aided in the development and implementation of this study.

We would also like to thank the participants and their families for their contributions.

Conflict of interest statement: This investigator-initiated protocol was supported in part by BioMarin Pharmaceutical Inc. Rani H. Singh and Meghan E. Quirk currently have an investigator-initiated protocol with a material supply agreement with BioMarin Pharmaceutical Inc. Additionally, Rani H. Singh is involved in four sponsor-initiated protocols in collaboration with BioMarin Pharmaceutical Inc.

Subjects:

Research Funding:

The data presented are part of an investigator-initiated trial funded by BioMarin Pharmaceutical Inc.

This study was also supported in part by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources.

Keywords:

  • Phenylketonuria
  • Tetrahydrobiopterin
  • Sapropterin dihydrochloride
  • BH4
  • Phenylalanine hydroxylase
  • Genotype

Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria

Tools:

Journal Title:

Molecular Genetics and Metabolism

Volume:

Volume 107, Number 0

Publisher:

, Pages 31-36

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background A need exists to expand the characterization of tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria (PKU), beyond simply evaluating change in blood phenylalanine concentrations. The clinical interpretation of BH4 responsiveness should be evaluated within the context of phenylalanine hydroxylase (PAH) genotype. Aim 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 BH4 responsive groups. Methods BH4 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 BH4 responsiveness. Provisional responders were classified with the definitive responders then the non-responders to see with which group they best aligned. Results 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. Conclusions 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 BH4 response is determined by relying solely on change in plasma phenylalanine concentrations. PAH genotype should be incorporated in the clinical evaluation of BH4 responsiveness.

Copyright information:

© 2012 Published by Elsevier Inc.

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