Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: a semi-mechanistically-based, nonlinear mixed-effect modeling

Molecular Genetics and Metabolism
Friedrich TrefzAlain Munafo

Abstract

Neonatal loading studies with tetrahydrobiopterin (BH4) are used to detect hyperphenylalaninemia due to BH4 deficiency by evaluating decreases in blood phenylalanine (Phe) concentrations post BH4 load. BH4 responsiveness in phenylalanine hydroxylase (PAH)-deficient patients introduced a new diagnostic aspect for this test. In older children, a broad spectrum of different levels of responsiveness has been described. The primary objective of this study was to develop a pharmacodynamic model to improve the description of individual sensitivity to BH4 in the neonatal period. Secondary objectives were to evaluate BH4 responsiveness in a large number of PAH-deficient patients from a neonatal screening program and in patients with various confirmed BH4 deficiencies from the BIODEF database. Descriptive statistics in patients with PAH deficiency with 0-24-h data available showed that 129 of 340 patients (37.9%) had a >30% decrease in Phe levels post load. Patients with dihydropteridine reductase deficiency (n = 53) could not be differentiated from BH4-responsive patients with PAH deficiency. The pharmacologic turnover model, "stimulation of loss" of Phe following BH4 load, fitted the data best. Using the model, 193 of 194 (99.5%) patie...Continue Reading

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Citations

Jun 25, 2017·Molecular Genetics and Metabolism·Eileen K Jaffe
Dec 28, 2018·Pharmacological Reviews·Johan GabrielssonStephan Hjorth
Oct 14, 2017·Orphanet Journal of Rare Diseases·A M J van WegbergF J van Spronsen

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