Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype
1 Division of Metabolic Diseases, University Medical Center Groningen, Beatrix Children’s Hospital CA33, PO box 30.001, Groningen 9700 RB, The Netherlands
2 University Medical Center Utrecht, Wilhelmina Children’s Hospital, Utrecht, The Netherlands
3 Academic Medical Center, University Hospital of Amsterdam, Amsterdam, The Netherlands
4 Maastricht University Medical Center, Maastricht, The Netherlands
5 Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
6 Leiden University Medical Center, Leiden, The Netherlands
7 University Children’s Hospital, Heidelberg, Germany
8 University Children’s Hospital, Zürich, Switzerland
Orphanet Journal of Rare Diseases 2013, 8:103 doi:10.1186/1750-1172-8-103Published: 10 July 2013
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.
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.
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.
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.