New evidence for assessing tetrahydrobiopterin (BH4 ) responsiveness

• Published in: Metabolism, clinical and experimental Vol. 61; no. 12; pp. 1809 - 1816
• Main Authors: Bueno, María A, Lage, Sergio, Delgado, Carmen, Andrade, Fernando, Couce, María L, González-Lamuño, Domingo, Pérez, Manuel, Aldámiz-Echevarría, Luis
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-12-2012; Elsevier
• Subjects: Adolescent; Biological and medical sciences; Biopterins - administration & dosage; Biopterins - analogs & derivatives; Biopterins - blood; Child; Child, Preschool; Cofactor; Endocrinology & Metabolism; Feeding. Feeding behavior; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Genotype; Humans; Infant; Loading test; Male; Phenylalanine - administration & dosage; Phenylketonuria; Phenylketonurias - blood; Phenylketonurias - diet therapy; Phenylketonurias - drug therapy; Pilot Projects; Reproducibility of Results; Spain; Treatment Outcome; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Young Adult; Spain; NO; FDA; BH 4; World Health Organisation; Phe; Cofactor; RDA; SD; recommended dietary allowance; phenylketonuria; Food and Drug Administration; HPLC; WHO; nitric oxide; phenylalanine; phenylalanine hydroxylase; denaturing gradient gel electrophoresis; Tyr; Loading test; high performance liquid chromatography; PAH; (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin; PKU; tyrosine; DGGE; standard deviation; Phenylketonuria; BH4; Tetrahydrobiopterin; Endocrinology
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2012.07.015

Abstract Objective To evaluate the protocol we propose for detecting BH4 -responsive patients and the possibility of delimiting more precisely the population to be tested. Methods We recruited 102 phenylketonuric patients on a phenylalanine (Phe)-restricted diet. The initial stage of the protocol was a 24-h BH4 loading test involving Phe loading and subsequent ingestion of the cofactor, a 50% fall in blood Phe levels being considered a positive response. The non-responders at this stage then completed a one-week therapeutic test combining BH4 administration and daily protein intake meeting recommended dietary allowances, to assess whether the 24-h test had detected all responders. Results The 24-h test detected almost all BH4 responders (30.3% of the 99 patients included in the analysis), with just two patients (2.0%) subsequently responding positively to the therapeutic test. The 24-h test did not give any false positive results. Conclusions The 24-h BH4 loading test is clinically useful for screening phenylketonuric patients. Specifically, 95% of patients with Phe levels < 700 μmol/L, and none with Phe levels > 1500 μmol/L were BH4 -responsive. Given these results, we conclude that patients with Phe levels < 700 μmol/L or > 1500 μmol/L probably do not need to be tested, prioritising the identification of BH4 -responsiveness among individuals with intermediate Phe concentrations, between the aforementioned values. Additionally, our results suggest that the therapeutic test only needs to be performed in cases where the reduction in blood Phe levels after cofactor administration is within the range 40%–50%.