Blau, Nenad

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EDITORIALDefining tetrahydrobiopterin (BH4)-responsivenessin PKUNenad Blau# SSIEM and Springer 2007BH4-responsive hyperphenylalaninaemia (HPA) is arecently described variant of phenylalanine hydroxy-lase (PAH) deficiency caused by specific mutations inthe PAH gene. Diagnosis is performed by the tetrahy-drobiopterin (BH4) loading test (20 mg/kg body weight)and the overall prevalence of BH4-responsiveness withinpatients with phenylketonuria (PKU) for blood phenyl-alanine reduction of 20%, 30%, 40% and 50% wasfound to be 48%, 38%, 31% and 24%, respectively, 8 hafter the administration, and 55%, 46%, 41% and33%, respectively, 24 h after the administration. Usingthe standard 30% cut-off, BH4-responsiveness was sim-ilar regardless of the two modalities in patients withmild hyperphenylalaninaemia (79–83% responders),mild PKU (49–60% responders), and classical PKU(7–10% responders). About 46% of all HPA patientswere responders 24 h post loading (Fiege and Blau2007). BH4 (drug name Kuvan or Sapropterin) isregistered in the USA (FDA) and is currently underpreregistration in Europe (EMEA) (Burnett 2007).A number of publications have documented that a24-hour protocol with 20 mg/kg BH4 is the most com-monly used method and that multiple administrationsof BH4 and extension of the test to up to one weekmay detect some additional Fslow_ responders. How-ever, some authors use lower doses of BH4 (10 mg/kg)or a combination of phenylalanine (100 mg/kg) andBH4 (20 mg/kg), and some authors monitor bloodphenylalanine levels after repeated administration ofBH4 over a period of up to two weeks. In addition,some of the loading test experiments are performedunder dietary supplementation with a low-phenylalaninefood. This may result in a relative high number ofinitially positive responders (>50%) who did notrespond to a long-term treatment, as documented by arecent multicentre study (Levy et al 2007).In this issue of the Journal (pp. 67–72), U. Langenbeckproposes another approach for the classification ofBH4-responsiveness. He calculated the half-life (t1/2) ofblood phenylalanine at different time points followingBH4 administration. Using a log-linear regression, hecompared data from several published reports with themodel of a single exponential decay (SED) of bloodphenylalanine. The conclusion is that only during thefirst 15 h after BH4 administration does the kineticbehaviour of plasma phenylalanine obey first-orderkinetics and that, with a test duration of 24 h, com-patibility with the SED model is only partial. Indeed,Fiege and Blau (2007) observed that 2.7% of patientsin whom the loading test was performed over 24 h weredefined as responders only at 8 h. Also, 8.8% of patientswere responders at 24 h, but not at 8 h. In about 15% ofall patients who responded to BH4 by 20%, bloodphenylalanine levels increased from 8 h to 24 h by atleast 10%. Accordingly, they suggest that the BH4loading test should be modified to include a secondadministration of 10–20 mg/kg BH4 at time 12 h andassessment of plasma phenylalanine levels at times 0, 8,12 and 24 h after BH4 administrations. Thus, additionalinvestigations are necessary in order to evaluate theimportance of the 12– or 15-hour blood phenylalaninevalues. Long-term (1–2 weeks) loading tests are moreexpensive and definitely not practical for the initialscreening.J Inherit Metab Dis (2008) 31:2–3DOI 10.1007/s10545-007-9979-1N. Blau (*)Division of Clinical Chemistry and Biochemistry,University Children_s Hospital,Steinwiesstrasse 75, CH-8032 Zu¨rich, Switzerlande-mail: nenad.blau@kispi.uzh.chLangenbeck further suggests in his article thatgenotype–phenotype analysis may benefit from thet1/2-driven diagnostic approach and that knowledge ofindividual t1/2 values and age-specific protein synthesiscould improve therapeutic decisions. Data from theBIOPKU database demonstrate that the genotype-predicted BH4-responsiveness is on average higherthan that obtained from the BH4 loading test and thatthe patient_s genotype may certainly exclude non-responsiveness and to some extent predict a potentialresponder (Zurflu¨h et al 2008). A combination of theBH4 loading test and genotype analysis together withthe phenylalanine kinetics (t1/2) may certainly improvethe definition of the BH4-responsiveness.On the basis of present knowledge, guidelines forthe definition of BH4-responsiveness should includethe following investigations: (1) Single loading testwith BH4 (20 mg/kg) and monitoring of blood phenyl-alanine at 0, 8, 12 (15), and 24 h. (2) Reduction ofblood phenylalanine levels of >20–30% as an indicatorfor a trial with BH4 (initial doses of 10 mg/kg) overseveral weeks. (3) Titration of the individual BH4requirement (5–20 mg/kg) to maintain optimal bloodphenylalanine levels. (4) Determination of the dailyphenylalanine tolerance. (5) Genotyping.ReferencesBurnett JR (2007) Sapropterin dihydrochloride (Kuvan/Phenop-tin), an orally active synthetic form of BH4 for the treatmentof phenylketonuria. IDrugs 10(11): 805–813.Fiege B, Blau N (2007) Assessment of tetrahydrobiopterin (BH4)-responsiveness in phenylketonuria. J Pediatr 150: 627–630.Levy L, Milanowski A, Chakrapani A, et al (2007) Efficacy ofsapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4)for reduction of phenylalanine concentration in patientswith phenylketonuria: a phase III randomized placebo-controlled study. Lancet 370: 504–510.Zurflu¨h MR, Zschocke J, Lindner M, et al (2008) Moleculargenetics of tetrahydrobiopterin responsive phenylalaninehydroxylase deficiency. Hum Mutat 29(1): 167–175J Inherit Metab Dis (2008) 31:2–3 3

Defining tetrahydrobiopterin (BH4)-responsiveness in PKU

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Defining tetrahydrobiopterin (BH4)-responsiveness in PKU

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