Tetrahydrobiopterin responsiveness after extended loading test of 12 Danish PKU patients with the Y414C mutation

Abstract

Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation due to defects in the enzyme phenylalanine hydroxylase (PAH). Phe accumulation can lead to cognitive impairment. Some individuals with PKU respond to tetrahydrobiopterin (BH4) treatment, the natural cofactor of PAH, by a reduction in blood Phe concentrations.We tested 12 patients with PKU, 8-29 years of age, all carrying the common Y414C mutation in the PAH gene. Three were homozygous and nine were compound heterozygous, with the second mutation being a putative null mutation. During the study period, genuine protein was increased to approximately 1 g/kg. The patients were treated with 20, 10, and 5 mg BH4/kg/day for 1 week on each dose, starting with 20 mg/kg. A positive response was defined as a decline in blood Phe>30%. Blood Phe was measured four times a week. Nonresponding children were excluded from the study. Eleven of 12 patients had a positive response with 20 mg/kg, 5/10 responded on 10 mg/kg, and 1/9 on 5 mg/kg. Two were late responders, with a response on 20 mg/kg after >48 h. We could confirm the previously reported inconsistent responsiveness of Y414C in the nine heterozygous patients, whereas the three homozygous patients had early median Phe declines of 73%, 51%, and 27%, respectively, on the three different doses. The varying responses despite uniform trial conditions and genotypes may be due to individual differences in BH4 absorption or metabolism. No side effects were observed.

Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?

“…Other factors that could contribute to an inconsistency in our findings could include once again the limited methodology with unmonitored changes in diet or other external factors such as intercurrent illness (Burton et al 2007) and variability between individuals that may reflect sapropterin absorption and pharmacokinetics or bioavailability of the cofactor in the individual patient (Fiege et al 2004;Leuzzi et al 2006;Nielsen et al 2010;Shintaku et al 2005). Meanwhile, studying the residual PAH activity arising from the interaction of the mutant PAH subunits, carried by the PKU patients, is essential and may also influence BH 4 -responsiveness.…”

Long-term treatment with tetrahydrobiopterin in phenylketonuria: Treatment strategies and prediction of long-term responders

“…Various BH4 loading tests for identifying BH4 responders have been described; however, both, negative and positive false BH4 responders have been reported, e.g. due to late BH4 responsiveness, a low BH4 dose, a missing Phe challenge, a lack of compliance or catabolism [25,26]. Most interfering factors are more likely to disturb BH4 loading in older patients than in neonates.…”

Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype

“…Indeed in this study we confirm that patients with true BH4 responsiveness can be missed in a 24 hour test. Other studies suggest extending the BH4 loading test to beyond 48 hours [9,28,34]. We detected some patients who tend to show a response at T = 48.…”