Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias

Langenbeck, U.

doi:10.1007/s10545-007-0572-4

Cited by 13 publications

(8 citation statements)

References 28 publications

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“…Accordingly, it is relevant to know which among the several hundred PAH alleles (see www.pahdb.mcgill.ca) are associated with sapropterin responsiveness. We classified the PAH mutant alleles (Table 1) and genotypes (Table 2), identified in the participants of the Phase II and III clinical trials, as either responsive, ambiguously responsive and unresponsive to sapropterin or unclassifiable, by using a simple metabolic (phenotypic) response as measured in these studies; while recognizing that other methods of response classification exist (Langenbeck 2008), which may influence the estimates of response prevalence. We used homozygous or hemizygous: null genotypes to classify the alleles, as was done earlier to describe PKU/HPA phenotypes (Guldberg et al 1998;Kayaalp et al 1997).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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Prospectively enrolled phenylketonuria patients (n ¼ 485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN ® ). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5-20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…This topic has been reviewed 32. Recent published data have revealed that the decrease in blood phenylalanine following a single BH 4 dose obeys a first-order kinetic model only over the first eight hours after BH 4 administration 33. Accordingly, a single BH 4 loading test (20 mg/kg) with monitoring of blood phenylalanine at 0, 8, 12, and 24 hours has been proposed as an evaluation of responsiveness 34.…”

Section: Post-approval Clinical Use Of Sapropterinmentioning

confidence: 99%

New era in treatment for phenylketonuria: Pharmacologic therapy with sapropterin dihydrochloride

Harding¹

2010

BTT

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Oral administration of sapropterin hydrochloride, recently approved for use by the US Food and Drug Administration and the European Commission, is a novel approach for the treatment of phenylketonuria (PKU), one of the most common inborn errors of metabolism. PKU is caused by an inherited deficiency of the enzyme phenylalanine hydroxylase (PAH), and the pathophysiology of the disorder is related to chronic accumulation of the free amino acid phenylalanine in tissues. Contemporary therapy is based upon restriction of dietary protein intake, which leads to reduction of blood phenylalanine levels. This therapy is difficult to maintain throughout life, and dietary noncompliance is commonplace. Sapropterin dihydrochloride is a synthetic version of tetrahydrobiopterin, the naturally occurring pterin cofactor that is required for PAH-mediated phenylalanine hydroxylation. In a subset of individuals with PAH deficiency, sapropterin administration leads to reduction in blood phenylalanine levels independent of dietary protein. For these individuals, sapropterin is an effective novel therapy for PKU.

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“…The model of statistical process control shows many similarities to the kinetic analysis of BH 4 response described as a single exponential decay (SED) by Langenbeck (2008). That author criticizes the 30% criterion for the same reasons as we do.…”

Section: Discussionmentioning

confidence: 74%

Blood phenylalanine concentrations in patients with PAH‐deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control

Gramer

Garbade

Burgard

2009

J of Inher Metab Disea

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Tetrahydrobiopterin (BH(4)) cofactor loading is a standard procedure to differentiate defects of BH(4) metabolism from phenylalanine hydroxylase (PAH) deficiency. BH(4) responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH(4) responsive, too. BH(4) responsiveness has been defined either by a >or=30% reduction of blood Phe concentration after a single BH(4) dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH(4) responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH(4) applied in a double-blind randomized cross-over design. Results are compared for >or=30% reduction and SPC. The effect of BH(4) by >or=30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH(4) responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH(4) doses) and between the two models. We conclude that a comparison of protein loadings without and with BH(4) combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.

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Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias

Abstract: With t (1/2) as a reliable parameter of BH(4) responsiveness, therapeutic decisions would be more rational and genotype-phenotype analysis may also profit.

Cited by 13 publications

References 28 publications

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

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

New era in treatment for phenylketonuria: Pharmacologic therapy with sapropterin dihydrochloride

Blood phenylalanine concentrations in patients with PAH‐deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control

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