The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency

Leuzzi, Vincenzo; Carducci, Claudia; Chiarotti, Flavia; Artiola, Cristiana; Giovanniello, Teresa; Antonozzi, I.

doi:10.1007/s10545-006-0096-3

Cited by 47 publications

(37 citation statements)

References 25 publications

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“…Previous reports cite a BH 4 responsiveness of 30-45% in the general PKU population, with reported associations to clinical phenotype and the frequency of responsive cases being 80-100% for mild HPA, 40-60% for mild PKU and o10% for classical PKU. 21,[38][39][40] Most of the patients in the current study who showed BH 4 responsiveness suffer from mild PKU or mild HPA; these patients responded to BH 4 loading and showed an increase in in vivo PAH activity by phenylalanine breath test, 15,31 which is proportional to the residual PAH activity by BH 4 dosing under the regulation system of BH 4 and phenylalanine in in vivo PAH activity. 31,41 Therefore, a residual PAH activity resulting from a combination of both alleles is useful to predict the BH 4 responsiveness in PKU patients.…”

Section: Genotypes and Bh 4 Responsiveness In Pku Y Okano Et Almentioning

confidence: 63%

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

et al. 2011

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Phenylketonuria (PKU) is a heterogeneous metabolic disorder caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). On the basis of phenotype/genotype correlations, determination of phenylketonuric genotype is important for classification of the clinical phenotype and treatment of PKU, including tetrahydrobiopterin therapy. We characterized the genotypes of 203 Japanese patients with PKU and hyperphenylalaninemia using the following systems: (1) denaturing high-performance liquid chromatography with a GC-clamped primer; (2) direct sequencing; and, (3) multiplex ligation-dependent probe amplification. Of 406 mutant alleles, 390 (96%) were genotyped; 65 mutations were identified, including 22 new mutations. R413P, R241C, IVS4-1g4a, R111X and R243Q were prevalent mutations. Mutations prevalent in the Japanese cohort are also common in Korean and Northern Chinese populations, suggesting same origin. The spectrum of prevalent mutations was not significantly different among six Japanese districts, indicating that Japan comprises a relatively homogeneous ethnic group. We classified the mutations by clinical phenotypes and in vivo PAH activity and estimated the mutations with potential tetrahydrobiopterin (BH 4 ) responsiveness. The frequency of BH 4 responsiveness based on the genotype was 29.1% in Japanese PKU patients. A catalog of PKU genotypes would be useful for predicting clinical phenotype, deciding on the subsequent treatment of PKU including BH 4 therapy, and genetic counseling in East Asia.

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Section: Genotypes and Bh 4 Responsiveness In Pku Y Okano Et Almentioning

confidence: 63%

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

et al. 2011

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“…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.…”

Section: Discussionmentioning

confidence: 94%

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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“…A decrease of Phe of 30 %, compared to pre-BH 4 level, was deemed to be clinically significant (Mitchell et al 2005). Patients are classed as 'positive' if they reached a decrease of 30% after 8 h, 'intermediate' if a decrease of 30 % was observed at 32 h or at the 7th day and 'negative' if no decrease of 30% or greater was observed at any point (Leuzzi et al 2006), but one of our patient's homozygous for this mutation was not responsive (data not shown). The other discrepant results were observed (patients #50 and #55).…”

Section: Resultsmentioning

confidence: 99%

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutation screening was carried out in a large cohort of PKU patients from New South Wales, Australia. Pathogenic mutations were identified in 99% of the alleles screened, with the two most common mutations (p.R408W and IVS12+1G>A) accounting for 30.7% of alleles. Most individuals were compound heterozygotes for previously reported mutations, but four novel mutations (c. 163+1G>T, c.164-2A>G, c.461A>T [p.Y154F], and c.510-1G>A) and a novel polymorphism (c.60+62C>T) were also identified.A number of patients have been previously tested for their response to dietary supplementation of tetrahydrobiopterin (BH 4 ), the cofactor of PAH. Correlation between genotype and the responses revealed that although genotype is a major determinant of BH 4 responsiveness, patients with the same genotype may also show disparate responses to this treatment. A clinical and biochemical evaluation should be undertaken to determine the effectiveness of PKU treatment by supplementation of BH 4 .

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The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency

Cited by 47 publications

References 25 publications

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan

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

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

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