Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Zurflüh, Marcel R.; Zschocke, Johannes; Feillet, François; Chéry, Céline; Burlina, Alberto; Stevens, Raymond C.; Thöny, Beat; Blau, Nenad

doi:10.1002/humu.20821

Cited by 24 publications

(34 citation statements)

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“…Conversely, the response rate among patients with classic PKU (little or no residual PAH activity) is very low. A number of PAH mutations associated with BH4 responsiveness have been identified and genotyping is a useful additional tool for predicting responsiveness [21,22] (see below). Fig.…”

Section: Bh4 Loading Testmentioning

confidence: 99%

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Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

Blau

Hennermann

Langenbeck

et al. 2011

Molecular Genetics and Metabolism

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This article summarizes the present knowledge, recent developments, and common pitfalls in the diagnosis, classification, and genetics of hyperphenylalaninemia, including tetrahydrobiopterin (BH4) deficiency. It is a product of the recent workshop organized by the European Phenylketonuria Group in March 2011 in Lisbon, Portugal. Results of the workshop demonstrate that following newborn screening for phenylketonuria (PKU), using tandem mass-spectrometry, every newborn with even slightly elevated blood phenylalanine (Phe) levels needs to be screened for BH4 deficiency. Dried blood spots are the best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen. Following diagnosis, the patient's phenotype and individually tailored treatment should be established as soon as possible. Not only blood Phe levels, but also daily tolerance for dietary Phe and potential responsiveness to BH4 are part of the investigations. Efficiency testing with synthetic BH4 (sapropterin dihydrochloride) over several weeks should follow the initial 24-48-hour screening test with 20mg/kg/day BH4. The specific genotype, i.e. the combination of both PAH alleles of the patient, helps or facilitates to determine both the biochemical phenotype (severity of PKU) and the responsiveness to BH4. The rate of Phe metabolic disposal after Phe challenge may be an additional useful tool in the interpretation of phenotype-genotype correlation. This article summarizes the present knowledge, recent developments, and common pitfalls in the diagnosis, classification, and genetics of hyperphenylalaninemia, including tetrahydrobiopterin (BH4) deficiency. It is a product of the recent workshop organized by the European Phenylketonuria Group in March 2011 in Lisbon, Portugal. Results of the workshop demonstrate that following newborn screening for phenylketonuria (PKU), using tandem mass-spectrometry, every newborn with even slightly elevated blood phenylalanine (Phe) levels needs to be screened for BH4 deficiency. Dried blood spots are the best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen. Following diagnosis, the patient's phenotype and individually tailored treatment should be established as soon as possible. Not only blood Phe levels, but also daily tolerance for dietary Phe and potential responsiveness to BH4 are part of the investigations. Efficiency testing with synthetic BH4 (sapropterin dihydrochloride) over several weeks should follow the initial 24-48-hour screening test with 20 mg/kg/day BH4. The specific genotype, i.e. the combination of both PAH alleles of the patient, helps or facilitates to determine both the biochemical phenotype (severity of PKU) and the responsiveness to BH4. The rate of Phe metabolic disposal after Phe challenge may be an additional useful tool in the interp...

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Section: Bh4 Loading Testmentioning

confidence: 99%

“…We therefore recommend determining Phe tolerance under standardized in-patient conditions with precise dietary protocols. In clinical follow-up, Phe tolerance is used for phenotyping patients with PKU in 70% of metabolic centers queried [21].…”

Section: Phenylalanine Tolerancementioning

confidence: 99%

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

Blau

Hennermann

Langenbeck

et al. 2011

Molecular Genetics and Metabolism

Self Cite

199

168

View full text Add to dashboard Cite

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“…The first study which suggested that BH4-responsiveness could be deduced from PAH genotype stated that at least one BH4-responsive mutation would be enough to lead to the physiological BH4 responsiveness (Zurfl€ uh et al 2008). In this study on Serbian PKU patients, total frequency of BH4-responsive mutations was 52.6%.…”

Section: Bh4 Responsiveness In Serbiamentioning

confidence: 52%

“…The p.L48S mutation as well as seven others (p.R158Q, p.R261Q, p.I306V, p.E390G, p.A403V, p.R413P, and p.Y414C) were characterized as BH4-responsive ones in previous European studies (Zurfl€ uh et al 2008;Trefz et al 2009a;Karacic et al 2009). Accordingly, the sum of relative frequencies of BH4-responsive mutations for Serbian population is 52.6%.…”

Section: Bh4 Responsivenessmentioning

confidence: 94%

“…Also, it was shown that PAH function and response to BH4 administration result from interplay between genotype, metabolic state, and cofactor concentration (Staudigl et al 2011). Several studies analyzed the correlation of genotype and patient's responsiveness to BH4 and made an attempt to predict the BH4-responsiveness on the basis of genotype (Zurfl€ uh et al 2008;Karacic et al 2009;Rivera et al 2011;Sterl et al 2012). In the Kuvan era, genotypization of patients became important, not only because of the definitive diagnosis and prediction of the optimal diet, but also to point out those patients that could benefit from new therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Genetics and Genotype-Based Estimation of BH4-Responsiveness in Serbian PKU Patients: Spotlight on Phenotypic Implications of p.L48S

et al. 2012

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The mechanism of BH4-responsive hyperphenylalaninemia-As it occurs in the ENU1/2 genetic mouse model

et al. 2012

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The Pah(enu1/enu2) (ENU1/2) mouse is a heteroallelic orthologous model displaying blood phenylalanine (Phe) concentrations characteristic of mild hyperphenylalaninemia. ENU1/2 mice also have reduced liver phenylalanine hydroxylase (PAH) protein content (∼20% normal) and activity (∼2.5% normal). The mutant PAH protein is highly ubiquitinated, which is likely associated with its increased misfolding and instability. The administration of a single subcutaneous injection of l-Phe (1.1 mg l-Phe/g body weight) leads to an approximately twofold to threefold increase of blood Phe and phenylalanine/tyrosine (Phe/Tyr) ratio, and a 1.6-fold increase of both nonubiquitinated PAH protein content and PAH activity. It also results in elevated concentrations of liver 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)), potentially through the influence of Phe on GTP cyclohydrolase I and its feedback regulatory protein. The increased BH(4) content seems to stabilize PAH. Supplementing ENU1/2 mice with BH(4) (50 mg/kg/day for 10 days) reduces the blood Phe/Tyr ratio within the mild hyperphenylalaninemic range; however, PAH content and activity were not elevated. It therefore appears that BH(4) supplementation of ENU1/2 mice increases Phe hydroxylation levels through a kinetic rather than a chaperone stabilizing effect. By boosting blood Phe concentrations, and by BH(4) supplementation, we have revealed novel insights into the processing and regulation of the ENU1/2-mutant PAH.

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Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Cited by 24 publications

References 0 publications

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

Molecular Genetics and Genotype-Based Estimation of BH4-Responsiveness in Serbian PKU Patients: Spotlight on Phenotypic Implications of p.L48S

The mechanism of BH4-responsive hyperphenylalaninemia-As it occurs in the ENU1/2 genetic mouse model

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