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Background: Phenylketonuria (PKU) is an inborn error of metabolism characterized by increased blood concentrations of phenylalanine (Phe)., Objectives: The aim of the present study was to assess the association between the metabolic compliance of adult patients affected by classic PKU and the characteristics of their present and past occupations., Methods: The study population consisted of working adults, affected by classic PKU, and following a dietary treatment. Univariate linear-mixed models and multivariate analysis were applied to assess the association between Phe blood levels and individual covariates: age, sex, time at diagnosis, educational level and work characteristics., Results: A linear relationship was found with age (an average annual increase of 30.56 μMol/L (C.I. 95%: 7.53; 53.60) in the mean Phe blood levels). Full-time work appeared to be associated with a worse metabolic compliance when compared to part-time work (mean Phe blood levels >281.11 μMol/L). Shift work was related to a worse metabolic compliance, with mean Phe plasmatic levels >356.73 μMol/L., Conclusions: Our data suggests that work may influence the metabolic compliance in adults with PKU. In particular, a part-time employment could allow for a better metabolic compliance, while daily work should be preferred to shift work.

Objective: Sapropterin dihydrochloride, the synthetic form of 6R-tetrahydrobiopterin (BH4), is an approved drug for the treatment of patients with BH4-responsive phenylketonuria (PKU). The purpose of this study was to assess genotypes and data on the long-term effects of BH4/sapropterin on metabolic control and patient-related outcomes in 6 large European countries., Methods: A questionnaire was developed to assess phenotype, genotype, blood phenylalanine (Phe) levels, Phe tolerance, quality of life, mood changes, and adherence to diet in PKU patients from 16 medical centers., Results: One hundred forty-seven patients, of whom 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU, were followed up over ≤12 years. A total of 85 different genotypes were reported. With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity. Median Phe tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported., Conclusions: Our data document a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving the metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life. Patient genotypes help in predicting BH4 responsiveness.

Introduction: Pharmacological levels of the phenylalanine hydroxylase enzyme cofactor, tetrahydrobiopterin (BH4), reduce plasma phenylalanine levels in some patients with phenylketonuria (PKU), providing the first pharmacological therapy for PKU. Responsiveness to this therapy must be determined empirically through a BH4 loading test or trial. The authors have analyzed the loading tests currently in use in light of the numerous factors that can influence their results. Sapropterin dihydrochloride is a stable, synthetic form of BH4 approved for treatment of PKU in responsive patients., Methods: An expert panel identified evidence from published reports of clinical experience. Reports of research involving at least 25 patients and published in English were considered., Results: In all, 14 studies met both criteria; eight employing the sapropterin dihydrochloride preparation from Schircks Laboratories and six the sapropterin dihydrochloride preparation from Biomarin/Merck Serono., Conclusion: The arbitrary responsiveness definition of a >30% reduction in blood phenylalanine appears to be a good compromise between sensitivity and specificity for the initial screening test. However, individual patient characteristics should be considered when interpreting results, especially in patients with low baseline phenylalanine levels.

Patients with tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency may benefit from BH4 therapy instead or in addition to the low-phenylalanine diet. Different loading test protocols are currently used to detect these patients. As a consequence, data on the rate of BH4-responsiveness within patients with mild phenylketonuria (PKU) and/or more severe phenotypes show high variation and a more sensitive and standardised BH4 loading test protocol needs to be defined. We modified the current standard BH4 loading test (20 mg/kg) to a second administration of 20 mg/kg after 24 h and extended blood sampling to 48 h in 24 patients with PAH deficiency. Using this extended loading test (2 x 20 mg BH4/kg), the rate of BH4-responsiveness was calculated at 8, 24, and 48 h after BH4 administration. We defined three groups of patients: "rapid responders" in 10/24 patients (4 mild HPA, 2 mild PKU, 2 moderate PKU, and 2 classic PKU), "moderate responders" in 4/24 patients (4 classic PKU), and "slow responder" in 4/24 patients (4 mild PKU). Six out of 24 patients (1 mild HPA, 1 moderate PKU, and 4 classic PKU) were found to be "non-responder." Individual phenylalanine profiles show variations in responsiveness at different time points and sampling over 48 h was more informative than over 24h in patients with mild and moderate PKU compared to mild HPA. Analysis of BH4 loading tests in 209 patients with the standard BH4 loading test protocol confirms only minor importance of the 24 h response: the rate of responsiveness to BH4 after 24 h was shown to be equal to or even lower than after 8h among most phenotypes. However, extension of the BH4 loading test to 48 h and repeated BH4 administration seems to be useful to detect BH4-responsiveness in more severe phenotypes and allows detecting "slow responders" who may benefit from BH4 therapy.

Background: Hyperphenylalaninemia (HPA) is an inherited metabolic disorder due to deficiency of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4). BH4-responsiveness in PAH-deficient HPA is a recently described characteristic of most milder phenotypes. BH4-responsive patients show reduction of plasma phenylalanine (phe) levels after oral administration of BH4., Aim: Determination of the incidence of BH4-responsiveness among a non-selected, cohort population of PAH-deficient hyperphenylalaninemic patients and evaluation of phenotype-genotype correlations., Patients and Methods: All patients born in Lombardy (Italy) between January 2000 and December 2004, and affected by HPA (107 patients) were classified after BH4 loading test, analysis of urinary pterins, and determination of DHPR activity in blood, and investigated for BH4-responsiveness. 6R-BH4 (20 mg/kg) was administered orally as a single dose and plasma samples were obtained at time-points 0, 4, 8, and 24 h after BH4 administration. In patients with basal plasma phe levels

Despite recent advances in the management of phenylketonuria and hyperphenylalaninemia, important questions on the management of this disorder remain unanswered. Consensus exists on the need for neonatal screening and early treatment, yet disagreement persists over threshold levels of blood phenylalanine for starting treatment, target blood phenylalanine levels, and the management of older patient groups. The mainstay of treatment is a phenylalariine-restricted diet, but its application varies between and within countries. Beyond diet treatment, there is a lack of consensus on the use of newer treatments such as tetrahydrobiopterin. Although neonatal screening and early treatment has meant that most well-treated children grow up with near-normal IQ scores, the effect of relaxing metabolic control on cognitive and executive function later in life is still not fully understood. Although it is clear from the available literature that the active control of blood phenylalanine levels is of vital importance, there are other treatment-related factors that affect outcome. A uniform and firmly evidence-based approach to the management of phenylketonuria is required. [ABSTRACT FROM AUTHOR]

Abstract: To gain better insight in the most current diagnosis and treatment practices for phenylketonuria (PKU) from a broad group of experts, a European PKU survey was performed. The questionnaire, consisting of 33 questions, was sent to 243 PKU professionals in 165 PKU centers in 23 European countries. The responses were compiled and descriptive analyses were performed. One hundred and one questionnaires were returned by 93/165 centers (56%) from 19/23 European countries (83%). The majority of respondents (77%) managed patients of all age groups and more than 90% of PKU teams included physicians or dieticians/nutritionists. The greatest variability existed especially in the definition of PKU phenotypes, therapeutic blood phenylalanine (Phe) target concentrations, and follow-up practices for PKU patients. The tetrahydrobiopterin (BH4; sapropterin) loading test was performed by 54% of respondents, of which 61% applied a single dose test (20mg/kg over 24h). BH4 was reported as a treatment option by 34%. This survey documents differences in diagnostic and treatment practices for PKU patients in European centers. In particular, recommendations for the treatment decision varied greatly between different European countries. There is an urgent need to pool long-term data in PKU registries in order to generate an evidence-based international guideline. [Copyright &y& Elsevier]

Abstract: Background: Hyperphenylalaninemia (HPA) is an inherited metabolic disorder due to deficiency of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4). BH4-responsiveness in PAH-deficient HPA is a recently described characteristic of most milder phenotypes. BH4-responsive patients show reduction of plasma phenylalanine (phe) levels after oral administration of BH4. Aim: Determination of the incidence of BH4-responsiveness among a non-selected, cohort population of PAH-deficient hyperphenylalaninemic patients and evaluation of phenotype–genotype correlations. Patients and methods: All patients born in Lombardy (Italy) between January 2000 and December 2004, and affected by HPA (107 patients) were classified after BH4 loading test, analysis of urinary pterins, and determination of DHPR activity in blood, and investigated for BH4-responsiveness. 6R-BH4 (20mg/kg) was administered orally as a single dose and plasma samples were obtained at time-points 0, 4, 8, and 24h after BH4 administration. In patients with basal plasma phe levels ⩽360mmol/L a combined phe (100mg phe/kg) and BH4 (20mg/kg) loading test was performed. Patients were defined “responsive to BH4” when plasma phe levels decreased by 30% 8h after oral BH4 administration. Results: BH4 significantly lowered blood phe levels in 91 (85%) of 107 patients affected by PAH-deficient HPA. Most responsive patients were affected by mild HPA (77%), a smaller percentage by mild (7%) and moderate (7%) phenylketonuria (PKU). One patient with classical PKU was responsive to BH4. Eighteen mutations were found to be associated to the BH4-responsive phenotype. Conclusions: BH4-responsiveness is shown by a consistent number of PAH-deficient hyperphenylalaninemic patients and seems to be common in milder phenotypes. Genotype is not the only factor determining BH4-responsiveness. [Copyright &y& Elsevier]