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Optimizing the use of sapropterin (BH4) in the management of phenylketonuria

Division of Clinical Chemistry and Biochemistry, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland.
Molecular Genetics and Metabolism (Impact Factor: 2.83). 03/2009; 96(4):158-63. DOI: 10.1016/j.ymgme.2009.01.002
Source: PubMed

ABSTRACT Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to deficient conversion of phenylalanine (Phe) to tyrosine and accumulation of toxic levels of Phe. A Phe-restricted diet is essential to reduce blood Phe levels and prevent long-term neurological impairment and other adverse sequelae. This diet is commenced within the first few weeks of life and current recommendations favor lifelong diet therapy. The observation of clinically significant reductions in blood Phe levels in a subset of patients with PKU following oral administration of 6R-tetrahydrobiopterin dihydrochloride (BH(4)), a cofactor of PAH, raises the prospect of oral pharmacotherapy for PKU. An orally active formulation of BH(4) (sapropterin dihydrochloride; Kuvan is now commercially available. Clinical studies suggest that treatment with sapropterin provides better Phe control and increases dietary Phe tolerance, allowing significant relaxation, or even discontinuation, of dietary Phe restriction. Firstly, patients who may respond to this treatment need to be identified. We propose an initial 48-h loading test, followed by a 1-4-week trial of sapropterin and subsequent adjustment of the sapropterin dosage and dietary Phe intake to optimize blood Phe control. Overall, sapropterin represents a major advance in the management of PKU.

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    • "In responsive patients BH4 treatment was started and dietary changes were made, while unresponsive patients needed to continue their usual diet. The very strict and socially demanding diet is a severe burden on the patients and the families [10] [12] [13]. A dietary relaxation may therefore positively affect the quality of life of the patients. "
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    ABSTRACT: Background Phenylketonuria (PKU) is a rare inborn error of metabolism caused by phenylalanine hydroxylase enzyme (PAH) deficiency. Treatment constitutes a strict Phe restricted diet with unpalatable amino acid supplements. Residual PAH activity enhancement with its cofactor tetrahydrobiopterin (BH4) is a novel treatment which increases dietary tolerance in some patients and permits dietary relaxation. Relaxation of diet may improve health related quality of life (HRQoL). This prospective cohort study aims to evaluate HRQoL of patients with PKU and effects of BH4 treatment on HRQoL. Methods Patients aged 4 years and older, diagnosed through newborn screening and early and continuously treated, were recruited from eight metabolic centers. Patients and mothers completed validated generic and chronic health-conditions HRQoL questionnaires (PedsQL, TAAQOL, and DISABKIDS) twice: before and after testing BH4 responsivity. Baseline results were compared to the general population. Data collected after BH4 testing was used to find differences in HRQoL between BH4 unresponsive patients and BH4 responsive patients after one year of treatment with BH4. Also a within patient comparison was performed to find differences in HRQoL before and after treatment with BH4. Results 69/81 (85%) patients completed the questionnaires before BH4 responsivity testing, and 45/69 (65%) participated again after testing. Overall PKU patients demonstrated normal HRQoL. However, some significant differences were found when compared to the general population. A significantly higher (thus better) score on the PedsQL was reported by children 8–12 years on physical functioning and by children 13–17 years on total and psychosocial functioning. Furthermore, adult patients reported significantly lower (thus worse) scores in the TAAQOL cognitive domain. 10 patients proved to be responsive to BH4 treatment; however improvement in their HRQoL after relaxation of diet could not be demonstrated. Abbreviations AMC, Academic Medical Center, Amsterdam; BH4, tetrahydrobiopterin (BH4); DISABKIDS, The DISABKIDS chronic generic module; HRQoL, health related quality of life; PAH, phenylalanine hydroxylase; PedsQL, Pediatric Quality of Life Inventory Measurement Model ™; Phe, phenylalanine; PKU, phenylketonuria; TAAQOL, TNO-AZL Adult Quality of Life; SD, standard deviation Keywords PKU; Phenylketonuria; Health related quality of life; Quality of life; HRQoL; QoL
    Molecular Genetics and Metabolism 10/2013; · 2.83 Impact Factor
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    • "Although calculating residual PAH activity from information available in in-vitro experiments (PRA) may be useful in predicting potential candidates for BH4 therapy (Dobrowolski et al., 2011), complete genotype has greater value in estimation of BH4-responsiveness (Karacic et al., 2009; Trefz et al., 2009). Despite this estimation ability provided by the genotype and phenotype, the only precise method of determining patients' response to the drug is the BH4-loading test (Blau et al., 2009). This is particularly important in genotypes with mutations p.R158Q and p.R261Q. "
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    ABSTRACT: We investigated the mutation spectrum of the phenylalanine hydroxylase gene (PAH) in a cohort of patients from 135 Slovak PKU families. Mutational screening of the known coding region, including conventional intron splice sites, was performed using high-resolution melting analysis, with subsequent sequencing analysis of the samples showing deviated melting profiles compared to control samples. The PAH gene was also screened for deletions and duplications using MLPA analysis. Forty-eight different disease causing mutations were identified in our patient group, including 30 missense, 8 splicing, 7 nonsense, 2 large deletions and 1 small deletion with frameshift; giving a detection rate of 97.6%. The most prevalent mutation was the p.R408W, occurring in 47% of all alleles, which concurs with results from neighbouring and other Slavic countries. Other frequent mutations were: p.R158Q (5.3%), IVS12+1G>A (5.3%), p.R252W (5.1%), p.R261Q (3.9%) and p.A403V (3.6%). We also identified three novel missense mutations: p.F233I, p.R270I, p.F331S and one novel variant: c.-30A>T in the proximal part of the PAH gene promoter. A spectrum of 84 different genotypes was observed and a genotype based predictions of BH4-responsiveness were assessed. Among all genotypes, 36 were predicted to be BH4-responsive represented by 51 PKU families. In addition, genotype-phenotype correlations were performed.
    Gene 06/2013; 526(2). DOI:10.1016/j.gene.2013.05.057 · 2.08 Impact Factor
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    • "ase during the conversion of Phe to Tyr . HPA does not only result from lower enzymatic activity but also from low cofactor avail - ability depending on the affected genetic mutations ( Quirk et al . 2012 ) . Sapropterin dihydrochloride is the synthetic form of BH4 and was approved for PKU treatment by the US Food and Drug Administration in 2007 ( Blau et al . 2009 ) . Since this approval , sapropterin loading tests and genetic evaluations have been made to determine who can take advantage of this BH 4 administration ( Anjema et al . 2011 ; Sterl et al . 2012 ; Nalin et al . 2011 ; Utz et al . 2012 ) , including children under 4 years old ( Leuret et al . 2012 ) . Furthermore , BH4 depletion was f"
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    ABSTRACT: Hyperphenylalaninemia (HPA) leads to increased oxidative stress in patients with phenylketonuria (PKU) and in animal models of PKU. Early diagnosis and immediate adherence to a phenylalanine-restricted diet prevents HPA and, consequently, severe brain damage. However, treated adolescent and adult PKU patients have difficulties complying with the diet, leading to an oscillation of phenylalanine levels and associated oxidative stress. The brain is especially susceptible to reactive species, and oxidative stress might add to the impaired cognitive function found in these patients. The restricted PKU diet has a very limited nutrient content from natural foods and almost no animal protein, which reduces the intake of important compounds. These specific compounds can act as scavengers of reactive species and can be co-factors of antioxidant enzymes. Supplementation with nutrients, vitamins, and tetrahydropterin has given quite promising results in patients and animal models. Antioxidant supplementation has been studied in HPA, however there is no consensus about its always beneficial effects. In this way, regular exercise could be a beneficial addition on antioxidant status in PKU patients. A deeper understanding of PKU molecular biochemistry, and genetics, as well as the need for improved targeted treatment options, could lead to the development of new therapeutic strategies.
    Metabolic Brain Disease 05/2013; 28(4). DOI:10.1007/s11011-013-9414-2 · 2.40 Impact Factor
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