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: 2.63). 03/2009; 96(4):158-63. DOI: 10.1016/j.ymgme.2009.01.002
Source: PubMed


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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    • "Although calculating residual PAH activity from information available in in-vitro experiments (PRA) may be useful in predicting potential candidates for BH 4 therapy [4], complete genotype has greater value in estimation of BH 4 -responsiveness [5] [33] and is a useful tool in identifying those patients who could take advantage of this simple and inexpensive treatment. But at the moment the only precise method of determining patients' response to the drug is the BH 4 -loading test [34]. "
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    ABSTRACT: We investigated the mutation spectrum of the phenylalanine hydroxylase gene (PAH) in a cohort of patients from 33 Italian PKU families. Mutational screening of the known coding region, including conventional intron splice sites, was performed by direct sequencing of the patients' genomic DNA. Thirty-three different disease causing mutations were identified in our patient group, including 19 missense, 6 splicing, 3 nonsense, 5 deletions, with a detection rate of 100%. The most prevalent mutation was the IVS10-11G>A, accounting for 12.1% of PKU alleles studied. Other frequent mutations were: p.R261Q (9.1%), p.P281L (7.6%), p.R408W (6.1%). We also identified one novel missense mutations, p.H290Q. A spectrum of 31 different genotypes was observed and a genotype based predictions of BH4-responsiveness were assessed. Among all genotypes, 13 were predicted to be BH4-responsive represented by thirteen PKU families. In addition, genotype-phenotype correlations were performed. This study reveals the importance of a full genotyping of PKU patients and the prediction of BH4-responsiveness, 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. They may potentially benefit from BH4 therapy which, combined with a less strict diet, or eventually in special cases as monotherapy, may contribute to reduce nutritional deficiencies and minimize neurological and psychological dysfunctions. Copyright © 2015 Elsevier B.V. All rights reserved.
    Clinica chimica acta; international journal of clinical chemistry 07/2015; 450. DOI:10.1016/j.cca.2015.07.014 · 2.82 Impact Factor
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    • "Maintaining adequate adherence to this diet is challenging, but effective in preventing the severe brain damage associated with uncontrolled blood phenylalanine, and allowing individuals with PKU to lead full and successful lives [5,7-9]. A pharmacologic treatment option, sapropterin, is available for prescription in a growing number of counties [10,11]. A number of other potential treatments that may contribute increasingly to the management of PKU in the future include better and more palatable phenylalanine-free foods, glycomacropeptide (a natural protein free of phenylalanine), large, neutral amino acids, phenylalanine-ammonia lyase (an injectable enzyme that metabolises phenylalanine) and – for the longer term – gene therapy approaches; these have been reviewed elsewhere [12]. "
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    ABSTRACT: Phenylketonuria (PKU, ORPHA716) is an inherited disorder that affects about one in every 10,000 children born in Europe. Early and continuous application of a modified diet is largely successful in preventing the devastating brain damage associated with untreated PKU. The management of PKU is inconsistent: there are few national guidelines, and these tend to be incomplete and implemented sporadically. In this article, the first-ever pan- European patient/carer perspective on optimal PKU care, the European Society for Phenylketonuria and Allied Disorders (E.S.PKU) proposes recommendations for a minimum standard of care for PKU, to underpin the development of new pan-European guideline for the management of PKU. New standards of best practice should guarantee equal access to screening, treatment and monitoring throughout Europe. Screening protocols and interpretation of screening results should be standardised. Experienced Centres of Expertise are required, in line with current European Union policy, to guarantee a defined standard of multidisciplinary treatment and care for all medical and social aspects of PKU. Women of childbearing age require especially intensive management, due to the risk of severe risks to the foetus conferred by uncontrolled PKU. All aspects of treatment should be reimbursed to ensure uniform access across Europe to guideline-driven, evidence-based care. The E.S.PKU urges PKU healthcare professionals caring for people with PKU to take the lead in developing evidence based guidelines on PKU, while continuing to play an active role in serving as the voice of patients and their families, whose lives are affected by the condition.
    Orphanet Journal of Rare Diseases 12/2013; 8(1):191. DOI:10.1186/1750-1172-8-191 · 3.36 Impact Factor
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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; · 2.63 Impact Factor
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