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.
    Full-text · Article · Jul 2015 · Clinica chimica acta; international journal of clinical chemistry
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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.
    Full-text · Article · Dec 2013 · Orphanet Journal of Rare Diseases
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    • "The 48-hour BH4 loading test was largely based on recommendations made by the European working group on PKU [11], requiring baseline Phe concentrations over 400 μmol/L. Dutch treatment guidelines recommend blood Phe concentrations of 120–360 μmol/L in patients under twelve years of age and 120–600 μmol/L in patients over twelve years of age [30]. "
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    ABSTRACT: How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with >=30% phenylalanine reduction at >=1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term >=30% reduction in mean phenylalanine concentration and/or >=4 g/day and/or >=50% increase of natural protein intake. Genotype was collected if available. 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with >=1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing.
    Full-text · Article · Jul 2013 · Orphanet Journal of Rare Diseases
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