START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients

Utz, Jeanine; Lorentz, Cindy Pham; Markowitz, Dorothy J.; Rudser, Kyle; Diethelm‐Okita, Brenda; Erickson, David C.C.; Whitley, Chester B.

doi:10.1016/j.ymgme.2011.10.014

Cited by 42 publications

(35 citation statements)

References 23 publications

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“…of genotypes containing at least one allele with a PRA of at least 25% are BH 4 responsive [45]. Only 73.3% of genotypes containing at least one allele with a PRA of at least 30% were found to be BH 4 responsive in our study.…”

Section: Bh 4 -Responsivenesscontrasting

confidence: 62%

Assessment of tetrahydrobiopterin (BH4)-responsiveness and spontaneous phenylalanine reduction in a phenylalanine hydroxylase deficiency population

Tanšek

Grošelj

Murko

et al. 2012

Molecular Genetics and Metabolism

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Section: Bh 4 -Responsivenesscontrasting

confidence: 62%

Assessment of tetrahydrobiopterin (BH4)-responsiveness and spontaneous phenylalanine reduction in a phenylalanine hydroxylase deficiency population

Tanšek

Grošelj

Murko

et al. 2012

Molecular Genetics and Metabolism

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“…Approximately 25-50% of the patients with PAH deficiency are sapropterin-responsive. 19,[35][36][37] Patients with mild PAH deficiency are most likely to respond because some stable protein is required for sapropterin to function; nonetheless, responsive patients are identified even among those with complete PAH deficiency. Genotype may be predictive of sapropterin response, but genotype-phenotype correlations thus far are imperfect.…”

Section: Pharmacotherapymentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

526

443

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Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU) due to characteristic phenylketones accumulating in the urine of affected individuals, has a significant place in history as the first inborn error of metabolism identified through population-based screening, initiating a new era in the diagnosis and treatment of genetic disorders. PKU was first described in 1934 by the Norwegian physician Asbjörn Fölling, but it was not until the mid-1950s that a patient with PAH deficiency was treated with a low phenylalanine (PHE) diet. Although this first patient already had irreversible Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder.Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medica...

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“…6 It has been shown that genotypes are useful in predicting BH4 responsiveness in PKU patients. [7][8][9][10] The aim of PKU treatment is to maintain Phe blood concentrations within the therapeutic range, which is mainly achieved by a natural protein-restricted diet and synthetic amino acid supplementation without Phe. 11 However, the recommended low-Phe diet potentially impairs quality of life by decreasing patients' flexibility and autonomy.…”

Section: Discussionmentioning

confidence: 99%

Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study

et al. 2013

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WHAT'S KNOWN ON THIS SUBJECT: Pharmacologic treatment with sapropterin dihydrochloride (6R-tetrahydrobiopterin; BH4) has been an effective option for some phenylketonuria patients since its approval by the US Food and Drug Administration in 2007 and the European Medicines Agency in 2008. WHAT THIS STUDY ADDS:This retrospective multicenter study revealed the long-term effects of sapropterin on metabolic control, dietary tolerance, and the outcome of BH4-responsive phenylketonuria patients harboring specific phenotypes and genotypes. It also confirmed that the minor adverse events disappeared by lowering the dose. abstract 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.

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START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients

Cited by 42 publications

References 23 publications

Assessment of tetrahydrobiopterin (BH4)-responsiveness and spontaneous phenylalanine reduction in a phenylalanine hydroxylase deficiency population

Assessment of tetrahydrobiopterin (BH4)-responsiveness and spontaneous phenylalanine reduction in a phenylalanine hydroxylase deficiency population

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study

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