Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study

Levy, Harvey L.; Milanowski, Andrzej; Chakrapani, Anupam; Cleary, Maureen; Lee, Philip; Trefz, Friedrich K.; Whitley, Chester B.; Feillet, François; Feigenbaum, Annette; Bebchuk, Judith D.; Christ‐Schmidt, Heidi; Dorenbaum, Alex

doi:10.1016/s0140-6736(07)61234-3

Cited by 274 publications

(259 citation statements)

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“…That said, an individual's specific PAH genotype is still the major determinant of metabolic phenotype. 18,19 Mutation analysis should be obtained for all infants with elevated PHE to provide information that may affect the extent of dietary PHE restriction and the likelihood of response to cofactor (BH 4 ; sapropterin) supplementation, with submission of results to the PAH databases. [20][21][22][23] …”

Section: Genotypingmentioning

confidence: 99%

“…Sapropterin (Kuvan, BioMarin Pharmaceutical, Novato, CA) is a synthetic form of the naturally occurring cofactor, tetrahydrobiopterin. 19,34 Although not deficient in endogenous tetrahydrobiopterin, some patients with PAH deficiency who have some residual enzyme activity respond to administration of sapropterin with an increase in the metabolism of PHE to TYR. The mechanism by which residual PAH activity enhanced is unclear, but BH 4 may act as a pharmacologic chaperone leading to improved folding and increased stability of the mutant protein.…”

Section: Pharmacotherapymentioning

confidence: 99%

“…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%

“…Genotype may be predictive of sapropterin response, but genotype-phenotype correlations thus far are imperfect. 19 Therefore, every PAH-deficient patient should be offered a trial of sapropterin therapy to assess responsiveness except those with two null mutations in trans.…”

Section: Pharmacotherapymentioning

confidence: 99%

“…38,39 During clinical trials, no serious side effects of sapropterin were identified. 19,34 Before routine treatment with sapropterin is initiated, a test should be conducted to determine if the patient is responsive. 39 While testing is typically done in Europe at the time of initial diagnosis, this is not the practice in the United States.…”

Section: Pharmacotherapymentioning

confidence: 99%

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Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

540

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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