ThePAH gene, phenylketonuria, and a paradigm shift

Scriver, Charles R.

doi:10.1002/humu.20526

Cited by 292 publications

(218 citation statements)

References 153 publications

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“…This "paradigm shift" in our outlook on genetic diseases and their treatment began with PAH deficiency, but the journey is far from over. 96 Looking forward, better tools and strategies are required to optimize care for the individual and improve long-term outcomes. Better biomarkers are also needed to monitor therapy and predict outcome.…”

Section: Future Directionsmentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

544

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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Section: Future Directionsmentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

544

443

View full text Add to dashboard Cite

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“…This regimen became an epitome of human biochemical genetics (Donlon et al 2010;Scriver 2007;Scriver and Clow 1980a, b). However, dietary treatment of PKU is difficult to maintain (Burgard et al 1999) and is easily compromised, with three out of four PKU patients becoming noncompliant by late adolescence.…”

Section: Introductionmentioning

confidence: 99%

Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?

et al. 2011

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Prospectively enrolled phenylketonuria patients (n ¼ 485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN ® ). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5-20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.

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“…AF404777). PAH gene is mapped to human chromosome 12q24.1, it spans approximately 90 kb and contains 13 exons and 12 large introns (Scriver 2007).…”

Section: Introductionmentioning

confidence: 99%