title: Phenylalanine hydroxylase deficiency: diagnosis and management guideline.
abstract: 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 medications, or combination of therapies that help to achieve that goal in an individual, without other negative consequences, should be considered appropriate therapy. Significant evidence gaps remain in our understanding of the optimum therapies for phenylalanine hydroxylase deficiency, nonphenylalanine effects of these therapies, and long-term sequelae of even well-treated disease in children and adults.
authors.affiliation: 1] Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA [2] Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.affiliation: Hayward Genetics Center, Tulane University Medical School, New Orleans, Louisiana, USA.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Andersson
authors.affiliation: Department of Psychology, Syracuse University, Syracuse, New York, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Antshel
authors.affiliation: Department of Human Genetics and Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Braverman
authors.affiliation: Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, USA.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Burton
authors.affiliation: Department of Pediatrics, University of North Carolina, at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Frazier
authors.affiliation: Department of Human Genetics and Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Mitchell
authors.affiliation: Department of Pediatrics, Maine Medical Center, Portland, Maine, USA1.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Smith
authors.affiliation: The American College of Medical Genetics and Genomics, Bethesda, Maryland, USA.
authors.forename: Barry H
authors.initials: BH
authors.lastname: Thompson
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Berry
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives / Q000627:therapeutic use; D002675:Child, Preschool; D003131:Combined Modality Therapy; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D010649:Phenylalanine / Q000097:blood*; D010661:Phenylketonurias / Q000175:diagnosis* / Q000628:therapy*; D014481:United States
chemical_list: D001708:Biopterins; D010649:Phenylalanine; C003402:sapropterin