title: Phenylketonuria Scientific Review Conference: state of the science and future research needs.
abstract: New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.
authors.affiliation: Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: campkm@od.nih.gov.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Camp
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: parisima@mail.nih.gov.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Parisi
authors.affiliation: Emory University, Atlanta, GA 30033, USA. Electronic address: pja1933@gmail.com.
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Acosta
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: gerard.berry@childrens.harvard.edu.
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Electronic address: deborah.bilder@hsc.utah.edu.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Bilder
authors.affiliation: University Children's Hospital, Heidelberg, Germany; University Children's Hospital, Zürich, Switzerland. Electronic address: nenad.blau@med.uni-heidelberg.de.
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.affiliation: University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: obodamer@med.miami.edu.
authors.forename: Olaf A
authors.initials: OA
authors.lastname: Bodamer
authors.affiliation: University of Miami Mailman Center for Child Development, Miami, FL 33101, USA. Electronic address: jbrosco@med.miami.edu.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Brosco
authors.affiliation: National PKU Alliance, USA. Electronic address: christine.brown@npkua.org.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Brown
authors.affiliation: University Hospital, 35128 Padova, Italy. Electronic address: alberto.burlina@unipd.it.
authors.forename: Alberto B
authors.initials: AB
authors.lastname: Burlina
authors.affiliation: Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA. Electronic address: bburton@luriechildrens.org.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Burton
authors.affiliation: Agency for Healthcare Research and Quality, Rockville, MD 20850, USA. Electronic address: christine.chang@ahrq.hhs.gov.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Chang
authors.affiliation: Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: coatesp@od.nih.gov.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Coates
authors.affiliation: Tulane University Medical School, Hayward Genetics Center, New Orleans, LA 70112, USA. Electronic address: acunnin@tulane.edu.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Cunningham
authors.affiliation: University of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: dobrowolskis@upmc.edu.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Dobrowolski
authors.affiliation: Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: jferg@helix.nih.gov.
authors.forename: John H
authors.initials: JH
authors.lastname: Ferguson
authors.affiliation: National PKU Alliance, USA. Electronic address: tom.franklin@npkua.org.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Franklin
authors.affiliation: University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: dianne_frazier@med.unc.edu.
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Frazier
authors.affiliation: Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. Electronic address: grange_d@kids.wustl.edu.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: cgreene@peds.umaryland.edu.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Greene
authors.affiliation: Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: stephen.groft@nih.gov.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Groft
authors.affiliation: Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: hardingc@ohsu.edu.
authors.forename: Cary O
authors.initials: CO
authors.lastname: Harding
authors.affiliation: University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: rhowell@miami.edu.
authors.forename: R Rodney
authors.initials: RR
authors.lastname: Howell
authors.affiliation: Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: huntingt@ohsu.edu.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Huntington
authors.affiliation: Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: henrietta.hyatt-knorr@nih.gov.
authors.forename: Henrietta D
authors.initials: HD
authors.lastname: Hyatt-Knorr
authors.affiliation: Office of Research on Women's Health, National Institutes of Health, Bethesda, MD 20817, USA. Electronic address: indira.jevaji@cms.hhs.gov.
authors.forename: Indira P
authors.initials: IP
authors.lastname: Jevaji
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: harvey.levy@childrens.harvard.edu.
authors.forename: Harvey L
authors.initials: HL
authors.lastname: Levy
authors.affiliation: George Washington University, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: ulichter@cnmc.org.
authors.forename: Uta
authors.initials: U
authors.lastname: Lichter-Konecki
authors.affiliation: Vanderbilt University School of Medicine, Nashville TN 37203, USA. Electronic address: marylou.lindegren@vanderbilt.edu.
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Lindegren
authors.affiliation: Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: lloydpuryearma@od.nih.gov.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Lloyd-Puryear
authors.affiliation: University of Houston, Houston, TX 77204, USA. Electronic address: kmatalon@uh.edu.
authors.forename: Kimberlee
authors.initials: K
authors.lastname: Matalon
authors.affiliation: Birmingham Children's Hospital, Birmingham B4 6NH, UK. Electronic address: anita.macdonald@bch.nhs.uk.
authors.forename: Anita
authors.initials: A
authors.lastname: MacDonald
authors.affiliation: Vanderbilt Evidence-based Practice Center, Institute for Medicine and Public Health, Nashville, TN 37203, USA. Electronic address: melissa.mcpheeters@vanderbilt.edu.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: McPheeters
authors.affiliation: McGill University Health Center, Montreal, Quebec H3H 1P3, Canada. Electronic address: john.mitchell@muhc.mcgill.ca.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mitchell
authors.affiliation: Maria Fareri Children's Hospital of Westchester Medical Center, Valhalla, NY 10595, USA. Electronic address: shideh_mofidi@nymc.edu.
authors.forename: Shideh
authors.initials: S
authors.lastname: Mofidi
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. Electronic address: kmoseley@usc.edu.
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Moseley
authors.affiliation: Office of Orphan Products Development, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: christine.mueller@nih.gov.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Mueller
authors.affiliation: Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: andrew.mulberg@fda.hhs.gov.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Mulberg
authors.affiliation: Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: lnerurkar@gmail.com.
authors.forename: Lata S
authors.initials: LS
authors.lastname: Nerurkar
authors.affiliation: University of Washington, Seattle, WA 98195, USA. Electronic address: bogata@uw.edu.
authors.forename: Beth N
authors.initials: BN
authors.lastname: Ogata
authors.affiliation: Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: anne.pariser@fda.hhs.gov.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Pariser
authors.affiliation: BioMarin Pharmaceutical Inc., San Rafael, CA 94901, USA. Electronic address: sprasad@bmrn.com.
authors.forename: Suyash
authors.initials: S
authors.lastname: Prasad
authors.affiliation: Tulane University Medical School, Hayward Genetics Center, New Orleans, LA 70112, USA. Electronic address: pridjian@tulane.edu.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pridjian
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. Electronic address: skr9@cdc.gov.
authors.forename: Sonja A
authors.initials: SA
authors.lastname: Rasmussen
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: reddyu@mail.nih.gov.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Reddy
authors.affiliation: Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: frances.rohr@childrens.harvard.edu.
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Rohr
authors.affiliation: Emory University, Atlanta, GA 30033, USA. Electronic address: rsingh@emory.edu.
authors.forename: Rani H
authors.initials: RH
authors.lastname: Singh
authors.affiliation: Vancouver General Hospital, University of British Columbia, Vancouver V5Z 1M9, Canada. Electronic address: sandra.sirrs@vch.ca.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sirrs
authors.affiliation: PKU & Allied Disorders of Wisconsin, Madison, WI 53705, USA. Electronic address: sstremer@yahoo.com.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Stremer
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: danilo.tagle@nih.gov.
authors.forename: Danilo A
authors.initials: DA
authors.lastname: Tagle
authors.affiliation: The Children's Hospital at Westmead, Sydney, NSW 2145, Australia. Electronic address: sue.thompson@health.nsw.gov.au.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Thompson
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: urvtiin@mail.nih.gov.
authors.forename: Tiina K
authors.initials: TK
authors.lastname: Urv
authors.affiliation: University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: jutz1@fairview.org.
authors.forename: Jeanine R
authors.initials: JR
authors.lastname: Utz
authors.affiliation: University of Groningen, University Medical Center of Groningen, Beatrix Children's Hospital, Netherlands. Electronic address: f.j.van.spronsen@umcg.nl.
authors.forename: Francjan
authors.initials: F
authors.lastname: van Spronsen
authors.affiliation: University of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: vockleyg@upmc.edu.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: susan.waisbren@childrens.harvard.edu.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waisbren
authors.affiliation: National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: weglickils@mail.nih.gov.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Weglicki
authors.affiliation: Department of Psychology, Washington University, St. Louis, MO 63130, USA. Electronic address: dawhite@wustl.edu.
authors.forename: Desirée A
authors.initials: DA
authors.lastname: White
authors.affiliation: University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: whitley@umn.edu.
authors.forename: Chester B
authors.initials: CB
authors.lastname: Whitley
authors.affiliation: Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA 98101, USA. Electronic address: benjamin.wilfond@seattlechildrens.org.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Wilfond
authors.affiliation: Nutricia North America, Rockville, MD 20850, USA. Electronic address: steven.yannicelli@nutricia.com.
authors.forename: Steven
authors.initials: S
authors.lastname: Yannicelli
authors.affiliation: The Young Face, Facial Plastic and Reconstructive Surgery, Cumming, GA 30041, USA. Electronic address: jmichaelyoung@yahoo.com.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Young
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004035:Diet Therapy; D019468:Disease Management; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D009316:National Institutes of Health (U.S.); D010661:Phenylketonurias / Q000097:blood* / Q000175:diagnosis / Q000628:therapy*; D017410:Practice Guidelines as Topic; D011247:Pregnancy; D014481:United States
chemical_list: D001708:Biopterins; C003402:sapropterin
keywords: Glycomacropeptide; Hyperphenylalaninemia; Large neutral amino acids; Maternal PKU; Phenylketonuria; Sapropterin