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Mol Genet Metab. 2014 Jun;112(2):87-122. doi: 10.1016/j.ymgme.2014.02.013. Epub 2014 Mar 6.

Phenylketonuria Scientific Review Conference: state of the science and future research needs.

Author information

1
Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: campkm@od.nih.gov.
2
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.
3
Emory University, Atlanta, GA 30033, USA. Electronic address: pja1933@gmail.com.
4
Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: gerard.berry@childrens.harvard.edu.
5
Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Electronic address: deborah.bilder@hsc.utah.edu.
6
University Children's Hospital, Heidelberg, Germany; University Children's Hospital, Zürich, Switzerland. Electronic address: nenad.blau@med.uni-heidelberg.de.
7
University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: obodamer@med.miami.edu.
8
University of Miami Mailman Center for Child Development, Miami, FL 33101, USA. Electronic address: jbrosco@med.miami.edu.
9
National PKU Alliance, USA. Electronic address: christine.brown@npkua.org.
10
University Hospital, 35128 Padova, Italy. Electronic address: alberto.burlina@unipd.it.
11
Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA. Electronic address: bburton@luriechildrens.org.
12
Agency for Healthcare Research and Quality, Rockville, MD 20850, USA. Electronic address: christine.chang@ahrq.hhs.gov.
13
Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: coatesp@od.nih.gov.
14
Tulane University Medical School, Hayward Genetics Center, New Orleans, LA 70112, USA. Electronic address: acunnin@tulane.edu.
15
University of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: dobrowolskis@upmc.edu.
16
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.
17
National PKU Alliance, USA. Electronic address: tom.franklin@npkua.org.
18
University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: dianne_frazier@med.unc.edu.
19
Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. Electronic address: grange_d@kids.wustl.edu.
20
University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: cgreene@peds.umaryland.edu.
21
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.
22
Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: hardingc@ohsu.edu.
23
University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: rhowell@miami.edu.
24
Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: huntingt@ohsu.edu.
25
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.
26
Office of Research on Women's Health, National Institutes of Health, Bethesda, MD 20817, USA. Electronic address: indira.jevaji@cms.hhs.gov.
27
Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: harvey.levy@childrens.harvard.edu.
28
George Washington University, Children's National Medical Center, Washington, DC 20010, USA. Electronic address: ulichter@cnmc.org.
29
Vanderbilt University School of Medicine, Nashville TN 37203, USA. Electronic address: marylou.lindegren@vanderbilt.edu.
30
Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: lloydpuryearma@od.nih.gov.
31
University of Houston, Houston, TX 77204, USA. Electronic address: kmatalon@uh.edu.
32
Birmingham Children's Hospital, Birmingham B4 6NH, UK. Electronic address: anita.macdonald@bch.nhs.uk.
33
Vanderbilt Evidence-based Practice Center, Institute for Medicine and Public Health, Nashville, TN 37203, USA. Electronic address: melissa.mcpheeters@vanderbilt.edu.
34
McGill University Health Center, Montreal, Quebec H3H 1P3, Canada. Electronic address: john.mitchell@muhc.mcgill.ca.
35
Maria Fareri Children's Hospital of Westchester Medical Center, Valhalla, NY 10595, USA. Electronic address: shideh_mofidi@nymc.edu.
36
University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. Electronic address: kmoseley@usc.edu.
37
Office of Orphan Products Development, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: christine.mueller@nih.gov.
38
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: andrew.mulberg@fda.hhs.gov.
39
Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address: lnerurkar@gmail.com.
40
University of Washington, Seattle, WA 98195, USA. Electronic address: bogata@uw.edu.
41
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: anne.pariser@fda.hhs.gov.
42
BioMarin Pharmaceutical Inc., San Rafael, CA 94901, USA. Electronic address: sprasad@bmrn.com.
43
Tulane University Medical School, Hayward Genetics Center, New Orleans, LA 70112, USA. Electronic address: pridjian@tulane.edu.
44
Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. Electronic address: skr9@cdc.gov.
45
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.
46
Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: frances.rohr@childrens.harvard.edu.
47
Emory University, Atlanta, GA 30033, USA. Electronic address: rsingh@emory.edu.
48
Vancouver General Hospital, University of British Columbia, Vancouver V5Z 1M9, Canada. Electronic address: sandra.sirrs@vch.ca.
49
PKU & Allied Disorders of Wisconsin, Madison, WI 53705, USA. Electronic address: sstremer@yahoo.com.
50
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: danilo.tagle@nih.gov.
51
The Children's Hospital at Westmead, Sydney, NSW 2145, Australia. Electronic address: sue.thompson@health.nsw.gov.au.
52
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.
53
University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: jutz1@fairview.org.
54
University of Groningen, University Medical Center of Groningen, Beatrix Children's Hospital, Netherlands. Electronic address: f.j.van.spronsen@umcg.nl.
55
University of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: vockleyg@upmc.edu.
56
Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: susan.waisbren@childrens.harvard.edu.
57
National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: weglickils@mail.nih.gov.
58
Department of Psychology, Washington University, St. Louis, MO 63130, USA. Electronic address: dawhite@wustl.edu.
59
University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: whitley@umn.edu.
60
Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, WA 98101, USA. Electronic address: benjamin.wilfond@seattlechildrens.org.
61
Nutricia North America, Rockville, MD 20850, USA. Electronic address: steven.yannicelli@nutricia.com.
62
The Young Face, Facial Plastic and Reconstructive Surgery, Cumming, GA 30041, USA. Electronic address: jmichaelyoung@yahoo.com.

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.

KEYWORDS:

Glycomacropeptide; Hyperphenylalaninemia; Large neutral amino acids; Maternal PKU; Phenylketonuria; Sapropterin

PMID:
24667081
DOI:
10.1016/j.ymgme.2014.02.013
[Indexed for MEDLINE]

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