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Adjuvant Treatment for Phenylketonuria (PKU)
Comparative Effectiveness Reviews, No. 56
Investigators: Mary Louise Lindegren, MD, Shanthi Krishnaswami, MBBS, MPH, Chris Fonnesbeck, PhD, Tyler Reimschisel, MD, Jill Fisher, PhD, Katie Jackson, BA, MSIV, Tracy Shields, MIS, Nila A Sathe, MA, MLIS, and Melissa L McPheeters, PhD, MPH.
Author Information and AffiliationsStructured Abstract
Objectives:
We systematically reviewed evidence on adjuvant treatment of phenylketonuria (PKU) and evidence for a target phenylalanine (Phe) level to minimize cognitive impairment.
Data Sources:
We searched MEDLINE, PsycINFO, Embase Drugs and Pharmacology, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), the National Agricultural Library (AGRICOLA), and the reference lists of included studies. We searched the unpublished literature for additional data.
Review Methods:
We included studies published in English before August 2011. We excluded studies with fewer than 10 individuals; individual case reports; and studies lacking relevance to PKU treatment or Phe levels and measures of cognition (intelligence quotient [IQ] or core domains of executive function). We meta-analyzed studies addressing Phe level and IQ, and summarized studies of treatment in tabular form.
Results:
We located 17 studies providing data regarding blood Phe levels and IQ changes, 10 studies addressing sapropterin dihydrochloride (BH4), and 3 addressing the use of large neutral amino acid formulations (LNAAs). Blood Phe level is positively correlated with the probability of having an IQ of less than 85. This predicted probability exceeds the population probability (approximately 15 percent) at 400 μmol/L and reaches a maximum of about 80 percent at 2000 μmol/L. Currently, findings on the association of Phe levels and measures of executive function are inconsistent, and too few studies have used the same outcome measures to combine data meaningfully. BH4 research to date includes two randomized controlled trials (RCTs) and three uncontrolled open-label trials. Phe levels were reduced by at least 30 percent in up to half of treated participants (32 to 50 percent). In the one RCT that compared the effect of placebo on likelihood of a 30-percent reduction in Phe, only 9 percent of those on placebo achieved this effect after 6 weeks, compared with 44 percent of the treated group. Three very small studies (total number of participants, 47) assessed LNAAs and reported no evidence that Phe levels were reduced to clinically meaningful levels.
Conclusions:
The strength of the evidence is moderate for a threshold effect of a Phe level of 400 μmol/L associated with IQ <85. Evidence on the association of Phe and measures of executive function is insufficient. The use of adjuvant therapy in PKU is novel; the strength of the evidence is currently moderate for short-term effects on reducing Phe in a subset of initially responsive individuals and low for longer term effects on cognition.
Contents
- Preface
- Acknowledgments
- Key Informants
- Technical Expert Panel
- Peer Reviewers
- Executive Summary
- Introduction
- Methods
- Results
- Article Selection
- Key Question 1a What is the evidence that any specific phenylalanine (Phe) levels are optimal for minimizing or avoiding cognitive impairment in individuals with PKU?
- Key Question 1b What is the evidence that different target Phe levels are appropriate for minimizing or avoiding cognitive impairment for different age groups?
- Key Question 2 What is the comparative effectiveness of BH4 with dietary intervention versus dietary intervention alone for affecting outcomes including measures of cognition (including executive function), quality of life, and nutritional status?
- Key Question 3 What is the comparative effectiveness of BH4 with dietary intervention versus dietary intervention alone in pregnant women with PKU for affecting outcomes in their infants, including prevention of neurological impairment, microcephaly, and cardiac defects?
- Key Question 4 What is the comparative effectiveness of large neutral amino acids (LNAAs) with dietary intervention versus dietary intervention alone for affecting outcomes including measures of cognition (including executive function), quality of life, and nutritional status?
- Key Question 5 What is the comparative effectiveness of LNAAs with dietary intervention versus dietary intervention alone in pregnant women with PKU for affecting outcomes in their infants, including prevention of neurological impairment, microcephaly, and cardiac defects?
- Key Question 6 What are the harms, including adverse events, associated with the use of BH4 or LNAAs in individuals with PKU?
- Key Question 7 What is the evidence for the effectiveness of the addition of BH4 or LNAAs to dietary intervention for affecting outcomes in subgroups of patients?
- Grey Literature
- Discussion
- References
- Acronyms and Abbreviations
- Appendixes
- Appendix A Search Strategies
- Appendix B Data Extraction Forms
- Appendix C Evidence Tables
- Appendix D Tools Used To Assess the Quality of the Literature
- Appendix E Quality of the Literature
- Appendix F Meta-analysis Methods
- Appendix G Excluded Studies
- Appendix H Studies Addressing Executive Function
- Appendix I Studies Addressing Maternal PKU
- Appendix J Summary of New Drug Application Studies of Sapropterin
- Appendix K Recent Conference Abstracts Addressing Adjuvant Treatment
Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, Contract No. HHSA 290-2007-10065-I. Prepared by: Vanderbilt Evidence-based Practice Center, Nashville, TN
Suggested citation:
Lindegren ML, Krishnaswami S, Fonnesbeck C, Reimschisel T, Fisher J, Jackson K, Shields T, Sathe NA, McPheeters ML. Adjuvant Treatment for Phenylketonuria (PKU). Comparative Effectiveness Review No. 56. (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No. HHSA 290-2007-10065-I.) AHRQ Publication No. 12-EHC035-EF. Rockville, MD: Agency for Healthcare Research and Quality; February 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm.
This report is based on research conducted by the Vanderbilt Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA 290-2007-10065-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.
The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.
This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report.
- 1
540 Gaither Road, Rockville, MD 20850; www
.ahrq.gov
- Review Adjuvant Treatment for Phenylketonuria: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 56[ 2012]Review Adjuvant Treatment for Phenylketonuria: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 56McPheeters ML, Lindegren ML, Sathe N, Reimschisel T. 2012 Sep
- A Systematic Review of BH4 (Sapropterin) for the Adjuvant Treatment of Phenylketonuria.[JIMD Rep. 2013]A Systematic Review of BH4 (Sapropterin) for the Adjuvant Treatment of Phenylketonuria.Lindegren ML, Krishnaswami S, Reimschisel T, Fonnesbeck C, Sathe NA, McPheeters ML. JIMD Rep. 2013; 8:109-19. Epub 2012 Jul 29.
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- Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis.[Mol Genet Metab. 2007]Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis.Waisbren SE, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, Levy H. Mol Genet Metab. 2007 Sep-Oct; 92(1-2):63-70. Epub 2007 Jun 25.
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