PKU Nutrition Management Guidelines
Second Edition
March 2022, v.2.4
Current version: v.2.5
Updated: March 2022
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The Nutrition Guideline for PKU is an evidence- and consensus-based management guideline created through a rigorous, transparent and systematic development process. The process was adapted from the Academy of Nutrition and Dietetics with the addition of procedures to include gray literature and draw on expertise from clinical practice where research is lacking. During guideline development and updating, SERN/Emory provided infrastructure (portal development and maintenance, technology support, project coordination and management, librarian) while GMDI provided content expertise. Experienced GMDI metabolic dietitians were selected to comprise the PKU Workgroups to develop the original guideline as well as updated guidance for management of alternate pharmacotherapies (see Contributors section).The process is published in the Journal of Evaluation in Clinical Practice and is available at . The process is illustrated in Figure 1 below:

Figure 1: Nutrition Guideline Development Process

Many members of the PKU workgroup were participants in the year-long NIH sponsored project that reviewed and evaluated  PKU research since 2000 and culminated with the "Phenylketonuria Scientific Review Conference: State of the Science and Future Research Needs" in February 2012.  The need for evidence-based and consistent guidelines was supported by the summary findings of this project (F.2629).

Question Formulation

PKU workgroup members independently identified questions where uncertainty or variation in practice existed. These were categorized into topics by the workgroup chairs and resubmitted to members for prioritization. From these, seven research questions were identified to guide evidence analysis and guideline development:

  1. For individuals with PKU, what nutrient intakes are associated with positive outcomes?
  2. For individuals with PKU, what blood phenylalanine concentrations are associated with positive outcomes?
  3. For individuals with PKU, what nutrition interventions are associated with positive outcomes?
  4. For individuals with PKU, monitoring of what parameters is associated with positive outcomes?
  5. For individuals with PKU, whose therapy includes adjunctive therapy or other therapy options (sapropterin or large neutral amino acids) what dietary considerations are needed for positive outcomes?
  6. For pregnant individuals with PKU, what nutritional therapies are associated with positive outcomes during pregnancy planning, pregnancy, and the post-partum period including lactation? 

    In 2020, workgroup members commenced an update of the PKU guidelines by adding a seventh research question:
  7. For individuals with PKU whose therapy includes pegvaliase as a treatment option, what medical and nutritional considerations are associated with positive outcomes?

Research questions for each topic were formulated in the PICO (population, intervention, comparison, and outcomes) format, and a separate systematic review and evidence analysis was done for each question.

Search Process

The search process included both published scientific studies and gray (practice) literature.

Scientific Literature: Search terms were specific to each question, but inclusion and exclusion criteria were the same for all questions. Eligibility was limited to human studies published in English from 1980 to Fall 2000 and from 2011 to February 2014 for the original six questions, and from 2015 to 2021 for the seventh question. Additional search terms were developed specific to the addition of research question 7. There were no study design, age or setting restrictions. PubMed was the primary database used. Searches were conducted by a librarian at Emory University working in close collaboration with the project principal investigators, workgroup chairs and project coordinator. The titles and abstracts of identified articles were adjudicated by core group members for relevance and matched with inclusion/exclusion criteria. The following were considered exclusion factors:

  • Animal study
  • Not published in English
  • Not pertaining to PKU
  • Genetic studies not related to phenotype
  • Case studies not specifically related to nutrition
  • Not related to treatment or outcomes
  • General overview intended to educate those not familiar with PKU
  • Published before 2000; material assumed to have been reviewed for 2000 NIH PKU Consensus Statement.
  • Reviewed for 2012 NIH State of the Science Conference and publication, or 2014 ACMG, or GMDI/SERC publications

Excluded articles were noted, with reason for exclusion documented, and qualifying articles were gathered for review and abstracting. Reference lists within the identified articles were examined for additional resources. These were added if they contributed pertinent information. Pertinent studies published before 2000 were assumed to have been reviewed for the 2000 NIH PKU Consensus Statement (L.130), and this publication is referenced in lieu of those individual articles. Studies published from 2000 through 2010 were reviewed and summarized for the NIH State of the Science Conference (Feb 2012) by dietitians who were members of the NIH Working Groups on Diet Management or Maternal PKU, and who are also involved in the GMDI/SERC effort. The summary statement  from the NIH conference (F.2629) is referenced in this guideline in lieu of individual articles used in preparation of the summary statement. Similarly, the ACMG (F.2626) and GMDI/SERC (F.2627) treatment and management publications are referenced in lieu of individual articles used in their preparation. Scientific literature is referenced by "F" codes with each linked to the full article.

Gray Literature: Gray literature refers to reports of clinical practice and research that cannot be accessed through standard search systems and includes: abstracts and presentations from scientific and practice-based meetings, clinical protocols and guidelines, unpublished research, communication among experts (including listserv postings), professional newsletters, and book chapters. Work group members collected gray literature materials related to nutrition and PKU. Identified resources were screened and prioritized for inclusion based on relevance, substantive information not available in scientific literature, and currency. Gray literature is referenced by "G" codes with each linked to the full article.

Reference Materials: Reference materials refer to reports or publications not formally analyzed but used as background or supporting material within the guideline. Reference materials are referenced by the codes “L” (for peer reviewed literature) or “Y” (for non-peer reviewed literature).

Critical Appraisal and Abstraction

Each peer-reviewed publication was critically reviewed by a trained analyst using a Quality Criteria Checklist adapted for this purpose. Quality criteria included selection and retention of subjects, appropriate controls, intervention clearly described, other intervening variables tracked, outcomes defined, measures valid and statistical analyses appropriate. Based on the number of criteria met, each article was given a quality rating of positive, neutral or negative. Workgroup members were assigned articles pertinent to a particular research question, which they reviewed and abstracted. Description included: study sample, intervention or factors of interest, findings, limitations of the study, and the article's contribution to the evidence analysis research question.

Workgroup members, using a specially designed tool, subjected eligible gray literature to similar quality assessment and abstraction.

Evidence Summary

Key information from all eligible evidence sources (peer-reviewed and gray literature) for each question was summarized. Summarized evidence was used to draft preliminary conclusion statements and recommendations.

Through two separate Delphi surveys and a nominal group process meeting clinical expertise was gathered regarding practices not addressed sufficiently in the literature, or for which evidence was inconclusive. The goal was to develop consensus or to note where consensus does not exist. Participants in the Delphi surveys were metabolic dietitians and metabolic physicians representing all geographical regions in the US. Participants in each of the nominal group meetings included: a general pediatrician, a researcher, and an advocate for the PKU community, in addition to metabolic physicians and dietitians. The Delphi and nominal group process was repeated for the addition of the seventh research question.

The final conclusion statement for each research question is based on a synthesis of evidence from peer-reviewed publications, gray literature, and Delphi and nominal group consensus techniques.

Development of Recommendations

Final recommendations for the nutrition management of individuals with PKU, in each of the seven topic areas, were derived from all evidence and consensus sources. These were written, reviewed and edited by the core group. A consultant, not involved in development of the recommendations, rated each recommendation with respect to strength of the evidence (strong, fair, limited, consensus, insufficient evidence) and need for clinical action (imperative or conditional).

See Appendix A for definitions of recommendations.

These practice recommendations, along with background and other information to support their implementation are contained in the PKU Nutrition Management Guideline.

Portal Application

Development of guidelines is achieved with a secure, web-based application written in PHP, MySQL and hosted by Apache HTTP running on a Linux server. Guidelines for an unlimited number of IMD can be supported with the application. For each IMD, forms exist for literature management, Delphi survey and nominal group outcome management, and final guideline development. Published literature data is initially obtained via XML through the NCBI E-Utilities API. User-entered data is archived as changes are made, and content is locked through internal publishing prior to final guideline development. References for literature and tables are managed natively. Users are kept apprised of guideline development with automated email notifications. Built-in discussion forums are utilized for online group dialogue. Application security is maintained through use of SSL, user accounts and user-level access controls for each form. Backups are performed nightly. The complete PKU Nutrition Management Guideline can be accessed through both the SERC and GMDI websites.

Plan for Updating

As a result of the evidence analysis and consensus processes, important areas where research is needed were identified. Further, the practice recommendations outlined should lead to greater standardization of care and enable outcomes studies within and across centers. This guideline will be reviewed every 2 years and updated when warranted by new developments in PKU research or change in accepted clinical practice. The guideline will be updated following the processes of publication search then formal evidence and consensus analysis used for original guideline development. The addition of a seventh research question regarding alternate therapy constitutes the first update to this guideline.