- Executive Summary

➡️Introduction

 Phenylketonuria (PKU) is an inborn error of metabolism (IEM) caused by inherited deficiency of the enzyme phenylalanine hydroxylase (PAH), which catalyzes the hydroxylation of phenylalanine (Phe) to generate tyrosine (Tyr) [20]. It is considered the most common IEM of amino acid metabolism; estimated worldwide average incidence 1:15000 [21], and of 2638 live births in Egypt [24]. It has been long known that introduction of treatment as early as possible can ameliorate the neurotoxic sequalae of Phe on the developing brain tissue, hence the importance of newborn screening aiming at early diagnosis and management. [22].

➡️Scope

This guideline focuses on diagnosis and management of PAH deficiency in children in Egypt. It is developed to help health care personnel (general practitioners, general pediatricians, family medicine physicians, neonatologists, nutritionists, dieticians, psychologists and nurses  aiming at preventing morbidity and neurocognitive disabilities in PKU

Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

1- The complete European guidelines on phenylketonuria : diagnosis and treatment. Orphanet J Rare Dis. 2017 Oct 12 ;12(1) :162

2- Breast feeding in infants diagnosed with phenylketonuria (PKU) : a scoping review. BMJ Paediatr Open. 2023 Oct ;7(1): e002066

3- Epilepsy and vaccinations : Italian guidelines. Epilepsia, 54(Suppl. 7) :13–22, 2013

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -  Adoption for most of the guideline recommendations.

         -   Adaptation for 2 recommendations according to GRADE criteria to be suitable to our Economic implications (Evidence-to-Decision (EtD) table was done)

         -  Development of Good Practice Statements

Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

A. Diagnosis of Phenylketonuria (PAH deficiency)

This guideline emphasizes the best practice on diagnosis of PAH deficiency based on phenylalanine level, type and timing of blood sample and the role of molecular testing in children’s age group from day 1 to 18 years.

B. Management of PAH deficiency

This section includes recommendations and good practice statements on dietary management, follow up and monitoring of PKU children.

C. Prevention of neurocognitive impairments in PAH deficiency

This section includes recommendations and good practice statements on monitoring to prevent neurocognitive impairment of PKU children.

We can summarize the guidelines’ recommendations in the following:

▪️  We recommend that newborn screening should be considered as a national obligation as this has proven to be cost effective, (Intermediate quality evidence, strong recommendation).

▪️  In the differential diagnosis of hyperphenylalaninemia, of any degree, we suggest that BH4 deficiency should be excluded by measuring petrins and dihydropetredine reductase activity in dried blood spot, (low quality evidence, Weak (conditional) recommendation).

▪️  As petrins and dihydropetredine reductase activity in dried blood spot tests are not available in Egypt, careful follow up of patients  neurodevelopment after positive newborn screening is highly recommended, (Good practice statement).

▪️   To maintain blood levels in the recommended range, we suggest That patients with PAH deficiency can be classified as either:   Not requiring treatment, Requiring diet, BH4 or both, (Very low quality evidence, Weak (conditional) recommendation).

▪️  Patient genotyping should be considered for diagnosing BH4 responsiveness and may help to define the metabolic phenotype and could help in prevention by offering reproductive options, (Very low quality evidence, Weak (conditional) recommendation).

▪️    We suggest that all patients with untreated blood Phe levels >360 µmol/I should be treated.  Treatment should start as soon as possible, ideally before 10 days of age, (Very low quality evidence, Weak (conditional) recommendation)

▪️  We suggest that no treatment is recommended when untreated blood levels are <360 µmol/I.  But, monitoring of blood Phe (at a lower frequency) until 1 year of age as a minimum is recommended to determine whether levels rise above 360 µmol/l, (Very low quality evidence, Weak (conditional) recommendation).

▪️ We suggest that patients with untreated Phe levels 360-600 µmol/I should be treated until the age of 12 years, (Very low quality evidence, Weak (conditional) recommendation).

▪️  We recommend that, in treated PKU patients up to the age of 12 years, target Phe level should be 120-360 µmol/L, (Intermediate quality evidence, strong  recommendation).

▪️  We suggest that, in treated PKU patients aged ≥ 12 years target Phe level should be 120-600 µmol/L, (Very low quality evidence, Weak (conditional) recommendation).

·       We recommend that blood Phe levels should be measured to monitor metabolic control, as they are the most clinically relevant biomarkers, (Intermediate quality evidence, strong recommendation).

▪️   We suggest that there is insufficient evidence to support routine evaluation of the Phe fluctuations and the measurement of Phe/tyr ratio in PKU, (Very low quality evidence, Weak (conditional) recommendation).

▪️  We suggest that frequency of blood PHE measurement should be at minimum:

0-1 year               Weekly    

1-12 years           fortnightly

>12 years             monthly, (Good practice statement).

▪️  We suggest that all PKU patients should be followed up in a specialized metabolic center, (Very low quality evidence, Weak (conditional) recommendation).

▪️  We suggest that an annual nutritional review is required for any patient who is prescribed in low Phe diet or is self-restricting high protein food. Such a clinical review includes a clinical examination including the anthropometric parameters (weight, height, BMI). It is also recommended that plasma amino acids, plasma homocysteine, and /or methylmalonic acid, hemoglobin, MCV and ferritin are measured. All other micronutrients (vitamins, minerals including calcium, zinc, selenium) or hormones (parathyroid hormones) can be considered if clinically indicated. (low quality evidence, Weak (conditional) recommendation).

▪️  Outpatient clinic visit should be at minimum, given good clinical and metabolic control:

0-1       year: every 2 months

1-18 years: twice per year, (Good practice statement).

▪️    We suggest that health professional support is required throughout life to encourage normal healthy feeding behaviors, with a positive acceptance of a low Phe diet, (Low quality evidence, Weak (conditional) recommendation).

▪️  We suggest that Phe intake should be methodically titrated until Phe is consistently maintained within the Phe target range. If there is stability of control, a challenge with additional Phe should be performed systematically to maximize natural protein permitted, Phe deficiency should be avoided. (Low quality evidence, Weak (conditional) recommendation).

▪️  We suggest that total protein intake should supply the age-related safe level of protein intake (FAQ/WHO/UNU 2007) with an additional 40% from L- amino acid supplements. (Low quality evidence, Weak (conditional) recommendation).

▪️ In PKU, the nutritional intake of energy, macronutrients and micronutrients, should meet the average estimated amounts/ dietary reference values for healthy population. For all age groups, there should be focus on achieving balanced intake of all nutrients, avoiding catabolism or deficiency but preventing excess of any nutrient that may lead to over nutrition or toxicity. Supplementary nutrients (vitamins, minerals and LC-PUFA's) added to Phe -free L-amino acid supplements should be in the amounts that will at least meet normal population dietary reference values. Assessment of dietary intake should be performed in every clinic visit with extra attention directed to patients who are non-adherent, do not have prescribed Phe free L-amino acid supplements (with added micronutrients) or who are at the higher risk of nutritional deficiency, (Low quality evidence, Weak (conditional) recommendation).

▪️ We recommend that fruits and vegetables (except potatoes containing Phe ≤ 75 mg/100 g of food can be safely given without measurements or estimation in a low Phe-diet without loss of Phe control. Some unrestricted fruits and vegetables should be encouraged in the diet in early life to encourage long-term healthy feeding patterns. (Intermediate quality evidence, Strong recommendation).

▪️ We recommend that the artificial sweetener aspartame, particularly from beverages and tables top sweetener’s is best avoided in patients on a low Phe-diet. (Intermediate quality evidence, Strong recommendation).

▪️ The Phe-free protein substitute, in the form of L-amino acids, should be provided in any patient with PKU treated with a low Phe diet consuming less than the FAQ/WHO/UNU 2007 safe levels of natural protein intake. The Phe-free L-amino acid formula should be evenly administered at least 3 times throughout the day. To aid adherence, all patients with PKU should receive a choice of suitable age-appropriate Phe-free L-amino acid supplements. (Intermediate quality evidence, strong recommendation).

▪️  In infants with PKU Breast-Feeding in combination with a Phe-free infant L-amino acid formula should be encouraged, (Low quality evidence, Weak (conditional) recommendation).

▪️ Breast-Feeding Techniques:
Demand Breast-Feeding with Supplementation: Breast-feed on demand but give a measured volume of Phe-free infant formula before breast-feeding to reduce breast milk stimulation and Phe intake.
Alternating Method: Alternate between breast-feeding and Phe-free L-amino acid infant formula bottle-feeding to achieve acceptable blood Phe control.
Individualized Feeding Plans: Each infant may require a tailored approach based on their individual blood Phe levels and responses to feeding techniques.

(Low quality evidence, Weak (conditional) recommendation).

▪️   We suggest that in children with PKU, during illness to prevent an excessive rise in blood Phe concentration, it is prudent to encourage the intake of Phe-free L-amino acid supplements and high carbohydrate supplements, (Very low quality evidence, Weak (conditional) recommendation).

▪️ Neurocognitive evaluations should be performed at 12 and 18 years of age in all patients.                                                                                                                                                                         If any of the stated risk factors applies, perform (additional) neurocognitive tests:
-Non-optimal metabolic control; >50% of the Phe levels are out of target range over period of 6-12 months (depending on age <12 or 212 years).

-Problems at school or work; not showing progress in school for 6 months
- Concern of parents / caregivers or family

-Concern of PKU patient

-Concern of metabolic team

Proposed domains of neurocognitive testing:

IQ perception/visuospatial functioning, EF (divided into inhibitory control, working memory and cognitive flexibility), and motor control.

(Good practice statement).

▪️  It is advisable to measure and discuss psychosocial functioning and wellbeing during clinic visits in PKU as this has been demonstrated to improve psychosocial outcomes in patients with other chronic diseases. This should be done in the easiest possible way for each center by interview, paper or electronically, (Intermediate quality evidence,  strong recommendation).

▪️   Health related quality of life should be discussed at least annually in the outpatient clinic. It is suggested to consider a questionnaire (preferably PKU specific) to support this at least once during childhood, adolescence and adulthood and during major changes in life, (Very low quality evidence, Weak (conditional) recommendation).

▪️  Adaptive issues (e.g. clinically relevant behavioral problems) should be discussed on an annual basis.  Adaptive issues should be screened at 12 and 18 years together with neurocognitive functioning.  When adaptive problems occur, a psychology referral should be sought, (Good practice statement).

▪️ Neuroimaging should not be performed in routine care but reserved for PKU patients presenting with unexpected clinical course/and or unexpected neurological deficit, (Very low quality evidence, Weak (conditional) recommendation).

▪️   Patients with PKU should receive the compulsory vaccines and extra vaccines without restriction even if they have convulsions, (Good practice statement).

▪️   We recommend that vaccinations should be performed without contraindication in children with idiopathic or symptomatic epilepsy (Intermediate quality evidence, Strong recommendation).

▪️  We recommend that the risk of epilepsy should not discourage parents from vaccinating their children (Intermediate quality evidence, Strong recommendation).

➡️Guideline Registration

- Recommendations

- Acknowledgements

▪️The GDG/ GAG acknowledge EPG for its help in completing this project.

▪️  We acknowledge:

-  The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017 Oct 12 ;12(1):162

-  Breast feeding in infants diagnosed with phenylketonuria (PKU): A scoping review. BMJ Paediatr Open. 2023 Oct ;7(1): e002066

-   Epilepsy and vaccinations: Italian guidelines Epilepsia, 54(Suppl. 7):13–22, 2013

▪️ Finally, we wish the best for all our patients and their families who inspired us. It is for them this work is being finalized.

Funding

▪️  This work is not related to any pharmaceutical or industrial company. The members of the GDG/ GAG and their institutes and universities volunteered their participation and contributions

- Abbreviations

- Introduction

Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), responsible for breaking down phenylalanine to Tyrosine (Tyr). Being a rare disease, the estimated global incidence is approximately 1 in 10,000 to 15,000 live births. However, the prevalence can vary significantly by geographic region and ethnic background [23]. The incidence among Egyptians was estimated to be 1: 2638 live births, with higher rates in Lower Egypt and South Sinai [24]. This higher rate is attributed to the high rate of consanguineous marriages in the country, that reaches 35.3% on average, especially among first cousins (86%) [25].

The PAH gene is located on chromosome 12, and over 1,000 pathogenic variants have been identified in this gene eventually leading to a reduction or complete absence of functional PAH enzyme [26]. High Phe concentrations may disrupt brain development, myelination, and neurotransmitter synthesis. The transport of large neutral amino acids (LNAAs) within the brain tissue is hindered by increased Phe concentration and this explains the deficiency of dopamine and serotonin in the brain tissue of PKU patients [27].

Because of widespread ոеwborn screening programs, overt clinical manifestations of РKU are rare. Neonates are asymptomatic until the initiation of feeds containing Phe (e.g., breast milk or standard infant formula). The serious manifestations of PKU include irreversible intellectual disability, developmental delays, seizures, behavioral abnormalities, microcephaly, and eczematous rash, decreased skin pigmentation and in some cases gait abnormalities [27].

The cornerstone in the diagnosis of PKU, is the direct estimation of Phe level in blood. The most useful laboratory method for screening for PKU is tandem mass spectrometry. In addition to being a high through output method, it can measure additional amino acids including tyrosine and acylcarnitine ester. A high concentration of Phe together with elevated Phe/tyrosine ratio suggests the diagnosis of PKU [28]. Enzyme assay is not performed to confirm the diagnosis, because PΑH activity is expressed only in the liver [27].

Once the biochemical diagnosis is established, treatment should be initiated as soon as possible to avoid irreversible brain damage. Lifetime dietary restriction of Phe has been the mainstay of treatment of PKU children [27]. The diet consists of Phe-free protein substitute in addition to normal (intact) protein calculated in reference to the age and body weight of each child and adjusted according to Phe tolerance. The intact protein includes breast milk, standard infant formula in neonates or vegetarian diet in older children [29].

Rocha and Macdonald, 2016 stated that the goal of dietary management is to reduce the blood phenylalanine concentration into the treatment range of 120–360 μmol/L (2–6 mg/dL) and to provide sufficient macronutrients and micronutrients essential for normal growth [29].

Sapropterin, a biologically active synthetic form of ΒH4, was approved by the US Food and Drug Administration (FDA) in December 2007 [30]. Ѕарrοptеriո may be used as an adjunct to dietary restriction in only ΡΚU patients who are responsive to ѕарrорtеriո [31].

The prognosis of PKU patients vary significantly depending on the timing of initiation of therapy and effectiveness of treatment. Early diagnosis and strict adherence to the phenylalanine-restricted diet from a young age can greatly improve outcomes. With appropriate management, individuals with PKU can often achieve normal or near-normal intellectual and cognitive development, as well as a good quality of life.

➡️Purpose and Scope

These guidelines have been developed to standardize the delivery of services and to implement guidance on diagnosis and management of PAH deficiency in children. It provides guidance and recommendations to primary health care providers, general practitioners, general pediatricians, family medicine physicians, neonatologists, nutritionists, psychologists, and nurses aiming at preventing morbidity and neurocognitive disabilities in PAH in children.

- Methods

➡️Methods of search:

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation. Keywords used for searching are:

Phenylketonuria, PKU, Phenylalanine hydroxylase, PAH, nutritional management, PKU treatment.

Inclusion / exclusion criteria followed in the search and retrieval of guidelines to be adapted:

• Selecting only evidence-based guidelines (guideline must include a report on methodology of development including the systematic literature searches and explicit links between individual recommendations and their supporting evidence)

• Selecting national and/or international guidelines

• Specific range of dates for publication (using Guidelines published or updated 2013 and later)

• Selecting peer-reviewed publications only

• Selecting guidelines written in English language

• Excluding guidelines written by a single author

The following three categories of databases and websites were searched:

1.  CPG databases and libraries (e.g., GIN, ECRI, SIGN, DynaMed, BIGG-REC PAHO)

2. Bibliographic databases (e.g., PubMed, Google Scholar)

3. Specialized professional societies (related to the pediatric subspecialty)

All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) by at least two members. The panel decided a cut-off point or rank the guidelines (any guideline scoring above 60% on the rigor dimension was retained)

After reviewing all the previous criteria, the GDG/ GAG recommended using 3 guidelines:

Guideline (1): The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017 Oct 12;12(1):162

Guideline (2):  Breast feeding in infants diagnosed with phenylketonuria (PKU): a scoping review. BMJ Paediatr Open. 2023 Oct;7(1): e002066

Guideline (3): Epilepsy and vaccinations: Italian guidelines. Epilepsia, 54(Suppl. 7):13–22, 2013

We did Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -   Adoption for most of the guideline recommendations.

         -   Adaptation for two recommendations according to GRADE criteria to be suitable to our Economic implications (Evidence to Decision (EtD) table was done)

         -  Development of Good Practice Statement.

Contributors to the guideline development process:

Guideline Development Group (GDG)/ Guideline Adaptation Group (GAG):

The GDG/ GAG included two subgroups: the clinicians/ healthcare providers subgroup and the guideline methodologists’ subgroup.

➡️Clinicians Subgroups

The clinicians’ subgroup or clinical panel for this guideline included experts with a range of knowledge, technical skills and diverse perspectives in the field of medical genetics and pediatric genetics/metabolic specialists.

The main functions of the clinical panel were adolopment of PAH deficiency Guidelines, determining the scope of the guideline and guideline, reviewing the evidence, and formulating evidence-informed recommendations in case of changing the strength of recommendations.

➡️Guideline Methodologists Subgroup

There were 7 guideline methodologists with expertise in guidelines development, adaptation, GRADE and translation of evidence into recommendations. Methodologists provided orientation and overview of evidence-informed guideline development processes using the GRADE approach, guideline adaptation using the Adapted ADAPTE, provided AGREE II assessment of the source guidelines in collaboration with the clinician’s subgroup, generation of the EtD frameworks whenever applicable.

 ➡️External Review Group:

The External Review Group for this guideline comprises 2 clinical national experts who have interest and expertise in as well as eminent international reviewers.

They were identified by Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) as people who can provide valuable insights during the guideline development process.

The External Review Group was asked to comment on (peer review) the final guideline to identify any criticism on the content and to comment on clarity and applicability as well as issues relating to implementation, dissemination, ethics, regulations, or monitoring, but not to change the recommendations formulated by the GDG/ GAG. The members of the External Review Group were required to submit declarations of interest before the peer review process.

➡️Guideline Development/ Adaptation Group meetings:

GDG/ GAG meetings were organized virtually (weekly/bimonthly). Due to the extensive scope of the guideline, EPG was responsible for overseeing the adolopment process. the timetable and objectives of each meeting. GDG/ GAG meetings were also attended by members of the methodologists. Working rules for each contributor type were outlined by the chair at the start of each meeting, covering aspects such as vocal rights, voting, and evidence to decision and recommendation formulating processes.

➡️Declarations of interest:

Prospective members of the GDG/ GAG were asked to fill in and sign the standard WHO declaration of interest and confidentiality undertaking forms. All guideline members and methodologists were also asked to fill in and sign the standard WHO declaration-of-interests.

Members of the external review group will be asked to fill in and sign the standard WHO declaration-of-interests form before the peer review process.

➡️Evidence for the guideline:

We used the GRADE system (Grading of Recommendations, Assessment, Development and Evaluation) for assigning the quality of evidence and strength of recommendations that includes the following definitions [13]. Informed by the evidence required for the GRADE Evidence to Decision (EtD) framework(s) was(were) done while considering changing strength of recommendations according to availability of some resources in the recommendations (both ETD and changing strength of recommendation were not done in this guideline).

Description of the interpretation of the GRADE four levels of certainty of evidence:

Table 1. Classification of the Quality of Evidence

GRADE EtD’s contextual factors, criteria and considerations that link to the strength of recommendations:

Criteria and Considerations:

1.  Benefits and harms: When a new recommendation is developed, desirable effects (benefits) need to be weighed against undesirable effects (risks/harms), considering any previous recommendation or another alternative. The larger the gap or gradient in favor of the desirable effects over the undesirable effects, the more likely that a strong recommendation will be made.

2. Certainty of the evidence about the effects: The higher the certainty of the scientific evidence base, the more likely that a strong will be made.

3. Values and preferences: If there is no important uncertainty or variability in how much people value the main outcomes, it is likely that a strong recommendation will be made. Uncertainty or variability around these values that could likely lead to different decisions, is more likely to lead to a conditional recommendation.

4. Economic implications: Lower costs (monetary, infrastructure, equipment or human resources) or greater cost-effectiveness are more likely to support a strong recommendation.

5. Equity and human rights: If an intervention will reduce inequity, improve equity or contribute to the realization of human rights, the greater the likelihood of a strong recommendation.

6. Feasibility: The greater the feasibility of an intervention to all stakeholders, the greater the likelihood of a strong recommendation.

7. Acceptability: If a recommendation is widely supported by health workers and program managers and there is widespread acceptance for implementation within the health service, the likelihood of a strong recommendation is greater.

Table 2. Classification of the Strengths of Recommendations

➡️Developing good practice statements:

The GDG/ GAG also developed good practice statements for this guideline, which are actionable messages relevant to the guideline questions. The justification for each good practice statement was carefully considered by the GDG/ GAG with an emphasis that they are clearly needed. Good practice statements were developed, guided by the following GRADE criteria:

1- Message is necessary about actual healthcare practice

2- Have large net positive consequences (relevant outcomes and downstream consequences) (GRADE EtD domains)

3- Collecting and summarizing the evidence is a poor use of time and resources

4- Include a well-documented, clear rationale connecting indirect evidence

5- Are clear and actionable statements.

The GDG/ GAG collectively drafted and finalized good practice statements with relevant justifications and remarks to help with their interpretation, with close support and input from the consultant and guideline methodologists.

We have used the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension for adapted guidelines (RIGHT-Ad@pt Tool) as a reporting checklist for this guideline adaptation process as recommended by the EQUATOR network.

- Evidence to recommendations: Considerations

The GDG/ GAG was guided by the results of the AGREE II appraisals of the eligible CPGs and thoroughly reviewed the recommendations of the original source WHO CPGs in consideration of local contextual factors related to the national Egyptian health system like burden of the disease, equity, acceptability, feasibility, and other relevant factors. The GDG decided through an informal consensus process to adopt most recommendations, however, there was a need to change the strength of 2 recommendations (B2 and B3) as they lack feasibility. Also, GDG/ GAG develops a group of good practice statements to improve acceptability and feasibility.

- Implementation Tools and Considerations

To improve healthcare provision, quality, safety, and patient outcome, evidence-based recommendations must not only be developed, but also disseminated and implemented at national and local levels and integrated into clinical practice.

Dissemination involves educating related healthcare providers to improve their awareness, knowledge and understanding of the guideline’s recommendations. It is one part of implementation, which involved translation of evidence-based guidelines into real life practice with improvement of health outcomes for the patients.

Implementation requires an evidence-based strategy involving professional groups and stakeholders and should consider the local cultural and socioeconomic conditions. Cost-effectiveness of implementation programs should be assessed.

Specific steps need to be followed before clinical practice recommendations can be integrated into local clinical practice, particularly in low resource settings.

Steps of implementing PAH diagnosis, treatment, and prevention of neurocognitive impairment strategies into the Egyptian health system:

1. Develop a multidisciplinary working group.

2.  Assess the status of nutritional care delivery, care gaps and current needs.

3. Select the material to be implemented, agree on the main goals, identify the key recommendations for diagnosis, treatment and prevention and adapt them to the local context or environment.

4.  Identify barriers to, and facilitators of implementation.

5. Select an implementation framework and its component strategies.

6.  Develop a step-by-step implementation plan:

▪️ Select the target populations and evaluate the outcome.

▪️   Identify the local resources to support the implementation.

▪️    Set timelines.

▪️  Distribute the tasks to the members.

▪️ Evaluate the outcomes.

7.  Continuously review the progress and results to determine if the strategy requires modification.

Guideline implementation strategies will focus on the following: -

1. For Practitioners

▪️Educational meetings: conferences, lectures, workshops, grand rounds, seminars, and symposia.

▪️  Educational materials: printed or electronic information (software).

▪️ Web-based education: computer-based educational activities.

▪️  A trained person meets with providers in their practice setting to provide information with the intention of changing the provider’s practice. The information may include feedback on the performance of the provider(s).

▪️ Reminders: the provision of information verbally, on paper or on a computer screen to prompt a health professional to recall information or to perform or avoid a particular action related to patient care.

▪️Optimize professional-patient interactions, through mass media campaigns, reminders, and education materials.

▪️  Practice tools: tools designed to facilitate behavioral/practice changes, e.g., flow charts (figure 1,2).

2. For Patients and care givers

▪️ Patient education materials (Arabic booklet): Printed/electronic information aimed at the patient/consumer, family, caregivers, etc.

▪️Reminders: the provision of information verbally, on paper or electronically to remind a patient/consumer to perform a particular health-related behaviors.

▪️ Mass media campaigns.

3.  For Nurses

▪️Educational meetings: lectures, workshops or training courses, seminars, and symposia.

▪️ Educational materials: printed.

▪️ A trained person meets with nurses in their practice setting to provide information with the intention of changing the provider’s practice.

▪️  Reminders: the provision of information verbally, on paper or on a computer screen to prompt them to recall information or to perform or avoid a particular action related to patient care.

▪️ Practice tools: tools designed to facilitate behavioral/practice changes.

4. For Stakeholders

Plans have been made to contact with all the health sectors in Egypt including all sectors of the Ministry of Health and Population, National Nutrition Institute, University Hospitals, Ministry of Interior, Ministry of Defense, Non-Governmental Organizations, Private sector, and all Health Care Facilities.

▪️  Information and communication technology: Electronic decision support, order sets, care maps, electronic health records, office-based personal digital assistants, etc.

▪️ Any summary of clinical provision of health care over a specified period may include recommendations for clinical action. The information is obtained from medical records, databases, or observations by patients. Summary may be targeted at the individual practitioner or the organization.

▪️ Administrative policies and procedures.

▪️Formularies: Drug safety programs, electronic medication administration records.

5. Other activities to assist the implementation of the adapted guideline’s recommendations include:

▪️ International initiative: Dissemination of the presented adapted CPG internationally via sending the final adapted CPG to the Guidelines International Network (GIN) Adaptation Working Group and contacting the CPG developers.

▪️  Gantt chart has been designed to manage the dissemination and implementation stages for the adapted CPG over an accurate time frame (Appendix).

➡️Guideline Implementation Tools

Educational materials based on this Adapted CPG for treatment of CAP in children have been made available in several forms including:

1. Manual for physicians for diagnosis and algorithm for management of acute malnutrition

3. Arabic Educational materials for nurses and mothers

- Limitations and suggestions for further research needs

Future research recommendations for the management of PKU in children in the Egyptian context could include:

▪️  Documents for detailed available food allowed with Phe content.

▪️  An educational supplementary material to schools, teachers, and nurses

▪️ A guideline for management of PKU in adults and in pregnanacy

▪️Adding the new therapies once available in Egypt

These recommendations aim to address specific challenges and characteristics of the Egyptian context, potentially leading to more effective management strategies for PAH defeciency in children.

➡️Challenges

▪️  The small number of specialized physicians in relation to the large number of newly diagnosed PKU patients each year.

▪️  The maldistribution of specialized metabolic clinics being focused on the capital and large universities

▪️  The lack of specialized nurses and health workers in metabolic specialty

Strengthen the evidence base of the next update of this guideline by generating GRADE summary of finding tables, evidence profiles, and EtD frameworks.

- Monitoring and evaluating the impact of the guideline.

The following are three performance measures or indicators for implementing this adapted CPG for PKU in children:

1.  Adherence to PKU Guidelines

▪️ Numerator: Number of children with PAH deficiency who received treatment as per guideline recommendations.

▪️   Denominator: Total number of children diagnosed with PAH deficiency.

▪️  Data Source: Metabolic outpatients/ clinic patient records.

2.  Neurocognitive outcome

▪️   Numerator: Total number of children with PAH deficiency with average IQ and neurocognitive functions.

▪️   Denominator: Total number of children diagnosed with PAH deficeinc.

▪️   Data Source: Metabolic outpatients/ clinic patient records..

These key performance indicators are designed to measure the effectiveness and adherence to the guidelines, the efficiency of the treatment in terms of resource utilization and the success of the treatment in preventing further complications (neurocognitive outcome).

- Updating of the guideline

The EPG genetics GAG has decided to conduct the next review of this adapted CPG for updates after five years. This should be carried out in 2029 after checking for updates in the source CPGs, consultation of expert opinion on the changes needed for updating according to the newest evidence and recommendations published in this area and the clinical audit and feedback from implementation efforts in the local healthcare settings except if any breakthrough evidence- based recommendations are published before that date. The process will be guided by the Checklist for the Reporting of Updated Guidelines (CheckUp) Tool that is freely provided by the AGREE Enterprise and by the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension for adapted guidelines RIGHT-Ad@pt Checklist.

- References

1.     Abdel Baky A, Omar TEI, Amer YS; Egyptian Pediatric Clinical Practice Guidelines Committee (EPG). Adapting global evidence-based practice guidelines to the Egyptian healthcare context: the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) initiative. Bull Natl Res Cent. 2023;47(1):88. https://doi.org/10.1186%2Fs42269-023-01059-0

2.     Alshehri A, Almazrou S, Amer Y. Methodological frameworks for adapting global practice guidelines to national context in the Eastern Mediterranean Region. Eastern Mediterranean Health Journal. 2023 Jul 1;29(7). https://www.emro.who.int/emhj-volume-29-2023/volume-29-issue-7/methodological-frameworks-for-adapting-global-practice-guidelines-to-national-context-in-the-eastern-mediterranean-region.html

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- Annexes

Annex Table 2. Results of the AGREE II assessment of the three source guidelines for The complete European guidelines on phenylketonuria: diagnosis and treatment.

Results of the AGREE II assessment of the three source guidelines for Epilepsy and vaccinations: Italian guidelines.

PRISMA-ScR-scoping review-Checklist, Breast feeding in infants diagnosed with phenylketonuria (PKU) a scoping review.

JBI = Joanna Briggs Institute; PRISMA-ScR = Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews.

* Where sources of evidence (see second footnote) are compiled from, such as bibliographic databases, social media platforms, and Web sites.

† A more inclusive/heterogeneous term used to account for the different types of evidence or data sources (e.g., quantitative and/or qualitative research, expert opinion, and policy documents) that may be eligible in a scoping review as opposed to only studies. This is not to be confused with information sources (see first footnote).

‡ The frameworks by Arksey and O’Malley (6) and Levac and colleagues (7) and the JBI guidance (4, 5) refer to the process of data extraction in a scoping review as data charting.

§ The process of systematically examining research evidence to assess its validity, results, and relevance before using it to inform a decision. This term is used for items 12 and 19 instead of "risk of bias" (which is more applicable to systematic reviews of interventions) to include and acknowledge the various sources of evidence that may be used in a scoping review (e.g., quantitative and/or qualitative research, expert opinion, and policy document).

From: Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMAScR): Checklist and Explanation. Ann Intern Med. 2018;169:467–473. doi: 10.7326/M18-0850.

Annex Table 3. Annex Nurses and Parents Educational Guide in Arabic

Figure (1): Treatment of PAH deficiency according to Phe level

   Figure (2): Target Phe levels for optimal management in  PAH deficiency