Phenylalanine hydroxylase deficiency in children

➡️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

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/