Hulya Gokmen-Ozel

The reality of dietary compliance in the management of phenylketonuria

In phenylketonuria (PKU), it is common for blood phenylalanine (Phe) concentrations to be outside optimal target ranges, particularly in teenagers and adults, indicating inadequate compliance. It is well known that significant noncompliance exists, and the situation in PKU would appear no different than other chronic conditions. In PKU, compliance is complex, being subject to diverse definitions, and factors influencing compliance include the nature and nurture of the patient, as well as the inconvenience, cost and availability of dietary treatment. It is also a dynamic process, with many patients changing between a state of compliance and partial and noncompliance. In PKU, compliance has received little rigorous study, and there have been few observational reports identifying barriers and behaviors impacting dietary compliance. Compliance assessment measures remain inadequately defined. The direct assessment of blood Phe concentration is perhaps the best overall measure, but there is no universal agreement about the number of Phe concentrations that should be within target range and frequency or timing of measurement. Although no one strategy for improving compliance is universally effective, and an individualized approach to noncompliance is essential, it is important to have clear evidence about the most effective strategies in achieving long-term dietary adherence in PKU.

Blood phenylalanine control in phenylketonuria: a survey of 10 European centres

Background:Only limited data are available on the blood phenylalanine (Phe) concentrations achieved in European patients with phenylketonuria (PKU) on a low-Phe diet.Objective:A survey was conducted to compare blood Phe control achieved in diet-treated patients with PKU of different age groups in 10 European centres.Methods:Centres experienced in the management of PKU from Belgium, Denmark, Germany, Italy, The Netherlands, Norway, Poland, Spain, Turkey and the United Kingdom provided retrospective audit data of all patients with PKU treated by diet over a 1-year period. Standard questions were used to collect median data on blood Phe concentrations, percentage of blood Phe concentrations below upper target reference ranges and frequency of blood Phe sampling.Results:Data from 1921 patients on dietary management were included. Blood Phe concentrations were well controlled and comparable across centres in the early years of life. The percentages of blood Phe concentrations meeting each centres local and national target ranges were 88% in children aged up to 1 year, 74% for 1–10 years, 89% for 11–16 years and 65% for adults (>16 years). The frequency of home blood sampling, compared with local and national recommendations for monitoring Phe concentrations, appeared to decline with age (from approximately 100% in infancy to 83% in teenagers and 55% in adults).Conclusions:Although blood Phe control generally deteriorated with age, some improvement was observed in adolescent years across the 10 European centres. The blood Phe control achieved seemed comparable in many of the European centres irrespective of different dietary treatments or national policies.

Optimising growth in phenylketonuria: Current state of the clinical evidence base

Patients with phenylketonuria (PKU) must follow a strict low-phenylalanine (Phe) diet in order to minimise the potentially disabling neuropsychological sequelae of the disorder. Research in this area has unsurprisingly focussed largely on managing blood Phe concentrations to protect the brain. Protein requirements in dietary management of PKU are met mostly from Phe-free protein substitutes with the intake of natural protein restricted to patient tolerance. Several reports have suggested that growth in early childhood in PKU is sub-optimal, relative to non-PKU control groups or reference populations. We reviewed the literature searching for evidence regarding PKU and growth as well as possible links between dietary management of PKU and growth. The search retrieved only limited evidence on the effect of PKU and its dietary management on growth. Physical development in PKU remains an under-studied aspect of this disorder.

Diet in phenylketonuria: A snapshot of special dietary costs and reimbursement systems in 10 international centers

BACKGROUND AND AIMS To gather exploratory data on the costs and reimbursement of special dietary foods used in the management of phenylketonuria (PKU) from ten international specialist PKU centers. METHODS Experts from each center provided data on retail costs of the three most frequently used phenylalanine-free protein substitutes and low-protein foods at their center; reimbursement of protein substitutes and low-protein foods; and state monetary benefits provided to PKU patients. RESULTS The mean annual cost of protein substitutes across 4 age groups (2 y, 8 y, 15 y and adults) ranged from €4273 to €21,590 per patient. The cost of low-protein products also differed; the mean cost of low-protein bread varied from €0.04 to €1.60 per 100 kcal. All protein substitutes were either fully reimbursed or covered by health insurance. However, reimbursement for low-protein products varied and state benefits differed between centers. CONCLUSIONS The variation in the cost and reimbursement of diet therapy and the level of additional state benefits for PKU patients demonstrates the large difference in expenditure on and access to PKU dietary products. This highlights the inequality between healthcare systems and access to special dietary products for people with PKU, ultimately leading to patients in some countries receiving better care than others.

Adjusting diet with sapropterin in phenylketonuria: what factors should be considered?

The usual treatment for phenylketonuria (PKU) is a phenylalanine-restricted diet. Following this diet is challenging, and long-term adherence (and hence metabolic control) is commonly poor. Patients with PKU (usually, but not exclusively, with a relatively mild form of the disorder) who are responsive to treatment with pharmacological doses of tetrahydrobiopterin (BH4) have either lower concentrations of blood phenylalanine or improved dietary phenylalanine tolerance. The availability of a registered formulation of BH4 (sapropterin dihydrochloride, Kuvan®) has raised many practical issues and new questions in the dietary management of these patients. Initially, patients and carers must understand clearly the likely benefits (and limitations) of sapropterin therapy. A minority of patients who respond to sapropterin are able to discontinue the phenylalanine-restricted diet completely, while others are able to relax the diet to some extent. Care is required when altering the phenylalanine-restricted diet, as this may have unintended nutritional consequences and must be undertaken with caution. New clinical protocols are required for managing any dietary change while maintaining control of blood phenylalanine, ensuring adequate nutrition and preventing nutritional deficiencies, overweight or obesity. An accurate initial evaluation of pre-sapropterin phenylalanine tolerance is essential, and the desired outcome from treatment with sapropterin (e.g. reduction in blood phenylalanine or relaxation in diet) must also be understood by the patient and carers from the outset. Continuing education and support will be required thereafter, with further adjustment of diet and sapropterin dosage as a young patient grows.

Protein substitutes for phenylketonuria in Europe: access and nutritional composition

Background/Objectives:Protein substitutes (PS) are an essential component in the dietary management of phenylketonuria (PKU). PS are available as phenylalanine-free amino-acid mixtures (AAM), glycomacropeptide-based PS (GMP) and large neutral amino acids (LNAA). There is a lack of information regarding their availability in different countries and comparison of their nutritional composition is limited. The objectives of this study were to identify the number of PS available in different European countries and Turkey and to compare their nutritional composition.Subjects/Methods:Members of the European Nutritionist Expert Panel on PKU (ENEP) (Portugal, Spain, Belgium, Italy, Germany, Netherlands, United Kingdom, Denmark and Turkey) provided data on PS available in each country. The nutritional composition of PS available in Portugal was analyzed.Results:The number of PS available in each country varied from 30 (Turkey) to 105 (Germany), with a median of 64. GMP was available only in Portugal, whereas LNAA was an option in Portugal, Italy, Turkey and Denmark. Some PS were designed for weaning. Many PS did not contain added fat and fiber. GMP contained the highest carbohydrate (CHO) and energy content as well as higher LNAA content compared with AAM. Only one AAM contained added fructo-oligosaccharides and galacto-oligosaccharides. AAM designed for the first year of life had the highest CHO, fat and LNAA contribution. Liquid AAM had lower CHO and fat contents compared with powdered AAM, but contained higher LNAA.Conclusions:There was widely dissimilar numbers of PS available in different countries. Nutritional composition of different PS was variable and should be considered before prescription.

Nutritional content of modular feeds: how accurate is feed production?

Objective This prospective, observational study examined the accuracy of modular feed preparation for children with complex medical conditions requiring specialist feeds. Methods and design Participants who regularly prepare special feeds at home were observed preparing two feeds with equivalent nutrient composition: a 2-ingredient (2-IF) and 6-ingredient feed (6-IF) under research-conditions, and 8 weeks later under home-conditions. The same feeds (2-IF and 6-IF) prepared by a trained feed-maker served as controls. Biochemical analysis of nutrient content was performed as an objective measure of feed preparation accuracy. Results 52 participants were studied: one patient and 51 caregivers. Biochemical nutrient analysis was inaccurate for both feeds including control-feeds but was better for the 2-IF. Both feeds were lower in fat than the expected calculation but more so in the 6-IF than the 2-IF (median: 34% vs 84% of calculated research-condition values and 66% vs 90% home-conditions; p<0.0001). Conversely zinc was higher in the 6-IF than the 2-IF (median: 127% vs 87% research-conditions and 130% vs 89% home-conditions; p<0.0001). Preparation errors included: incorrect use of equipment, poor recipe adherence and ingredient measurement mistakes. Even in control-feeds there was equipment inaccuracy, poor ingredient emulsification and ingredient residue left in mixing/measuring containers. Fewer errors occurred with powdered than liquid ingredients. Conclusions Many errors associated with special feed production are difficult to control. Carers of children with complex medical conditions require improved preparation equipment and techniques and the development of premeasured or combined ingredient preparations to maximise feed accuracy and minimise clinical risk.