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Clinical Nutrition

Protein substitutes for phenylketonuria in Europe: access and nutritional composition

Abstract

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.

Introduction

Nutritional treatment of patients with phenylketonuria (PKU) involves the restriction of phenylalanine (Phe), found in natural protein-containing foods, in combination with a protein replacement/substitute without Phe. Protein substitutes (PS) are mainly phenylalanine-free (Phe-free), but supplemented with carbohydrate (CHO), micronutrients and sometimes fat. Amino-acid mixtures (AAM) and large neutral amino-acid (LNAA) supplements are prescribed in the nutritional management of PKU, although the former represent the most common approach.1 Depending on disorder severity, protein intake derived from PS can supply 80% of the total protein intake.2, 3 They have had an important role in helping prevent neurological disability,4 improving growth5 and preventing micronutrient deficiency.6, 7 Although there is a general recognition that PS presentation has improved, its nutritional profile and its potential effect on nutritional outcome and nutrient imbalance still generate important discussion.8 There has been recent focus about their energy profile, addition of novel nutrients and even excess amounts of some micronutrients9, 10, 11 (Figure 1).

Figure 1
figure1

Evolution of protein substitutes over history. Abbreviations: AAM, amino-acid mixtures; PE, protein equivalent; GMP, glycomacropeptide-based PS; LNAA, large neutral amino acids.

Avoiding protein insufficiency, increasing Phe tolerance, improving blood Phe control and providing a higher intake of LNAA are some of the main functions of AAM.12 LNAA (leucine, tyrosine, tryptophan, threonine, isoleucine, valine, methionine, histidine, except Phe) are important in terms of aiding amino-acid transport across the blood–brain barrier13 and the gut as they share the same Phe transporter system, reducing Phe absorption and brain levels.14 The results of a double-blind, placebo-controlled trial demonstrated a significantly lower blood Phe levels after 1 week of treatment with LNAA in 20 patients with PKU.15 Nevertheless, their long-term clinical efficacy still need further research,1 and supplementation with LNAA, only compared with traditional AAM, do not seem to provide an important advantage.16 Glycomacropeptide-based PS (GMP) is an alternative to synthetic l-amino acids because their main nitrogen source is from a peptide derived from whey protein produced during cheese production.17 Animal studies have demonstrated that GMP significantly decreases blood Phe levels compared with AAM and casein18 and it is more acceptable to patients,19 although it does contain residual Phe content that should be considered. There is clearly a need for more robust clinical data to understand its functionality compared with AAM,1 particularly its metabolic and nutritional effects. There is also a need to examine energy intake provided by all PS and the role this may have in the etiology of overweight and obesity in PKU, particularly in females,20 as well as maintenance of acceptable metabolic control.

The nutritional composition of PS is regulated by the European legislation ‘Foods for Special Medical Purposes’ (Commission Directive 1999/21/EC of 25 March 1999; amended in Directive 2006/141/EC). This Directive sets out rules for the composition and labeling of foods that are specifically formulated, processed and intended for the dietary management of diseases, disorders or medical conditions of individuals who are being treated under medical supervision. Also, the nutritional substances that may be used in the manufacture of foods for special medical purposes are also outlined in legislation: Commission Regulation (EC) No. 953/2009.21 In addition, all ‘Foods for Special Medical Purposes’ have to follow the European Food Information to Consumers Regulation No. 1169/2011 and Regulation No. 609/2013.

The objectives of this study were to identify the number and types of PS available across Europe and Turkey and to compare the nutritional composition of PS accessible in Portugal.

Materials and methods

In July 2013, comprehensive nutritional composition data on the PS suitable for PKU (provided per 1 g of protein equivalent of each PS) reimbursed by the Portuguese government (available at http://www.dgs.pt/) was collected from dietary companies. Data obtained were compared with that listed in the compendiums and vademecum of each brand. PS were subdivided into three categories: AAM, GMP and LNAA.

Product databases with nutritional data were stored on an excel database. All PS was grouped by their brand documenting target age group, presentation format (liquid, powder, tablet and bar), pack size, volume/weight and flavor. For each PS the full nutritional composition was documented and we compared energy, protein, amino-acid, fat and CHO content. Each type of flavor of the same PS was considered as one individual PS as there were minor differences in nutritional composition. Other participants from the European Nutritionist Expert Panel on PKU (ENEP) (a group of dietitians/medical doctors from PKU centers in Europe (Spain, Belgium, Italy, Germany, Netherlands, UK, Denmark) and Turkey) were invited to participate. Each country member contributed a list of all available PS suitable for PKU in their countries.

Results

Number of PS available in Europe and Turkey

One hundred and seventy-nine different PS were available for the treatment of patients with PKU from nine different countries, although not all of these PS are available in each country (Table 1). Table 2 presents the number of different AAM available in each country based on target age and presentation form. One hundred and sixty-seven (93.3%) were AAM, 5 (2.8%) were GMP and 7 (3.9%) were LNAA. The number of PS varied widely in each country, with a median of 64 (range 30 in Turkey; 105 in Germany). LNAA were available in four countries and GMP only in Portugal (Table 1).

Table 1 Number of different PS available in each country
Table 2 Number of different AAM available by target age and presentation in each country

All PS were from 11 different companies, although not all products were available in each country/treatment center. Between countries, the nutritional composition of the same type/brand of PS did not vary in the centers/countries studied (data not shown). All countries except Turkey have PS targeted specifically for the weaning age, the transition phase to solid foods. Some authors have suggested that an early food experience may constitute an advantage in the acceptance of a wide variety of foods by PKU children.22 In Portugal, there were equal numbers of powdered and liquid AAM. In the other countries, the number of powder AAM outweighed the remaining presentation forms (Table 2).

Nutritional composition of Portuguese PS

Table 3 presents the nutritional composition of PS available in Portugal. Out of the 64 PS available in Portugal, 14 (21.9%) did not contain added fat, particularly products aimed at the weaning infant. In all PS analyzed, only 27 (42.2%) were supplemented with docosahexaenoic acid (DHA), and only 6 (9.4%) were supplemented with both DHA and arachidonic acid. Their CHO content and sources were also variable. In 13 AAM (23.2%), the primary source of CHO was sugars (all liquid AAM), and in 9 AAM (16.1%), the majority of CHO was from complex CHO. However, in 34 AAM (60.7%), 5 GMP (100%) and 3 LNAA (100%), this information was unstated. Only 26 AAM (46.4%) and 2 GMP (40%) products identified any fiber content on the nutritional compositional label. Fructo-oligosaccharides and galacto-oligosaccharides content were only identified in one AAM (1.8%).

Table 3 Nutritional profile of all PS available in Portugal (N=64) (expressed per 1 g PE)

Excluding infant PS, GMP contained the highest CHO and energy content. When only AAM were analyzed, the ready to drink formulations contained the lowest fat, CHO and energy content. The essential amino-acid/total amino-acid ratio (EAA/TAA) was similar in all AAM, whereas the large neutral amino-acid/total amino-acid ratio (LNAA/TAA) was lower in the AAM targeted for pregnancy. In the GMP, more than half of the TAAs were EAA, and LNAA were at a higher percentage compared with AAM (38% of protein contents in GMP were from free amino acids added). The mean Phe content of GMP was 1.8 mg/g of protein equivalent. LNAA products revealed the highest contribution in EAA and LNAA.

Although the mean nutritional composition of AAM designed for different age ranges may be similar, the wide range within each age category may be important.

Discussion

This study identified that in PKU, there was no uniform availability of PS in eight European countries and Turkey. Some of this may be due to different government policies and reimbursement strategies.23, 24, 25 It was also clear that PS developed for specific age ranges or clinical situations of patients varied widely in nutrient composition, and not all were formulated to meet the specific nutritional requirements of patients or the widely varying disorder severity spectrum. It would appear that more emphasis has been placed on their presentation format rather than nutrient composition in recent years.

Almost all PS used were based on AAM, with limited availability of LNAA and GMP. There is still inadequate research to support the use of LNAA and GMP,1 and the l-amino-acid profile in GMP may be inappropriate for children under a certain age. It is concerning that manufacturers recommend GMP for patients over 1 year old even though there is no published evidence supporting its safety in patients <11 years of age and maternal PKU, particularly when GMP contributes to Phe intake and this impact is unknown. LNAA products are only recommended by the manufacturers for patients >8 years old, excluding maternal PKU patients. Denmark does not allow full LNAA treatment and semi-free diet before 18 years old. The UK authorities have not yet permitted GMP or LNAA products owing to lack of supporting efficacy data.

In PKU, adequate nutrition in the first years of life is essential for long-term health,26 although there is a very limited range of AAM, especially designed for this age group. Although AAM provide a high percentage of total daily nutrition for infants with PKU, the full nutritional characteristics of these products do not usually mirror the nutrient profile typically found in the regular infant formulas. The absence of prebiotics to some infant AAM has been previously highlighted.27 There was only one AAM formulated to help with transition from liquid to solids at weaning age in Portugal, and it was unavailable in some countries. The example of Portugal further shows that not all PS designed for the first year contain fat nor are enriched in LCPUFAS.28

Probably, one of the reasons why so many adult patients (>16 years) do not adhere to diet is inability to take PS. They now represent the majority of the PKU patient population and manufacturers appear to have directed their efforts into this patient age group, which has led to the development of a wide range of PS presentations for older patients, for example, ready to drink pouches, amino-acid tablets, bars and granules added to food. Although ready to drink AAM have become popular,29 their nutritional composition is different in terms of non-protein energy content, and as consequence their efficacy needs further evaluation.30 Although the long-term efficacy has been studied,30 more detailed investigations are needed to determine the ideal amino-acid and nutrient profile in the adult population.

In parallel, there is clear recognition that PKU is a heterogeneous condition, varying from mild to severe in severity. More tailored AAM are necessary to respond to different non-Phe protein tolerance determined by individual disorder severity and Phe tolerance.31 AAM that are designed for patients aged >12 years with a reduced LNAA/TAA ratio undermine any suggestion that administration of LNAA in late adolescence may be an important strategy.32, 33, 34 Also, an area that is commonly neglected is the ratio of nitrogen/energy content in each PS and its potential impact on protein anabolism.35 Higher nitrogen needs for growth should be underlined by a careful balance between protein and energy to prevent catabolism and the provision of PS without or with reduced CHO and lipids deserves further research, especially for growing children. Equally, the specific nutritional characteristics of a PS designed for pregnancy should be defined as our data analysis indicates that the nutritional formulation of PS aimed at pregnancy are similar to others designed for adults and teenagers. Also, the tyrosine, iodine, folic acid and iron may need adjustment in products directed at pregnancy.36

Our study did not explore the micronutrient profile of PS as this has been carried out previously.37 Although, in recent years, companies have fortified AAM with vitamins and minerals,37 micronutrient deficiencies still occur in patients with PKU, especially those with poor intake of PS.11 Also, this study did not compare nutritional profile of all products from all countries, but the composition of the same branded products between countries was the same.

The need for European guidelines is unquestionable for consistent patient management based on the best research evidence.23 However, guidelines should not only be directed at patients and health-care professionals but at decision-making bodies. The differences found in the availability of these products and their nutritional composition solicit many questions about individual government policies within Europe and Turkey, the controls on nutritional composition of PS and the priorities of manufacturers in ensuring that nutritional formulations meet the requirements of specific age groups and situations.

There was no uniform availability of PS found between the countries we studied. Although these disparities contribute to different management practices around Europe, a careful analysis of nutritional profile of all products is desirable to better match each product to the nutrient and metabolic needs of each patient.

References

  1. 1

    Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N et al. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab 2014; 112: 87–122.

    CAS  Article  Google Scholar 

  2. 2

    MacDonald A . Diet and compliance in phenylketonuria. Eur J Pediatr 2000; 159 (Suppl 2), S136–S141.

    CAS  Article  Google Scholar 

  3. 3

    Yi SH, Singh RH . Protein substitute for children and adults with phenylketonuria. Cochrane Database Syst Rev 2008 (4), CD004731.

  4. 4

    Blau N, MacDonald A, van Spronsen F . There is no doubt that the early identification of PKU and prompt and continuous intervention prevents mental retardation in most patients. Mol Genet Metab 2011; 104 (Suppl), S1.

    CAS  Article  Google Scholar 

  5. 5

    Rocha JC, van Spronsen FJ, Almeida MF, Ramos E, Guimaraes JT, Borges N . Early dietary treated patients with phenylketonuria can achieve normal growth and body composition. Mol Genet Metab 2013; 110 (Suppl), S40–S43.

    CAS  Article  Google Scholar 

  6. 6

    Dokoupil K, Gokmen-Ozel H, Lammardo AM, Motzfeldt K, Robert M, Rocha JC et al. Optimising growth in phenylketonuria: current state of the clinical evidence base. Clin Nutr 2012; 31: 16–21.

    Article  Google Scholar 

  7. 7

    Rocha JC, Martins MJ . Oxidative stress in phenylketonuria: future directions. J Inherit Metab Dis 2012; 35: 381–398.

    CAS  Article  Google Scholar 

  8. 8

    Enns GM, Koch R, Brumm V, Blakely E, Suter R, Jurecki E . Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol Genet Metab 2010; 101: 99–109.

    CAS  Article  Google Scholar 

  9. 9

    Robert M, Rocha JC, van Rijn M, Ahring K, Belanger-Quintana A, MacDonald A et al. Micronutrient status in phenylketonuria. Mol Genet Metab 2013; 110 (Suppl), S6–S17.

    CAS  Article  Google Scholar 

  10. 10

    Stolen LH, Lilje R, Jorgensen JV, Bliksrud YT, Almaas R . High dietary folic acid and high plasma folate in children and adults with phenylketonuria. JIMD Rep 2014; 13: 83–90.

    Article  Google Scholar 

  11. 11

    Evans S, Daly A, MacDonald J, Preece MA, Santra S, Vijay S et al. The micronutrient status of patients with phenylketonuria on dietary treatment: an ongoing challenge. Ann Nutr Metab 2014; 65: 42–48.

    CAS  Article  Google Scholar 

  12. 12

    Aguiar A, Ahring K, Almeida MF, Assoun M, Belanger Quintana A, Bigot S et al. Practices in prescribing protein substitutes for PKU in Europe: no uniformity of approach. Mol Genet Metab 2015; 115: 17–22.

    CAS  Article  Google Scholar 

  13. 13

    Pietz J, Kreis R, Rupp A, Mayatepek E, Rating D, Boesch C et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest 1999; 103: 1169–1178.

    CAS  Article  Google Scholar 

  14. 14

    Strisciuglio P, Concolino D . New strategies for the treatment of phenylketonuria (PKU). Metabolites 2014; 4: 1007–1017.

    Article  Google Scholar 

  15. 15

    Matalon R, Michals-Matalon K, Bhatia G, Burlina AB, Burlina AP, Braga C et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J Inherit Metab Dis 2007; 30: 153–158.

    CAS  Article  Google Scholar 

  16. 16

    Schindeler S, Ghosh-Jerath S, Thompson S, Rocca A, Joy P, Kemp A et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab 2007; 91: 48–54.

    CAS  Article  Google Scholar 

  17. 17

    Ney DM, Blank RD, Hansen KE . Advances in the nutritional and pharmacological management of phenylketonuria. Curr Opin Clin Nutr Metab Care 2014; 17: 61–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Ney DM, Hull AK, van Calcar SC, Liu X, Etzel MR . Dietary glycomacropeptide supports growth and reduces the concentrations of phenylalanine in plasma and brain in a murine model of phenylketonuria. J Nutr 2008; 138: 316–322.

    CAS  Article  Google Scholar 

  19. 19

    van Calcar SC, MacLeod EL, Gleason ST, Etzel MR, Clayton MK, Wolff JA et al. Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids. Am J Clin Nutr 2009; 89: 1068–1077.

    CAS  Article  Google Scholar 

  20. 20

    Rocha JC, MacDonald A, Trefz F . Is overweight an issue in phenylketonuria? Mol Genet Metab 2013; 110 (Suppl), S18–S24.

    CAS  Article  Google Scholar 

  21. 21

    European Commission. Foods for Special Medical Purposes. Available at: http://ec.europa.eu/food/food/labellingnutrition/medical/index_en.htm (last accessed 10th November 2014).

  22. 22

    MacDonald A, Evans S, Cochrane B, Wildgoose J . Weaning infants with phenylketonuria: a review. J Hum Nutr Diet 2012; 25: 103–110.

    CAS  Article  Google Scholar 

  23. 23

    Hagedorn TS, van Berkel P, Hammerschmidt G, Lhotakova M, Saludes RP . Requirements for a minimum standard of care for phenylketonuria: the patients' perspective. Orphanet J Rare Dis 2013; 8: 191.

    Article  Google Scholar 

  24. 24

    Blau N, Belanger-Quintana A, Demirkol M, Feillet F, Giovannini M, MacDonald A et al. Management of phenylketonuria in Europe: survey results from 19 countries. Mol Genet Metab 2010; 99: 109–115.

    CAS  Article  Google Scholar 

  25. 25

    van Spronsen FJ, Ahring KK, Gizewska M . PKU—What is daily practice in various centres in Europe? Data from a questionnaire by the scientific advisory committee of the European Society of Phenylketonuria and Allied Disorders. J Inherit Metab Dis 2009; 32: 58–64.

    CAS  Article  Google Scholar 

  26. 26

    Koletzko B, Beyer J, Brands B, Demmelmair H, Grote V, Haile G et al. Early influences of nutrition on postnatal growth. Nestle Nutr Inst Workshop Ser 2013; 71: 11–27.

    PubMed  PubMed Central  Google Scholar 

  27. 27

    MacDonald A, Cochrane B, Wopereis H, Loveridge N . Specific prebiotics in a formula for infants with phenylketonuria. Mol Genet Metab 2011; 104 (Suppl), S55–S59.

    CAS  Article  Google Scholar 

  28. 28

    Koletzko B, Brands B, Chourdakis M, Cramer S, Grote V, Hellmuth C et al. The Power of Programming and the EarlyNutrition Project: opportunities for health promotion by nutrition during the first thousand days of life and beyond. Ann Nutr Metab 2014; 64: 187–196.

    CAS  Article  Google Scholar 

  29. 29

    MacDonald A, Lilburn M, Davies P, Evans S, Daly A, Hall SK et al. 'Ready to drink' protein substitute is easier is for people with phenylketonuria. J Inherit Metab Dis 2006; 29: 526–531.

    CAS  Article  Google Scholar 

  30. 30

    Gokmen-Ozel H, MacDonald A, Daly A, Hall K, Ryder L, Chakrapani A . Long-term efficacy of 'ready-to-drink' protein substitute in phenylketonuria. J Hum Nutr Diet 2009; 22: 422–427.

    CAS  Article  Google Scholar 

  31. 31

    MacDonald A, Ahring K, Dokoupil K, Gokmen-Ozel H, Lammardo AM, Motzfeldt K et al. Adjusting diet with sapropterin in phenylketonuria: what factors should be considered? Br J Nutr 2011; 106: 175–182.

    CAS  Article  Google Scholar 

  32. 32

    Rocha JC, Martel F . Large neutral amino acids supplementation in phenylketonuric patients. J Inherit Metab Dis 2009; 32: 472–480.

    CAS  Article  Google Scholar 

  33. 33

    van Spronsen FJ, de Groot MJ, Hoeksma M, Reijngoud DJ, van Rijn M . Large neutral amino acids in the treatment of PKU: from theory to practice. J Inherit Metab Dis 2010; 33: 671–676.

    CAS  Article  Google Scholar 

  34. 34

    Ahring KK . Large neutral amino acids in daily practice. J Inherit Metab Dis 2010; 33 (Suppl 3), S187–S190.

    Article  Google Scholar 

  35. 35

    Humphrey M, Truby H, Boneh A . New ways of defining protein and energy relationships in inborn errors of metabolism. Mol Genet Metab 2014; 112: 247–258.

    CAS  Article  Google Scholar 

  36. 36

    Kaiser L, Allen LH . Position of the American Dietetic Association: nutrition and lifestyle for a healthy pregnancy outcome. J Am Diet Assoc 2008; 108: 553–561.

    CAS  Article  Google Scholar 

  37. 37

    Lammardo AM, Robert M, Rocha JC, van Rijn M, Ahring K, Belanger-Quintana A et al. Main issues in micronutrient supplementation in phenylketonuria. Mol Genet Metab 2013; 110 (Suppl), S1–S5.

    CAS  Article  Google Scholar 

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Correspondence to J C Rocha.

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Competing interests

All authors have received compensation from Merck Serono as members of the European Nutritionist Expert Panel in PKU. AM has received research funding and honoraria from Nutricia, Vitaflo International, Arla, Sobi and Merck Serono. She is a member of the European Nutrition Expert Panel (Merck Serono international), a member of Sapropterin Advisory Board (Merck Serono international) and a member of the Advisory Board ELEMENT (Danone-Nutricia). MJP and MFdA declare no conflict of interest.

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Pena, M., de Almeida, M., van Dam, E. et al. Protein substitutes for phenylketonuria in Europe: access and nutritional composition. Eur J Clin Nutr 70, 785–789 (2016). https://doi.org/10.1038/ejcn.2016.54

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