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Table of Contents
Vol. 68, No. 2, 2010
Issue release date: June 2010
Section title: Paper
Free Access
Ann Nestlé [Engl] 2010;68:58–69
(DOI:10.1159/000312813)

Nutritional Management of Phenylketonuria

MacLeod E.L. · Ney D.M.
Department of Nutritional Sciences, University of Wisconsin, Madison, Wisc., USA
email Corresponding Author

Abstract

Phenylketonuria (PKU) is caused by deficient activity of the enzyme phenylalanine hydroxylase, needed to convert the essential amino acid (AA) phenylalanine (phe) to tyrosine. In order to prevent neurological damage, lifelong adherence to a low-phe diet that is restricted in natural foods and requires ingestion of a phe-free AA formula to meet protein needs is required. The goal of nutritional management for those with PKU is to maintain plasma phe concentrations that support optimal growth, development, and mental functioning while providing a nutritionally complete diet. This paper reviews developing a lifelong dietary prescription for those with PKU, outcomes of nutritional management, compliance with the low-phe diet across the life cycle, and new options for nutritional management. An individualized dietary prescription is needed to meet nutrient requirements, and the adequacy of phe intake is monitored with assessment of blood phe levels. Elevated phe concentrations may occur due to illness, excessive or inadequate phe intake, or inadequate intake of AA formula. Although normal growth and development occurs with adherence to the low-phe diet, it is important to monitor vitamin, mineral and essential fatty acid status, especially in those who do not consume sufficient AA formula. Given the growing population of adults with PKU, further research is needed to understand the risks for developing osteoporosis and cardiovascular disease. There are promising new options to liberalize the diet and improve metabolic control such as tetrahydrobiopterin therapy or supplementation with large neutral AAs. Moreover, foods made with glycomacropeptide, an intact protein that contains minimal phe, improves the PKU diet by offering a palatable alternative to AA formula. In summary, continued efforts are needed to overcome the biggest challenge to living with PKU – lifelong adherence to the low-phe diet.

© 2010 Nestec Ltd., Vevey/S. Karger AG, Basel


  

Key Words

  • Phenylketonuria
  • Phenylalanine
  • Phenylalanine hydroxylase
  • Long-chain polyunsaturated fatty acids
  • Tetrahydrobiopterin
  • Amino acid

References

  1. Donlon J, Levy H, Scriver C: Hyperphenylalaninemia: Phenylalanine hydroxylase deficiency; in Scriver C, Beaudet A, Sly W, Valle D (eds): Metabolic and Molecular Basis of Inherited Disease. New York, McGraw-Hill, chapter 77, 2007.
  2. Bickel H, Gerrard J, Hickmans EM: Influence of phenylalanine intake on phenylketonuria. Lancet 1953;265:812–813.
  3. Bickel H, Gerrard J, Hickmans EM: The influence of phenylalanine intake on the chemistry and behaviour of a phenyl-ketonuric child. Acta Paediatr 1954;43:64–77.
  4. NIH: Phenylketonuria (PKU): screening and management. NIH Consensus Statement 2000;17:1–33.
  5. Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria. Arch Dis Child 1993;68:426–427.
  6. Acosta PB, Matalon KM: Nutrition management of patients with inherited disorders of aromatic amino acid metabolism; in Acosta PB (ed): Nutrition Management of Patients with Inherited Metabolic Disorders. Boston, Jones and Bartlett Publishers, 2010, pp 119–174.
  7. Guttler F, Azen C, Guldberg P, et al: Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study. Pediatrics 1999;104:258–262.
  8. Abadie V, Berthelot J, Feillet F, et al: Management of phenylketonuria and hyperphenylalaninemia: the French guidelines (in French). Arch Pediatr 2005;12:594–601.
  9. Burgard P, Bremer HJ, Buhrdel P, et al: Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr 1999;158:46–54.
  10. Acosta P, Yannicelli S: Protocol 1 – phenylketonuria (PKU); in The Ross Metabolic Formula System Nutrition Support Protocols, ed 4. Columbus, Ross Products Division/Abbot Laboratories, 2001.
  11. Camfield CS, Joseph M, Hurley T, et al: Optimal management of phenylketonuria: a centralized expert team is more successful than a decentralized model of care. J Pediatr 2004;145:53–57.
  12. Metges CC, El-Khoury AE, Selvaraj AB, et al: Kinetics of L-[1-(13)C]leucine when ingested with free amino acids, unlabeled or intrinsically labeled casein. Am J Physiol Endocrinol Metab 2000;278:E1000–E1009.
  13. Dangin M, Boirie Y, Garcia-Rodenas C, et al: The digestion rate of protein is an independent regulating factor of postprandial protein retention. Am J Physiol Endocrinol Metab 2001;280:E340–E348.
  14. van Rijn M, Hoeksma M, Sauer P, Szczerbak B, Gross M, Reijngoud DJ, van Spronsen F: Protein metabolism in adult patients with phenylketonuria. Nutrition 2007;23:445–453.
  15. Kindt E, Halvorsen S: The need of essential amino acids in children. An evaluation based on the intake of phenylalanine, tyrosine, leucine, isoleucine, and valine in children with phenylketonuria, tyrosine amino transferase defect, and maple syrup urine disease. Am J Clin Nutr 1980;33:279–286.
  16. IOM: Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Protein and Amino Acids (Macronutrients). Washington, National Academy Press, 2002.
  17. WHO: Protein and Amino Acid Requirements in Human Nutrition. Geneva, WHO, 2007.
  18. Bross R, Ball RO, Clarke JT, Pencharz PB: Tyrosine requirements in children with classical PKU determined by indicator amino acid oxidation. Am J Physiol Endocrinol Metab 2000;278:E195–E201.
  19. Zello GA, Pencharz PB, Ball RO: Phenylalanine flux, oxidation, and conversion to tyrosine in humans studied with L-[1–13C]phenylalanine. Am J Physiol 1990;259:E835– E843.
  20. Courtney-Martin G, Bross R, Raffi M, et al: Phenylalanine requirement in children with classical PKU determined by indicator amino acid oxidation. Am J Physiol Endocrinol Metab 2002;283:E1249–E1256.
  21. MacLeod EL, Gleason ST, van Calcar SC, Ney DM: Reassessment of phenylalanine tolerance in adults with phenylketonuria is needed as body mass changes. Mol Genet Metab 2009;98:331–337.
  22. 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.
  23. Azen CG, Koch R, Friedman EG, et al: Intellectual development in 12-year-old children treated for phenylketonuria. Am J Dis Child 1991;145:35–39.
  24. Waisbren SE, Noel K, Fahrbach K, et al: Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab 2007;92:63–70.
  25. Weigel C, Kiener C, Meier N, et al: Carnitine status in early-treated children, adolescents and young adults with phenylketonuria on low phenylalanine diets. Ann Nutr Metab 2008;53:91–95.
  26. Barretto JR, Silva LR, Leite ME, et al: Poor zinc and selenium status in phenylketonuric children and adolescents in Brazil. Nutr Res 2008;28:208–211.
  27. van Bakel MM, Printzen G, Wermuth B, Wiesmann UN: Antioxidant and thyroid hormone status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients. Am J Clin Nutr 2000;72:976–981.
  28. Schulz B, Bremer HJ: Nutrient intake and food consumption of adolescents and young adults with phenylketonuria. Acta Paediatr 1995;84:743–748.
  29. Hvas AM, Nexo E, Nielsen JB: Vitamin B12 and vitamin B6 supplementation is needed among adults with phenylketonuria (PKU). J Inherit Metab Dis 2006;29:47–53.
  30. Acosta PB, Yannicelli S, Singh RH, et al: Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors. Genet Med 2004;6:96–101.
  31. Van Calcar SC, Macleod EL, Gleason ST, 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.
  32. Schulpis KH, Papassotiriou I, Tsakiris S, et al: Increased plasma adiponectin concentrations in poorly controlled patients with phenylketonuria normalize with a strict diet: evidence for catecholamine-mediated adiponectin regulation and a complex effect of phenylketonuria diet on atherogenesis risk factors. Metabolism 2005;54:1350–1355.
  33. Agostoni C, Scaglioni S, Bonvissuto M, et al: Biochemical effects of supplemented long-chain polyunsaturated fatty acids in hyperphenylalaninemia. Prostaglandins Leukot Essent Fatty Acids 2001;64:111–115.
  34. Moseley K, Koch R, Moser AB: Lipid status and long-chain polyunsaturated fatty acid concentrations in adults and adolescents with phenylketonuria on phenylalanine-restricted diet. J Inherit Metab Dis 2002;25:56–64.
  35. Agostoni C, Massetto N, Biasucci G, et al: Effects of long-chain polyunsaturated fatty acid supplementation on fatty acid status and visual function in treated children with hyperphenylalaninemia. J Pediatr 2000;137:504–509.
  36. Huemer M, Huemer C, Moslinger D, et al: Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. J Inherit Metab Dis 2007;30:694–699.
  37. Perez-Duenas B, Cambra FJ, Vilaseca MA, et al: New approach to osteopenia in phenylketonuric patients. Acta Paediatr 2002;91:899–904.
  38. Zeman J, Bayer M, Stepan J: Bone mineral density in patients with phenylketonuria. Acta Paediatr 1999;88:1348–1351.
  39. Yannicelli S, Medeiros DM: Elevated plasma phenylalanine concentrations may adversely affect bone status of phenylketonuric mice. J Inherit Metab Dis 2002;25:347–361.
  40. Deglaire A, Fromentin C, Fouillet H, et al: Hydrolyzed dietary casein as compared with the intact protein reduces postprandial peripheral, but not whole-body, uptake of nitrogen in humans. Am J Clin Nutr 2009;90:1011–1022.
  41. Schuett V: Low Protein Food List for PKU, ed 2, Seattle, National PKU News, 2002.
  42. Owada M, Aoki K, Kitagawa T: Taste preferences and feeding behaviour in children with phenylketonuria on a semisynthetic diet. Eur J Pediatr 2000;159:846–850.
  43. MacDonald A, Rylance G, Hall SK, et al: Factors affecting the variation in plasma phenylalanine in patients with phenylketonuria on diet. Arch Dis Child 1996;74:412–417.
  44. MacDonald A, Lilburn M, Davies P, et al: ‘Ready to drink’ protein substitute is easier is for people with phenylketonuria. J Inherit Metab Dis 2006;29:526–531.
  45. Prince AP, McMurray MP, Buist NR: Treatment products and approaches for phenylketonuria: improved palatability and flexibility demonstrate safety, efficacy and acceptance in US clinical trials. J Inherit Metab Dis 1997;20:486–498.
  46. Walter JH, White FJ, Hall SK, et al: How practical are recommendations for dietary control in phenylketonuria? Lancet 2002;360:55–57.
  47. Singh RH, Kable JA, Guerrero NV, et al: Impact of a camp experience on phenylalanine levels, knowledge, attitudes, and health beliefs relevant to nutrition management of phenylketonuria in adolescent girls. J Am Diet Assoc 2000;100:797–803.
  48. Schuett VE, Brown ES, Michals K: Reinstitution of diet therapy in PKU patients from twenty-two US clinics. Am J Public Health 1985;75:39–42.
  49. Bik-Multanowski M, Didycz B, Mozrzymas R, et al: Quality of life in noncompliant adults with phenylketonuria after resumption of the diet. J Inherit Metab Dis 2008, Epub ahead of print.
  50. Gassio R, Campistol J, Vilaseca MA, et al: Do adult patients with phenylketonuria improve their quality of life after introduction/resumption of a phenylalanine-restricted diet? Acta Paediatr 2003;92:1474–1478.
  51. Waisbren SE, Hanley W, Levy HL, et al: Outcome at age 4 years in offspring of women with maternal phenylketonuria: the Maternal PKU Collaborative Study. JAMA 2000;283:756–762.
  52. Rohr F, Munier A, Sullivan D, et al: The Resource Mothers Study of Maternal Phenylketonuria: preliminary findings. J Inherit Metab Dis 2004;27:145–155.
  53. Fiege B, Blau N: Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr 2007;150:627–630.
  54. Trefz FK, Burton BK, Longo N, et al: Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr 2009;154:700–707.
  55. Burlina A, Blau N: Effect of BH(4) supplementation on phenylalanine tolerance. J Inherit Metab Dis 2009;32:40–45.
  56. Hennermann JB, Buhrer C, Blau N, et al: Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 2005;86(suppl 1):S86–S90.
  57. Blau N, Belanger-Quintana A, Demirkol M, et al: Optimizing the use of sapropterin (BH4) in the management of phenylketonuria. Mol Genet Metab 2009;96:158–163.
  58. Singh R, Jurecki E, Rohr F: Recommendations for personalized dietary adjustments based on patient response to tetrahydrobiopterin (BH4) in phenylketonuria. Top Clin Nutr 2008;23:149–157.
  59. Broer S: Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev 2008;88:249–286.
  60. Weglage J, Wiedermann D, Denecke Jet al: Individual blood-brain barrier phenylalanine transport determines clinical outcome in phenylketonuria. Ann Neurol 2001;50:463–467.
  61. Pietz J, Kreis R, Rupp A, et al: Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest 1999;103:1169–1178.
  62. Schindeler S, Ghosh-Jerath S, Thompson S, et al: The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab 2007;91:48–54.
  63. Matalon R, Michals-Matalon K, Bhatia G, 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.
  64. Ney DM, Hull AK, van Calcar SC, et al: 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.
  65. Etzel MR: Manufacture and use of dairy protein fractions. J Nutr 2004;134:996S–1002S.
  66. Veldhorst MA, Nieuwenhuizen AG, Hochstenbach-Waelen A, et al: Effects of complete whey-protein breakfasts versus whey without GMP-breakfasts on energy intake and satiety. Appetite 2009;52:388–395.
  67. MacLeod EL, Clayton MK, van Calcar SC, et al: Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria. Mol Genet Metab 2010, E-pub ahead of print. DOI: 10.1016/j.ymgme.2010.04.003.

    External Resources

  68. Ney DM, Gleason ST, van Calcar SC, et al: Nutritional management of PKU with glycomacropeptide from cheese whey. J Inherit Metab Dis 2009;32:32–39.
  69. Sanjurjo P, Aldamiz L, Georgi G, et al: Dietary threonine reduces plasma phenylalanine levels in patients with hyperphenylalaninemia. J Pediatr Gastroenterol Nutr 2003;36:23–26.
  70. van Spronsen FJ, Burgard P: The truth of treating patients with phenylketonuria after childhood: the need for a new guideline. J Inherit Metab Dis 2008;31:673–679.

  

Author Contacts

Denise M. Ney
Department of Nutritional Sciences
University of Wisconsin
1415 Linden Drive, Madison, WI 53706 (USA)
Tel. +1 608 262 4386, Fax +1 608 262 5860, E-Mail ney@nutrisci.wisc.edu

  

Article Information

Published online: June 22, 2010
Number of Print Pages : 12
Number of Figures : 2, Number of Tables : 2, Number of References : 70

  

Publication Details

Annales Nestlé (English ed.)

Vol. 68, No. 2, Year 2010 (Cover Date: June 2010)

ISSN: 0517-8606 (Print), eISSN: 1661-4011 (Online)

For additional information: http://www.karger.com/ANE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Phenylketonuria (PKU) is caused by deficient activity of the enzyme phenylalanine hydroxylase, needed to convert the essential amino acid (AA) phenylalanine (phe) to tyrosine. In order to prevent neurological damage, lifelong adherence to a low-phe diet that is restricted in natural foods and requires ingestion of a phe-free AA formula to meet protein needs is required. The goal of nutritional management for those with PKU is to maintain plasma phe concentrations that support optimal growth, development, and mental functioning while providing a nutritionally complete diet. This paper reviews developing a lifelong dietary prescription for those with PKU, outcomes of nutritional management, compliance with the low-phe diet across the life cycle, and new options for nutritional management. An individualized dietary prescription is needed to meet nutrient requirements, and the adequacy of phe intake is monitored with assessment of blood phe levels. Elevated phe concentrations may occur due to illness, excessive or inadequate phe intake, or inadequate intake of AA formula. Although normal growth and development occurs with adherence to the low-phe diet, it is important to monitor vitamin, mineral and essential fatty acid status, especially in those who do not consume sufficient AA formula. Given the growing population of adults with PKU, further research is needed to understand the risks for developing osteoporosis and cardiovascular disease. There are promising new options to liberalize the diet and improve metabolic control such as tetrahydrobiopterin therapy or supplementation with large neutral AAs. Moreover, foods made with glycomacropeptide, an intact protein that contains minimal phe, improves the PKU diet by offering a palatable alternative to AA formula. In summary, continued efforts are needed to overcome the biggest challenge to living with PKU – lifelong adherence to the low-phe diet.

© 2010 Nestec Ltd., Vevey/S. Karger AG, Basel


  

Author Contacts

Denise M. Ney
Department of Nutritional Sciences
University of Wisconsin
1415 Linden Drive, Madison, WI 53706 (USA)
Tel. +1 608 262 4386, Fax +1 608 262 5860, E-Mail ney@nutrisci.wisc.edu

  

Article Information

Published online: June 22, 2010
Number of Print Pages : 12
Number of Figures : 2, Number of Tables : 2, Number of References : 70

  

Publication Details

Annales Nestlé (English ed.)

Vol. 68, No. 2, Year 2010 (Cover Date: June 2010)

ISSN: 0517-8606 (Print), eISSN: 1661-4011 (Online)

For additional information: http://www.karger.com/ANE


Article / Publication Details

First-Page Preview
Abstract of Paper

Published online: 6/22/2010
Issue release date: June 2010

Number of Print Pages: 12
Number of Figures: 2
Number of Tables: 2

ISSN: 0517-8606 (Print)
eISSN: 1661-4011 (Online)

For additional information: http://www.karger.com/ANE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Donlon J, Levy H, Scriver C: Hyperphenylalaninemia: Phenylalanine hydroxylase deficiency; in Scriver C, Beaudet A, Sly W, Valle D (eds): Metabolic and Molecular Basis of Inherited Disease. New York, McGraw-Hill, chapter 77, 2007.
  2. Bickel H, Gerrard J, Hickmans EM: Influence of phenylalanine intake on phenylketonuria. Lancet 1953;265:812–813.
  3. Bickel H, Gerrard J, Hickmans EM: The influence of phenylalanine intake on the chemistry and behaviour of a phenyl-ketonuric child. Acta Paediatr 1954;43:64–77.
  4. NIH: Phenylketonuria (PKU): screening and management. NIH Consensus Statement 2000;17:1–33.
  5. Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria. Arch Dis Child 1993;68:426–427.
  6. Acosta PB, Matalon KM: Nutrition management of patients with inherited disorders of aromatic amino acid metabolism; in Acosta PB (ed): Nutrition Management of Patients with Inherited Metabolic Disorders. Boston, Jones and Bartlett Publishers, 2010, pp 119–174.
  7. Guttler F, Azen C, Guldberg P, et al: Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study. Pediatrics 1999;104:258–262.
  8. Abadie V, Berthelot J, Feillet F, et al: Management of phenylketonuria and hyperphenylalaninemia: the French guidelines (in French). Arch Pediatr 2005;12:594–601.
  9. Burgard P, Bremer HJ, Buhrdel P, et al: Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr 1999;158:46–54.
  10. Acosta P, Yannicelli S: Protocol 1 – phenylketonuria (PKU); in The Ross Metabolic Formula System Nutrition Support Protocols, ed 4. Columbus, Ross Products Division/Abbot Laboratories, 2001.
  11. Camfield CS, Joseph M, Hurley T, et al: Optimal management of phenylketonuria: a centralized expert team is more successful than a decentralized model of care. J Pediatr 2004;145:53–57.
  12. Metges CC, El-Khoury AE, Selvaraj AB, et al: Kinetics of L-[1-(13)C]leucine when ingested with free amino acids, unlabeled or intrinsically labeled casein. Am J Physiol Endocrinol Metab 2000;278:E1000–E1009.
  13. Dangin M, Boirie Y, Garcia-Rodenas C, et al: The digestion rate of protein is an independent regulating factor of postprandial protein retention. Am J Physiol Endocrinol Metab 2001;280:E340–E348.
  14. van Rijn M, Hoeksma M, Sauer P, Szczerbak B, Gross M, Reijngoud DJ, van Spronsen F: Protein metabolism in adult patients with phenylketonuria. Nutrition 2007;23:445–453.
  15. Kindt E, Halvorsen S: The need of essential amino acids in children. An evaluation based on the intake of phenylalanine, tyrosine, leucine, isoleucine, and valine in children with phenylketonuria, tyrosine amino transferase defect, and maple syrup urine disease. Am J Clin Nutr 1980;33:279–286.
  16. IOM: Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Protein and Amino Acids (Macronutrients). Washington, National Academy Press, 2002.
  17. WHO: Protein and Amino Acid Requirements in Human Nutrition. Geneva, WHO, 2007.
  18. Bross R, Ball RO, Clarke JT, Pencharz PB: Tyrosine requirements in children with classical PKU determined by indicator amino acid oxidation. Am J Physiol Endocrinol Metab 2000;278:E195–E201.
  19. Zello GA, Pencharz PB, Ball RO: Phenylalanine flux, oxidation, and conversion to tyrosine in humans studied with L-[1–13C]phenylalanine. Am J Physiol 1990;259:E835– E843.
  20. Courtney-Martin G, Bross R, Raffi M, et al: Phenylalanine requirement in children with classical PKU determined by indicator amino acid oxidation. Am J Physiol Endocrinol Metab 2002;283:E1249–E1256.
  21. MacLeod EL, Gleason ST, van Calcar SC, Ney DM: Reassessment of phenylalanine tolerance in adults with phenylketonuria is needed as body mass changes. Mol Genet Metab 2009;98:331–337.
  22. 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.
  23. Azen CG, Koch R, Friedman EG, et al: Intellectual development in 12-year-old children treated for phenylketonuria. Am J Dis Child 1991;145:35–39.
  24. Waisbren SE, Noel K, Fahrbach K, et al: Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab 2007;92:63–70.
  25. Weigel C, Kiener C, Meier N, et al: Carnitine status in early-treated children, adolescents and young adults with phenylketonuria on low phenylalanine diets. Ann Nutr Metab 2008;53:91–95.
  26. Barretto JR, Silva LR, Leite ME, et al: Poor zinc and selenium status in phenylketonuric children and adolescents in Brazil. Nutr Res 2008;28:208–211.
  27. van Bakel MM, Printzen G, Wermuth B, Wiesmann UN: Antioxidant and thyroid hormone status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients. Am J Clin Nutr 2000;72:976–981.
  28. Schulz B, Bremer HJ: Nutrient intake and food consumption of adolescents and young adults with phenylketonuria. Acta Paediatr 1995;84:743–748.
  29. Hvas AM, Nexo E, Nielsen JB: Vitamin B12 and vitamin B6 supplementation is needed among adults with phenylketonuria (PKU). J Inherit Metab Dis 2006;29:47–53.
  30. Acosta PB, Yannicelli S, Singh RH, et al: Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors. Genet Med 2004;6:96–101.
  31. Van Calcar SC, Macleod EL, Gleason ST, 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.
  32. Schulpis KH, Papassotiriou I, Tsakiris S, et al: Increased plasma adiponectin concentrations in poorly controlled patients with phenylketonuria normalize with a strict diet: evidence for catecholamine-mediated adiponectin regulation and a complex effect of phenylketonuria diet on atherogenesis risk factors. Metabolism 2005;54:1350–1355.
  33. Agostoni C, Scaglioni S, Bonvissuto M, et al: Biochemical effects of supplemented long-chain polyunsaturated fatty acids in hyperphenylalaninemia. Prostaglandins Leukot Essent Fatty Acids 2001;64:111–115.
  34. Moseley K, Koch R, Moser AB: Lipid status and long-chain polyunsaturated fatty acid concentrations in adults and adolescents with phenylketonuria on phenylalanine-restricted diet. J Inherit Metab Dis 2002;25:56–64.
  35. Agostoni C, Massetto N, Biasucci G, et al: Effects of long-chain polyunsaturated fatty acid supplementation on fatty acid status and visual function in treated children with hyperphenylalaninemia. J Pediatr 2000;137:504–509.
  36. Huemer M, Huemer C, Moslinger D, et al: Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. J Inherit Metab Dis 2007;30:694–699.
  37. Perez-Duenas B, Cambra FJ, Vilaseca MA, et al: New approach to osteopenia in phenylketonuric patients. Acta Paediatr 2002;91:899–904.
  38. Zeman J, Bayer M, Stepan J: Bone mineral density in patients with phenylketonuria. Acta Paediatr 1999;88:1348–1351.
  39. Yannicelli S, Medeiros DM: Elevated plasma phenylalanine concentrations may adversely affect bone status of phenylketonuric mice. J Inherit Metab Dis 2002;25:347–361.
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    External Resources

  68. Ney DM, Gleason ST, van Calcar SC, et al: Nutritional management of PKU with glycomacropeptide from cheese whey. J Inherit Metab Dis 2009;32:32–39.
  69. Sanjurjo P, Aldamiz L, Georgi G, et al: Dietary threonine reduces plasma phenylalanine levels in patients with hyperphenylalaninemia. J Pediatr Gastroenterol Nutr 2003;36:23–26.
  70. van Spronsen FJ, Burgard P: The truth of treating patients with phenylketonuria after childhood: the need for a new guideline. J Inherit Metab Dis 2008;31:673–679.