What we know that could influence future treatment of phenylketonuria

BH4 and PKU

Summary

Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism that can result in impaired postnatal cognitive development. The phenotypic outcome is multifactorial in origin, based both in nature, the mutations in the gene encoding the l-phenylalanine hydroxylase enzyme, and nurture, the nutritional experience introducing l-phenylalanine into the diet. The PKU story contains many messages including a framework to appreciate the complexity of this disease where phenotype reflects both locus-specific and genomic components. This knowledge is now being applied in the development of patient-specific therapies.

Abbreviations

PKU

phenylketonuria

PAH

phenylalanine hydroxylase gene

PAH

phenylalanine hydroxylase

Phe

phenylalanine

Tyr

tyrosine

HPA

hyperphenylalaninaemia

LSDB

locus-specific database

PAHdb

phenylalanine hydroxylase locus-specific mutation database

BH4

(6R)-l-erythro-5,6,7,8-tetrahydrobiopterin

LNAA

large neutral amino acids

PAL

phenylalanine ammonia lyase

PEG

polyethylene glycol

References

  1. Armstrong MD, Tyler FH (1955) Studies on phenylketonuria. I. Restriction phenylalanine intake in phenylketonuria. J Clin Invest 34: 565–580.PubMedCrossRefGoogle Scholar
  2. Bernegger C, Blau N (2002) High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: A study of 1,919 patients observed from 1988 to 2002. Mol Genet Metab 77: 304–313.PubMedCrossRefGoogle Scholar
  3. Bickel H, Gerrard J, Hickmans EM (1954) Influence of phenylalanine intake on the chemistry and behaviour of a phenylketonuric child. Acta Paediat 43: 64–77.CrossRefGoogle Scholar
  4. Burton BK, Grange DK, Milanowski A, et al (2007) The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis 30: 700–707. PubMedCrossRefGoogle Scholar
  5. Chen L, Woo SL (2005) Complete and persistent phenotypic correction of phenylketonuria in mice by site-specific genome integration of murine phenylalanine hydroxylase cDNA. Proc Natl Acad Sci USA 102: 15581–15586.PubMedCrossRefGoogle Scholar
  6. Chen L, Woo SL (2007) Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. Mol Ther 15: 1789–1795.PubMedCrossRefGoogle Scholar
  7. Cristiano RJ, Smith LC, Woo SL (1993) Hepatic gene therapy: adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes. Proc Natl Acad Sci U S A 90(6): 2122–2126.PubMedCrossRefGoogle Scholar
  8. Cockburn F, Clark BJ (1996) Recommendations for protein and amino acid intake in phenylketonuric patients. Eur J Pediatr 155(S1): S125–S129.PubMedCrossRefGoogle Scholar
  9. Cockburn F, Clark BJ, Caine EA, et al (1996) Fatty acids in the stability of neuronal membrane: Relevance to PKU. Int Pediatr 11: 56–60.Google Scholar
  10. Danks DM, Bartholomé K, Clayton BE, et al (1978) Malignant hyperphenylalaninemia - current status (June 1977). J Inherit Metab Dis 1: 49–53.PubMedCrossRefGoogle Scholar
  11. Dent CE (1957) Relation of biochemical abnormality to development of mental defect in phenylketonuria. Discussion to paper by Armstrong, M.D. In Ross Labs., ed. Report of 23rd Ross Pediatric Research Conference. Etiological Factors in Mental Retardation. Ohio: Ross Labs., 32.Google Scholar
  12. Desviat LR, Perez B, Gámez A, et al (1999) Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions. Eur J Hum Genet 7: 386–392.PubMedCrossRefGoogle Scholar
  13. Ding Z, Harding CO, Thöny B (2004) State-of-the-art 2003 on PKU gene therapy. Mol Genet Metab 81: 3–8.PubMedCrossRefGoogle Scholar
  14. Ding Z, Georgiev P, Thöny B (2006) Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. Gene Ther 13: 587–593.PubMedCrossRefGoogle Scholar
  15. Ding Z, Harding CO, Rebuffat A, Elzaouk L, Wolff JA, Thöny B (2008) Correction of murine PKU following AAV-mediated intramuscular expression of a complete phenylalanine hydroxylating system. Mol Ther 16: 673–681.PubMedCrossRefGoogle Scholar
  16. Donlon J, Levy H, Scriver CR (2008) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Valle D, Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A, eds.; Scriver CR, Childs B, Sly WS, emeritus eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, Chapter 77. Online. http://genetics.accessmedicine.com.Google Scholar
  17. Eavri R, Lorberboum-Galski H (2007) A novel approach for enzyme replacement therapy. The use of phenylalanine hydroxylase-based fusion proteins for the treatment of phenylketonuria. J Biol Chem 282: 23402–23409.PubMedCrossRefGoogle Scholar
  18. Eisensmith RC, Woo SL (1996) Gene therapy for phenylketonuria. Eur J Pediatr 155(S1): S16–S19.PubMedCrossRefGoogle Scholar
  19. Embury JE, Charron CE, Martynyuk A, et al (2007) PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah(enu2) mice. Brain Res 1127(1): 136–150.PubMedCrossRefGoogle Scholar
  20. Erlandsen H, Stevens RC (1999) The structural basis of phenylketonuria. Mol Genet Metab 68: 103–125.PubMedCrossRefGoogle Scholar
  21. Erlandsen H, Stevens RC (2008) Structural studies of phenylalanine hydroxylase enzyme. In Valle D, Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A, eds.; Scriver CR, Childs B, Sly WS, emeritus eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, Chapter 77S2. Online. http://genetics.accessmedicine.com.Google Scholar
  22. Erlandsen H, Pey AL, Gamez A, et al (2004) Correction of kinetic and stability defects by the tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Nat Acad Sci U S A 101: 16903–16908.CrossRefGoogle Scholar
  23. Fang B, Eisensmith RC, Li XH, et al (1994) Gene therapy for phenylketonuria: phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer. Gene Ther 1: 247–254.PubMedGoogle Scholar
  24. Fölling A (1934) Uber Ausscheidung von Phenylbrenztraubensaure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitat. Hoppe-Seylers Z Physiol Chem 277: 169–176.Google Scholar
  25. Gámez A, Sarkissian C, Wang L, et al (2005) Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria. Mol Ther 11: 986–989.PubMedCrossRefGoogle Scholar
  26. Gámez A, Sarkissian CN, Wang L, et al (2008) The changing face of PKU therapy (Part I): What are the options? Abstract. International Conference: Tetrahydrobiopterin, PKU, and NOS. 23–28 March, St. Moritz, Switzerland.Google Scholar
  27. Guldberg P, Rey F, Zschocke J, et al (1998) A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 63(1): 71–79.PubMedCrossRefGoogle Scholar
  28. Guthrie R, Susi A (1963) A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32: 338–343.Google Scholar
  29. Hanley WB, Azen C, Koch R (2004) Matenal Phenylketonuria Collaborative Study (MPKUCS)—the ‘outliers’. J Inherit Metab Dis 27: 711–723.PubMedCrossRefGoogle Scholar
  30. Hardelid P, Cortina-Borja M, Munro A, et al (2007) The Birth Prevalence of PKU in Populations of European, South Asian and Sub-Saharan African Ancestry Living in South East England. Ann Hum Genet 72(Pt 1): 65–71.Google Scholar
  31. Harding CO (2004) Recent advances in cell and gene therapy for PKU. National PKU News 16: 1–5.Google Scholar
  32. Harding CO, Wild K, Chang D, Messing A, Wolff JA (1998) Metabolic engineering as therapy for inborn errors of metabolism-development of mice with phenylalanine hydroxylase expression in muscle. Gene Ther 5: 677–683.PubMedCrossRefGoogle Scholar
  33. Harding CO, Gillingham MB, Hamman K, et al (2006) Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. Gene Ther 13: 457–462.PubMedCrossRefGoogle Scholar
  34. Hodgins DS (1971) Yeast phenylalanine ammonia-lyase. Purification, properties, and the identification of catalytically essential dehydroalanine. J Biol Chem 246: 2977–2985.Google Scholar
  35. Hoskins JA, Holliday SB, Greenway AM (1984) The metabolism of cinnamic acid by healthy and phenylketonuric adults: a kinetic study. Biomed Mass Spectrom 11: 296–300.PubMedCrossRefGoogle Scholar
  36. Jervis GA (1953) Phenylpyruvic oligophrenia: deficiency of phenylalanine oxidizing system. Proc Soc Exp Biol Med 82: 514–515.PubMedGoogle Scholar
  37. John SW, Rozen R, Scriver CR, Laframboise R, Laberge C (1990) Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: Evidence in French- Canadians and a catalog of mutations. Am J Hum Genet 46: 970–974.PubMedGoogle Scholar
  38. Kane JF, Fiske JM (1985) Regulation of phenylalanine ammonia lyase in Rhodotorula glutinis. J Bacteriol 161: 963–966.PubMedGoogle Scholar
  39. Kaufman S (1963) The structure of phenylalanine hydroxylation cofactor. Proc Natl Acad Sci U S A 50: 1085–1093.PubMedCrossRefGoogle Scholar
  40. Kayaalp E, Treacy E, Waters PJ, Byck S, Nowacki P, Scriver CR (1997) Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype–phenotype correlations. Am J Hum Genet 61: 1309–1317.PubMedCrossRefGoogle Scholar
  41. Koch R, Moseley KD, Yano S, Nelson M Jr, Moats RA (2003) Large neutral amino acid therapy and phenylketonuria: a promising approach to treatment. Mol Genet Metab 79: 110–113.PubMedCrossRefGoogle Scholar
  42. Kure S, Hou D-C, Ohura T, et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135: 375–378.PubMedCrossRefGoogle Scholar
  43. Kure S, Sato K, Fujii K, et al (2004) Wild-type phenylalanine activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 83: 150–156.PubMedCrossRefGoogle Scholar
  44. Kwok SCM, Ledley FD, DiLella AG, Robson KJH, Woo SLC (1985) Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry 24: 556–561.PubMedCrossRefGoogle Scholar
  45. Leader B, Baca QJ, Golan DE (2008) Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 7: 21–39.PubMedCrossRefGoogle Scholar
  46. Ledley FD, Grenett HE, DiLella AG, Kwok SCM, Woo SLC (1985) Gene transfer and gene expression of human phenylalanine hydroxylase. Science 228: 77–79.PubMedCrossRefGoogle Scholar
  47. Ledley FD, Grenett HE, McGinnis-Shelnutt M, Woo SLC (1986) Retroviral-mediated gene transfer of human phenylalanine hydroxylase into NIH 3T3 and hepatoma cells. Proc Natl Acad Sci U S A 83: 409–413.PubMedCrossRefGoogle Scholar
  48. Lenke RR, Levy HL (1980) Maternal phenylketonuria and hyperphenylalaninemia. An international survey of untreated and treated pregnancies. N Engl J Med 303: 1202–1208.PubMedGoogle Scholar
  49. Levy HL (1999) Phenylketonuria: old disease, new approach to treatment [comment]. Proc Natl Acad Sci U S A 96: 1811–1813.PubMedCrossRefGoogle Scholar
  50. Levy HL, Milanowski A, Chakrapani A, et al (2007) Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 370: 504–510.PubMedCrossRefGoogle Scholar
  51. Lichter-Konecki U, Hipke CM, Konecki D (1999) Human phenylalanine hydroxylase gene expression in kidney and other nonhepatic tissues. Molec Genet Metab 67: 308–316.CrossRefPubMedGoogle Scholar
  52. Lin CM, Tan Y, Lee YM, Chang CC, Hsiao KJ (1997) Expression of human phenylalanine hydroxylase activity in T lymphocytes of classical phenylketonuria children by retroviral-mediated gene transfer. J Inherit Metab Dis 20: 742–754.PubMedCrossRefGoogle Scholar
  53. Matalon R, Michals-Matalon K, Bhatia G, et al (2006) Large neutral amino acids in the treatment of phenylketonuria (PKU). J Inherit Metab Dis 29: 732–738.PubMedCrossRefGoogle Scholar
  54. Medical Research Council (UK) (1993) Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. BMJ 306: 115–119.Google Scholar
  55. Medical Research Council Working Party on Phenylketonuria [Cockburn F, Barwell BE, Brenton DP et al] (1993) Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria. Arch Dis Child 68: 426–427.CrossRefGoogle Scholar
  56. Mitchell JJ, Scriver CR (2007) Phenylalanine hydroxylase deficiency. www.genereviews.org.
  57. Moats RA, Koch T, Moseley K, et al (2000) Brain phenylalanine concentration in the management of adults with phenylketonuria. J Inherit Metab Dis 23: 7–14.PubMedCrossRefGoogle Scholar
  58. Mochizuki S, Mizukami H, Ogura T, et al (2004) Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice. Gene Ther 11: 1081–1086.PubMedCrossRefGoogle Scholar
  59. Möller HE, Weglage J, Widermann D, Ullrich K (1998) Blood-brain barrier phenylalanine transport and individual vulerability in phenylketonuria. J Cereb Blood Flow Metab 18: 1184–1191.PubMedCrossRefGoogle Scholar
  60. Muntau AC, Roschinger W, Habich M, et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347: 2122–2132.PubMedCrossRefGoogle Scholar
  61. National Academy of Sciences. Committee for the Study of Inborn Errors of Metabolism DoMSAoLS. 1975. Genetic Screening: Programs, Principles, and Research. Washington, DC: National Academy Press.Google Scholar
  62. National Institutes of Health Consensus Development Panel (2001) National Institutes of Health Consensus Development Conference Statement: Phenylketonuria: Screening and management, October 16–18, 2000. Pediatrics 108: 972–982.CrossRefGoogle Scholar
  63. Oltvai ZN, Barabasi AL (2002) Systems biology. Life’s complexity pyramid. Science 298: 763–764.PubMedCrossRefGoogle Scholar
  64. Penrose LS (1935) Inheritance of phenylpyruvic amentia (Phenylketonuria). Lancet 226: 192–194.CrossRefGoogle Scholar
  65. Ramus SJ, Forrest SM, Pitt DB, Saleeba JA, Cotton RGH (1993) Comparison of genotype and intellectual phenotype in untreated PKU patients. J Med Genet 30: 401–405.PubMedCrossRefGoogle Scholar
  66. Riva E, Agostoni C, Biasucci G, et al (1996) Early breastfeeding is linked to higher intelligence quotient scores in dietary treated phenylketonuric children. Acta Paediatr 85: 56–58.PubMedCrossRefGoogle Scholar
  67. Salter M, Knowles RG, Pogson CI (1986) Quantification of the importance of individual steps in the control of aromatic amino acid metabolism. Biochem J 234: 635–647.PubMedGoogle Scholar
  68. Santos LL, Magalhães Mde C, Januário JN, Aguiar MJ, Carvalho MR (2006) The time has come: a new scene for PKU treatment. Genet Mol Res 5: 33–44.PubMedGoogle Scholar
  69. Sarkissian CN (2006) Enzyme therapy for PKU. In: Blau N, ed. PKU and BH 4 —Advances in Phenylketonuria and Tetrahydrobiopterin. Heilbronn: SPS Verlagsgesellschaft mbH, 350–369.Google Scholar
  70. Sarkissian CN, Gámez A (2005) Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? Mol Genet Metab 86(Supplement 1): S22–S26.PubMedCrossRefGoogle Scholar
  71. Sarkissian CN, Shao Z, Blain F, et al (1999) A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc Natl Acad Sci U S A 96: 2339–2344.PubMedCrossRefGoogle Scholar
  72. Sarkissian CN, Boulais DM, McDonald JD, Scriver CR (2000) A heteroallelic mutant mouse model: a new orthologue for human hyperphenylalaninemia. Mol Genet Metab 69: 188–194.PubMedCrossRefGoogle Scholar
  73. Sarkissian CN, Gámez A, Wang L, et al (2008) The changing face of PKU therapy (Part II): Who will benefit? Abstract. International Conference: Tetrahydrobiopterin, PKU, and NOS. 23–28 March, St. Moritz, Switzerland.Google Scholar
  74. Scriver CR (1967) Treatment in medical genetics. In: Crow JF, Neel JV, eds. Proceedings of the Third International Congress of Human Genetics. Baltimore: The Johns Hopkins Press, 45–56.Google Scholar
  75. Scriver CR (2007) Wiley 200th Anniversary Tribute Article. The PAH Gene, phenylketonuria, and a paradigm shift. Hum Mut 28: 831–845.PubMedCrossRefGoogle Scholar
  76. Scriver CR, Waters PJ, Sarkissian C, et al (2000) PAHdb: A locus-specific knowledgebase. Hum Mut 15: 99–104.PubMedCrossRefGoogle Scholar
  77. Scriver CR, Hurtubise M, Konecki D, et al (2003) PAHdb 2003: What a locus-specific knowledgebase can do. Hum Mutat 21: <H6>333–344.PubMedCrossRefGoogle Scholar
  78. Scriver CR, Hardelid P, Cortina-Borja M, et al (2006) Did Phenylketonuria (PKU) arise after the Out-of-Africa migration? Am J Hum Genet Abstracts 196 (#995-A).Google Scholar
  79. Shedlovsky A, McDonald JD, Symula D, Dove WF (1993) Mouse models of human phenylketonuria. Genetics 134: 1205–1210.PubMedGoogle Scholar
  80. Smith I (1994) Treatment of phenylalanine hydroxylase deficiency. Acta Paediatr Suppl 407: 60–65.PubMedCrossRefGoogle Scholar
  81. Snapper I, Yu TF, Chiang YT (1940) Cinnamic acid metabolism in man. Proc Soc Exp Biol Med 44: 30–34.Google Scholar
  82. Spaapen LJ, Rubio-Gozalbo ME (2003) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state-of-the-art. Mol Genet Metab 78: 93–99.PubMedCrossRefGoogle Scholar
  83. Tessari P, Deferrari G, Robaudo C, et al (1999) Phenylalanine hydroxylation across the kidney in humans. Kidney Int 56: 2168–2172.PubMedGoogle Scholar
  84. Treacy E, Pitt JJ, Seller J, Thompson GN, Ramus S, Cotton RGH (1996) In vivo disposal of phenylalanine in phenylketonuria: A study of two siblings. J Inherit Metab Dis 19: 595–602.PubMedCrossRefGoogle Scholar
  85. Vajro P, Strisciuglio P, Houssin D, et al (1993) Correction of phenylketonuria after liver transplantation in a child with cirrhosis. N Engl J Med 329: 363.PubMedCrossRefGoogle Scholar
  86. Waters PJ, Parniak MA, Nowacki P, Scriver CR (1998) In vitro expression analysis of mutations in phenylalanine hydroxylase: Linking genotype to phenotype and structure to function. Hum Mutat 11: 4–17.PubMedCrossRefGoogle Scholar
  87. Weglage J, Moller HE, Wiedermann D, Cipcic-Schmidt S, Zschocke J, Ullrich K (1998a) In vivo NMR spectroscopy in patients with phenylketonuria. Clinical significance of interindividual differences in brain phenylalanine concentrations. J Inherit Metab Dis 21: 81–82.PubMedCrossRefGoogle Scholar
  88. Weglage J, Wiedermann D, Moller H, Ullrich K (1998b) Pathogenesis of different clinical outcomes in spite of identical genotypes and comparable blood phenylalanine concentration in phenylketonurics. J Inherit Metab Dis 21: 181–182.PubMedCrossRefGoogle Scholar
  89. Woolf LI, Griffiths R, Moncrieff A (1955) Treatment of phenylketonuria with a diet low in phenylalanine. Br Med J 1: 57–64.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • C. N. Sarkissian
    • 1
    • 2
  • A. Gámez
    • 3
  • C. R. Scriver
    • 1
    • 2
  1. 1.Departments of Biology, Human Genetics and PediatricsMcGill UniversityMontrealCanada
  2. 2.DeBelle Laboratory for Biochemical GeneticsMontreal Children’s Hospital Research InstituteMontrealCanada
  3. 3.Centro de Biología Molecular Severo Ochoa, Nicolás Cabrera 1 Laboratorio 204. Campus CantoblancoUniversidad Autónoma de MadridCantoblancoSpain

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