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Overview of phenylketonuria

Olaf A Bodamer, MD, PhD, FAAP, FACMG
Section Editor
Sihoun Hahn, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS


Phenylketonuria (PKU, MIM #261600) is a disorder affecting the aromatic amino acid, phenylalanine. It results from a deficiency of phenylalanine hydroxylase (PAH) and if untreated is characterized by intellectual disability.

An overview of PKU is presented here. A general discussion of amino acid disorders is presented separately. (See "Inborn errors of metabolism: Classification".)


The incidence of phenylketonuria (PKU) is 1 in 13,500 to 19,000 births in the United States [1]. It is less common in the African-American population, with an incidence of approximately 1 in 50,000 based on newborn screening data from the state of Maryland [2]. PKU is rare in Finland and Japan [3,4].


The hepatic enzyme, phenylalanine hydroxylase (PAH), catalyzes the conversion of the essential amino acid phenylalanine to tyrosine (figure 1). Tetrahydrobiopterin (BH4) is a cofactor required for PAH activity. This pathway accounts for most of the catabolism and is responsible for the disposal of approximately 75 percent of dietary phenylalanine, with the remainder used for protein synthesis [5]. Phenylketonuria (PKU), in most cases, is caused by deficiency of PAH [6,7]. This results in elevated blood and urine concentrations of phenylalanine and its metabolites, phenylacetate and phenyllactate. Tyrosine concentration is normal or low normal. Occasionally tyrosine concentrations are low. Defects in BH4 metabolism account for approximately 2 percent of patients with elevated phenylalanine levels. (See 'Tetrahydrobiopterin (BH4) deficiency' below.)

Complete enzyme deficiency results in classic PKU, in which serum phenylalanine concentration exceeds 20 mg/dL (1200 micromol/L). Residual enzyme activity causes moderate PKU (phenylalanine concentrations 900 to 1200 micromol/L), mild PKU (phenylalanine concentrations 600 to 900 micromol/L), mild hyperphenylalaninemia (HPA; phenylalanine concentrations 360 to 600 micromol/L), and benign mild HPA not requiring treatment (phenylalanine concentrations 120 to 360 micromol/L) [8].


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  1. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics 2001; 108:972.
  2. Hofman KJ, Steel G, Kazazian HH, Valle D. Phenylketonuria in U.S. blacks: molecular analysis of the phenylalanine hydroxylase gene. Am J Hum Genet 1991; 48:791.
  3. Guldberg P, Henriksen KF, Sipilä I, et al. Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland. J Med Genet 1995; 32:976.
  4. Tada K, Tateda H, Arashima S, et al. Follow-up study of a nation-wide neonatal metabolic screening program in Japan. A collaborative study group of neonatal screening for inborn errors of metabolism in Japan. Eur J Pediatr 1984; 142:204.
  5. Erlandsen H, Stevens RC. The structural basis of phenylketonuria. Mol Genet Metab 1999; 68:103.
  6. Fölling A. Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Zschr Physiol Chem 1934; 227:169.
  7. Scriver CR, Kaufman S. The hyperphenylalaninemias. Phenylalanine hydroxylase deficiency. In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1667.
  8. Camp KM, Parisi MA, Acosta PB, et al. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab 2014; 112:87.
  9. Ushakova GA, Gubkina HA, Kachur VA, Lepekhin EA. Effect of experimental hyperphenylalaninemia on the postnatal rat brain. Int J Dev Neurosci 1997; 15:29.
  10. Kienzle Hagen ME, Pederzolli CD, Sgaravatti AM, et al. Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim Biophys Acta 2002; 1586:344.
  11. Infante JP, Huszagh VA. Impaired arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acid synthesis by phenylalanine metabolites as etiological factors in the neuropathology of phenylketonuria. Mol Genet Metab 2001; 72:185.
  12. Glushakov AV, Dennis DM, Morey TE, et al. Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria. Mol Psychiatry 2002; 7:359.
  13. Agency for Healthcare Research and Quality. Comparative Effectiveness of Treatment for Phenylketonuria (PKU). Comparative Effectiveness Review No. 56. Prepared by the Vanderbilt Evidence-Based Practice Center under Contract No. 290-2007-10065-I. AHRQ Publication No. 12-EHC035-EF. 2011. http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. (Accessed on June 08, 2015).
  14. Wappner RS. Disorders of amino acid and organic acid metabolism. In: Oski's pediatrics. Principles and practice, 4th ed, McMillan JA, Feigin RD, DeAngelis C, Jones MD (Eds), Lippincott, Williams & Wilkins, Philadelphia 2006. p.2153.
  15. Fusetti F, Erlandsen H, Flatmark T, Stevens RC. Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. J Biol Chem 1998; 273:16962.
  16. PAINE RS. The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria). Pediatrics 1957; 20:290.
  17. Christ SE, Huijbregts SC, de Sonneville LM, White DA. Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Mol Genet Metab 2010; 99 Suppl 1:S22.
  18. Leuzzi V, Pansini M, Sechi E, et al. Executive function impairment in early-treated PKU subjects with normal mental development. J Inherit Metab Dis 2004; 27:115.
  19. Demirdas S, Coakley KE, Bisschop PH, et al. Bone health in phenylketonuria: a systematic review and meta-analysis. Orphanet J Rare Dis 2015; 10:17.
  20. Weglage J, Bick U, Schuierer G, et al. Progression of cerebral white matter abnormalities in early treated patients with phenylketonuria during adolescence. Neuropediatrics 1997; 28:239.
  21. Leuzzi V, Trasimeni G, Gualdi GF, Antonozzi I. Biochemical, clinical and neuroradiological (MRI) correlations in late-detected PKU patients. J Inherit Metab Dis 1995; 18:624.
  22. Bick U, Ullrich K, Stöber U, et al. White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings. Eur J Pediatr 1993; 152:1012.
  23. Thompson AJ, Tillotson S, Smith I, et al. Brain MRI changes in phenylketonuria. Associations with dietary status. Brain 1993; 116 ( Pt 4):811.
  24. Bick U, Fahrendorf G, Ludolph AC, et al. Disturbed myelination in patients with treated hyperphenylalaninaemia: evaluation with magnetic resonance imaging. Eur J Pediatr 1991; 150:185.
  25. Cleary MA, Walter JH, Wraith JE, et al. Magnetic resonance imaging of the brain in phenylketonuria. Lancet 1994; 344:87.
  26. Bodamer OA. Screening for phenylketonuria. In: Phenylketonuria: Special Issue: Annales Nestle, English ed, Lentze MJ (Ed), S Karger Pub, 2010. Vol Vol 68, No 2, p.53.
  27. Levy HL, Waisbren SE, Lobbregt D, et al. Maternal mild hyperphenylalaninaemia: an international survey of offspring outcome. Lancet 1994; 344:1589.
  28. Feillet F, van Spronsen FJ, MacDonald A, et al. Challenges and pitfalls in the management of phenylketonuria. Pediatrics 2010; 126:333.
  29. MacLeod EL, Ney DM. Nutritional management of phenylketonuria. In: Phenylketonuria: Special issue: Annales Nestle, English ed, Lentze MJ (Ed), S Karger Pub, 2010. Vol Vol 68, No 2, p.58.
  30. Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria. Arch Dis Child 1993; 68:426.
  31. Burgard P, Bremer HJ, Bührdel P, et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr 1999; 158:46.
  32. Abadie V, Berthelot J, Feillet F, et al. [Management of phenylketonuria and hyperphenylalaninemia: the French guidelines]. Arch Pediatr 2005; 12:594.
  33. MacDonald A. Diet and compliance in phenylketonuria. Eur J Pediatr 2000; 159 Suppl 2:S136.
  34. Yi SH, Singh RH. Protein substitute for children and adults with phenylketonuria. Cochrane Database Syst Rev 2015; :CD004731.
  35. Clemens PC, Heddrich-Ellerbrok M, Wachtel V, Link RM. Plasma amino acids in adolescents and adults with phenylketonuria on three different levels of protein intake. Acta Paediatr Scand 1991; 80:577.
  36. 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.
  37. Acosta PB, Yannicelli S. Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatr Suppl 1994; 407:66.
  38. Kindt E, Motzfeldt K, Halvorsen S, Lie SO. Is phenylalanine requirement in infants and children related to protein intake? Br J Nutr 1984; 51:435.
  39. Duran GP, Rohr FJ, Slonim A, et al. Necessity of complete intake of phenylalanine-free amino acid mixture for metabolic control of phenylketonuria. J Am Diet Assoc 1999; 99:1559.
  40. MacDonald A, Chakrapani A, Hendriksz C, et al. Protein substitute dosage in PKU: how much do young patients need? Arch Dis Child 2006; 91:588.
  41. Webster D, Wildgoose J. Tyrosine supplementation for phenylketonuria. Cochrane Database Syst Rev 2013; :CD001507.
  42. Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 2014; 16:188.
  43. Koch R, Burton B, Hoganson G, et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 2002; 25:333.
  44. Bosch AM, Tybout W, van Spronsen FJ, et al. The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis 2007; 30:29.
  45. Lou HC, Güttler F, Lykkelund C, et al. Decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents. Eur J Pediatr 1985; 144:17.
  46. Channon S, Goodman G, Zlotowitz S, et al. Effects of dietary management of phenylketonuria on long-term cognitive outcome. Arch Dis Child 2007; 92:213.
  47. Rey F, Abadie V, Plainguet F, Rey J. Long-term follow up of patients with classical phenylketonuria after diet relaxation at 5 years of age. The Paris Study. Eur J Pediatr 1996; 155 Suppl 1:S39.
  48. Cerone R, Schiaffino MC, Di Stefano S, Veneselli E. Phenylketonuria: diet for life or not? Acta Paediatr 1999; 88:664.
  49. ten Hoedt AE, de Sonneville LM, Francois B, et al. High phenylalanine levels directly affect mood and sustained attention in adults with phenylketonuria: a randomised, double-blind, placebo-controlled, crossover trial. J Inherit Metab Dis 2011; 34:165.
  50. Blau N. Tetrahydrobiopterin control in phenylketonuria. Genet Med 2003; 5:57.
  51. Bernegger C, Blau N. High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002. Mol Genet Metab 2002; 77:304.
  52. Muntau AC, Röschinger W, Habich M, et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 2002; 347:2122.
  53. Fiege B, Blau N. Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr 2007; 150:627.
  54. The Pink Sheet" FDC Reports. Chevy Chase, MD. 2007; 69(51):9.
  55. Kuvan™ (sapropterin dihydrochloride) Tablets. Product label. BioMarin Pharmaceutical Inc, Novato, CA December 2007.
  56. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Kuvan. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails (Accessed on January 07, 2008).
  57. Hennermann JB, Bührer 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.
  58. Lambruschini N, Pérez-Dueñas B, Vilaseca MA, et al. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab 2005; 86 Suppl 1:S54.
  59. Trefz FK, Scheible D, Frauendienst-Egger G, et al. Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. Mol Genet Metab 2005; 86 Suppl 1:S75.
  60. 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.
  61. Shintaku H, Ohura T. Sapropterin is safe and effective in patients less than 4-years-old with BH4-responsive phenylalanine hydrolase deficiency. J Pediatr 2014; 165:1241.
  62. Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev 2015; :CD008005.
  63. Blau N, Bélanger-Quintana A, Demirkol M, et al. Optimizing the use of sapropterin (BH(4)) in the management of phenylketonuria. Mol Genet Metab 2009; 96:158.
  64. Levy HL, Milanowski A, Chakrapani A, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 2007; 370:504.
  65. Keil S, Anjema K, van Spronsen FJ, et al. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics 2013; 131:e1881.
  66. Douglas TD, Jinnah HA, Bernhard D, Singh RH. The effects of sapropterin on urinary monoamine metabolites in phenylketonuria. Mol Genet Metab 2013; 109:243.
  67. Longo N, Harding CO, Burton BK, et al. Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet 2014; 384:37.
  68. Giovannini M, Biasucci G, Agostoni C, et al. Lipid status and fatty acid metabolism in phenylketonuria. J Inherit Metab Dis 1995; 18:265.
  69. 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.
  70. Agostoni C, Verduci E, Massetto N, et al. Long term effects of long chain polyunsaturated fats in hyperphenylalaninemic children. Arch Dis Child 2003; 88:582.
  71. Beblo S, Reinhardt H, Demmelmair H, et al. Effect of fish oil supplementation on fatty acid status, coordination, and fine motor skills in children with phenylketonuria. J Pediatr 2007; 150:479.
  72. Cunnane SC, Francescutti V, Brenna JT. Docosahexaenoate requirement and infant development. Nutrition 1999; 15:801.
  73. Millward DJ, Fereday A, Gibson NR, Pacy PJ. Human adult amino acid requirements: [1-13C]leucine balance evaluation of the efficiency of utilization and apparent requirements for wheat protein and lysine compared with those for milk protein in healthy adults. Am J Clin Nutr 2000; 72:112.
  74. 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.
  75. 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.
  76. Singh RH, Rohr F, Frazier D, et al. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med 2014; 16:121.
  77. Albrecht J, Garbade SF, Burgard P. Neuropsychological speed tests and blood phenylalanine levels in patients with phenylketonuria: a meta-analysis. Neurosci Biobehav Rev 2009; 33:414.
  78. Jahja R, Huijbregts SC, de Sonneville LM, et al. Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. J Pediatr 2014; 164:895.
  79. Acosta PB, Matalon KM. Nutrition management of patients with inherited disorders of aromatic amino acid metabolism. In: Nutrition management of patients with inherited metabolic disorders, Acosta PB (Ed), Jones and Bartlett Publishers, Boston 2010. p.119.
  80. Pérez-Dueñas B, Cambra FJ, Vilaseca MA, et al. New approach to osteopenia in phenylketonuric patients. Acta Paediatr 2002; 91:899.
  81. Zeman J, Bayer M, Stepán J. Bone mineral density in patients with phenylketonuria. Acta Paediatr 1999; 88:1348.
  82. Yannicelli S, Medeiros DM. Elevated plasma phenylalanine concentrations may adversely affect bone status of phenylketonuric mice. J Inherit Metab Dis 2002; 25:347.
  83. Koch R, Azen C, Friedman EG, Williamson ML. Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. J Inherit Metab Dis 1984; 7:86.
  84. Burgard P. Development of intelligence in early treated phenylketonuria. Eur J Pediatr 2000; 159 Suppl 2:S74.
  85. 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.
  86. Smith I, Knowles J. Behaviour in early treated phenylketonuria: a systematic review. Eur J Pediatr 2000; 159 Suppl 2:S89.
  87. Jones SJ, Turano G, Kriss A, et al. Visual evoked potentials in phenylketonuria: association with brain MRI, dietary state, and IQ. J Neurol Neurosurg Psychiatry 1995; 59:260.
  88. Leuzzi V, Rinalduzzi S, Chiarotti F, et al. Subclinical visual impairment in phenylketonuria. A neurophysiological study (VEP-P) with clinical, biochemical, and neuroradiological (MRI) correlations. J Inherit Metab Dis 1998; 21:351.
  89. Blau N, Thony B, Cotton RGH, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1725.
  90. Shintaku H. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab 2002; 3:123.
  91. Feillet F, Chery C, Namour F, et al. Evaluation of neonatal BH4 loading test in neonates screened for hyperphenylalaninemia. Early Hum Dev 2008; 84:561.
  92. Maternal phenylketonuria. Pediatrics 2008; 122:445.
  93. Prick BW, Hop WC, Duvekot JJ. Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr 2012; 95:374.
  94. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 449: Maternal phenylketonuria. Obstet Gynecol 2009; 114:1432.
  95. Schoonheyt WE, Clarke JT, Hanley WB, et al. Feto-maternal plasma phenylalanine concentration gradient from 19 weeks gestation to term. Clin Chim Acta 1994; 225:165.
  96. Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies. N Engl J Med 1980; 303:1202.
  97. Levy HL, Ghavami M. Maternal phenylketonuria: a metabolic teratogen. Teratology 1996; 53:176.
  98. Koch R, Friedman E, Azen C, et al. The International Collaborative Study of Maternal Phenylketonuria: status report 1998. Eur J Pediatr 2000; 159 Suppl 2:S156.
  99. Levy HL, Guldberg P, Güttler F, et al. Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study. Pediatr Res 2001; 49:636.
  100. Rouse B, Azen C. Effect of high maternal blood phenylalanine on offspring congenital anomalies and developmental outcome at ages 4 and 6 years: the importance of strict dietary control preconception and throughout pregnancy. J Pediatr 2004; 144:235.
  101. Lee PJ, Ridout D, Walter JH, Cockburn F. Maternal phenylketonuria: report from the United Kingdom Registry 1978-97. Arch Dis Child 2005; 90:143.
  102. Rohr FJ, Lobbregt D, Levy HL. Tyrosine supplementation in the treatment of maternal phenylketonuria. Am J Clin Nutr 1998; 67:473.