Advertisement

Phenylketonuria: Phenylalanine Neurotoxicity

Chapter

Abstract

  • Phenylketonuria (PKU) was the first inherited metabolic disease identified by newborn screening and treated with diet to prevent the development of intellectual disability.

  • Classification of the severity of phenylketonuria is based on the genetic mutation, dietary phenylalanine tolerance, and pretreatment blood phenylalanine concentrations.

  • The etiology of brain damage in PKU has not been fully elucidated; however, high blood phenylalanine concentrations are associated with changes in brain morphology (gray and white matter) and decreased neurotransmitter synthesis.

Keywords

Newborn Screening Phenylalanine Hydroxylase Large Neutral Amino Acid Severe Intellectual Disability Phenylalanine Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Acosta PB. Nutrition management of patients with inherited metabolic disorders. Acosta PB, editor. Jones and Bartlett Publishers, LLC, Sudbury, Massachusetts; 2010. p. 476.Google Scholar
  2. 2.
    Christ SE. Asbjorn Folling and the discovery of phenylketonuria. J Hist Neurosci. Sudbury, Massachusetts. 2003;12(1):44–54.Google Scholar
  3. 3.
    Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat. 2007;28(9):831–45.PubMedCrossRefGoogle Scholar
  4. 4.
    Scriver CR, Kaufman S. In: Beaudet A, Scriver CR, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B, editors. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency, 8th ed. New York, NY: McGraw-Hill; 2001:1667–724.Google Scholar
  5. 5.
    Bickel H, Gerrard AJ, Hickman EM. Influence of phenylalanine intake on phenylketonuria. Lancet. 1953;2:812–9.CrossRefGoogle Scholar
  6. 6.
    Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963;32:338–43.PubMedGoogle Scholar
  7. 7.
    Chace DH, Millington D, Terada N, Kahler SG, Roe CR, Lindsay FH. Rapid diagnosis of phenylketonuria by quantitative analysis for phenylalanine and tyrosine in neonatal blood spots by tandem mass spectrometry. Clin Chem. 1993;39(1):66–71.PubMedGoogle Scholar
  8. 8.
    Gibson M, Duran M. Simple tests. In: Blau N, editor. Physician’s guide to the diagnosis, treatment, and follow-up of inherited metabolic diseases. New York: Springer; 2014.Google Scholar
  9. 9.
    Williams RA, Mamotte CD, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev. 2008;29(1):31–41.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Blau N, Yue W, Perez B. BioPKU. 2014 [cited 2014 July 7]; PKU mutation database. Available from: http://www.biopku.org/pah/.
  11. 11.
    Touati G, Mochel F, Rabier D. Diagnostic procedures: functional tests and post-mortem protocol. In: Saudubray JM, Van den Berghe G, Walter J, editors. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Berlin: Springer; 2012.Google Scholar
  12. 12.
    Berry SA, et al. Newborn screening 50 years later: access issues faced by adults with PKU. Genet Med. 2013;15(8):591–9.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16–18, 2000. Pediatrics 2001;108(4):972–82.Google Scholar
  14. 14.
    Ozalp I, et al. Newborn PKU screening in Turkey: at present and organization for future. Turk J Pediatr. 2001;43(2):97–101.PubMedGoogle Scholar
  15. 15.
    Zhan J-Y, Qin Y-F, Zhao Z-Y. Neonatal screening for congenital hypothyroidism and phenylketonuria in China. World J Pediatr. 2009;5(2):136–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Maitusong R, Japaer R, Zheng-yan Z, Yang R-L, Huang X-L, Mao H-Q. Newborn screening in Zhejiang, China. Chin Med J. 2012;125(4):702–4.PubMedGoogle Scholar
  17. 17.
    Zschocke J. Phenylketonuria mutations in Europe. Hum Mutat. 2003;21(4):345–56.PubMedCrossRefGoogle Scholar
  18. 18.
    Pangkanon S, Charoensiriwatana W, Janejai N, Boomwanich W, Chaisomchit S. Detection of phenylketonuria by the newborn screening program in Thailand. Southeast Asian J Trop Med Public Health. 2009;40(3):525–9.PubMedGoogle Scholar
  19. 19.
    Hardelid P, et al. The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England. Ann Hum Genet. 2008;72(Pt 1):65–71.PubMedGoogle Scholar
  20. 20.
    Camp KM, et al. Phenylketonuria scientific review conference: state of the science and future research needs. Mol Genet Metab. 2014;112(2):87–122.PubMedCrossRefGoogle Scholar
  21. 21.
    Janos AL, et al. Processing speed and executive abilities in children with phenylketonuria. Neuropsychology. 2012;26(6):735–43.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Brumm VL, Bilder D, Waisbren SE. Psychiatric symptoms and disorders in phenylketonuria. Mol Genet Metab. 2010;99 Suppl 1:S59–63.PubMedCrossRefGoogle Scholar
  23. 23.
    White DA, Waisbren S, van Spronsen FJ. The psychology and neuropathology of phenylketonuria. Mol Genet Metab. 2010;99 Suppl 1:S1–2.PubMedCrossRefGoogle Scholar
  24. 24.
    Cleary M, et al. Fluctuations in phenylalanine concentrations in phenylketonuria: a review of possible relationships with outcomes. Mol Genet Metab. 2013;110(4):418–23.PubMedCrossRefGoogle Scholar
  25. 25.
    Horner FA, Streamer C, Alejandrino LL, Reed LH, Ibbott F. Termination of dietary treatment of phenylketonuria. N Engl J Med. 1962;266(11):79–81.PubMedCrossRefGoogle Scholar
  26. 26.
    Vandeman P. Termination of dietary treatment for phenylketonuria. Arch J Dis Child. 1963;106:492–5.Google Scholar
  27. 27.
    Hudson FP. Termination of dietary treatment of phenylketonuria. Arch J Dis Child. 1967;42:198–200.CrossRefGoogle Scholar
  28. 28.
    Singh RH, et al. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16(2):121–31.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Cerone R, et al. Phenylketonuria: diet for life or not? Acta Paediatr. 1999;88(6):664–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Smith I, et al. Effect of stopping low-phenylalanine diet on intellectual progress of children with phenylketonuria. Br Med J. 1978;2(6139):723–6.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Seashore MR, et al. Loss of intellectual function in children with phenylketonuria after relaxation of dietary phenylalanine restriction. Pediatrics. 1985;75(2):226–32.PubMedGoogle Scholar
  32. 32.
    Ahring K, et al. Dietary management practices in phenylketonuria across European centres. Clin Nutr. 2009;28(3):231–6.PubMedCrossRefGoogle Scholar
  33. 33.
    van Spronsen FJ, Hoeksma M, Reijngoud DJ. Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause? J Inherit Metab Dis. 2009;32(1):46–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417–27.PubMedCrossRefGoogle Scholar
  35. 35.
    Martynyuk AE, et al. Impaired glutamatergic synaptic transmission in the PKU brain. Mol Genet Metab. 2005;86 Suppl 1:S34–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Feksa LR, et al. Characterization of the inhibition of pyruvate kinase caused by phenylalanine and phenylpyruvate in rat brain cortex. Brain Res. 2003;968(2):199–205.PubMedCrossRefGoogle Scholar
  37. 37.
    Huttenlocher PR. The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr. 2000;159 Suppl 2:S102–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Joseph B, Dyer CA. Relationship between myelin production and dopamine synthesis in the PKU mouse brain. J Neurochem. 2003;86(3):615–26.PubMedCrossRefGoogle Scholar
  39. 39.
    Hartwig C, et al. Elevated phenylalanine levels interfere with neurite outgrowth stimulated by the neuronal cell adhesion molecule L1 in vitro. FEBS Lett. 2006;580(14):3489–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Brenton DP, Pietz J. Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Eur J Pediatr. 2000;159 Suppl 2:S114–20.PubMedCrossRefGoogle Scholar
  41. 41.
    Antshel KM, Waisbren SE. Timing is everything: executive functions in children exposed to elevated levels of phenylalanine. Neuropsychology. 2003;17(3):458–68.PubMedCrossRefGoogle Scholar
  42. 42.
    Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria. Mol Genet Metab. 2010;99 Suppl 1:S3–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Sijens PE, et al. 1H MR chemical shift imaging detection of phenylalanine in patients suffering from phenylketonuria (PKU). Eur Radiol. 2004;14(10):1895–900.PubMedCrossRefGoogle Scholar
  44. 44.
    Daelman L, Sedel F, Tourbah A. Progressive neuropsychiatric manifestations of phenylketonuria in adulthood. Rev Neurol (Paris). 2014;170(4):280–7.CrossRefGoogle Scholar
  45. 45.
    de Groot MJ, et al. Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. Mol Genet Metab. 2010;99 Suppl 1:S86–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Surtees R, Blau N. The neurochemistry of phenylketonuria. Eur J Pediatr. 2000;159(S2):S109–13.PubMedCrossRefGoogle Scholar
  47. 47.
    van Spronsen FJ, et al. Large neutral amino acids in the treatment of PKU: from theory to practice. J Inherit Metab Dis. 2010;33(6):671–6.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Pardridge WM. Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res. 1998;23(5):635–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Smith QR. Glutamate and glutamine in the brain. J Nutr. 2000;130:1016S–22.PubMedGoogle Scholar
  50. 50.
    Dyer CA. Pathophysiology of phenylketonuria. Ment Retard Dev Disabil Res Rev. 1999;5:102–12.CrossRefGoogle Scholar
  51. 51.
    Diamond A, et al. Prefrontal cortex cognitive deficits in children treated early and continuously for PKU. Monogr Soc Res Child Dev. 1997;62(4):i–v, 1–208.PubMedCrossRefGoogle Scholar
  52. 52.
    Filley CM. The behavioral neurology of cerebral white matter. Neurology. 1998;50(6):1535–40.PubMedCrossRefGoogle Scholar
  53. 53.
    Malamud N. Neuropathology of phenylketonuria. J Neuropathol Exp Neurol. 1966;25(2):254–68.PubMedCrossRefGoogle Scholar
  54. 54.
    Pietz J. Neurological aspects of adult phenylketonuria. Curr Opin Neurol. 1998;11(6):679–88.PubMedCrossRefGoogle Scholar
  55. 55.
    Pearsen KD, et al. Phenylketonuria: MR imaging of the brain with clinical correlation. Radiology. 1990;177(2):437–40.PubMedCrossRefGoogle Scholar
  56. 56.
    Kirkpatrick LL, Brady ST. Modulation of the axonal microtubule cytoskeleton by myelinating Schwann cells. J Neurosci. 1994;14(12):7440–50.PubMedGoogle Scholar
  57. 57.
    Dyer CA. Comments on the neuropathology of phenylketonuria. Eur J Pediatr. 2000;159 Suppl 2:S107–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Cleary MA, et al. Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr. 1995;127(2):251–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Shah SN, Peterson NA, McKean CM. Cerebral lipid metabolism in experimental hyperphenylalaninaemia: incorporation of 14C-labelled glucose into total lipids. J Neurochem. 1970;17(2):279–84.PubMedCrossRefGoogle Scholar
  60. 60.
    Dyer CA, et al. Evidence for central nervous system glial cell plasticity in phenylketonuria. J Neuropathol Exp Neurol. 1996;55(7):795–814.PubMedCrossRefGoogle Scholar
  61. 61.
    Hommes FA. Amino acidaemias and brain maturation: interference with sulphate activation and myelin metabolism. J Inherit Metab Dis. 1985;8 Suppl 2:121–2.PubMedCrossRefGoogle Scholar
  62. 62.
    Villasana D, et al. Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis. 1989;12(4):451–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Shaw DW, Weinberger E, Maravilla KR. Cranial MR in phenylketonuria. J Comput Assist Tomogr. 1990;14(3):458–60.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and CardiologyPomeranian Medical UniversitySzczecinPoland

Personalised recommendations