Journal of Inherited Metabolic Disease

, Volume 8, Issue 3, pp 113–117 | Cite as

Outcome of pregnancy in the rat with mild hyperphenylalaninaemia and hypertyrosinaemia: Implications for the management of “human maternal PKU”

  • S. A. Lewis
  • I. C. T. Lyon
  • R. B. Elliott


In attempting to determine the effects of mildly elevated maternal phenylalanine (Phe) blood levels on the developing fetal rat brain, a dietary supplement of Phe was given, under taste cover of Aspartame. Phe and tyrosine (Tyr) levels were mildly elevated throughout pregnancy without evidence of malnutrition. Mild hyperphenylalaninaemia with concurrent hypertyrosinaemia induced in rats prior to conception resulted in microcephaly and lasting behavioural problems in the offspring, specifically hyperactivity and learning difficulties. Dams fed Tyr to produce Tyr levels equivalent to the Phe-fed animals showed only the learning difficulties among the offspring.

α-Methyl Phe, a Phe hydroxylase inhibitor, fed in conjunction with Phe, at the level relevant to these experiments, resulted in raised Tyr levels and does not provide a better method of determining whether mildly elevated maternal Phe levels alone, or Phe and Tyr in combination, cause the abnormality found in the offspring of Phe-supplemented dams.

Therapeutic addition of Tyr to diets of mothers with even mild hyperphenylalaninaemia should be approached with caution as mild co-elevation of Phe and Tyr in the fetus may be harmful.

In the face of such a possible therapeutic dilemma alternatives, such as dietary additions of other essential amino acids to limit fetal brain damage, need to be explored.


  1. Anderson, V.E. and Guroff, G. Enduring behavioural changes in rats with experimental phenylketonuria.Proc. Natl. Acad. Sci. USA 69 (1972) 863–867PubMedGoogle Scholar
  2. Anderson, V. E. and Siegel, F. S. Behavioural and biochemical correlates of diet change in phenylketonuria.Pediatr. Res. 10 (1976) 10–17PubMedGoogle Scholar
  3. Cloninger, M. R. and Baldwin, R. E. Aspartylphenylalanine methyl ester: A low calorie sweetner.Science 170 (1970) 81–82PubMedGoogle Scholar
  4. Delvalle, J. A., Dienel, G. and Greengard, O. Comparison of α-methylphenylalanine andp-chlorophenylalanine as inducers of chronic hyperphenylalaninaemia in developing rats.Biochem. J. 170 (1978) 449–459PubMedGoogle Scholar
  5. Delvalle, J. A. and Greengard, O. Phenylalanine hydroxlase and tyrosine aminotransferase in human fetal and adult liver.Pediatr. Res. 11 (1977) 2PubMedGoogle Scholar
  6. Duncan, D. B.t-Tests and intervals for comparisons suggested by the data.Biometrics 31 (1975) 339–359Google Scholar
  7. Fujimoto, A., Crawford, R. and Bessman, S. P. Relative inability of mother and child to convert phenylalanine to tyrosine.Biochem. Med. 21 (1979) 271–276PubMedGoogle Scholar
  8. Kelly, C. J. and Johnson, T. C. Effects ofp-chlorophenylalanine and α-methylphenylalanine on amino acid uptake and protein synthesis in mouse neuroblastoma cells.Biochem. J. 174 (1978) 931–938PubMedGoogle Scholar
  9. Kimble, D. P. The effects of bilateral hippocampal lesions in rats.J. Comp. Physiol. Psychol. 56 (1963) 273–283PubMedGoogle Scholar
  10. Lenke, R. R. and Levy, L. L. Maternal phenylketonuria and hyperphenylalaninaemia: An international survey of the outcome of untreated and treated pregnancies.N. Engl. J. Med. 303 (1980) 1201–1208Google Scholar
  11. Levy, H. L. and Waisbren, S. E. Effects of untreated maternal phenylketonuria and hyperphenylalaninaemia on the fetus.N. Engl. J. Med. 309 (1983) 1269–1274PubMedGoogle Scholar
  12. McKean, C. M., Boggs, D. E. and Peterson, N. A. The influence of high phenylalanine and tyrosine on the concentrations of essential amino acids in the brain.J. Neurochem. 15 (1968) 235–324PubMedGoogle Scholar
  13. Rice, D. N., Houston, I. B., Lyon, I. C. T., MacArthur, B. A., Mullins, P. R., Veale, A. M. O. and Guthrie, R. Transient neonatal tyrosinaemia in neonatal screening.Exerpta Medica Int. Congr. Series 606 (1983) 306–310Google Scholar
  14. G. D. Searle & Co. Toxicology Report, Evansville, Il, USA (1972)Google Scholar
  15. Wang, H. L. and Waisman, H. A. Experimental phenylketonuria in rats.Proc. Soc. Exp. Biol. Med. 108 (1961) 332–335PubMedGoogle Scholar

Copyright information

© SSIEM and MTP Press Limited 1985

Authors and Affiliations

  • S. A. Lewis
    • 1
  • I. C. T. Lyon
    • 1
  • R. B. Elliott
    • 1
  1. 1.Department of Paediatrics and Department of Community Health University of Auckland School of MedicineAucklandNew Zealand

Personalised recommendations