Skip to main content

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


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.

This is a preview of subscription content, access via your institution.


  1. Anderson, V.E. and Guroff, G. Enduring behavioural changes in rats with experimental phenylketonuria.Proc. Natl. Acad. Sci. USA 69 (1972) 863–867

    PubMed  Google Scholar 

  2. Anderson, V. E. and Siegel, F. S. Behavioural and biochemical correlates of diet change in phenylketonuria.Pediatr. Res. 10 (1976) 10–17

    PubMed  Google Scholar 

  3. Cloninger, M. R. and Baldwin, R. E. Aspartylphenylalanine methyl ester: A low calorie sweetner.Science 170 (1970) 81–82

    PubMed  Google 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) 449–459

    PubMed  Google Scholar 

  5. Delvalle, J. A. and Greengard, O. Phenylalanine hydroxlase and tyrosine aminotransferase in human fetal and adult liver.Pediatr. Res. 11 (1977) 2

    PubMed  Google Scholar 

  6. Duncan, D. B.t-Tests and intervals for comparisons suggested by the data.Biometrics 31 (1975) 339–359

    Google 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) 271–276

    PubMed  Google 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) 931–938

    PubMed  Google Scholar 

  9. Kimble, D. P. The effects of bilateral hippocampal lesions in rats.J. Comp. Physiol. Psychol. 56 (1963) 273–283

    PubMed  Google 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) 1201–1208

    Google 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) 1269–1274

    PubMed  Google 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) 235–324

    PubMed  Google 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) 306–310

    Google Scholar 

  14. G. D. Searle & Co. Toxicology Report, Evansville, Il, USA (1972)

  15. Wang, H. L. and Waisman, H. A. Experimental phenylketonuria in rats.Proc. Soc. Exp. Biol. Med. 108 (1961) 332–335

    PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to R. B. Elliott.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lewis, S.A., Lyon, I.C.T. & Elliott, R.B. Outcome of pregnancy in the rat with mild hyperphenylalaninaemia and hypertyrosinaemia: Implications for the management of “human maternal PKU”. J Inherit Metab Dis 8, 113–117 (1985).

Download citation


  • Phenylalanine
  • Dietary Supplement
  • Behavioural Problem
  • Essential Amino Acid
  • Fetal Brain