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

Abstract

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. alpha-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.

Maternal and fetal tyrosinemia type I

“…Both neonates developed normally during fetal life and in the first months, despite hypertyrosinemia. However, careful follow-up would be required since hypertyrosinemia during fetal life may be responsible for learning difficulties at a later stage (Lewis et al 1985).…”

Maternal tyrosinaemia II: Management and successful outcome

“…Infants who have suffered transient neonatal tyrosinaemia have been shown subsequently to have difficulty with a range of psychometric tests [21], although these problems may simply reflect an increased incidence of other pathologies in these infants. In rats, mild elevations in plasma tyrosine (150-360 txmol/1) induced by dietary tyrosine supplementation during pregnancy have been shown to result in learning difficulties in offspring [18]. These data collectively suggest that there is an increased risk of abnormal brain function when maternal plasma tyrosine concentration is markedly increased.…”

Pregnancy in phenylketonuria: dietary treatment aimed at normalising maternal plasma phenylalanine concentration.

“…However, it is likely that the concentration was even higher one to two hours postprandially on this occasion and the possibility that raised tyrosine concentrations may in themselves cause fetal damage should not be ignored. 17 Excessive tyrosine supplementation should be avoided. In summary, we have now documented for the first time implementation of a frequently discussed strategy of maintaining normal phenylalanine concentrations in maternal PKU.…”