The Effects of Hyperphenylalaninemia on Fetal Development: a New Animal Model of Maternal Phenylketonuria

Abstract

SummaryA new model has been developed for the study of maternal phenylketonuria. Beginning on the 12th day of gestation the diet of pregnant rats was supplemented with 0.5% a-methylphenylalanine and 3% phenylalanine. This resulted in an 83% reduction of hepatic phenylalanine hydroxylase activity. The maternal plasma phenylalanine ;vas elevated 10-20-fold for two-thirds of the day, but the degree and persistence of the fetal hyperphenylalaninemia may have been even greater. The brain phenylalanine concentrations in the fetus were raised up to 2900 nmole/g brain, whereas the highest level observed in the dam was 382 nmole/g. Experimentally-treated fetuses showed small reductions in both body and brain weight when compared to age-matched controls; however, no differences were seen in crown to rump length, litter size, DNA and protein concentrations per g, or in postnatal survival. Initiation of the diet at conception rather than on the 12th day caused a significantly greater inhibition of fetal growth, and 21% mortality.The fetal cerebral concentrations of metbionine and the branched chain amino acids (valine, leucine and isoleucine) were decreased by hyperphenylalaninemia. From the 16th day on, the concentration of the inhibitor neurotransmitter glycine was elevated. Cerebral serotonin showed a 20-30% deficit and its primary metabolite 5-hydroxyindoleacetic acid a 71-77% deficit.Of twelve enzymes quantified in the brains of hyperphenylalaninemic fetuses only phosphoserine phosphatase showed any change. From the 20th to the 22nd day of gestation its activity was 46-67% higher in experimental than in normal fetuses. Measurement on the 22nd day of gestation showed that the increases in phosphoserine phosphatase activity and glycine content were present in brain stem, cerebellum, and forebrain. SpeculationThis new animal model of maternal phenylketonuria is suitable for elucidating the mechanisms of abnormal development of heterozygous children of phenylketonuric mothers. ~6 r~h e n~l a l aninemia in the dam is responsible for gross elevations in fetal brain phenylalanine content and the bioch'kmical consequences of this elevation, such as pertubations in the levels of glycine, serotonin and branched chain amino acids, which may be responsible for the lasting damage to cerebral function.Several studies have indicated that mental retardation is associated not only with phenylketonuria but also with the majority of heterozygous infants of phenylketonuric mothers (8,16,17,30,38). This indicates that permanent damage of cerebral functions can occur if severe hyperphenylalaninemia is restricted to intrauterine life. The common end result. mental retardation. does not necessarily imply a common pathogenic pathway: the &mediate impact of the same metabolic abnormality may well be different at different stages of ontogeny. Studies of phenylketonurics and rats subjected to experimental hyperphenylalaninemia have provided some insights into the postnatal biochemical changes; however, little is known about those occurring in ute...

Maternal Phenylketonuria

“…If appli cable to human maternal PKU, this hypoth esis would provide a reasonable explanation for the fetal brain effect but would leave still unanswered questions such as why the heart is not always defective and why certain other organs are not affected. nylalaninemia have been approximately 10-20% below controls [13,20]. This reduction is an order of magnitude similar to the re duced birth weight noted in maternal PKU offspring.…”

Scientific Opinion on the re‐evaluation of aspartame (E 951) as a food additive

“…In support of this hypothesis, the Panel noted that administration of a dose of L-phenylalanine (1800 mg/kg bw/day) that was equimolar to 4000 mg aspartame/kg bw/day led to a similar decrease in maternal and pup body weight as observed in a concurrent aspartame group (E49, 1973). Furthermore, supplementation of the diet with L-phenylalanine (5-7 %) (Kerr and Waisman, 1967) or the combination of 3 % Lphenylalanine and 0.5 % α-methylphenylalanine (Brass et al, 1982) has been shown to result in severe nutritional imbalance in rats (Kerr and Waisman, 1967) and to lead to a reduction in pup body weight at birth (Brass et al, 1982). In addition, milk production in mothers exposed to excessive Lphenylalanine intake has been reported to be decreased, which could further contribute to malnutrition of the pups during weaning and result in pup mortality (Boggs and Waisman, 1962;Kerr and Waisman, 1967).…”

Toxicological and Teratogenic Effect of Various Food Additives: An Updated Review

“…The reduction in brain protein synthesis has also been linked to high amounts of other amino acids. During brain development, hyperphenylalaninemia can diminish myelin production, as seen by decreased incorporation of methionine into myelin proteins [39], decreased total lipid content, decreased myelin yield, [40], and overall lower brain weight [41]. Aspartame and its constituent amino acids have been studied for their impact on baby development.…”