Serotonin deficiency in phenylketonuria embryopathy

The development and evolution of PKU can be prevented by prescribing an appropriate diet at an early age. A systematic neonatal screening has been set up in most countries. However, young women suffering from PKU give birth to very severely malformed children (PKU embryopathy: microcephaly, mental retardation, hypotrophy, cardiopathy) unless they again take up the specific diet, until the PHE level has lowered down to normal, before the beginning of gestation. The treatment has to be continued at least during the first months of gestation. This management is very unpleasant and sometimes not easily accepted. The mechanism of this embryopathy is still unknown. It is possible that (1) the excess of PHE or the presence of abnormal metabolites, or (2) serotonin deficiency (which is a feature of PKU) could be responsible for the maldevelopment of the embryo. Some authors consider that serontonin has a morphogenetic role in normal embryogenesis. Previously we described an experimental animal model using in vitro culture of rat embryos in human PKU sera. Mouse embryos have been subsequently used, since they show a greater sensitivity. Malformations, consisting essentially of neural tube defects, were present in almost 100% of the embryos cultured in serum from PKU patients. Using this animal model, we tested the hypothesis of serotonin deficiency. For this purpose, mouse embryos were cultured in human serum depleted of serotonin. Under these conditions, 100% of the embryos showed oculo-neural malformations characteristic of the experimental embryopathy. These results indicate the importance of serotonin deficiency in the occurrence of PKU embryopathy.