This research is to develop and evaluate in an animal model a new treatment for maternal phenylketonuria (PKU). Maternal PKU produces a high incidence of children born with mental retardation (up to 92%), growth retardation, microcephaly and congenetal malformations, particularly cardiac defects. Dietary treatment of PKU women during pregnancy by restricting phenylalanine intake has not veen very successful in preventing the intrauterine damage. In recent years, we have been developing a new treatment for older PKU individuals that involves the administration of the amino acids valine, isoleucine and leucine (VIL). The treatment was developed because of the difficulty in being able to adequately restrict dietary phenylalanine in PKU adults whose protein requirements are low compared to children. VIL is able to reduce CSF phenylalanine and improve symptoms of acute phenylalanine toxicity in adults with PKU. We now propose to test the feasibility of the VIL treatment in cases of maternal PKU. As a first step, studies in rats will be undertaken using an animal model of PKU involving the administration of L-phenylalanine and p-chlorophenylalanine. We will use the PKU-inducing diet to induce malformations, growth retardation and behavioral impairments in utero in pregnant rats. Once the timing of administration, exact dosage of phenylalanine and p-chlorophenylalanine are established, we will test the ability of varying doses of VIL to counteract the adverse effects of the PKU diet. We will use a range of control procedures to rule out explanations for our findings due to inadequate food or fluid intake, the influence of p-chlorophenylalanine or phenylalanine separately, VIL alone, and for the postnatal studies, of postnatal maternal influences. The data obtained will lay the groundwork for human trials of the VIL treatment in pregnant PKU women.
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