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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD019090-03
Application #
3316277
Study Section
Biopsychology Study Section (BPO)
Project Start
1984-08-01
Project End
1988-07-31
Budget Start
1986-08-01
Budget End
1988-07-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Vorhees, C V; Acuff-Smith, K D; Weisenburger, W P et al. (1992) Branched chain amino acids improve radial-arm maze acquisition and water maze forced-choice learning in rat offspring exposed in utero to hyperphenylalaninemia. Neurotoxicol Teratol 14:35-41
Vorhees, C V; Acuff, K D; Weisenburger, W P et al. (1990) Teratogenicity of carbamazepine in rats. Teratology 41:311-7
Vorhees, C V; Minck, D R (1989) Long-term effects of prenatal phenytoin exposure on offspring behavior in rats. Neurotoxicol Teratol 11:295-305
Minck, D R; Erway, L C; Vorhees, C V (1989) Preliminary findings of a reduction of otoconia in the inner ear of adult rats prenatally exposed to phenytoin. Neurotoxicol Teratol 11:307-11
Vorhees, C V; Berry, H K (1989) Branched chain amino acids improve complex maze learning in rat offspring prenatally exposed to hyperphenylalaninemia: implications for maternal phenylketonuria. Pediatr Res 25:568-72
Vorhees, C V; Minck, D R; Berry, H K (1988) Anticonvulsants and brain development. Prog Brain Res 73:229-44
Vorhees, C V (1987) Maze learning in rats: a comparison of performance in two water mazes in progeny prenatally exposed to different doses of phenytoin. Neurotoxicol Teratol 9:235-41
Vorhees, C V (1987) Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats. Psychopharmacology (Berl) 92:173-9
Vorhees, C V (1987) Fetal hydantoin syndrome in rats: dose-effect relationships of prenatal phenytoin on postnatal development and behavior. Teratology 35:287-303
Vorhees, C V (1987) Teratogenicity and developmental toxicity of valproic acid in rats. Teratology 35:195-202

Showing the most recent 10 out of 12 publications