AN ANIMAL-MODEL OF EARLY-TREATED PKU

Phenylketonuria (PKU) is a genetic disorder in which the hydroxylation of phenylalanine (Phe) to tyrosine is severely disrupted. If PKU is l eft untreated, severe mental retardation results. The accepted treatme nt is to restrict dietary intake of Phe. It has generally been thought that cognitive impairments are prevented if levels of Phe in plasma a re maintained at or below five times the normal level. However, we rec ently documented that children treated early and continuously for PKU or children mildly hyperphenylalaninemic, who have levels of Phe in pl asma approximately three to five times normal, still have cognitive im pairments. These impairments are specific to the functions of frontal cortex (A. Diamond, W. Hurwitz, E. Lee, W. Grover, and C. Minarcik, un published observations). To investigate the mechanism underlying these cognitive deficits, an animal model of this condition was developed a nd characterized. Thirty-six rat pups were divided into three groups. The first group was treated pre- and postnatally with Phe and alpha-me thylphenylalanine (a phenylalanine hydroxylase inhibitor). The second group was injected postnatally with Phe and alpha-methylphenylalanine. The third group received postnatal control injections. The mild plasm a Phe elevations in the two experimental groups produced significant b ehavioral and neurochemical effects. Both experimental groups were imp aired on a task dependent on frontal cortex, delayed alternation. Leve ls of dopamine, homovanillic acid (HVA), norepinephrine, and 5-hydroxy indole acetic acid (5-HIAA) were measured in medial prefrontal cortex, anterior cingulate cortex, striatum, and nucleus accumbens. The large st neurochemical reductions observed were in HVA and were in the two f rontal cortical areas (medial prefrontal cortex and anterior cingulate cortex). There were modest reductions in HVA in the nucleus accumbens but no significant changes in HVA, or in any other metabolite or neur otransmitter, in the striatum. The levels of 5-HIAA were also reduced in all brain regions examined. There was no effect on norepinephrine i n any of the four regions examined. Reduced levels of HVA in medial pr efrontal cortex were the only neurochemical effect that significantly correlated with every measure of performance on the delayed alternatio n task. This study provides evidence of deleterious effects from mild elevations in the levels of Phe in plasma previously considered small enough to be safe. These effects include impaired performance on a cog nitive task dependent on frontal cortex and reduced HVA levels in fron tal cortex. It is not possible to rule out a role for other neurotrans mitter systems from this study alone, but the results of other investi gations suggest that the behavioral impairment is due to the alteratio ns in the dopamine system in frontal cortex.