An animal model of early-treated PKU
Abstract
Phenylketonuria (PKU) is a genetic disorder in which the hydroxylation of phenylalanine (Phe) to tyrosine is severely disrupted. If PKU is left untreated, severe mental retardation results. The accepted treatment is to restrict dietary intake of Phe. It has generally been thought that cognitive impairments are prevented if levels of Phe in plasma are maintained at or below five times the normal level. However, we recently documented that children treated early and continuously for PKU or children mildly hyperphenylalaninemic, who have levels of Phe in plasma approximately three to five times normal, still have cognitive impairments. These impairments are specific to the functions of frontal cortex (A. Diamond, W. Hurwitz, E. Lee, W. Grover, and C. Minarcik, unpublished observations). To investigate the mechanism underlying these cognitive deficits, an animal model of this condition was developed and characterized. Thirty-six rat pups were divided into three groups. The first group was treated pre- and postnatally with Phe and alpha-methylphenylalanine (a phenylalanine hydroxylase inhibitor). The second group was injected postnatally with Phe and alpha-methylphenylalanine. The third group received postnatal control injections. The mild plasma Phe elevations in the two experimental groups produced significant behavioral and neurochemical effects. Both experimental groups were impaired on a task dependent on frontal cortex, delayed alternation. Levels of dopamine, homovanillic…
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