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An animal model of early-treated PKU
A Diamond1, V Ciaramitaro, E Donner
1Department of Psychology, University of Pennsylvania School of Medicine, Philadelphia.
Insights
Phenylketonuria (PKU) treatment may not fully prevent cognitive impairments. Mildly elevated phenylalanine (Phe) levels in plasma, even below five times normal, can harm frontal cortex function and reduce dopamine metabolites in the brain.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Phenylketonuria (PKU) is a genetic disorder disrupting phenylalanine (Phe) metabolism.
- Current PKU treatment involves dietary Phe restriction, aiming to maintain plasma Phe below five times normal.
- Recent findings indicate cognitive impairments persist even with mild hyperphenylalaninemia.
Purpose of the Study:
- To investigate the neurobiological mechanisms underlying cognitive deficits in mild hyperphenylalaninemia.
- To develop and characterize an animal model for studying PKU-related cognitive impairments.
Main Methods:
- Developed a rat model using Phe and alpha-methylphenylalanine to induce mild hyperphenylalaninemia.
- Administered Phe and inhibitor prenatally/postnatally or postnatally.
- Assessed cognitive function using a delayed alternation task and measured neurotransmitter metabolites in brain regions.
Main Results:
- Mildly elevated plasma Phe impaired performance on a frontal cortex-dependent task (delayed alternation).
- Neurochemical analysis revealed significant reductions in homovanillic acid (HVA) in frontal cortical areas.
- Reduced HVA in the medial prefrontal cortex correlated significantly with cognitive task performance.
Conclusions:
- Mildly elevated plasma phenylalanine levels, previously considered safe, can cause significant cognitive deficits.
- These deficits are linked to neurochemical changes, particularly reduced HVA in the frontal cortex.
- The study highlights the need to re-evaluate safe Phe level thresholds in PKU management.
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 acid (HVA), norepinephrine, and 5-hydroxyindole acetic acid (5-HIAA) were measured in medial prefrontal cortex, anterior cingulate cortex, striatum, and nucleus accumbens. The largest neurochemical reductions observed were in HVA and were in the two frontal 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 neurotransmitter, in the striatum. The levels of 5-HIAA were also reduced in all brain regions examined. There was no effect on norepinephrine in any of the four regions examined. Reduced levels of HVA in medial prefrontal cortex were the only neurochemical effect that significantly correlated with every measure of performance on the delayed alternation 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 cognitive task dependent on frontal cortex and reduced HVA levels in frontal cortex.(ABSTRACT TRUNCATED AT 400 WORDS)