Phenylalanine levels of 6-10 mg/dl may not be as benign as once thought

Area of Science:

• Neuroscience
• Developmental Psychology
• Metabolic Disorders

Background:

• Phenylketonuria (PKU) is a genetic disorder requiring early treatment to prevent severe intellectual disability.
• Longitudinal studies indicate potential cognitive impairments even with early and continuous treatment for PKU.
• Prefrontal cortex functions, crucial for executive functions, may be particularly vulnerable to phenylalanine toxicity.

Purpose of the Study:

• To investigate the cognitive effects of early-treated phenylketonuria (PKU) on prefrontal cortex functions in children.
• To explore the biological mechanisms underlying these cognitive deficits using an animal model.

Main Methods:

• Longitudinal assessment of cognitive functions in children with PKU treated from infancy.
• Performance evaluation on tasks assessing prefrontal cortex-dependent functions versus control tasks.
• Development of an animal model of PKU with mild, chronic hyperphenylalaninemia for neurochemical analysis.

Main Results:

• Children with PKU, even when treated early, exhibited deficits in cognitive functions reliant on the prefrontal cortex, specifically in tasks requiring working memory and inhibitory control.
• These deficits were selective, as children performed normally on control tasks tapping parietal cortex or medial temporal lobe functions.
• The animal model demonstrated cognitive impairments (delayed alternation task) and reduced dopamine metabolism in the frontal cortex, correlating with elevated phenylalanine levels.

Conclusions:

• Early and continuous treatment for PKU may not fully prevent cognitive deficits associated with prefrontal cortex dysfunction.
• Mildly elevated phenylalanine levels can selectively impair higher-order cognitive functions.
• Reduced dopamine metabolism in the frontal cortex is a potential neurobiological mechanism underlying cognitive deficits in PKU.