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Prefrontal cortex cognitive deficits in children treated early and continuously for PKU
A Diamond1, M B Prevor, G Callender
1Center for Developmental Cognitive Neuroscience, Eunice Kennedy Shriver Center, Waltham, Massachusetts, USA.
Insights
Phenylketonuria (PKU) children with high phenylalanine levels show impaired executive functions, particularly working memory and inhibitory control, due to reduced dopamine in the prefrontal cortex. This deficit is evident early and affects girls more than boys.
Area of Science:
- Neuroscience
- Developmental Psychology
- Biochemistry
Background:
- Phenylketonuria (PKU) is a metabolic disorder causing elevated phenylalanine (Phe) and reduced tyrosine (Tyr), the dopamine precursor.
- Dopamine is crucial for prefrontal cortex functions, including executive functions.
- Early and continuous PKU treatment reduces but does not eliminate the Phe:Tyr imbalance.
Purpose of the Study:
- To investigate the impact of dopamine reduction in the prefrontal cortex on executive functions in early childhood.
- To examine the relationship between phenylalanine levels and cognitive performance in children with PKU.
Main Methods:
- A 4-year longitudinal study of children with PKU and matched controls.
- Assessment of working memory and inhibitory control abilities dependent on the dorsolateral prefrontal cortex.
- Correlation of plasma phenylalanine levels with cognitive task performance.
Main Results:
- PKU children with Phe levels 3-5 times normal performed significantly worse on executive function tasks than controls, siblings, and general population children.
- The cognitive impairment was consistent across age ranges (6 months to 7 years).
- Higher Phe levels correlated with poorer performance; girls were more adversely affected than boys.
Conclusions:
- Reduced prefrontal cortex dopamine, secondary to PKU, selectively impairs executive functions in early childhood.
- The findings highlight the critical role of dopamine in developing cognitive abilities.
- Clinical implications exist for managing PKU and other neurodevelopmental disorders affecting dopamine pathways.
Abstract:
To begin to study the importance of dopamine for executive function abilities dependent on prefrontal cortex during early childhood, the present investigation studied children in whom we predicted reduced dopamine in prefrontal cortex but otherwise normal brains. These are children treated early and continuously for the metabolic disorder phenylketonuria (PKU). Untreated PKU is the most common biochemical cause of mental retardation. The root problem is an inability to convert one amino acid, phenylalanine (Phe), into another, tyrosine (Tyr), the precursor of dopamine. Phe levels in the bloodstream soar; Tyr levels fall. Treatment with a diet low in Phe reduces the Phe:Tyr imbalance but cannot eliminate it. We hypothesized that the resultant modest elevation in the ratio of Phe to Tyr in the blood, which results in slightly less Tyr reaching the brain, uniquely affects the cognitive functions dependent on prefrontal cortex because of the special sensitivity of prefrontally projecting dopamine neurons to small decreases in Tyr. In a 4-year longitudinal study, we found that PKU children whose plasma Phe levels were three to five times normal (6-10 mg/dl) performed worse than other PKU children with lower Phe levels, matched controls, their own siblings, and children from the general population on tasks that required the working memory and inhibitory control abilities dependent on dorsolateral prefrontal cortex. The impairment was as evident in our oldest age range (3 1/2-7 years) as it was in the youngest (6-12 months). The higher a child's Phe level, the worse that child's performance. Girls were more adversely affected than boys. The deficit appears to be selective, affecting principally one neural system, since even PKU children with Phe levels three to five times normal performed well on the 13 control tasks. Clinical implications for the treatment of PKU and other neurodevelopmental disorders are discussed.