Are Neuropsychological Impairments in Children with Early-Treated Phenylketonuria (PKU) Related to White Matter Abnormalities or Elevated Phenylalanine Levels?

Abstract

This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.

Notes

∗p < .01

^# adjusting for age

∗p < .01

^aMean SES for No WMA group significantly higher than Control (p < .01), Mild WMA (p < .05), and Moderate WMA (p < 0.01) groups.

^bModerate WMA group significantly older than the Control (p < .01), No WMA (p < .01) and Mild WMA (p < .01) groups.

^cControl group significantly higher full-scale IQ than Mild WMA (p < .05) and Moderate WMA (p < .01) groups.

^dConcurrent PHE significantly elevated in Moderate WMA group in comparison to No WMA (p < .01) and Mild WMA (p < .01) groups.

^eLifetime PHE significantly elevated in Moderate WMA group in comparison to No WMA (p < 0.01) and Mild WMA (p < 0.01) groups.

^#adjusting for age, SES, and gender.

^aModerate WMA group performed significantly poorer than the control group.

^#Partial correlation coefficients controlling for age.

∗p < .01

∘adjusting for SES and gender

^# adjusting for age, SES, and, gender