Age-Related Psychophysiological Vulnerability to Phenylalanine in Phenylketonuria

Abstract

Background: Phenylketonuria (PKU) is caused by the inherited defect of the phenylalanine hydroxylase enzyme, which converts phenylalanine (Phe) into tyrosine (Tyr). Neonatal screening programs and early treatment have radically changed the natural history of PKU. Nevertheless, an increased risk of neurocognitive and psychiatric problems in adulthood remains a challenging aspect of the disease. In order to assess the vulnerability of complex skills to Phe, we explored: (a) the effect of a rapid increase in blood Phe levels on event-related potentials (ERP) in PKU subjects during their second decade of life; (b) the association (if existing) between psychophysiological and neurocognitive features.Methods: Seventeen early-treated PKU subjects, aged 10–20, underwent ERP [mismatch negativity, auditory P300, contingent negative variation (CNV), and Intensity Dependence of Auditory Evoked Potentials] recording before and 2 h after an oral loading of Phe. Neurocognitive functioning, historical and concurrent biochemical values of blood Phe, Tyr, and Phe/Tyr ratio, were all included in the statistical analysis.Results: Event-related potential components were normally detected in all the subjects. In subjects younger than 13 CNV amplitude, W2-CNV area, P3b latency, and reaction times in motor responses were negatively influenced by Phe-loading. Independently from the psychophysiological vulnerability, some neurocognitive skills were more impaired in younger patients. No correlation was found between biochemical alterations and neurocognitive and psychophysiological findings.Conclusion: The vulnerability of the emerging neurocognitive functions to Phe suggests a strict metabolic control in adolescents affected by PKU and a neurodevelopmental approach in the study of neurocognitive outcome in PKU.

The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

“…Concerning this point it is of interest to notice that white matter signal on MRI may be found completely normal during the childhood even in untreated PKU patients with severe intellectual disability (Leuzzi unpublished data) and it was found normal in over 60% of our children younger than 10. So, like several other dysfunctions associated with PKU [31,32], an age-dependent individual susceptibility to phenylalanine may be considered even for the white matter signal alteration, whose consequences in term of myelin function remain to be elucidated. Neurophysiological studies failed in demonstrating any abnormality which could be linked to myelin alteration, even though a number of phenylalanine-linked alterations of short and long latency evoked potential have been reported [1,32].…”

“…So, like several other dysfunctions associated with PKU [31,32], an age-dependent individual susceptibility to phenylalanine may be considered even for the white matter signal alteration, whose consequences in term of myelin function remain to be elucidated. Neurophysiological studies failed in demonstrating any abnormality which could be linked to myelin alteration, even though a number of phenylalanine-linked alterations of short and long latency evoked potential have been reported [1,32]. More sophisticated DTI or functional MRI studies have recently focused on microstructural integrity of white matter in PKU [19,28,29,33,34].…”

Neuropsychological Profile of Children with Early and Continuously Treated Phenylketonuria: Systematic Review and Future Approaches

“…Only few studies employed withinsubject designs where phenylalanine levels are manipulated through dietary changes. Strong effects of phenylalanine manipulation were found on EF performances (Huijbregts et al, 2002b) and reaction time (Leuzzi et al, 2014a), but not on short-term and long-term memory, or fine motor coordination . Sensitivity to increase of phenylalanine was higher in younger (i.e., under 13 years) as compared to older people with PKU (Leuzzi et al, 2014a).…”

Clinical and neuropsychological outcomes for children with phenylketonuria in Upper Egypt; a single-center study over 5 years

“…Another longitudinal study including adolescents showed that 2 brain function measurements, one for complex neurocognitive skills and the other for specific information network processing, were more impaired when there is rapid rise of Phe level, and this is also associated with younger age. 48 Furthermore, another study reported that IQ remains stable over the second decade of life; however, other patients showed an increase or decrease in their IQ scores that was not explained by the quality of metabolic control and could be related to hidden subjective factors. 49 …”