Associations between Phenylalanine‐to‐Tyrosine Ratios and Performance on Tests of Neuropsychological Function in Adolescents Treated Early and Continuously for Phenylketonuria

Abstract

Phenylketonuria (PKU) is a genetic disorder characterized by hyperphenylalaninemia. Treatment involves dietary phenylalanine restriction to prevent mental retardation. Because phenylalanine is involved in tyrosine synthesis and tyrosine is a catecholamine precursor, low tyrosine may lead to brain dopamine deficiencies. Because dopamine is involved in the modulation of prefrontally orchestrated executive functions, deficiencies may lead to executive impairments. Despite treatment, impairments in executive cognitive functions have been reported in young children with PKU. Outcome beyond middle childhood has not been extensively investigated. In this study, PKU-affected adolescents (N = 18) with normal-range IQ scores completed neuropsychological tests, and their performance was compared with unaffected peers (N = 16) and chronically ill controls (N = 17). Results demonstrated that the overall performance of the PKU group did not differ from that of the other two groups, but that performance of the PKU proband was associated with phenylalanine and tyrosine levels, and most strongly with phenylalanine-to-tyrosine ratios at several points in development. These findings provide a preliminary test of the dopamine hypothesis of PKU as it applies to adolescents and young adults.

Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria

“…Of 15 studies reporting executive function assessments for adults with early-treated PKU and age/gender matched controls without PKU, 13 studies reported mean test scores with variance estimates and were subsequently included in the MA (Antenor-Dorsey et al, 2013;Burgard et al, 1997;Channon et al, 2007;Feldmann, Denecke, Grenzebach, & Weglage, 2005;Griffiths, Paterson, & Harvie, 1995;Luciana, Sullivan, & Nelson, 2001;Moyle, Fox, Bynevelt, Arthur, & Burnett, 2006Pietz et al, 1998Pietz et al, , 1995Ris et al, 1997;Sundermann et al, 2011;Ullrich et al, 1996). The MA effect sizes using Hedges g found significant differences between adults with early-treated PKU and unaffected controls of 0.74 for attention (11 study arms; 252 participants, p < 0.0001), 0.41 for inhibitory control (6 study arms; 119 participants, p = 0.047), and 0.43 for cognitive flexibility (7 study arms; 157 participants, p = 0.006).…”

Genetic and Neurochemical Modulation of Prefrontal Cognitive Functions in Children

“…Apparently because of that, working memory and inhibition functions that depend on the dorsolateral prefrontal cortex (but not cognitive functions dependent on other neural systems, such as the parietal cortex or the medial temporal lobe) are impaired in children treated for phenylketonuria whose serum phenylalanine levels are elevated enough to result in a modest reduction in tyrosine levels reaching the brain (14,15,21).…”

Executive dysfunction in treated phenylketonuric patients

“…Although the overall performance of the PKU group did not differ from that of the other two groups, the proficiency of the PKU group in a number of tests of executive and non-executive functions was associated with the concentrations of Phe and Tyr and most strongly with Phe to Tyr ratios measured at several points in development. Luciana introduced the ratio (Phe/Tyr) as one of the best indicators of dopamine availability in PKU [16]. However, in the study by White and colleagues in the field of working memory, no significant correlation between concurrent Phe levels and cognitive performance was reported [34].…”

“…Executive functions encompass the ability to maintain a problem-solving set that is appropriate for goal acquisition, including formulation, strategic planning, self-monitoring, mental flexibility, and the ability to change strategies in response to new information. In fact, EF can be viewed as an umbrella term for a set of cognitive functions critically supported by the pre-frontal cortex including regulation of attention, inhibition of inappropriate responses, coordination of information in working memory and cognitive flexibility [7,16]. Impairments in EF have been found in patients with a wide range of neurodevelopmental disorders including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) [11] and the fragile-X syndrome [12].…”