Fluctuations in phenylalanine concentrations in phenylketonuria: A review of possible relationships with outcomes

Abstract

Fluctuations in blood phenylalanine concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). This review evaluates the studies on phenylalanine fluctuations, factors affecting fluctuations, and if stabilizing phenylalanine concentrations affects outcomes, particularly neurocognitive outcome. Electronic literature searches of Embase and PubMed were performed for English-language publications, and the bibliographies of identified publications were also searched. In patients with PKU, phenylalanine concentrations are highest in the morning. Factors that can affect phenylalanine fluctuations include age, diet, timing and dosing of protein substitute and energy intake, dietary adherence, phenylalanine hydroxylase genotype, changes in dietary phenylalanine intake and protein metabolism, illness, and growth rate. Even distribution of phenylalanine-free protein substitute intake throughout 24h may reduce blood phenylalanine fluctuations. Patients responsive to and treated with 6R-tetrahydrobiopterin seem to have less fluctuation in their blood phenylalanine concentrations than controls. An increase in blood phenylalanine concentration may result in increased brain and cerebrospinal fluid phenylalanine concentrations within hours. Although some evidence suggests that stabilization of blood phenylalanine concentrations may have benefits in patients with PKU, more studies are needed to distinguish the effects of blood phenylalanine fluctuations from those of poor metabolic control.

Neuropsychological assessment among children and adolescents with phenylketonuria and hyperphenylalaninemia and its relationship with plasma phenylalanine levels

“…As our results show, specific increases in phenylalanine correlate with a lower performance in executive function tests. 9 This leads us to the idea that a more restricted diet could improve specific aspects of our patients' lives. At times when greater intellectual performance is needed, management with lower phenylalanine levels should be associated to better results in daily life, for example, at work or at school.…”

“…7 Therefore, it is critical to keep phenylalanine levels within normal ranges and monitor their variability, since the wider the variability the worse the outcome in IQ and executive functions. 8,9 In this study, the relation between plasma phenylalanine values and results of several neuropsychological tests was analyzed. Tests were performed on patients with phenylketonuria who were following a prescribed diet, and patients with benign hyperphenylalaninemia to assess their intelligence quotients and executive functions, and to look for a relationship with plasma phenylalanine values.…”

Improved Measurement of Brain Phenylalanine and Tyrosine Related to Neuropsychological Functioning in Phenylketonuria

“…Alternatively, the prefrontal cortex and not the PCG may be the relevant site for investigating variations in Tyr levels in the brain, as has been suggested by previous investigators (Diamond et al 1997;Bodner et al 2012). Blood Tyr levels, as well as blood Phe levels, are known to fluctuate depending on recent food intake (Cleary et al 2013). This potentially could also affect results of COSY measurements of brain Tyr.…”

Evaluación neuropsicológica en niños y adolescentes con fenilcetonuria e hiperfenilalaninemia y su relación con los niveles de fenilalanina plasmática

“…9 Esto nos introduce la idea de que una dieta más estricta de forma puntual podría mejorar los resultados en la vida diaria de nuestros pacientes. En momentos de necesidad de un mayor rendimiento intelectual, un control con menores niveles de fenilalaninemia debería ir asociado a mejores resultados en la vida diaria, como el rendimiento laboral o académico.…”

“…7 Por ello, es importante mantener los valores de fenilalanina en rangos de normalidad y controlar su variabilidad, ya que se ha observado que, a mayor variabilidad, peores resultados en el CI y las funciones ejecutivas. 8,9 En este estudio, se analizó la relación entre los valores de fenilalanina plasmática y los resultados de diversos tests neuropsicológicos aplicados a pacientes con fenilcetonuria que seguían tratamiento dietético y pacientes con hiperfenilalaninemia benigna para evaluar su nivel de inteligencia y las funciones ejecutivas, y buscar una relación con los valores de fenilalanina plasmática.…”