Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments

Abstract

Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations in the gene for phenylalanine hydroxylase (PAH). Reduced PAH activity results in significant hyperphenylalaninemia, which leads to alterations in cerebral myelin and protein synthesis, as well as reduced levels of serotonin, dopamine, and noradrenaline in the brain. When untreated, brain development is grossly disrupted and significant intellectual impairment and behavioral disturbance occur. The advent of neonatal heel prick screening has allowed for diagnosis at birth, and the institution of a phenylalanine restricted diet. Dietary treatment, particularly when maintained across neurodevelopment and well into adulthood, has resulted in markedly improved outcomes at a cognitive and psychiatric level for individuals with PKU. However, few individuals can maintain full dietary control lifelong, and even with good control, an elevated risk remains of—in particular—mood, anxiety, and attentional disorders across the lifespan. Increasingly, dietary recommendations focus on maintaining continuous dietary treatment lifelong to optimize psychiatric and cognitive outcomes, although the effect of long-term protein restricted diets on brain function remains unknown. While psychiatric illness is very common in adult PKU populations, very little data exist to guide clinicians on optimal treatment. The advent of new treatments that do not require restrictive dietary management, such as the enzyme therapy Pegvaliase, holds the promise of allowing patients a relatively normal diet alongside optimized mental health and cognitive functioning.

Psychological well‐being of early and continuously treated phenylketonuria patients

“…Already children and adolescents with chronic diseases more often suffer from depression, anxiety disorders, and disturbed emotional or behavioral functioning 28,29 . In patients with PKU, low self‐esteem, attentional problems, lack of autonomy, depressed mood, and general anxiety occur more frequently compared to metabolically healthy peers 8,30,31 . So far, there are only few systematic studies on psychological health in PKU 4,9,32 .…”

The Effect of Improved Dietary Control on Cognitive and Psychiatric Functioning in Adults With Phenylketonuria: The ReDAPT Study

“…Firstly, the restoration of central levels of key monoamines, results in a relative normalisation of monoaminergic tone and thus a reduction in dimensional levels of depression and anxiety. Secondly, the attenuation of impaired myelination (itself intimately related to monoaminergic signaling), improves cognitive functions that are underpinned by more widely distributed cortico-cortical and cortico-subcortical networks, such as working memory and processing speed (27). Improvements to cognitive functioning were not explained by improvement in mood, with only time on diet being a signi cant covariate.…”

Le dépistage de la phénylcétonurie en France

“…Le deuxième groupe comprend les patients dont les taux sont entre 6 et 15 mg/dL (360 et 900 µmol/L). Ces enfants, qui ont des mg/dL n triques [27] chez ces patients ayant arrêté leur régime, a conduit à une évolution de leur prise en charge. Ces atteintes sont réversibles après un retour à un contrôle métabolique strict.…”