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.
Highlights
Phenylketonuria (PKU; OMIM 261600 and 261630) is a rare autosomal recessive and inborn error of metabolism [1]
This review aims to discuss the range of neuropsychiatric and cognitive manifestations associated with PKU and their management
Tyr and Trp in conjunction serve to optimally ameliorate brain monoaminergic neurotransmitter concentrations [170]. They compared several large neutral amino acids (LNAAs) supplements with a very phenylalanine-restricted diet on measures of brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice, and the results indicated that the supplementation of the eight LNAAs was as effective as the highly Phe-restricted diet in restoring CNS monoamines, even while brain and plasma phenylalanine concentrations remained highly elevated [171]
Summary
Phenylketonuria (PKU; OMIM 261600 and 261630) is a rare autosomal recessive and inborn error of metabolism [1]. Depending on the genotype and severity of the enzyme defect, various forms of PKU with different clinical outcomes have been described [12] These can be classified on the basis of blood Phe levels at diagnosis and dietary Phe tolerance. When treatment is instituted from birth, PKU patients are likely to have a normal intellectual quotient (IQ), but it is apparent that there is often an IQ gap when compared to their non-PKU siblings, and these patients may have deficits in certain neuropsychological functioning, executive function [18] They may demonstrate elevated rates of neuropsychiatric illness, increasingly being recognized, which contribute to significant impairments in psychosocial functioning and quality of life in adults with treated PKU. This review aims to discuss the range of neuropsychiatric and cognitive manifestations associated with PKU and their management
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