1. In a nutshell
Phenylketonuria or PKU is an inborn disorder of metabolism. The name of the condition denotes the presence of elevated levels of phenylpyruvate and phenylacetate in the urine. These two compounds are ketone bodies and accumulate when blood levels of phenylalanine rise above the normal reference range (0.06mmol/L - 0.1mmol/L). Hyperphenylalaninemia in PKU is a consequence of deleterious mutations in a gene that codes for the enzyme phenylalanine hydroxylase; this enzyme converts phenylalanine to the amino acid tyrosine. PKU detrimentally affects the developing brain and can cause irreversible mental retardation if it goes untreated. Screening of neonates is commonplace and necessary to avoid the potentially catastrophic clinical consequences of this condition.
Fig 1. The heel-prick test is routinely used to identify PKU in the neonate.
2. What causes it?
PKU is a genetic disease, most commonly inherited in an autosomal recessive manner. Deleterious mutations in a single gene, the PAH gene, result in a deficiency of the enzyme phenylalanine hydroxylase.
3. What are the symptoms?
Untreated PKU can result in growth retardation, seizures, moderate-to-severe mental retardation, hypopigmentation and eczema. Cases where the treatment of PKU is only partial or ceased prematurely can cause a significant decline in IQ and increased incidences of behavioural and learning disabilities.
4. What’s going on?
Under normal circumstances the catabolism of phenylalanine is dependent on the enzyme phenylalanine hydroxylase. Through the action of this enzyme, phenylalanine is then converted to tyrosine. Tyrosine is an important non-essential amino acid that is a biosynthetic precursor for melanin and neurotransmitter development. In PKU, harmful mutations in the PAH gene (>600 have been described) result in the decreased production of phenylalanine hydroxylase which causes the substrate, phenylalanine, to accumulate. Tyrosine becomes an essential amino acid in PKU individuals as they can no longer synthesise it through dietary phenylalanine catabolism. Hyperphenylalaninemia affects the developing brain by disrupting energy production, protein synthesis and neurotransmitter homeostasis. Hypopigmentation in PKU is likely due to the inhibition of dopaquinone synthesis in melanocytes. Approximately 1% of PKU patients will also have defects in tetrahydrobiopterin (BH4) metabolism. This situation adds insult to injury as proper tetrahydrobiopterin metabolism is crucial for the formation of both phenylalanine hydroxylase and tryptophan and tyrosine hydroxylase. Thus, individuals with deranged tetrahydrobiopterin metabolism suffer from PKU and a lack of important serotenergic and catecholaminergic neurotransmitters. This further compounds and complicates the clinical picture and results in severe neurologic dysfunction.
Fig 2. Schematic diagram showing the metabolic fates of phenylalanine. (McPhee and Hammer, 2019).
5. How is it treated?
Dietary restriction of phenylalanine is initiated once the condition is detected. It is necessary to continue dietary restriction of phenylalanine indefinitely, as even mild hyperphenylalaninemia can have detrimental effects on cognition and overall CNS health. Additionally, hyperphenylalaninemia, in the context of PKU, can also deprive the brain of adequate levels of other, important amino acids and supplementation is therefore recommended.
6. That’s interesting...
As women with PKU reach child-bearing age, fetal hyperphenylalaninemia due to in uterine exposure becomes a possibility. This can occur irrespective of the fetal genotype; neonates affected by this situation display microcephaly, congenital heart defects and profound developmental delay. Rigorous control of maternal phenylalanine prior to conception and up to birthing is essential in minimising the risk of significant fetal abnormalities in maternal PKU.
